bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of in-hospital mortality in patients on mechanical ventilation post traumatic brain injury: machine learning approach
Authors: Abujaber Ahmad , Fadlalla Adam , Gammoh Diala , Abdelrahman Husham , Mollazehi Monira , El-Menyar Ayman
Published: December 2020

Background

The study aimed to introduce a machine learning model that predicts in-hospital mortality in patients on mechanical ventilation (MV) following moderate to severe traumatic brain injury (TBI).

Methods

A retrospective analysis was conducted for all adult patients who sustained TBI and were hospitalized at the trauma center from January 2014 to February 2019 with an abbreviated injury severity score for head region (HAIS) ≥ 3. We used the demographic characteristics, injuries and CT findings as predictors. Logistic regression (LR) and Artificial neural networks (ANN) were used to predict the in-hospital mortality. Accuracy, area under the receiver operating characteristics curve (AUROC), precision, negative predictive value (NPV), sensitivity, specificity and F-score were used to compare the models` performance.

Results

Across the study duration; 785 patients met the inclusion criteria (581 survived and 204 deceased). The two models (LR and ANN) achieved good performance with an accuracy over 80% and AUROC over 87%. However, when taking the other performance measures into account, LR achieved higher overall performance than the ANN with an accuracy and AUROC of 87% and 90.5%, respectively compared to 80.9% and 87.5%, respectively. Venous thromboembolism prophylaxis, severity of TBI as measured by abbreviated injury score, TBI diagnosis, the need for blood transfusion, heart rate upon admission to the emergency room and patient age were found to be the significant predictors of in-hospital mortality for TBI patients on MV.

Conclusions

Machine learning based LR achieved good predictive performance for the prognosis in mechanically ventilated TBI patients. This study presents an opportunity to integrate machine learning methods in the trauma registry to provide instant clinical decision-making support.
Risk-adapted treatment reduced chemotherapy exposure for clinical stage I pediatric testicular cancer
Authors: Ye Yun-lin , Chen Zhuang-fei , Bian Jun , Liang Hai-tao , Qin Zi-ke
Published: December 2020

Background

Different from adult clinical stage I (CS1) testicular cancer, surveillance has been recommended for CS1 pediatric testicular cancer. However, among high-risk children, more than 50% suffer a relapse and progression during surveillance, and adjuvant chemotherapy needs to be administered. Risk-adapted treatment might reduce chemotherapy exposure among these children.

Methods

A decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as the relapse rates of different groups during surveillance or after chemotherapy were collected from the literature. A survey of urologists was conducted to evaluate the toxicity of first-line and second-line chemotherapy. Using the decision analysis model, chemotherapy exposure of the risk-adapted treatment and surveillance strategies were compared based on this series of clinical utilities. One-way and two-way tests were applied to check the feasibility.

Results

In the base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment resulted in a lower exposure to chemotherapy than surveillance (average: 0.7965 cycles verse 1.3419 cycles). The sensitivity analysis demonstrated that when the relapse rate after primary chemotherapy was ≤ 0.10 and the relapse rate of the high-risk group was ≥ 0.40, risk-adapted treatment would result in a lower exposure to chemotherapy, without any association with the proportion of low-risk patients, the relapse rate of the low-risk group, the relapse rate after salvage chemotherapy or the toxicity utility of second-line chemotherapy compared to first-line chemotherapy.

Conclusions

Based on the decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients, and an evaluation after orchiectomy was critical to this process. Additional clinical studies are needed to validate this statement.
Early marriage and women’s empowerment: the case of child-brides in Amhara National Regional State, Ethiopia
Authors: Abera Mikyas , Nega Ansha , Tefera Yifokire , Gelagay Abebaw Addis
Published: December 2020

Background

Women, especially those who marry as children, experience various forms and degrees of exclusion and discrimination. Early marriage is a harmful traditional practice that continues to affect millions around the world. Though it has declined over the years, it is still pervasive in developing countries. In Ethiopia, Amhara National Regional State (or alternatively Amhara region) hosts the largest share of child-brides in the country. This study aimed at assessing the effects of early marriage on its survivors’ life conditions – specifically, empowerment and household decision-making – in western Amhara.

Methods

This study employed community-based cross-sectional study design. It adopted mixed method approach – survey, in-depth interview and focus group discussion (FGD) – to collect, analyse and interpret data on early marriage and its effects on household decision-making processes. The survey covered 1278 randomly selected respondents, and 14FGDs and 6 in-depth interviews were conducted. Statistical procedures – frequency distribution, Chi-square, logistic regression – were used to test, compare and establish associations between survey results on women empowerment for two groups of married women based on age at first marriage i.e., below 18 and at/after 18. Narratives and analytical descriptions were integrated to substantiate and/or explain observed quantitative results, or generate contextual themes.

Results

This study reported that women married at/after 18 were more involved in household decision-making processes than child-brides. Child-brides were more likely to experience various forms of spousal abuse and violence in married life. The study results illustrated how individual-level changes, mainly driven by age at first marriage, interplay with structural factors to define the changing status and roles of married women in the household and community.

Conclusion

Age at first marriage significantly affected empowerment at household level, and women benefited significantly from delaying marriage. Increase in age did not automatically and unilaterally empowered women in marriage, however, since age entails a cultural definition of one’s position in society and its institutions. We recommend further research to focus on the nexus between the household and the social-structural forms that manifest at individual and community levels, and draw insights to promote women’s wellbeing and emancipation.
Correction to: Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet
Authors: Yoshida Masatoki , Nakamura Kazufumi , Miyoshi Toru , Yoshida Masashi , Kondo Megumi , Akazawa Kaoru , Kimura Tomonari , Ohtsuka Hiroaki , Ohno Yuko , Miura Daiji , Ito Hiroshi
Published: December 2020

An amendment to this paper has been published and can be accessed via the original article.
Reduced oxidized LDL in T2D plaques is associated with a greater statin usage but not with future cardiovascular events
Authors: Singh Pratibha , Goncalves Isabel , Tengryd Christoffer , Nitulescu Mihaela , Persson Ana F. , To Fong , Bengtsson Eva , Volkov Petr , Orho-Melander Marju , Nilsson Jan , Edsfeldt Andreas
Published: December 2020

Background

Type 2 diabetes (T2D) patients are at a greater risk of cardiovascular events due to aggravated atherosclerosis. Oxidized LDL (oxLDL) has been shown to be increased in T2D plaques and suggested to contribute to plaque ruptures. Despite intensified statin treatment during the last decade the higher risk for events remains. Here, we explored if intensified statin treatment was associated with reduced oxLDL in T2D plaques and if oxLDL predicts cardiovascular events, to elucidate whether further plaque oxLDL reduction would be a promising therapeutic target.

Methods

Carotid plaque OxLDL levels and plasma lipoproteins were assessed in 200 patients. Plaque oxLDL was located by immunohistochemistry. Plaque cytokines, cells and scavenger receptor gene expression were quantified by Luminex, immunohistochemistry and RNA sequencing, respectively. Clinical information and events during follow-up were obtained from national registers.

Results

Plaque oxLDL levels correlated with markers of inflammatory activity, endothelial activation and plasma LDL cholesterol (r = 0.22-0.32 and p ≤ 0.01 for all). T2D individuals exhibited lower plaque levels of oxLDL, sLOX-1(a marker of endothelial activation) and plasma LDL cholesterol (p = 0.001, p = 0.006 and p = 0.009). No increased gene expression of scavenger receptors was identified in T2D plaques. The lower oxLDL content in T2D plaques was associated with a greater statin usage (p = 0.026). Supporting this, a linear regression model showed that statin treatment was the factor with the strongest association to plaque oxLDL and plasma LDL cholesterol (p < 0.001 for both). However, patients with T2D more frequently suffered from symptoms and yet plaque levels of oxLDL did not predict cardiovascular events in T2D (findings are summarized in Fig. 1a).

Conclusions

This study points out the importance of statin treatment in affecting plaque biology in T2D. It also implies that other biological components, beyond oxLDL, need to be identified and targeted to further reduce the risk of events among T2D patients receiving statin treatment.
Use of long-lasting insecticidal nets among women attending antenatal clinic at a tertiary hospital in Bayelsa State, Nigeria 2019
Authors: Ibegu Maria Imaobong , Hamza Khadeejah Liman , Umeokonkwo Chukwuma David , Numbere Tamuno-Wari , Ndoreraho Adolphe , Dahiru Tukur
Published: December 2020

Background

Malaria in pregnancy remains a major contributor to maternal and infant morbidity and mortality despite scale up in interventions. Its prevention is one of the major interventions in reducing maternal and infant morbidity and mortality. The ownership, utilization and predictors of use of long-lasting insecticide-treated nets (LLINs) for malaria prevention among women attending antenatal clinic (ANC) at a tertiary hospital in Bayelsa State Nigeria was assessed.

Methods

A cross-sectional study of 297 women recruited through systematic sampling was carried out. Information on sociodemographic characteristics, ownership, source and utilization of LLINs, were collected with a pre-tested structured interviewer-administered questionnaire. The relationship between use of LLIN and sociodemographic characteristics was examined using chi square and logistic regression at 5% level of significance.

Results

The mean age of respondents was 28.8 ± 2.6 years. Most (59.2%) had tertiary education and were mainly (88.2%) urban dwellers. Two hundred and fifty (84.2%) owned LLINs, and 196 (78%) used LLIN the night prior to the interview. Almost half of the respondents purchased their LLINs. Those who purchased LLINs were 3 times more likely to have used it (OR: 3.13, 95% CI 1.62–6.04) compared to those that got it free. Those who were gainfully employed (OR: 3.16, 95% CI 1.59–6.29) and those who earned above the minimum wage (OR: 2.88, 95% CI 1.45–5.72) were 3 times more likely to have used LLIN in their index pregnancy.

Conclusion

The use of LLIN as a preventive measure against malaria was relatively high among the participants in this study, though still below national target. The major factors determining the use of LLIN among these women were purchase of LLINs and being gainfully employed. It was recommended that efforts should be made to enforce the policy of free LLINs at ANC registration at the tertiary hospitals, as this would further drive up ownership and utilization rates.
Correction to: Predicting survival in melanoma patients treated with concurrent targeted- or immunotherapy and stereotactic radiotherapy
Authors: Schaule Jana , Kroeze Stephanie G. C. , Blanck Oliver , Stera Susanne , Kahl Klaus H. , Roeder Falk , Combs Stephanie E. , Kaul David , Claes An , Schymalla Markus M. , Adebahr Sonja , Eckert Franziska , Lohaus Fabian , Abbasi-Senger Nasrin , Henke Guido , Szuecs Marcella , Geier Michael , Sundahl Nora , Buergy Daniel , Dummer Reinhard , Guckenberger Matthias
Published: December 2020

An amendment to this paper has been published and can be accessed via the original article.
Unplanned hospitalizations in patients with locoregionally advanced head and neck cancer treated with (chemo)radiotherapy with and without prophylactic percutaneous endoscopic gastrostomy
Authors: Bojaxhiu Beat , Shrestha Binaya K. , Luterbacher Pascal , Elicin Olgun , Shelan Mohamed , Macpherson Andrew J. S. , Heimgartner Benjamin , Giger Roland , Aebersold Daniel M. , Zaugg Kathrin
Published: December 2020

Background

Current studies about percutaneous endoscopic gastrostomy (PEG) tube placement report equivalent patient outcomes with prophylactic PEG tubes (pPEGs) versus common nutritional support. Unreported was if omitting a pPEG is associated with an increased risk of complications leading to a treatment-related unplanned hospitalization (TRUH).

Methods

TRUHs were retrospectively analyzed in patients with advanced head and neck squamous cell carcinoma (n = 310) undergoing (chemo)radiotherapy with (pPEG) or without PEG (nPEG).

Results

In 88 patients (28%), TRUH was reported. One of the leading causes of TRUH in nPEG patients was inadequate oral intake (n = 16, 13%), and in pPEG patients, complications after PEG tube insertion (n = 12, 10%). Risk factors for TRUH were poor performance status, tobacco use, and surgical procedures.

Conclusions

Omitting pPEG tube placement without increasing the risk of an unplanned hospitalization due to dysphagia, dehydration or malnutrition, is an option in patients being carefully monitored. Patients aged > 60 years with hypopharyngeal carcinoma, tobacco consumption, and poor performance status appear at risk of PEG tube-related complications leading to an unplanned hospitalization.
RarERN Path: a methodology towards the optimisation of patients’ care pathways in rare and complex diseases developed within the European Reference Networks
Authors: Talarico Rosaria , Cannizzo Sara , Lorenzoni Valentina , Marinello Diana , Palla Ilaria , Pirri Salvatore , Ticciati Simone , Trieste Leopoldo , Triulzi Isotta , Terol Enrique , Bucher Anna , Turchetti Giuseppe
Published: December 2020

Background

In 2017, the European Commission has launched the European Reference Networks (ERNs), virtual networks involving healthcare providers across Europe. The aim of the ERNs is to tackle complex and rare diseases and conditions that require highly specialized treatment and a concentration of knowledge and resources. The ERN on rare and complex connective tissue and musculoskeletal diseases (ERN ReCONNET) is one of the 24 ERNs approved that aims to improve the management of Rare and Complex Connective Tissue and Musculoskeletal Diseases.

Objective

The RarERN Path methodology aims to create a single reference organisational model for patients’ care pathways which, if applied in different contexts, helps to ensure an improved, cost-effective and patient-centred equal care to rare and complex diseases.

Methods

Starting from existing standard methods for the creation and elaboration of patients’ care pathways, a specific methodology was created in order to take advantage of the distinctive and peculiar characteristics of the ERNs. Specifically, the development of the RarERN Path methodology involved different stakeholders: health economists, clinicians and researchers expert in rare and complex diseases, communication experts, experts in patients’ involvement and narrative medicine and policy-makers.

Results

The RarERN Path methodology foresees six consecutive phases, each with different and specific aims. Specifically, the six phases are represented by: Phase 1—mapping of existing patients’ care pathways and patients’ stories; Phase 2—design of an optimised common patients’ care pathway; Phase 3—consensus on an optimised common patients’ care pathway; Phase 4—key performance indicators definition; Phase 5—refinement; Phase 6—pilot phase (optional).

Conclusion

The application of RarERN Path to the different disease-specific and geographical contexts would help to ensure an improved, cost-effective and patient-centred equal care to rare and complex diseases across Europe as well as a possible tangible action towards the integration of ERNs into the different European healthcare systems.
Altered cleavage plane orientation with increased genomic aneuploidy produced by receptor-mediated lysophosphatidic acid (LPA) signaling in mouse cerebral cortical neural progenitor cells
Authors: McDonald Whitney S. , Miyamoto Kyoko , Rivera Richard , Kennedy Grace , Almeida Beatriz S. V. , Kingsbury Marcy A. , Chun Jerold
Published: December 2020

The brain is composed of cells having distinct genomic DNA sequences that arise post-zygotically, known as somatic genomic mosaicism (SGM). One form of SGM is aneuploidy—the gain and/or loss of chromosomes—which is associated with mitotic spindle defects. The mitotic spindle orientation determines cleavage plane positioning and, therefore, neural progenitor cell (NPC) fate during cerebral cortical development. Here we report receptor-mediated signaling by lysophosphatidic acid (LPA) as a novel extracellular signal that influences cleavage plane orientation and produces alterations in SGM by inducing aneuploidy during murine cortical neurogenesis. LPA is a bioactive lipid whose actions are mediated by six G protein-coupled receptors, LPA1–LPA6. RNAscope and qPCR assessment of all six LPA receptor genes, and exogenous LPA exposure in LPA receptor (Lpar)-null mice, revealed involvement ofLpar1andLpar2in the orientation of the mitotic spindle.Lpar1signaling increased non-vertical cleavage in vivo by disrupting cell–cell adhesion, leading to breakdown of the ependymal cell layer. In addition, genomic alterations were significantly increased after LPA exposure, through production of chromosomal aneuploidy in NPCs. These results identify LPA as a receptor-mediated signal that alters both NPC fate and genomes during cortical neurogenesis, thus representing an extracellular signaling mechanism that can produce stable genomic changes in NPCs and their progeny. Normal LPA signaling in early life could therefore influence both the developing and adult brain, whereas its pathological disruption could contribute to a range of neurological and psychiatric diseases, via long-lasting somatic genomic alterations.
Overexpression of astroglial major histocompatibility complex class I in the medial prefrontal cortex impairs visual discrimination learning in mice
Authors: Wulaer Bolati , Hada Kazuhiro , Sobue Akira , Itoh Norimichi , Nabeshima Toshitaka , Nagai Taku , Yamada Kiyofumi
Published: December 2020

Background

Immune molecules, such as cytokines, complement, and major histocompatibility complex (MHC) proteins, in the central nervous system are often associated with neuropsychiatric disorders. Neuronal MHC class I (MHCI), such as H-2D, regulate neurite outgrowth, the establishment and function of cortical connections, and activity-dependent refinement in mice. We previously established mice expressing MHCI specifically in astrocytes of the media prefrontal cortex (mPFC) using the adeno-associated virus (AAV) vector under the control of the GfaABC1D promoter. Mice expressing the soluble form of H-2D (sH-2D) in the mPFC (sH-2D-expressing mice) showed abnormal behaviors, including social interaction deficits and cognitive dysfunctions. However, the pathophysiological significance of astroglial MHCI on higher brain functions, such as learning, memory, and behavioral flexibility, remains unclear. Therefore, cognitive function in mice expressing sH-2D in astrocytes of the mPFC was tested using the visual discrimination (VD) task.

Methods

sH-2D-expressing mice were subjected to the VD and reversal learning tasks, and morphological analysis.

Results

In the pretraining, sH-2D-expressing mice required significantly more trials to reach the learning criterion than control mice. The total number of sessions, trials, normal trials, and correction trials to reach the VD criterion were also significantly higher in sH-2D-expressing mice than in control mice. A morphological study showed that dendritic complexity and spine density were significantly reduced in the dorsal striatum of sH-2D-expressing mice.

Conclusion

Collectively, the present results suggest that the overexpression of astroglial MHCI in the mPFC results in impaired VD learning, which may be accompanied by decreased dendritic complexity in the dorsal striatum and mPFC.
Prefrontal cortex, dorsomedial striatum, and dentate gyrus are necessary in the object-based attention test in mice
Authors: Wulaer Bolati , Kunisawa Kazuo , Kubota Hisayoshi , Suento Willy Jaya , Saito Kuniaki , Mouri Akihiro , Nabeshima Toshitaka
Published: December 2020

Disturbances of attention are a common behavioral feature associated with neuropsychiatric disorders with largely unknown underlying causes. We previously developed an object-based attention test (OBAT) as a simple and practical method for evaluating attention in mice. Since its establishment, the test has become a popular method for assessing attention and related underlying mechanisms in various mouse models. However, the underlying neuronal network involved in this test has yet to be studied. The purpose of this study was to identify the principal brain regions activated in the OBAT. Accordingly, C57BL/6J mice were subjected to the OBAT and thereafter prepared for immunohistochemical quantification of c-Fos, an immediate early gene that is frequently used as a marker of neuronal activity, in 13 different brain regions. The number of c-Fos-positive cells was significantly higher in the prefrontal cortex (PFC), dorsomedial striatum (DMS), and dentate gyrus (DG) in the test group as compared to the control group. The neuronal activation of these brain regions during the OBAT indicates that these brain regions are necessary for the regulation of attention in this test. This was supported by excitotoxic lesioning of these brain regions, leading to impaired attention without causing locomotor dysfunction. This study is one of the first attempts to analyze the brain regions that regulate attention in the OBAT. These findings provide an initial insight into the role of these brain regions and ideas for studying the underlying neural and molecular mechanisms.
MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer
Authors: Zhao Shuhua , Zhang Xiaohong , Shi Yuan , Cheng Lu , Song Tingting , Wu Bing , Li Jia , Yang Hong
Published: December 2020

Background

Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC).

Methods

The expression and clinical significance of MIEF2 were determined by qRT-PCR, western blot and immunohistochemistry analyses in tissues and cell lines of OC. The biological functions of MIEF2 in OC were determined by in vitro and in vivo cell growth and metastasis assays. Furthermore, the effect of MIEF2 on metabolic reprogramming of OC was determined by metabolomics and glucose metabolism analyses.

Results

MIEF2 expression was significantly increased in OC mainly due to the down-regulation of miR-424-5p, which predicts poor survival for patients with OC. Knockdown of MIEF2 significantly suppressed OC cell growth and metastasis both in vitro and in vivo by inhibiting G1-S cell transition, epithelial-to-mesenchymal transition (EMT) and inducing cell apoptosis, while forced expression of MIEF2 had the opposite effects. Mechanistically, mitochondrial fragmentation-suppressed cristae formation and thus glucose metabolism switch from oxidative phosphorylation to glycolysis was found to be involved in the promotion of growth and metastasis by MIEF2 in OC cells.

Conclusions

MIEF2 plays a critical role in the progression of OC and may serve as a valuable prognostic biomarker and therapeutic target in the treatment of this malignancy.
Resuscitation fluid types in sepsis, surgical, and trauma patients: a systematic review and sequential network meta-analyses
Authors: Tseng Chien-Hua , Chen Tzu-Tao , Wu Mei-Yi , Chan Ming-Cheng , Shih Ming-Chieh , Tu Yu-Kang
Published: December 2020

Background

Crystalloids and different component colloids, used for volume resuscitation, are sometimes associated with various adverse effects. Clinical trial findings for such fluid types in different patients’ conditions are conflicting. Whether the mortality benefit of balanced crystalloid than saline can be inferred from sepsis to other patient group is uncertain, and adverse effect profile is not comprehensive. This study aims to compare the survival benefits and adverse effects of seven fluid types with network meta-analysis in sepsis, surgical, trauma, and traumatic brain injury patients.

Methods

Searched databases (PubMed, EMBASE, and Cochrane CENTRAL) and reference lists of relevant articles occurred from inception until January 2020. Studies on critically ill adults requiring fluid resuscitation were included. Intervention studies reported on balanced crystalloid, saline, iso-oncotic albumin, hyperoncotic albumin, low molecular weight hydroxyethyl starch (L-HES), high molecular weight HES, and gelatin. Network meta-analyses were conducted using random-effects model to calculate odds ratio (OR) and mean difference. Risk of Bias tool 2.0 was used to assess bias. Confidence in Network Meta-Analysis (CINeMA) web application was used to rate confidence in synthetic evidence.

Results

Fifty-eight trials (n = 26,351 patients) were identified. Seven fluid types were evaluated. Among patients with sepsis and surgery, balanced crystalloids and albumin achieved better survival, fewer acute kidney injury, and smaller blood transfusion volumes than saline and L-HES. In those with sepsis, balanced crystalloids significantly reduced mortality more than saline (OR 0.84; 95% CI 0.74–0.95) and L-HES (OR 0.81; 95% CI 0.69–0.95) and reduced acute kidney injury more than L-HES (OR 0.80; 95% CI 0.65–0.99). However, they required the greatest resuscitation volume among all fluid types, especially in trauma patients. In patients with traumatic brain injury, saline and L-HES achieved lower mortality than albumin and balanced crystalloids; especially saline was significantly superior to iso-oncotic albumin (OR 0.55; 95% CI 0.35–0.87).

Conclusions

Our network meta-analysis found that balanced crystalloids and albumin decreased mortality more than L-HES and saline in sepsis patients; however, saline or L-HES was better than iso-oncotic albumin or balanced crystalloids in traumatic brain injury patients.

Trial registration

PROSPERO website, registration number: CRD42018115641).
Convergent network effects along the axis of gene expression during prostate cancer progression
Authors: Charmpi Konstantina , Guo Tiannan , Zhong Qing , Wagner Ulrich , Sun Rui , Toussaint Nora C. , Fritz Christine E. , Yuan Chunhui , Chen Hao , Rupp Niels J. , Christiansen Ailsa , Rutishauser Dorothea , Rüschoff Jan H. , Fankhauser Christian , Saba Karim , Poyet Cedric , Hermanns Thomas , Oehl Kathrin , Moore Ariane L. , Beisel Christian , Calzone Laurence , Martignetti Loredana , Zhang Qiushi , Zhu Yi , Martínez María Rodríguez , Manica Matteo , Haffner Michael C. , Aebersold Ruedi , Wild Peter J. , Beyer Andreas
Published: December 2020

Background

Tumor-specific genomic aberrations are routinely determined by high-throughput genomic measurements. It remains unclear how complex genome alterations affect molecular networks through changing protein levels and consequently biochemical states of tumor tissues.

Results

Here, we investigate the propagation of genomic effects along the axis of gene expression during prostate cancer progression. We quantify genomic, transcriptomic, and proteomic alterations based on 105 prostate samples, consisting of benign prostatic hyperplasia regions and malignant tumors, from 39 prostate cancer patients. Our analysis reveals the convergent effects of distinct copy number alterations impacting on common downstream proteins, which are important for establishing the tumor phenotype. We devise a network-based approach that integrates perturbations across different molecular layers, which identifies a sub-network consisting of nine genes whose joint activity positively correlates with increasingly aggressive tumor phenotypes and is predictive of recurrence-free survival. Further, our data reveal a wide spectrum of intra-patient network effects, ranging from similar to very distinct alterations on different molecular layers.

Conclusions

This study uncovers molecular networks with considerable convergent alterations across tumor sites and patients. It also exposes a diversity of network effects: we could not identify a single sub-network that is perturbed in all high-grade tumor regions.
Minimally invasive versus open radical trachelectomy for early-stage cervical cancer: protocol for a multicenter randomized controlled trial in China
Authors: Chao Xiaopei , Li Lei , Wu Ming , Wu Huanwen , Ma Shuiqing , Tan Xianjie , Zhong Sen , Lang Jinghe
Published: December 2020

Background

There are limited data comparing the oncologic and fertility outcomes of patients with early-stage cervical cancer (CC) treated by minimally invasive radical trachelectomy (MIRT) or abdominal radical trachelectomy (ART). The purpose of this multicenter study is to compare the oncologic and fertility outcomes of patients treated by MIRT or ART in a randomized controlled manner in China.

Methods

This is a noninferiority, randomized controlled trial performed at 28 Chinese centers; the study is designed to compare the oncologic and fertility outcomes of patients treated by MIRT (robot-assisted or laparoscopic RT) or ART. Patients will be recruited if they have been diagnosed with stage IA1 (with lymphovascular space invasion), IA2, or IB1 CC (with a maximum tumor diameter ≤ 2 cm) in the FIGO 2009 staging system and histological subtypes of squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma and if they are also aged 18 to 40 years. These candidates will be randomly assigned to undergo MIRT or ART. The primary endpoint will be disease-free survival. Secondary endpoints will consist of overall and disease-free survival rates, fertility outcomes, and quality of life. A total of 414 patients are needed to accomplish the study goal, with 90.1% power at a 0.050 significance level to detect an equivalence hazard ratio of 0.75 in the ART group, considering 20% loss to follow-up.

Discussion

The results of the trial should provide robust evidence to surgeons regarding options for the surgical approach in patients with early-stage CC who have a strong willingness to preserve fertility.

Trial registration

ClinicalTrials.gov NCT03739944. Registered on November 14, 2018
Correction to: A randomized, multicentre, open-label phase II proof-of-concept trial investigating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19: the Donated Antibodies Working against nCoV (DAWn-Plasma) trial
Authors: Devos Timothy , Geukens Tatjana , Schauwvlieghe Alexander , Ariën Kevin K. , Barbezange Cyril , Cleeren Myriam , Compernolle Veerle , Dauby Nicolas , Desmecht Daniël , Grimaldi David , Lambrecht Bart N. , Luyten Anne , Maes Piet , Moutschen Michel , Romano Marta , Seyler Lucie , Nevessignsky Michel Toungouz , Vandenberghe Katleen , van Griensven Johan , Verbeke Geert , Vlieghe Erika , Yombi Jean Cyr , Liesenborghs Laurens , Verhamme Peter , Meyfroidt Geert
Published: December 2020

An amendment to this paper has been published and can be accessed via the original article.
Metabolic engineering of Aspergillus niger via ribonucleoprotein-based CRISPR–Cas9 system for succinic acid production from renewable biomass
Authors: Yang Lei , Henriksen Mikkel Møller , Hansen Rasmus Syrach , Lübeck Mette , Vang Jesper , Andersen Julie Egelund , Bille Signe , Lübeck Peter Stephensen
Published: December 2020

Background

Succinic acid has great potential to be a new bio-based building block for deriving a number of value-added chemicals in industry. Bio-based succinic acid production from renewable biomass can provide a feasible approach to partially alleviate the dependence of global manufacturing on petroleum refinery. To improve the economics of biological processes, we attempted to explore possible solutions with a fungal cell platform. In this study, Aspergillus niger, a well-known industrial production organism for bio-based organic acids, was exploited for its potential for succinic acid production.

Results

With a ribonucleoprotein (RNP)-based CRISPR–Cas9 system, consecutive genetic manipulations were realized in engineering of the citric acid-producing strain A. niger ATCC 1015. Two genes involved in production of two byproducts, gluconic acid and oxalic acid, were disrupted. In addition, an efficient C4-dicarboxylate transporter and a soluble NADH-dependent fumarate reductase were overexpressed. The resulting strain SAP-3 produced 17 g/L succinic acid while there was no succinic acid detected at a measurable level in the wild-type strain using a synthetic substrate. Furthermore, two cultivation parameters, temperature and pH, were investigated for their effects on succinic acid production. The highest amount of succinic acid was obtained at 35 °C after 3 days, and low culture pH had inhibitory effects on succinic acid production. Two types of renewable biomass were explored as substrates for succinic acid production. After 6 days, the SAP-3 strain was capable of producing 23 g/L and 9 g/L succinic acid from sugar beet molasses and wheat straw hydrolysate, respectively.

Conclusions

In this study, we have successfully applied the RNP-based CRISPR–Cas9 system in genetic engineering of A. niger and significantly improved the succinic acid production in the engineered strain. The studies on cultivation parameters revealed the impacts of pH and temperature on succinic acid production and the future challenges in strain development. The feasibility of using renewable biomass for succinic acid production by A. niger has been demonstrated with molasses and wheat straw hydrolysate.
Outbreak of autochthonous cases of malaria in coastal regions of Northeast Brazil: the diversity and spatial distribution of species of Anopheles
Authors: Gomes Elainne Christine de Souza , Cruz Derciliano Lopes da , Santos Maria Alice Varjal Melo , Souza Renata Maria Costa , Oliveira Cláudia Maria Fontes de , Ayres Constância Flávia Junqueira , Domingos Renata Martins , Pedro Maria das Graça da Silva , Paiva Marcelo Henrique Santos , Pimentel Lílian Maria Lapa Montenegro
Published: December 2020

Background

Brazil has the fourth highest prevalence of malaria of all countries in the Americas, with an estimated 42 million people at risk of contracting this disease. Although most cases occur in the Amazon region, cases of an autochthonous nature have also been registered in the extra-Amazonian region where Anopheles aquasalis and An. albitarsis are the mosquito species of greatest epidemiological interest. In 2019, the municipality of Conde (state of Paraíba) experienced an epidemic of autochthonous cases of malaria. Here we present preliminary results of an entomological and case epidemiology investigation, in an attempt to correlate the diversity and spatial distribution of species of Anopheles with the autochthonous cases of this outbreak of malaria.

Methods

Case data were collected using case report forms made available by the Conde Municipal Health Department. The entomological survey was carried out from July to November 2019. The various methods of capture included the use of battery-powered aspirators, mouth aspirators, Shannon traps, BG-Sentinel traps (with and without dry ice) and CDC light traps. Captured mosquitoes were separated, packaged and sent to the laboratory for sexing and molecular identification of the various species of anophelines. The data were tabulated and analyzed using Microsoft Excel. Spatial analysis of the data was performed using ArcGis 10 software.

Results

In 2019, 20 autochthonous cases and one imported case of malaria caused by Plasmodium vivax were diagnosed, with three cases of relapses. A total of 3713 mosquitoes were collected, of which 3390 were culicines and 323 were anophelines. Nine species of genus Anopheles were identified, with the most abundant being An. aquasalis (38.9%), followed by An. minor (18.2%) and An. albitarsis (9.0%). Spatial analysis of the data showed that the area could be considered to be at risk of malaria cases and that there was a high prevalence of Anopheles.

Conclusions

The results presented indicate that this extra-Amazonian region has an environment conducive to maintenance of the malaria transmission cycle owing to the wide diversity of Anopheles species. This environment in combination with the high influx of people from endemic areas to the study area provides a perfect setting for the occurrence and maintenance of malaria.

Graphical Abstract
Insecticide resistance status of Aedes aegypti in Bangladesh
Authors: Al-Amin Hasan Mohammad , Johora Fatema Tuj , Irish Seth R. , Hossainey Muhammad Riadul Haque , Vizcaino Lucrecia , Paul Kishor Kumar , Khan Wasif A. , Haque Rashidul , Alam Mohammad Shafiul , Lenhart Audrey
Published: December 2020

Background

Arboviral diseases, including dengue and chikungunya, are major public health concerns in Bangladesh where there have been unprecedented levels of transmission reported in recent years. The primary approach to control these diseases is to control the vector Aedes aegypti using pyrethroid insecticides. Although chemical control has long been practiced, no comprehensive analysis of Ae. aegypti susceptibility to insecticides has been conducted to date. The aim of this study was to determine the insecticide resistance status of Ae. aegypti in Bangladesh and investigate the role of detoxification enzymes and altered target site sensitivity as resistance mechanisms.

Methods

Eggs of Aedes mosquitoes were collected using ovitraps from five districts across Bangladesh and in eight neighborhoods of the capital city Dhaka, from August to November 2017. CDC bottle bioassays were conducted for permethrin, deltamethrin, malathion, and bendiocarb using 3- to 5-day-old F0–F2 non-blood-fed female mosquitoes. Biochemical assays were conducted to detect metabolic resistance mechanisms, and real-time PCR was performed to determine the frequencies of the knockdown resistance (kdr) mutations Gly1016, Cys1534, and Leu410.

Results

High levels of resistance to permethrin were detected in all Ae. aegypti populations, with mortality ranging from 0 to 14.8% at the diagnostic dose. Substantial resistance continued to be detected against higher (2×) doses of permethrin (5.1–44.4% mortality). Susceptibility to deltamethrin and malathion varied between populations while complete susceptibility to bendiocarb was observed in all populations. Significantly higher levels of esterase and oxidase activity were detected in most of the test populations as compared to the susceptible reference Rockefeller strain. A significant association was detected between permethrin resistance and the presence of Gly1016 and Cys1534 homozygotes. The frequency of kdr (knockdown resistance) alleles varied across the Dhaka Aedes populations. Leu410 was not detected in any of the tested populations.

Conclusions

The detection of widespread pyrethroid resistance and multiple resistance mechanisms highlights the urgency for implementing alternate Ae. aegypti control strategies. In addition, implementing routine monitoring of insecticide resistance in Ae. aegypti in Bangladesh will lead to a greater understanding of susceptibility trends over space and time, thereby enabling the development of improved control strategies.

Graphical Abstract
Combined effect of water activity and pH on the growth of food-related ascospore-forming molds
Authors: Racchi Irene , Scaramuzza Nicoletta , Hidalgo Alyssa , Berni Elettra
Published: December 2020

Purpose

The contamination of raw materials, packaging, or processing environments by fungal ascospores is a real concern for food industries, where variable rates of spoilage can be reached in pasteurized acidic products such as fruit juices, fruit jams, or soft drinks. The aim of this work was to assess the combined effect of aw and pH on the growth of six isolates from three genera of ascospore-forming molds that may occur in raw materials and in food industrial environments, in order to determine the environmental conditions that prevent the spoilage of pasteurized foods and beverages.

Methods

Growth tests were carried out on 60-day-old ascospores from Aspergillus hiratsukae (≡Neosartorya hiratsukae), Aspergillus thermomutatus (≡Neosartorya pseudofischeri), Chaetomium flavoviride, Chaetomium globosum, Talaromyces bacillisporus, and Talaromyces trachyspermus. The tests were performed up to 90 days at 25 °C, using sucrose solutions at different aw (0.85, 0.88, 0.92, 0.95) and pH (3.20, 3.50, 3.80, 4.20, 4.60) values. Growth was characterized by fitting an ordinary logistic regression model to the collected growth data.

Results

The explained percentage of the growth/no growth models ranged between 81.0 and 99.3%: aw exerted the largest influence on the growth of all tested species, while pH was significant only for Chaetomium isolates. The minimum conditions for germination and growth were aw 0.92 and pH 3.50 or 3.80, respectively, for C. flavoviride (46 days) and C. globosum (39 days), aw 0.92 and pH 3.20 for T. trachyspermus (13 days), aw 0.88 and pH 3.20 for T. bacillisporus (39 days), and aw 0.88 and pH 3.20 for the two aspergilli (33 and 27 days, respectively, for A. hiratsukae and A. thermomutatus).

Conclusions

Most of the spoiling mycetes tested were well-adapted to the formulations considered; therefore, foods strategies aiming to inhibit their growth should explore also the hurdle effect exerted by other factors (e.g., antioxidants, organic acids, oxygen levels).
Potential of resveratrol in enrichment of neural progenitor-like cell induction of human stem cells from apical papilla
Authors: Songsaad Anupong , Gonmanee Thanasup , Ruangsawasdi Nisarat , Phruksaniyom Chareerut , Thonabulsombat Charoensri
Published: December 2020

Introduction

Stem cell transplantation of exogenous neural progenitor cells (NPCs) derived from mesenchymal stem cells (MSCs) has emerged as a promising approach for neurodegenerative disease. Human stem cells from apical papilla (hSCAPs) are derived from migratory neural crest stem cells and exhibit a potential of neuronal differentiation. However, their neuronal differentiation is low and unpredictable. Resveratrol has been described as a sirtuin 1 (SIRT1) activator which plays an important role in enhancing neuronal differentiation. In this study, we investigate the potential of resveratrol as an enhancer on neuronal differentiation through NPCs induction of hSCAPs.

Methods

Stem cells were isolated from human apical papilla and characterized as MSCs. The cellular toxicity of resveratrol treatment to the characterized hSCAPs was investigated by MTT assay. The non-cellular toxicity concentrations of resveratrol were assessed with various pre-treatment times to select the optimal condition that highly expressed the neural progenitor gene, NES. Consequently, the optimal condition of resveratrol pre-treatment was synergistically performed with a neuronal induction medium to trigger neuronal differentiation. The differentiated cells were visualized, the genes profiling was quantified, and the percentage of neuronal differentiation was calculated. Moreover, the intracellular calcium oscillation was demonstrated.

Results

The cellular toxicity of resveratrol was not observed for up to 50 μM for 12 h. Interestingly, hSCAPs pre-treated with 10 μM resveratrol for 12 h (RSV-hSCAPs) significantly expressed NES, which is determined as the optimal condition. Under neuronal induction, both of hSCAPs and RSV-hSCAPs were differentiated (d-hSCAPs and RSV-d-hSCAPs) as they exhibited neuronal-like appearances with Nissl substance staining. The highest expression of NES and SOX1 was observed in RSV-d-hSCAPs. Additionally, the percentage of neuronal differentiation of RSV-d-hSCAPs was significantly higher than d-hSCAPs for 4 times. Importantly, the neuronal-like cells exhibited slightly increasing pattern of calcium intensity.

Conclusion

This study demonstrated that pre-treatment of resveratrol strongly induces neural progenitor marker gene expression which synergistically enhances neural progenitor-like cells’ induction with neuronal induction medium.
A microbial ecosystem: agricultural Jiaosu achieves effective and lasting antifungal activity against Botrytis cinerea
Authors: Zhang Yue , Gao Youhui , Zheng Zehui , Meng Xingyao , Cai Yafan , Liu Jianbin , Hu Yuegao , Yan Shuangdui , Wang Xiaofen
Published: December 2020

Synthetic fungicides are eco-unfriendly to agriculture and the environment. Agricultural Jiaosu (AJ), which originates from organic wastes, has the potential to be a substitute for synthetic fungicides. In this study, the characteristics of AJ and its antifungal activity against Botrytis cinerea were investigated for the first time. AJ was rich in lactic acid (4.46 g/L), acetic acid (1.52 g/L), Lactobacillus (72.45%) and Acetobacter (15.23%), which was a microbial ecosystem consisting of acid-based substances (AS) and beneficial microorganisms (BM). The results of the antifungal assays suggested that B. cinerea was effectively inhibited by AJ, with the half-maximal inhibitory concentration (IC50) of 9.24%. AJ showed the strongest and most-lasting inhibitory effect compared to cell-free supernatant and microbial solution of AJ, indicating that AS and BM and their synergistic effect contributed to the antifungal activity of AJ. Two-step inhibition’ is an antifungal mode of AJ. Firstly, AS not only inhibited the pathogen directly but also provided a dominant niche for BM of AJ. Then, BM in AJ, especially Acetobacter, proliferated and metabolized acetic acid continuously. Thus, AJ achieved high-efficiency and long-acting inhibition. AJ is a promising biological agent considering its features of an eco-friendly, low-cost and easy-to-operate biological agent in rural areas.