bluuebunny/crossref_metadata_2025 huggingface dataset:
A mixed-methods study of pesticide exposures in Breastmilk and Community & Lactating Women’s perspectives from Haryana, India
Authors: Mehta Rukshan V. , Sreenivasa M. A. , Mathew Mathen , Girard Amy Webb , Taneja Sunita , Ranjan Samriddhi , Ramakrishnan Usha , Martorell Reynaldo , Ryan P. Barry , Young Melissa F.
Published: December 2020

Background

Population growth which has resulted in a need for increased crop yields to sustain food security, in addition to the effects of climate change, have led to the widespread use of chemical pesticides. The indiscriminate use of pesticides has in turn led to contamination of the environment, food commodities and bioaccumulation in human tissues, particularly in agrarian regions of India including the northern state of Haryana.

Methods

We conducted a pilot screening study to investigate the presence of organochlorine, organophosphate, and pyrethroid pesticides in breastmilk samples (n = 75) from Haryana, India. Pesticide analyses were conducted using gas chromatography mass spectrometry (GC-MS) for OC and OP pesticides and GC-electron capture detector for pyrethroids. The study was complemented by a qualitative evaluation of maternal and community perceptions, knowledge, attitudes and practices associated with pesticide use and risk of exposure (n = 30 in-depth interviews;n = 9 focus group discussions).

Results

Analysis of breastmilk showed the presence ofp,p’-dichlorodiphenyltrichloroethane (DDT) andp,p’-dichlorodiphenyldichloroethylene (DDE) in 4% (range: <LOQ - 28 μg/L) and 5% (range: < LOQ – 107 μg/L) of samples, respectively. No other pesticides were detected.

Our qualitative findings showed that community members commonly held perceptions of pesticides as medicines and poison but acknowledged their widespread use to ensure crop yields. Given the gendered engagement in farming in this setting, lactating women in study communities do not directly handle chemical pesticides, thus lowering risk of inhalation and dermal exposure.

Conclusions

In our small sample, breastmilk pesticide concentrations were low and did not pose a risk to infants. Based on the persistent nature of many organic pollutants and reported widespread use, we recommend more comprehensive and longitudinal investigation of upstream pesticide contamination in the food supply and exposures among mothers and children.

Trial registration

CTRI/2017/01/007636, Date Registered: 06/01/2017.

CTRI website:http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=17249&EncHid=&modid=&compid=%27,%2717249det%27
Hindsight is 2020 vision: a characterisation of the global response to the COVID-19 pandemic
Authors: Warne David J. , Ebert Anthony , Drovandi Christopher , Hu Wenbiao , Mira Antonietta , Mengersen Kerrie
Published: December 2020

Background

The global impact of COVID-19 and the country-specific responses to the pandemic provide an unparalleled opportunity to learn about different patterns of the outbreak and interventions. We model the global pattern of reported COVID-19 cases during the primary response period, with the aim of learning from the past to prepare for the future.

Methods

Using Bayesian methods, we analyse the response to the COVID-19 outbreak for 158 countries for the period 22 January to 9 June 2020. This encompasses the period in which many countries imposed a variety of response measures and initial relaxation strategies. Instead of modelling specific intervention types and timings for each country explicitly, we adopt a stochastic epidemiological model including a feedback mechanism on virus transmission to capture complex nonlinear dynamics arising from continuous changes in community behaviour in response to rising case numbers. We analyse the overall effect of interventions and community responses across diverse regions. This approach mitigates explicit consideration of issues such as period of infectivity and public adherence to government restrictions.

Results

Countries with the largest cumulative case tallies are characterised by a delayed response, whereas countries that avoid substantial community transmission during the period of study responded quickly. Countries that recovered rapidly also have a higher case identification rate and small numbers of undocumented community transmission at the early stages of the outbreak. We also demonstrate that uncertainty in numbers of undocumented infections dramatically impacts the risk of multiple waves. Our approach is also effective at pre-empting potential flare-ups.

Conclusions

We demonstrate the utility of modelling to interpret community behaviour in the early epidemic stages. Two lessons learnt that are important for the future are: i) countries that imposed strict containment measures early in the epidemic fared better with respect to numbers of reported cases; and ii) broader testing is required early in the epidemic to understand the magnitude of undocumented infections and recover rapidly. We conclude that clear patterns of containment are essential prior to relaxation of restrictions and show that modelling can provide insights to this end.
Receipt of infant HIV DNA PCR test results is associated with a reduction in retention of HIV-exposed infants in integrated HIV care and healthcare services: a quantitative sub-study nested within a cluster randomised trial in rural Malawi
Authors: Milanzi Elasma , Mwapasa Victor , Joseph Jessica , Jousset Aurelie , Tchereni Timothy , Gunda Andrews , Phiri Jennipher , Reece Jeanette C.
Published: December 2020

Background

Retention of HIV-infected mothers in integrated HIV and healthcare facilities is effective at reducing mother-to-child-transmission (MTCT) of HIV. In the context of Option B+, we examined maternal and HIV-exposed infant retention across three study arms to 18 months postpartum: mother-and-infant clinics (MIP), MIP with short-messaging service (MIP + SMS) and standard of care (SOC). In particular, we focused on the impact of mothers receiving an infant’s HIV PCR test result on maternal and infant study retention.

Methods

A quantitative sub-study nested within a cluster randomised trial undertaken between May 2013 and August 2016 across 30 healthcare facilities in rural Malawi enrolling HIV-infected pregnant mothers and HIV-exposed infants on delivery, was performed. Survival probabilities of maternal and HIV-exposed infant study retention was estimated using Kaplan-Meier curves. Associations between mother’s receiving an infant’s HIV test result and in particular, an infant’s HIV-positive result on maternal and infant study retention were modelled using time-varying multivariate Cox regression.

Results

Four hundred sixty-one, 493, and 396 HIV-infected women and 386, 399, and 300 HIV-exposed infants were enrolled across study arms; MIP, MIP + SMS and SOC, respectively. A total of 47.5% of mothers received their infant’s HIV test results < 5 months postpartum. Receiving an infant’s HIV result by mothers was associated with a 70% increase in infant non-retention in the study compared with not receiving an infant’s result (HR = 1.70; P-value< 0.001). Receiving a HIV-positive result was associated with 3.12 times reduced infant retention compared with a HIV-negative result (P-value< 0.001). Of the infants with a HIV-negative test result, 87% were breastfed at their final study follow-up.

Conclusions

Receiving an infant’s HIV test result was a driving factor for reduced infant study retention, especially an infant’s HIV-positive test result. As most HIV-negative infants were still breastfed at their last follow-up, this indicates a large proportion of HIV-exposed infants were potentially at future risk of MTCT of HIV via breastfeeding but were unlikely to undergo follow-up HIV testing after breastfeeding cessation. Future studies to identify and address underlying factors associated with infant HIV testing and reduced infant retention could potentially improve infant retention in HIV/healthcare facilities.

Trial registration

Pan African Clinical Trial Registry: PACTR201312000678196.
A multicenter randomized trial to assess the efficacy of CONvalescent plasma therapy in patients with Invasive COVID-19 and acute respiratory failure treated with mechanical ventilation: the CONFIDENT trial protocol
Authors: Misset Benoît , Hoste Eric , Donneau Anne-Françoise , Grimaldi David , Meyfroidt Geert , Moutschen Michel , Compernolle Veerle , Gothot André , Desmecht Daniel , Garigliany Mutien , Najdovski Tome , Laterre Pierre-François
Published: December 2020

Background

The COVID-19 pandemic reached Europe in early 2020. Convalescent plasma is used without a consistent evidence of efficacy. Our hypothesis is that passive immunization with plasma collected from patients having contracted COVID-19 and developed specific neutralizing antibodies may alleviate symptoms and reduce mortality in patients treated with mechanical ventilation for severe respiratory failure during the evolution of SARS-CoV-2 pneumonia.

Methods

We plan to include 500 adult patients, hospitalized in 16 Belgian intensive care units between September 2020 and 2022, diagnosed with SARS-CoV-2 pneumonia, under mechanical ventilation for less than 5 days and a clinical frailty scale less than 6. The study treatment will be compared to standard of care and allocated by randomization in a 1 to 1 ratio without blinding. The main endpoint will be mortality at day 28. We will perform an intention to treat analysis. The number of patients to include is based on an expected mortality rate at day 28 of 40 percent and an expected relative reduction with study intervention of 30 percent with α risk of 5 percent and β risk of 20 percent.

Discussion

This study will assess the efficacy of plasma in the population of mechanically ventilated patients. A stratification on the delay from mechanical ventilation and inclusion will allow to approach the optimal time use. Selecting convalescent plasmas with a high titer of neutralizing antibodies against SARS-CoV-2 will allow a homogeneous study treatment. The inclusion in the study is based on the consent of the patient or his/her legal representative, and the approval of the Investigational Review Board of the University hospital of Liège, Belgium. A data safety monitoring board (DSMB) has been implemented. Interim analyses have been planned at 100, 2002, 300 and 400 inclusions in order to decide whether the trail should be discontinued prematurely for ethical issues. We plan to publish our results in a peer-reviewed journal and to present them at national and international conferences.

Funding and registration

The trial is funded by the Belgian Health Care Knowledge Center KCE # COV201004

Trial registration

Clinicaltrials.gov registration number NCT04558476. Registered 14 September 2020—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04558476
Atlantoaxial dislocation with congenital “sandwich fusion” in the craniovertebral junction: a retrospective case series of 70 patients
Authors: Tian Yinglun , Xu Nanfang , Yan Ming , Passias Peter G. , Segreto Frank A. , Wang Shenglin
Published: December 2020

Background

In the setting of congenital C1 occipitalization and C2–3 fusion, significant strain is placed on the atlantoaxial joint. Vertebral fusion both above and below the atlantoaxial joint (i.e., a “sandwich”) creates substantial instability. We retrospectively report on a case series of “sandwich fusion” atlantoaxial dislocation (AAD), describing the associated clinical characteristics and detailing surgical treatment. To the best of our knowledge, the present study is the largest investigation to date of this congenital subgroup of AAD.

Methods

Seventy consecutive patients with sandwich fusion AAD, from one senior surgeon, were retrospectively reviewed. The clinical features and the surgical treatment results were assessed using descriptive statistics. No funding sources or potential conflict of interest-associated biases exist.

Results

The mean patient age was 42.2 years (range: 5–77 years); 36 patients were male, and 34 were female. Fifty-eight patients (82.9%) had myelopathy, with Japanese Orthopaedic Association (JOA) scores ranging 4–16 (mean: 12.9). Cranial neuropathy was involved in 10 cases (14.3%). The most common presentation age group was 31 to 40 years (24 cases, 34.3%). Radiological findings revealed brainstem and/or cervical-medullar compression (58 cases, 82.9%), syringomyelia (16 cases, 22.9%), Chiari malformation (12 cases, 17.1%), cervical spinal stenosis (10 cases, 14.3%), high scapula deformity (1 case, 1.4%), os odontoideum (1 case, 1.4%), and dysplasia of the atlas (1 case, 1.4%). Computed tomography angiography was performed in 27 cases, and vertebral artery (VA) anomalies were identified in 14 cases (51.9%). All 70 patients underwent surgical treatment, without spinal cord or VA injury. Four patients (5.7%) suffered complications, including 1 wound infection, 1 screw loosening, and 2 cases of bulbar paralysis. In the 58 patients with myelopathy, the mean JOA score increased from 12.9 to 14.5. The average follow-up time was 50.5 months (range: 24–120 months). All 70 cases achieved solid atlantoaxial fusion at the final follow-up.

Conclusions

Sandwich fusion AAD, a unique subgroup of AAD, has distinctive clinical features and associated malformations such as cervical-medullar compression, syringomyelia, and VA anomalies. Surgical treatment of AAD was associated with myelopathy improvement and minimal complication occurrence.
Dermatome Mapping Test in the analysis of anatomo-clinical correlations after inguinal hernia repair
Authors: Cirocchi Roberto , Mercurio Isabella , Nazzaro Claudio , De Sol Angelo , Boselli Carlo , Rettagliata George , Vanacore Nicola , Santoro Alberto , Mascagni Domenico , Renzi Claudio , Lancia Massimo , Suadoni Fabio , Zanghì Guido , Palumbo Piergaspare , Bruzzone Paolo , Tellan Guglielmo , Fedeli Piergiorgio , Marsilio Francucci , D’Andrea Vito
Published: December 2020

Background

Nerve identification is recommended in inguinal hernia repair to reduce or avoid postoperative pain. The aim of this prospective observational study was to identify nerve prevalence and find a correlation between neuroanatomy and chronic neuropathic postoperative inguinal pain (CPIP) after 6 months.

Material

A total of 115 patients, who underwent inguinal hernia mesh repair (Lichtenstein tension-free mesh repair) between July 2018 and January 2019, were included in this prospective observational study. The mean age and BMI respectively resulted 64 years and 25.8 with minimal inverse distribution of BMI with respect to age. Most of the hernias were direct (59.1%) and of medium dimension (47.8%). Furthermore, these patients were undergoing Dermatome Mapping Test in preoperatively and postoperatively 6 months evaluation.

Results

Identification rates of the iliohypogastric (IH), ilioinguinal (II) and genitofemoral (GF) nerves were 72.2%, 82.6% and 48.7% respectively. In the analysis of nerve prevalence according to BMI, the IH was statistically significant higher in patients with BMI < 25 than BMI ≥ 25 P (< 0.05). After inguinal hernia mesh repair, 8 patients (6.9%) had chronic postoperative neuropathic inguinal pain after 6 months. The CPIP prevailed at II/GF dermatome. The relation between the identification/neurectomy of the II nerve and chronic postoperative inguinal pain after 6 months was not significant (P = 0.542).

Conclusion

The anatomy of inguinal nerve is very heterogeneous and for this reason an accurate knowledge of these variations is needed during the open mesh repair of inguinal hernias. The new results of our analysis is the statistically significant higher IH nerve prevalence in patients with BMI < 25; probably the identification of inguinal nerve is more complex in obese patients. In the chronic postoperative inguinal pain, the II nerve may have a predominant role in determining postoperative long-term symptoms. Dermatome Mapping Test in an easy and safe method for preoperative and postoperative 6 months evaluation of groin pain. The most important evidence of our analysis is that the prevalence of chronic pain is higher when the nerves were not identified.
MicroRNA-219c-5p regulates bladder fibrosis by targeting FN1
Authors: Liu Bowen , Ding Yafei , Li Peng , Wang Tao , He Siyuan , Jia Zhankui , Yang Jinjian
Published: December 2020

Background

We found that the bladders of multiple sclerosis mice were significantly fibrotic. This study aimed to investigate the relationship between fibronectin 1 (FN1) and bladder fibrosis, as well as the microRNAs involved in FN1 regulation.

Methods

The degree of bladder smooth muscle fibrosis was observed by immunohistochemistry. In addition, we used quantitative real-time polymerase chain reaction (RT-qPCR) and Western blotting to determine FN1 expression in bladders with different grades of fibrosis. Bioinformatics analysis revealed that miR-199a-3p, miR-219c-5p and miR-3572-3p could inhibit FN1 synthesis. Therefore, miR-199a-3p, miR-219c-5p and miR-3572-3p were overexpressed or knocked down in bladder smooth muscle cells (BSMCs), and the respective transfection and FN1 knockdown efficiencies were detected by RT-qPCR. Only miR-219c-5p overexpression and knockdown produced the expected results. A dual luciferase reporter assay was used to determine the targeting relationship between miR-219c-5p and FN1. Flow cytometry and Cell Counting Kit 8 (CCK8) experiments confirmed that miR-219c-5p reduced FN1 expression and affected the biological activity of smooth muscle cells. Agomir and anagomir of miR-219c-5p were transfected in vivo to observe the change of bladder fibrosis in mice.

Results

With increasing bladder fibrosis, FN1 expression increased, while miR-199a-3p, miR-219c-5p, and miR-3572-3p expression levels decreased. The RT-qPCR results after transfection showed that only miR-219c-5p could regulate FN1. Indeed, the dual luciferase reporter assay results indicated that miR-219c-5p targeted FN1 directly. CCK8 and cell cycle assays showed that miR-219c-5p overexpression inhibited BSMC proliferation, while miR-219c-5p knockdown promoted BSMC proliferation. An apoptosis assay showed that miR-219c-5p overexpression promoted apoptosis, while miR-219c-5p knockdown inhibited BSMC apoptosis. The agomir and anagomir transfected with miR-219c-5p in vivo found that the bladder fibrosis of the mice in the agomir group was reduced, and the anagomir group was worse.

Conclusions

Our findings indicate that FN1 up-regulation and miR-219c-5p down-regulation play an important role in the development of bladder fibrosis, and miR-219c-5p participates in bladder fibrosis by regulating FN1 expression. Thus, a novel antifibrotic function of miR-219c-5p is proposed, which may represent a potential target for the diagnosis and treatment of bladder fibrosis.
Interplay between traumatic brain injury and intimate partner violence: data driven analysis utilizing electronic health records
Authors: Liu Larry Y. , Bush William S. , Koyutürk Mehmet , Karakurt Günnur
Published: December 2020

Background

It is estimated that a majority of intimate partner violence (IPV) victims suffer from blunt force to the head, neck and the face area. Injuries to head and neck are among the major causes for traumatic brain injury (TBI).

Methods

In this interdisciplinary study, we aimed to characterize the key associations between IPV and TBI by mining de-identified electronic health records data with more than 12 M records between 1999 to 2017 from the IBM Explorys platform. For this purpose, we formulated a data-driven analytical framework to identify significant health correlates among IPV, TBI and six control cohorts. Using this framework, we assessed the co-morbidity, shared prevalence, and synergy between pairs of conditions.

Results

Our findings suggested that health effects attributed to malnutrition, acquired thrombocytopenia, post-traumatic wound infection, local infection of wound, poisoning by cardiovascular drug, alcoholic cirrhosis, alcoholic fatty liver, and drug-induced cirrhosis were highly significant at the joint presence of IPV and TBI.

Conclusion

To develop a better understanding of how IPV is related to negative health effects, it is potentially useful to determine the interactions and relationships between symptom categories. Our results can potentially improve the accuracy and confidence of existing clinical screening techniques on determining IPV-induced TBI diagnoses.
Development of a data-driven COVID-19 prognostication tool to inform triage and step-down care for hospitalised patients in Hong Kong: a population-based cohort study
Authors: Tsui Eva L. H. , Lui Carrie S. M. , Woo Pauline P. S. , Cheung Alan T. L. , Lam Peggo K. W. , Tang Van T. W. , Yiu C. F. , Wan C. H. , Lee Libby H. Y.
Published: December 2020

Background

This is the first study on prognostication in an entire cohort of laboratory-confirmed COVID-19 patients in the city of Hong Kong. Prognostic tool is essential in the contingency response for the next wave of outbreak. This study aims to develop prognostic models to predict COVID-19 patients’ clinical outcome on day 1 and day 5 of hospital admission.

Methods

We did a retrospective analysis of a complete cohort of 1037 COVID-19 laboratory-confirmed patients in Hong Kong as of 30 April 2020, who were admitted to 16 public hospitals with their data sourced from an integrated electronic health records system. It covered demographic information, chronic disease(s) history, presenting symptoms as well as the worst clinical condition status, biomarkers’ readings and Ct value of PCR tests on Day-1 and Day-5 of admission. The study subjects were randomly split into training and testing datasets in a 8:2 ratio. Extreme Gradient Boosting (XGBoost) model was used to classify the training data into three disease severity groups on Day-1 and Day-5.

Results

The 1037 patients had a mean age of 37.8 (SD ± 17.8), 53.8% of them were male. They were grouped under three disease outcome: 4.8% critical/serious, 46.8% stable and 48.4% satisfactory. Under the full models, 30 indicators on Day-1 and Day-5 were used to predict the patients’ disease outcome and achieved an accuracy rate of 92.3% and 99.5%. With a trade-off between practical application and predictive accuracy, the full models were reduced into simpler models with seven common specific predictors, including the worst clinical condition status (4-level), age group, and five biomarkers, namely, CRP, LDH, platelet, neutrophil/lymphocyte ratio and albumin/globulin ratio. Day-1 model’s accuracy rate, macro-/micro-averaged sensitivity and specificity were 91.3%, 84.9%/91.3% and 96.0%/95.7% respectively, as compared to 94.2%, 95.9%/94.2% and 97.8%/97.1% under Day-5 model.

Conclusions

Both Day-1 and Day-5 models can accurately predict the disease severity. Relevant clinical management could be planned according to the predicted patients’ outcome. The model is transformed into a simple online calculator to provide convenient clinical reference tools at the point of care, with an aim to inform clinical decision on triage and step-down care.
Insulin directly stimulates mitochondrial glucose oxidation in the heart
Authors: Karwi Qutuba G. , Wagg Cory S. , Altamimi Tariq R. , Uddin Golam M. , Ho Kim L. , Darwesh Ahmed M. , Seubert John M. , Lopaschuk Gary D.
Published: December 2020

Background

Glucose oxidation is a major contributor to myocardial energy production and its contribution is orchestrated by insulin. While insulin can increase glucose oxidation indirectly by enhancing glucose uptake and glycolysis, it also directly stimulates mitochondrial glucose oxidation, independent of increasing glucose uptake or glycolysis, through activating mitochondrial pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. However, how insulin directly stimulates PDH is not known. To determine this, we characterized the impacts of modifying mitochondrial insulin signaling kinases, namely protein kinase B (Akt), protein kinase C-delta (PKC-δ) and glycogen synthase kinase-3 beta (GSK-3β), on the direct insulin stimulation of glucose oxidation.

Methods

We employed an isolated working mouse heart model to measure the effect of insulin on cardiac glycolysis, glucose oxidation and fatty acid oxidation and how that could be affected when mitochondrial Akt, PKC-δ or GSK-3β is disturbed using pharmacological modulators. We also used differential centrifugation to isolate mitochondrial and cytosol fraction to examine the activity of Akt, PKC-δ and GSK-3β between these fractions. Data were analyzed using unpaired t-test and two-way ANOVA.

Results

Here we show that insulin-stimulated phosphorylation of mitochondrial Akt is a prerequisite for transducing insulin’s direct stimulation of glucose oxidation. Inhibition of mitochondrial Akt completely abolishes insulin-stimulated glucose oxidation, independent of glucose uptake or glycolysis. We also show a novel role of mitochondrial PKC-δ in modulating mitochondrial glucose oxidation. Inhibition of mitochondrial PKC-δ mimics insulin stimulation of glucose oxidation and mitochondrial Akt. We also demonstrate that inhibition of mitochondrial GSK3β phosphorylation does not influence insulin-stimulated glucose oxidation.

Conclusion

We identify, for the first time, insulin-stimulated mitochondrial Akt as a prerequisite transmitter of the insulin signal that directly stimulates cardiac glucose oxidation. These novel findings suggest that targeting mitochondrial Akt is a potential therapeutic approach to enhance cardiac insulin sensitivity in condition such as heart failure, diabetes and obesity.
Enhancement of Monascus yellow pigments production by activating the cAMP signalling pathway in Monascus purpureus HJ11
Authors: Liu Jiawei , Du Yun , Ma Hongmin , Pei Xiaolin , Li Mu
Published: December 2020

Background

Monascus azaphilone pigments (MonAzPs), which were produced by Monascus species, have been used as important food colorant and food supplements for more than one billion people during their daily life. Moreover, MonAzPs recently have received more attention because of their diverse physiological activities. However, the high microbial production of MonAzPs is still not always guaranteed. Herein, the aim of this study was to develop an efficient biotechnological process for MonAzPs production.

Results

In this study, exogenous cyclic adenosine monophosphate (cAMP) treatment not only induced MonAzPs production, but also stimulated the expression of a cAMP phosphodiesterase gene, named as mrPDE, in M. purpureus HJ11. Subsequently, MrPDE was identified as a cAMP phosphodiesterase by in vitro enzymatic reaction with purified enzyme. Further, a gene knockout mutant of mrPDE was constructed to verify the activation of cAMP signalling pathway. Deletion of mrPDE in M. purpureus HJ11 improved cAMP concentration by 378% and enhanced PKA kinase activity 1.5-fold, indicating that activation of cAMP signalling pathway was achieved. The ΔmrPDE strain produced MonAzPs at 8563 U/g, with a 2.3-fold increase compared with the WT strain. Moreover, the NAPDH/NADP+ ratio of the ΔmrPDE strain was obviously higher than that of the wild type strain, which led to a higher proportion of yellow MonAzPs. With fed-batch fermentation of the ΔmrPDE strain, the production and yield of MonAzPs achieved 332.1 U/mL and 8739 U/g.

Conclusions

A engineered M. purpureus strain for high MonAzPs production was successfully developed by activating the cAMP signalling pathway. This study not only describes a novel strategy for development of MonAzPs-producing strain, but also provides a roadmap for engineering efforts towards the production of secondary metabolism in other filamentous fungi.
Development and validation of a VHL-associated immune prognostic signature for clear cell renal cell carcinoma
Authors: Zhang Jin , Yan Aiting , Cao Wei , Shi Honglei , Cao Kai , Liu Xiaowu
Published: December 2020

Background

VHL mutation is the most common mutation in clear cell renal cell carcinoma (ccRCC). Here, we developed and validated an immune-related signature to predict the prognosis of ccRCC with VHL mutations.

Methods

VHL mutation status and RNA expression were analysed in the TCGA datasets and our cohort. LASSO Cox analysis was performed to develop an immune-related signature. Candidate genes for the immune-related signature were differentially expressed between VHLwt and VHLmut ccRCC patients.

Results

VHL mutations resulted in the downregulation of the immune response in ccRCC. To develop an immune-related signature, LASSO Cox analysis was constructed by immune-related genes that were differentially expressed between VHLwt (WHL wild type) and VHLmut (VHL mutation) ccRCC patients. The signature was developed and validated in the TCGA and our own cohort to classify patients into groups based on having a low or high risk of poor survival. Functional enrichment analysis showed that the immune-related pathway represented the major function and pathway. In addition, patients in the high-risk group had a positive correlation with low fractions of CD4 + T cells and dendritic cells and presented a lower expression of CTLA-4 and PD-1 than the low-risk group.

Conclusion

In this study, we proposed a novel immune-related signature, which is a feasible biomarker for predicting the overall survival in VHLmut patients with ccRCC.
CD44, a marker of cancer stem cells, is positively correlated with PD-L1 expression and immune cells infiltration in lung adenocarcinoma
Authors: Zhang Chenyue , Wang Hui , Wang Xia , Zhao Chenglong , Wang Haiyong
Published: December 2020

Background

PD-L1 inhibitors is widely applied in lung adenocarcinoma patients. Tumor cells with high PD-L1 expression could trigger immune evasion. Cancer stem cells (CSCs) can evade from immunesurveillance due to their immunomodulating effects. However, the correlation between CSC and PD-L1 and some immune-related markers is seldom reported in patients with lung adenocarcinoma. Therefore, we aimed to ascertain their association in lung adenocarcinoma patients.

Methods

We assessed CD44 expression and its association with PD-L1 in lung adenocarcinoma, using Tumor Immune Estimation Resource (TIMER), which was further validated in our patient cohort. The immune cells infiltration was depicted by CIBERSORT using GEO database. The correlation between CD44 and immune cells was also analyzed. We further evaluated the prognostic role of CD44 in patients with lung adenocarcinoma both using Kaplan–Meier plotter and validated in our patient cohort.

Results

Positive association between CD44 and PD-L1 were found in lung adenocarcinoma patients. T cells CD4 memory resting cells and mast cells resting cells varied significantly between patients with CD44 high and those with CD44 low. Furthermore, positive association could be found between CD44 expression and immune cells. Arm-level depletion of CD44 was linked with B cell, CD4+T cell, neutrophil and dendritic cell infiltration. Patients with higher CD44 levels had worsened overall survival (OS).

Conclusions

In summary, these results demonstrate that CD44 was associated with PD-L1 and infiltration of immune cells, and was a negative prognostic factor for predicting worsened OS in lung adenocarcinoma.
Emerging roles of RNA methylation in gastrointestinal cancers
Authors: Xie Shanshan , Chen Wenwen , Chen Kanghua , Chang Yongxia , Yang Feng , Lin Aifu , Shu Qiang , Zhou Tianhua , Yan Xiaoyi
Published: December 2020

RNA methylation has emerged as a fundamental process in epigenetic regulation. Accumulating evidences indicate that RNA methylation is essential for many biological functions, and its dysregulation is associated with human cancer progression, particularly in gastrointestinal cancers. RNA methylation has a variety of biological properties, including N6-methyladenosine (m6A), 2-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C) and 7-methyl guanosine (m7G). Dynamic and reversible methylation on RNA is mediated by RNA modifying proteins called “writers” (methyltransferases) and “erasers” (demethylases). “Readers” (modified RNA binding proteins) recognize and bind to RNA methylation sites, which influence the splicing, stability or translation of modified RNAs. Herein, we summarize the biological functions and mechanisms of these well-known RNA methylations, especially focusing on the roles of m6A in gastrointestinal cancer development.
Long non-coding RNA LINC01194 promotes the proliferation, migration and invasion of lung adenocarcinoma cells by targeting miR-641/SETD7 axis
Authors: Meng Fanmei , Zhou Yijing , Dong Baohua , Dong Aiqin , Zhang Jingtao
Published: December 2020

Background

It is increasingly evidenced that long non-coding RNAs (lncRNAs) play an important role in various diseases. LncRNA LINC01194 acts as an oncogene in several cancer types. Nevertheless, the role of LINC01194 in lung adenocarcinoma (LUAD) has not yet been revealed.

Methods

qRT-PCR was used to detect the expression of LINC01194, miR-641 and SETD7 mRNA, while western blot was exploited to examine SETD7 protein level. Cell proliferation was detected by colony formation and EdU assays. Transwell assays detected cell migration and invasion. TUNEL assay and flow cytometry analysis were used to detect cell apoptosis. RIP, RNA pull down and luciferase reporter assays detected the binding among LINC01194, miR-641 and SETD7.

Results

LINC01194 was significantly upregulated in LUAD tissues and cell lines. Knockdown of LINC01194 resulted in decreased cell proliferation, migration and invasion, and increased apoptosis. Mechanistic experiments unveiled that LINC01194 augmented SETD7 expression in LUAD cells by competitively interacting with miR-641. Rescue experiments showed that miR-641 inhibition and SETD7 overexpression rescued the repressing impacts on LUAD cell proliferation, migration and invasion caused by LINC01194 knockdown.

Conclusion

LINC01194 promotes the progression of LUAD by enhancing miR-641-targeted SETD7. The LINC01194/miR-641/SETD7 axis might provide new molecular targets for treating LUAD.
Field performance of ultrasensitive and conventional malaria rapid diagnostic tests in southern Mozambique
Authors: Galatas Beatriz , Mayor Alfredo , Gupta Himanshu , Balanza Núria , Jang Ihn Kyung , Nhamussua Lidia , Simone Wilson , Cisteró Pau , Chidimatembue Arlindo , Munguambe Humberto , Saúte Francisco , Aide Pedro , Bassat Quique
Published: December 2020

Background

An ultrasensitive malaria rapid diagnostic test (RDT) was recently developed for the improved detection of low-density Plasmodium falciparum infections. This study aimed to compare the diagnostic performance of the PfHRP2-based Abbott Malaria Ag P. falciparum ultrasensitive RDT (uRDT) to that of the conventional SD-Bioline Malaria Ag P. falciparum RDT (cRDT) when performed under field conditions.

Methods

Finger-prick blood samples were collected from adults and children in two cross-sectional surveys in May of 2017 in southern Mozambique. Using real-time quantitative PCR (RT-qPCR) as the reference method, the age-specific diagnostic performance indicators of the cRDT and uRDT were compared. The presence of histidine-rich protein 2 (HRP2) and Plasmodium lactate dehydrogenase (pLDH) antigens was evaluated in a subset from dried blood spots by a quantitative antigen assay. pfhrp2 and pfhrp3 gene deletions were assessed in samples positive by RT-qPCR and negative by both RDTs.

Results

Among the 4,396 participants with complete test results, the sensitivity of uRDTs (68.2; 95% CI 60.8 to 74.9) was marginally better than that of cRDTs (61.5; 95% CI 53.9 to 68.6) (p-value = 0.004), while the specificities were similar (uRDT: 99.0 [95% CI 98.6 to 99.2], cRDT: 99.2 [95% CI 98.9 to 99.4], p-value = 0.02). While the performance of both RDTs was lowest in ≥ 15-year-olds, driven by the higher prevalence of low parasite density infections in this group, the sensitivity of uRDTs was significantly higher in this age group (54.9, 95% CI 40.3 to 68.9) compared to the sensitivity of cRDTs (39.2, 95% CI 25.8 to 53.9) (p-value = 0.008). Both RDTs detected P. falciparum infections at similar geometric mean parasite densities (112.9  parasites/μL for uRDTs and 145.5 parasites/μL for cRDTs). The presence of HRP2 antigen was similar among false positive (FP) samples of both tests (80.5% among uRDT-FPs and 84.4% among cRDT-FPs). Only one false negative sample was detected with a partial pfhrp2 deletion.

Conclusion

This study showed that the uRDTs developed by Abbott do not substantially outperform SD-Bioline Pf malaria RDTs in the community and are still not comparable to molecular methods to detect P. falciparum infections in this study setting.
Hyaluronic acid-coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating atherosclerosis
Authors: Mu Dan , Li Jianhui , Qi Yu , Sun Xuan , Liu Yihai , Shen Song , Li Yuyu , Xu Biao , Zhang Bing
Published: December 2020

Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Simvastatin (SIM)-loaded biodegradable polymeric micelles were constructed from hyaluronic acid (HA)-coated poly(ethylene glycol)-poly(tyrosine-ethyl oxalyl) (PEG-Ptyr-EO) for the purpose of simultaneously inhibiting macrophages and decreasing the level of reactive oxygen species (ROS) to treat atherosclerosis. HA coating endows the micelle system the ability of targeting CD44-positive inflammatory macrophages. Owing to the ROS-responsive nature of PEG-Ptyr-EO, the micelles can not only be degraded by enzymes, but also consumes ROS by itself at the pathologic sites, upon which the accumulation of pro-inflammatory macrophages is effectively suppressed and oxidative stress is alleviated. Consequently, the cellular uptake experiment demonstrated that SIM-loaded HA-coated micelles can be effectively internalized by LPS-induced RAW264.7 cells and showed high cytotoxicity against the cells, but low cytotoxicity against LO2 cells. In mouse models of atherosclerosis, intravenously SIM-loaded HA-coated micelles can effectively reduce plaque content of cholesterol, resulting in remarkable therapeutic effects. In conclusion, the SIM-loaded micelle system provides a promising and innovative option against atherosclerosis.
Association between number of dissected lymph nodes and survival in stage IA non-small cell lung cancer: a propensity score matching analysis
Authors: Wu Lei-Lei , Lai Jia-Jian , Liu Xuan , Huang Yang-Yu , Lin Peng , Long Hao , Zhang Lan-Jun , Ma Guo-Wei
Published: December 2020

Background

For patients with stage IA non-small cell lung cancer (NSCLC) with tumor size ≤ 2 cm, the prognostic significance of the number of removed lymph nodes (NLNs) through different surgical methods remains unclear. To determine the association of NLNs with cancer-specific survival (CSS) and overall survival (OS) in patients with stage IA NSCLC with tumor size ≤ 2 cm who underwent different lung surgeries.

Methods

We retrospectively enrolled 7293 patients from the Surveillance, Epidemiology and End Results database. Median NLNs was used to classify the patients into two groups: group A with NLNs ≤ 5 and group B with NLNs > 5. Propensity score matching (PSM) was performed to decrease selection bias. Kaplan–Meier analysis and Cox regression analysis were performed to identify the association between NLNs and survival outcomes.

Results

Group B had better survival than group A in the unmatched cohort and matched cohort (all P < 0.05). Multivariable analyses revealed that the NLNs significantly affected CSS and OS of eligible cases in the unmatched cohort and matched cohort. Additionally, we found that the NLNs was a protective prognostic predictor of OS for patients who underwent wedge resection, segmental resection, or lobectomy.

Conclusion

The NLNs was a protective prognostic factor in NSCLC patients with tumor size ≤ 2 cm. We demonstrated that patients with > 5 NLNs in the cohort of wedge resection, segmental resection, or lobectomy exhibited a significantly better OS.
Correction to: Outcome quality standards in advanced ovarian cancer surgery
Authors:   on behalf MUAPOS Working Group, Llueca Antoni , Serra Anna , Climent Maria Teresa , Segarra Blanca , Maazouzi Yasmine , Soriano Marta , Escrig Javier
Published: December 2020

An amendment to this paper has been published and can be accessed via the original article.
Growth hormone activates PI3K/Akt signaling and inhibits ROS accumulation and apoptosis in granulosa cells of patients with polycystic ovary syndrome
Authors: Gong Yan , Luo Shan , Fan Ping , Zhu Huili , Li Yujing , Huang Wei
Published: December 2020

Background

It is reported that growth hormone (GH) can alleviate oxidative stress (OS) induced apoptosis in some types of cells by activating the PI3K/Akt signaling pathway. This study investigated the role and underlying mechanism of GH in OS and apoptosis in granulosa cells (GCs) of patients with polycystic ovary syndrome (PCOS).

Methods

Primary GCs were collected from patients with and without PCOS (controls, n = 32) during oocyte retrieval. The patients with PCOS were randomly assigned to take GH treatment (PCOS-GH, n = 30) or without GH treatment (PCOS-C, n = 31). Reactive oxygen species (ROS) level was determined by spectrophotometry and fluorescence microscopy. GC apoptosis and mitochondrial membrane potential (MMP) were detected by Annexin V-FITC/PI double-staining and JC-1 staining, respectively (flow cytometry). The expression of apoptosis-related genes and proteins involved in PI3K/Akt signaling was determined by quantitative reverse-transcription polymerase chain reaction and western blotting, while active caspase-9 and caspase-3 levels of GCs were determined by enzyme-linked immunosorbent assay.

Results

Our study found that in GCs of the PCOS-GH group, the ROS levels and apoptotic rates were significantly decreased, whereas MMP was significantly increased when compared to those in the PCOS-C group (P < 0.05). The mRNA levels of FOXO1, Bax, caspase-9, and caspase-3 were significantly decreased, whereas Bcl-2 was increased in GCs of the PCOS-GH group than those in the PCOS-C group (P < 0.05). The protein levels of FOXO1, Bax, cleaved caspase-9/caspase-9 and cleaved caspase-3/caspase-3 were decreased, whereas p-PI3K/PI3K, p-Akt/Akt, p-FOXO1 and Bcl-2 were increased in GCs of the PCOS-GH group, compared with those in the PCOS-C group (P < 0.05).

Conclusion

OS induced apoptosis and downregulated the PI3K/Akt signaling pathway in patients with PCOS. GH could alleviate apoptosis and activate the PI3K/Akt signaling pathway.

Clinical trial registration number

Chinese Clinical Trial Registry. ChiCTR1800019437. Prospectively registered on October 20, 2018.
MicroRNA-302a is involved in folate deficiency-induced apoptosis through the AKT-FOXO1-BIM pathway in mouse embryonic stem cells
Authors: Liang Yan , Cao Dingding , Li Yuanyuan , Liu Zhuo , Wu Jianxin
Published: December 2020

Background

Our previous study had shown that microRNA (miR)-302a played a key role in folate deficiency-induced apoptosis in mouse embryonic stem cells. However, details regarding the mechanism remain unclear. Transcription factors (TFs) and miRNAs are two key elements in gene regulation. The aim of this study is to construct the TF-miRNA gene regulation network and demonstrate its possible mechanism.

Methods

The TF-miRNA gene regulation network was constructed via bioinformatics methods. Chromatin immuno-coprecipitation PCR was selected to confirm the binding between miR-302a and TF. mRNA and protein levels were detected by Real-time quantitative PCR and western blotting. TargetScan prediction and Dual-Luciferase Reporter Assay system were used to confirm whether the miRNA binded directly to the predicted target gene.

Results

FOXO1 and miR-302a were selected as the key TF and miRNA, respectively. FOXO1 was confirmed to bind directly to the upstream promoter region of miR-302a. Real-time quantitative PCR and immunoblotting showed that in folate-free conditions, miR-302a and AKT were down regulated, while FOXO1 and Bim were up-regulated significantly. Additionally, treatment with LY294002 inhibitor revealed the involvement of the Akt/FOXO1/Bim signaling pathway in folate deficiency-induced apoptosis, rather than the ERK pathway. Finally, TargetScan prediction and double luciferase reporting experiments illustrated the ability of miR-302a to target the Bim 3′UTR region.

Conclusion

The involvement of miR-302a in folate deficiency-induced apoptosis through the AKT-FOXO1-BIM pathway in mESCs is a unique demonstration of the regulation mechanism of nutrient expression in embryonic development.
Correction to: Formaldehyde formation in the glycine cleavage system and its use for an aldolase-based biosynthesis of 1,3-propanediol
Authors: Xu Yingying , Meng Hao , Ren Jie , Zeng An-Ping
Published: December 2020

An amendment to this paper has been published and can be accessed via the original article.
Primary gastroduodenal tuberculosis complicated with acute pancreatitis: a rare case report and literature review
Authors: Li Yuanhua , Liao Suhuan , Zuo Haijun , Yang Wei , Jiang Di
Published: December 2020

Background

Tuberculosis (TB) is a major health problem worldwide. Even in highly prevalent countries, primary gastroduodenal tuberculosis is a rare manifestation of extrapulmonary tuberculosis. In recent years, as the incidence of tuberculosis has increased year by year, the occur of gastroduodenal tuberculosis has also increased. Endoscopy is an important tool for diagnosing gastroduodenal tuberculosis. The performance of gastroduodenal tuberculosis under endoscopy is often non-specific, which may imitate other benign or malignant gastroduodenal diseases. Diagnosis of gastroduodenal tuberculosis relies on a combination of endoscopy and guided biopsy.

Case presentation

Here, we report a rare and interesting case of gastroduodenal tuberculosis with acute pancreatitis. The case initially mimicked gastroduodenal ulcers in morphology and appeared in a middle-aged person with normal immunity but with prolonged fever and abdominal pain. The disease was diagnosed through endoscopy and guided biopsy, and it responded well to antituberculosis drugs.

Conclusions

Clinicians must remember that even in the absence of immunodeficiency, as in this case, tuberculosis can affect any part of the gastrointestinal tract.
Sustainable housing development: role and significance of satisfaction aspect
Authors: Ibrahim Iman Abdelshahid
Published: December 2020

Providing quality public housing is one of the main goals of the United Arab Emirates (UAE) government. This paper assesses the level of satisfaction with public housing offered by the UAE government to its citizens based on the physical characteristics and traditional social aspects of the housing unit, urban design, and social environment in the residential area, whereas also their contribution to the residents' life quality under overall satisfaction with the place of living. At the same time, the study provides access to sustainability measurements applied at both the environmental and social levels within the Estidama accredited national rating system. The survey results of two residential complexes in Abu Dhabi show that the majority of residents are mostly satisfied, although the overall level of satisfaction with the functionality of the building and public facilities provided was generally higher than that related to the social environment in the residential district. The research focused on the application of new technologies that increase the level of sustainability in future housing projects.