bluuebunny/crossref_metadata_2025 huggingface dataset:
“Superbugs” in the Risk Society: Assessing the Reflexive Function of North American Newspaper Coverage of Antimicrobial Resistance
Authors: Capurro Gabriela
Published: January 2020

This article examines how antimicrobial resistance (AMR) is covered in four elite North American newspapers and whether the dailies act as sites of reflexive modernization. I draw on risk society theory to situate AMR as a modern risk and news media as key spaces for reflexivity. Through a qualitative content analysis of 89 news stories on AMR, this study shows that this risk is communicated through inaccurate definitions and oversimplified accounts of the causes, populations at risk, and preventive measures. Media representations of health risks affect public perceptions of risk and risk prevention. The dailies, however, seldom expressed reflexive modernization, a key function of “mass media” in the Risk Society, which I argue could be due to the very complexity of “modern risks.” Lack of reflexivity in the media regarding AMR could delay crucial policy and institutional changes necessary to tackle this risk.
Growing Our Own Timber! Lived Experiences of Five School Principals in Using a Systems Thinking Approach for School Development
Authors: Bhengu Thamsanqa Thulani , Mchunu Bongani Sibusiso , Bayeni Sibusiso Douglas
Published: January 2020

This article presents and discusses the findings from five principals about their experiences of using systems thinking approach to school development. This was an ethnographic multiple case study that was conducted in KwaZulu-Natal, South Africa. Literature demonstrates the efficacies of using systems thinking as an approach in dealing with complex school issues. Data were gathered by way of qualitative semi-structured interviews, focus group discussion, and shadowing techniques. Evidence suggests that participants had adequate understanding of systems thinking and were able to use it to the benefit of their respective schools. Furthermore, the findings point to the value of developing a holistic and multimethodological approach to systemic school development, particularly in deprived school contexts.
Assessment of Knowledge and Preferences Regarding Advance Directives Among Patients in University Family Medicine Outpatient Clinics
Authors: Koşar Ismet , Akdeniz Melahat , Kavukcu Ethem , Avci Hasan Huseyin
Published: January 2020

Aim: The aim of this study is to draw attention to the subject of “advanced directives,” to create awareness, whether or not they want to investigate to determine the preferences for medical care and applications in the period of end-of-life while individuals can specify their preferences and wishes for medical decisions and take steps for it. Materials and Methods: The study was carried out on individuals aged 20 years and older in family medicine outpatient clinics. A questionnaire consisting of 30 questions was applied to 300 people who volunteered to participate in the study by a face-to-face interview. Results: Of all participants, 70% had not heard of advance directives (ADs) before this survey. Three quarters of participants thought that advanced directives were necessary. The rate of requesting cardiopulmonary resuscitation (CPR) to prolong survival in the case of end-of-life care was 55%; the rate of requesting the continuation of life-sustaining treatment was 24%. Conclusion: Most participants want their own decision to be taken into account in end-of-life care. Family physicians should talk to their patients about ADs via effective communication when people are still healthy.
The parametric instability improvement of fully anisotropic composite plates with embedded shape memory alloy
Authors: Yusof Zarina , Rasid Zainudin A , Hassan Mohamad Zaki , Sapuan SM , Sarip Shamsul , Yahaya Hafizal , Yakub Fitri
Published: January 2020

The parametric resonance or instability challenge in designing laminated composite is crucial in areas such as aeronautical and marine where structures experience dynamic loading. Shape memory alloy (SMA), a type of smart material, has been used to improve the structural behaviours of composite plate using its well-known property of shape memory effect. It is also known that mechanical couplings that exist in unsymmetric composite can increase the instability of the composite. In this study, the SMA property has been exploited to generate recovery stress in the composite to improve its parametric instability problem. The unsymmetric composites were embedded with SMA fibres, and the formulation for the dynamic instability of this composites was developed using finite element method. The third-order shear deformation theory of composite was applied. The results were initially validated for the case of composite without SMA. Following that, the parametric instability behaviour of unsymmetric composites was studied under the effect of several parameters. It was found that the mechanical couplings that exist in the unsymmetric composite have increased the instability of the composite, but the presence of the SMA can significantly reduce this instability.
The protein C activator AB002 rapidly interrupts thrombus development in baboons
Authors: Tucker Erik I. , Verbout Norah G. , Markway Brandon D. , Wallisch Michael , Lorentz Christina U. , Hinds Monica T. , Shatzel Joseph J. , Pelc Leslie A. , Wood David C. , McCarty Owen J. T. , Di Cera Enrico , Gruber András
Published: January 2020

Although thrombin is a key enzyme in the coagulation cascade and is required for both normal hemostasis and pathologic thrombogenesis, it also participates in its own negative feedback via activation of protein C, which downregulates thrombin generation by enzymatically inactivating factors Va and VIIIa. Our group and others have previously shown that thrombin’s procoagulant and anticoagulant activities can be effectively disassociated to varying extents through site-directed mutagenesis. The thrombin mutant W215A/E217A (WE thrombin) has been one of the best characterized constructs with selective activity toward protein C. Although animal studies have demonstrated that WE thrombin acts as an anticoagulant through activated protein C (APC) generation, the observed limited systemic anticoagulation does not fully explain the antithrombotic potency of this or other thrombin mutants. AB002 (E-WE thrombin) is an investigational protein C activator thrombin analog in phase 2 clinical development (clinicaltrials.gov NCT03963895). Here, we demonstrate that this molecule is a potent enzyme that is able to rapidly interrupt arterial-type thrombus propagation at exceedingly low doses (<2 µg/kg, IV), yet without substantial systemic anticoagulation in baboons. We demonstrate that AB002 produces APC on platelet aggregates and competitively inhibits thrombin-activatable fibrinolysis inhibitor (carboxypeptidase B2) activation in vitro, which may contribute to the observed in vivo efficacy. We also describe its safety and activity in a phase 1 first-in-human clinical trial. Together, these results support further clinical evaluation of AB002 as a potentially safe and effective new approach for treating or preventing acute thrombotic and thromboembolic conditions. This trial was registered at www.clinicaltrials.gov as #NCT03453060.
The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria
Authors: Röth Alexander , Nishimura Jun-ichi , Nagy Zsolt , Gaàl-Weisinger Julia , Panse Jens , Yoon Sung-Soo , Egyed Miklos , Ichikawa Satoshi , Ito Yoshikazu , Kim Jin Seok , Ninomiya Haruhiko , Schrezenmeier Hubert , Sica Simona , Usuki Kensuke , Sicre de Fontbrune Flore , Soret Juliette , Sostelly Alexandre , Higginson James , Dieckmann Andreas , Gentile Brittany , Anzures-Cabrera Judith , Shinomiya Kenji , Jordan Gregor , Biedzka-Sarek Marta , Klughammer Barbara , Jahreis Angelika , Bucher Christoph , Peffault de Latour Régis
Published: January 2020

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade–naive (part 2) and C5 inhibitor–treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor–pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).
Early peripheral clearance of leukemia-associated immunophenotypes in AML: centralized analysis of a randomized trial
Authors: Gianfaldoni Giacomo , Mannelli Francesco , Intermesoli Tamara , Bencini Sara , Giupponi Damiano , Farina Giorgio , Cutini Ilaria , Bonetti Maria Ida , Masciulli Arianna , Audisio Ernesta , Ferrero Dario , Pavoni Chiara , Scattolin Anna Maria , Bosi Alberto , Rambaldi Alessandro , Bassan Renato
Published: January 2020

Although genetics is a relevant risk factor in acute myeloid leukemia (AML), it can be minimally informative and/or not readily available for the early identification of patients at risk for treatment failure. In a randomized trial comparing standard vs high-dose induction (ClinicalTrials.gov #NCT00495287), we studied early peripheral blast cell clearance (PBC) as a rapid predictive assay of chemotherapy response to determine whether it correlates with the achievement of complete remission (CR), as well as postremission outcome, according to induction intensity. Individual leukemia-associated immunophenotypes (LAIPs) identified pretherapy by flow cytometry were validated and quantified centrally after 3 days of treatment, expressing PBC on a logarithmic scale as the ratio of absolute LAIP+ cells on day 1 and day 4. Of 178 patients, 151 (84.8%) were evaluable. Patients in CR exhibited significantly higher median PBC (2.3 log) compared with chemoresistant patients (1.0 log; P < .0001). PBC < 1.0 predicted the worst outcome (CR, 28%). With 1.5 log established as the most accurate cutoff predicting CR, 87.5% of patients with PBC >1.5 (PBChigh, n = 96) and 43.6% of patients with PBC ≤1.5 (PBClow, n = 55) achieved CR after single-course induction (P < .0001). CR and PBChigh rates were increased in patients randomized to the high-dose induction arm (P = .04) and correlated strongly with genetic/cytogenetic risk. In multivariate analysis, PBC retained significant predictive power for CR, relapse risk, and survival. Thus, PBC analysis can provide a very early prediction of outcome, correlates with treatment intensity and disease subset, and may support studies of customized AML therapy.
Bacterial burden in the lower airways predicts disease progression in idiopathic pulmonary fibrosis and is independent of radiological disease extent
Authors: Invernizzi Rachele , Barnett Joseph , Rawal Bhavin , Nair Arjun , Ghai Poonam , Kingston Shaun , Chua Felix , Wu Zhe , Wells Athol U. , Renzoni Elizabeth R. , Nicholson Andrew G. , Rice Alexandra , Lloyd Clare M. , Byrne Adam J. , Maher Toby M. , Devaraj Anand , Molyneaux Philip L.
Published: January 2020

Increasing bacterial burden in the lower airways of patients with idiopathic pulmonary fibrosis confers an increased risk of disease progression and mortality. However, it remains unclear whether this increased bacterial burden directly influences progression of fibrosis or simply reflects the magnitude of the underlying disease extent or severity.

We prospectively recruited 193 patients who underwent bronchoscopy and received a multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Quantification of the total bacterial burden in bronchoalveolar lavage fluid was performed by 16S rRNA gene qPCR. Imaging was independently evaluated by two readers assigning quantitative scores for extent, severity and topography of radiographic changes and relationship of these features with bacterial burden was assessed.

Increased bacterial burden significantly associated with disease progression (HR 2.1; 95% CI 1.287–3.474; p=0.0028). Multivariate stepwise regression demonstrated no relationship between bacterial burden and radiological features or extent of disease. When specifically considering patients with definite or probable usual interstitial pneumonia there was no difference in bacterial burden between these two groups. Despite a postulated association between pleuroparenchymal fibroelastosis and clinical infection, there was no relationship between either the presence or extent of pleuroparenchymal fibroelastosis and bacterial burden.

We demonstrate that bacterial burden in the lower airways is not simply secondary to the extent of the underlying architectural destruction of the lung parenchyma seen in idiopathic pulmonary fibrosis. The independent nature of this association supports a relationship with the underlying pathogenic mechanisms and highlights the urgent need for functional studies.
Staphylococcus aureusand its IgE-inducing enterotoxins in asthma: current knowledge
Authors: Bachert Claus , Humbert Marc , Hanania Nicola A. , Zhang Nan , Holgate Stephen , Buhl Roland , Bröker Barbara M.
Published: January 2020

While immunoglobulin (Ig) E is a prominent biomarker for early-onset, its levels are often elevated in non-allergic late-onset asthma. However, the pattern of IgE expression in the latter is mostly polyclonal, with specific IgEs low or below detection level albeit with an increased total IgE. In late-onset severe asthma patients, specific IgE to Staphylococcal enterotoxins (se-IgE) can frequently be detected in serum, and has been associated with asthma, with severe asthma defined by hospitalisations, oral steroid use and decrease in lung function. Recently,se-IgE was demonstrated to even predict the development into severe asthma with exacerbations over the next decade.Staphylococcus aureusmanipulates the airway mucosal immunology at various levelsviaits proteins, including superantigens, serine-protease-like proteins (Spls), or protein A (SpA) and possibly others. Release of IL-33 from respiratory epithelium and activation of innate lymphoid cells (ILCs)viaits receptor ST2, type 2 cytokine release from those ILCs and T helper (Th) 2 cells, mast cell degranulation, massive local B-cell activation and IgE formation, and finally eosinophil attraction with consequent release of extracellular traps, adding to the epithelial damage and contributing to disease persistenceviaformation of Charcot–Leyden crystals are the most prominent hallmarks of the manipulation of the mucosal immunity byS. aureus. In summary,S. aureusclaims a prominent role in the orchestration of severe airway inflammation and in current and future disease severity. In this review, we discuss current knowledge in this field and outline the needs for future research to fully understand the impact ofS. aureusand its proteins on asthma.
Association between adiposity measures and COPD risk in Chinese adults
Authors: Li Jiachen , Zhu Lu , Wei Yuxia , Lv Jun , Guo Yu , Bian Zheng , Du Huaidong , Yang Ling , Chen Yiping , Zhou Yonglin , Gao Ruqin , Chen Junshi , Chen Zhengming , Cao Weihua , Yu Canqing , Li Liming
Published: January 2020

Bodyweight and fat distribution may be related to COPD risk. Limited prospective evidence linked COPD to abdominal adiposity. We investigated the association of body mass index (BMI) and measures of abdominal adiposity with COPD risk in a prospective cohort study.

The China Kadoorie Biobank recruited participants aged 30–79 years from 10 areas across China. Anthropometric indexes were objectively measured at the baseline survey during 2004–2008. After exclusion of participants with prevalent COPD and major chronic diseases, 452 259 participants were included and followed-up until the end of 2016. We used Cox models to estimate adjusted hazard ratios relating adiposity to risk of COPD hospitalisation or death.

Over an average of 10.1 years of follow-up, 10 739 COPD hospitalisation events and deaths were reported. Compared with subjects with normal BMI (18.5–<24.0 kg·m−2), underweight (BMI <18.5 kg·m−2) individuals had increased risk of COPD, with adjusted hazard ratio 1.78 (95% CI 1.66–1.89). Overweight (BMI 24.0–<28.0 kg·m−2) and obesity (BMI ≥28.0 kg·m−2) were not associated with an increased risk after adjustment for waist circumference. A higher waist circumference (≥85 cm for males and ≥80 cm for females) was positively associated with COPD risk after adjustment for BMI. Additionally, waist-to-hip ratio and waist-to-height ratio were positively related to COPD risk.

Abdominal adiposity and underweight were risk factors for COPD in Chinese adults. Both BMI and measures of abdominal adiposity should be considered in the prevention of COPD.
Associations of physical activity in detailed intensity ranges with body composition and physical function. a cross-sectional study among sedentary older adults
Authors: Savikangas Tiina , Tirkkonen Anna , Alen Markku , Rantanen Taina , Fielding Roger A. , Rantalainen Timo , Sipilä Sarianna
Published: January 2020

Background

Physical activity is crucial to maintain older adults’ health and functioning, but the health benefits of particular activity intensities remain unclear. The aim of this cross-sectional study was to peruse the distribution of physical activity, and to investigate the associations of particular physical activity intensities with body composition and physical function among older adults.

Methods

The sample comprised of 293 community-dwelling sedentary or at most moderately active older adults (42% men, mean age 74 ± 4 years). Physical activity was measured with a hip-worn tri-axial accelerometer over seven consecutive days, and investigated in detailed intensity range and in categories of sedentary, light and moderate-to-vigorous activity. Fat percent and appendicular lean mass were measured with DXA. Physical function was assessed by six-minutes walking test (6-min walk), maximal walking speed over 10 m (10-m walk) and Short Physical Performance Battery (SPPB). Associations were estimated with partial correlation adjusted for sex and age.

Results

Participants spent on average 602 min per day sedentary, 210 min in light activity and 32 min in moderate-to-vigorous activity. Light and moderate-to-vigorous activity were negatively associated with fat percent (r = − 0.360 and r = − 0.384, respectively, p < 0.001 for both), and positively with SPPB, 10-m walk and 6-min walk results (r = 0.145–0.279, p < 0.01, for light and r = 0.220–0.465, p < 0.001, for moderate-to-vigorous activity). In detailed investigation of the intensity range, associations of physical activity with fat percent, 6-min walk and 10-m walk were statistically significant from very light intensity activity onward, whereas significant associations between physical activity and SPPB were observed mostly at higher end of the intensity range. Sedentary time was positively associated with fat percent (r = 0.251, p < 0.001) and negatively with 6-min walk (r = − 0.170, p < 0.01).

Conclusion

Perusing the physical activity intensity range revealed that, among community-dwelling sedentary or at most moderately active older adults, physical activity of any intensity was positively associated with lower fat percent and higher walking speed over long and short distances. These findings provide additional evidence of the importance of encouraging older adults to engage in physical activity of any intensity. More intervention studies are required to confirm the health benefits of light-intensity activity.
The omics revolution: beyond genomics. A meeting report
Authors: Nice E. C.
Published: January 2020

The “omics revolution: beyond genomics” satellite meeting, run under the auspices of the Australian Peptide Association, The Human Proteome Organisation (HUPO) and the HUPO Australia/New Zealand Chromosome 7 initiative, was held at the Oaks Resort, Port Douglas, Queensland, Australia, on 8th September 2019, immediately prior to the 13th Australian Peptide Conference. The meeting, which had over 100 participants representing Australasia, Europe and America, focused on recent advances in omics-related technologies, including mass spectrometry, biosensors and CryoEM, which will assist in the clinical translation of proteomics towards precision/personalized medicine. An overview of the conference and a summary of the oral presentations are presented.
1-1-8 one-step sevoflurane wash-in scheme for low-flow anesthesia: simple, rapid, and predictable induction
Authors: Tribuddharat Sirirat , Sathitkarnmanee Thepakorn , Vattanasiriporn Naruemon , Thananun Maneerat , Nonlhaopol Duangthida , Somdee Wilawan
Published: January 2020

Background

Sevoflurane is suitable for low-flow anesthesia (LFA). LFA needs a wash-in phase. The reported sevoflurane wash-in schemes lack simplicity, target coverage, and applicability. We proposed a one-step 1-1-8 wash-in scheme for sevoflurane LFA to be used with both N2O and Air. The objective of our study was to identify time for achieving each level of alveolar concentration of sevoflurane (FAS) from 1 to 3.5% in both contexts.

Methods

We recruited 199 adults requiring general anesthesia with endotracheal intubation and controlled ventilation—102 in group N2O and 97 in group Air. After induction and intubation, a wash-in was started using a fresh gas flow of O2:N2O or O2:Air at 1:1 L·min− 1 plus sevoflurane 8%. The ventilation was controlled to maintain end-tidal CO2 of 30–35 mmHg.

Results

The rising patterns of FAS and inspired concentration of sevoflurane (FIS) are similar, running parallel between the groups. The FAS/FIS ratio increased from 0.46 to 0.72 within 260 s in group N2O and from 0.42 to 0.69 within 286 s in group Air. The respective time to achieve an FAS of 1, 1.5, 2, 2.5, 3, and 3.5% was 1, 1.5, 2, 3, 3.5, and 4.5 min in group N2O and 1, 1.5, 2, 3, 4, and 5 min in group Air. The heart rate and blood pressure of both groups significantly increased initially then gradually decreased as FAS increased.

Conclusions

The 1-1-8 wash-in scheme for sevoflurane LFA has many advantages, including simplicity, coverage, swiftness, safety, economy, and that it can be used with both N2O and Air. A respective FAS of 1, 1.5, 2, 2.5, 3, and 3.5% when used with N2O and Air can be expected at 1, 1.5, 2, 3, 3.5, and 4.5 min and 1, 1.5, 2, 3, 4, and 5 min.

Trial registration

This study was retrospectively registered with ClinicalTrials.gov (NCT03510013) on June 8, 2018.
General practitioners’ views on use of patient reported outcome measures in primary care: a cross-sectional survey and qualitative study
Authors: Turner Grace M. , Litchfield Ian , Finnikin Sam , Aiyegbusi Olalekan Lee , Calvert Melanie
Published: January 2020

Background

Patient reported outcome measures (PROMs) are increasingly used to assess impact of disease and treatment on quality of life and symptoms; however, their use in primary care is fragmented.

We aimed to understand how PROMs are currently being used in primary care, the barriers and facilitators of this use and if appropriate how it might be optimised.

Methods

Cross-sectional survey and semi-structured interviews among general practitioners (GPs) in England. GPs’ opinions were explored using an electronic, self-completed questionnaire disseminated to 100 GPs via an online doctors’ community and semi-structured qualitative interviews with 25 GPs.

Results

Most GPs surveyed (77/100; 77%) reported using one or more PROM, primarily to aid clinical management (n = 66) or as screening/diagnostic tools (n = 62).

Qualitative interviews highlighted challenges in identifying and selecting PROMs; however, some GPs valued PROMs for shared decision making and to direct patient discussions. The interviews identified key barriers to PROM use including: time constraints; insufficient knowledge; lack of integration into clinical systems; and PROMs being mandated without consultation or explanation. Evidence of the benefit of PROMs is required to promote uptake and use of PROMs in primary care.

Conclusion

Implementation of PROMs in primary care requires integration with clinical systems, a bottom-up approach to PROM selection and system design involving meaningful consultation with patients and primary care clinicians and training/support for use.
Unmet needs of patients with cancer in their last year of life as described by caregivers in a developing world setting: a qualitative study
Authors: Cox-Seignoret Karen , Maharaj Rohan G.
Published: January 2020

Background

Palliative care is in its infancy in most of the developing world. We set out to explore the lived experiences of families and caregivers of recently deceased cancer patients in Trinidad and Tobago and to determine the unmet needs of the patients and what recommendations could be derived to improve the current services.

Methods

A phenomenological approach with purposeful sampling was used. Participants were referred by key health professionals. Face-to-face interviews were conducted. Interviews were transcribed verbatim, with analysis and data collection occurring concurrently. Thematic content analysis was used to determine common domains, themes and sub-themes.

Results

Interviews were completed with 15 caregivers. All were spouses or children of the deceased. Ages of the deceased ranged from 43 to 93, the average being 65.5 years. The deceased experienced a variety of cancers including lung, colorectal and oesophageal.

Unmet needs were identified under 4 domains of institutions, community, the family unit and the wider society. Institutional unmet needs were delayed diagnosis and treatment and poor inter-institution coordination. Medical and nursing care failed in the areas of health care providers’ attitudes, pain management and communication. The family unit lacked physical and psychosocial support for the caregiver and financial aid for the family unit. Societal needs were for public education to address myths and cultural beliefs around cancer.

Conclusion

There is need for systemic interventions to improve the care of those dying from cancer in Trinidad and Tobago. Stakeholders need to commit to palliative care as a public health priority, implementing education, planning services and mobilizing community resources.
Prevention and management of CVD in LMICs: why do ethnicity, culture, and context matter?
Authors: Anand Shuchi , Bradshaw Christina , Prabhakaran Dorairaj
Published: January 2020

Background

Low- and middle-income countries now experience the highest prevalence and mortality rates of cardiovascular disease.

Main text

While improving the availability and delivery of proven, effective therapies will no doubt mitigate this burden, we posit that studies evaluating cardiovascular disease risk factors, management strategies and service delivery, in diverse settings and diverse populations, are equally critical to improving outcomes in low- and middle-income countries. Focusing on examples drawn from four cardiovascular diseases — coronary artery disease, stroke, diabetes and kidney disease — we argue that ethnicity, culture and context matter in determining the risk factors for disease as well as the comparative effectiveness of medications and other interventions, particularly diet and lifestyle interventions.

Conclusion

We believe that a host of cohort studies and randomized control trials currently being conducted or planned in low- and middle-income countries, focusing on previously understudied race/ethnic groups, have the potential to increase knowledge about the cause(s) and management of cardiovascular diseases across the world.
Retraction Note to: Randomized controlled trial testing weight loss and abdominal obesity outcomes of moxibustion
Authors: Hsieh Ching-Hsiu , Tseng Chi-Chuan , Shen Ju-Yu , Chuang Pei-Ying
Published: January 2020

The Editors-in-Chief have retracted this article [1] because, after publication, concerns were raised regarding the study design and statistical analysis. Post-publication review has confirmed firstly that within-group changes were highlighted rather than between-group differences as appropriate for a randomized trial, and secondly that there are baseline differences between the groups that exist despite randomization for which analyses were not controlled. The data reported in this article are therefore unreliable. Ching-Hsiu Hsieh and Pei-Ying Chuang agree with this retraction. Chi-Chuan Tseng and Ju-Yu Shen have not responded to any correspondence from the publisher about this retraction.
16S rDNA microbiome composition pattern analysis as a diagnostic biomarker for biliary tract cancer
Authors: Lee Huisong , Lee Hyeon Kook , Min Seog Ki , Lee Won Hee
Published: January 2020

Background

The aim of this study is to investigate the composition of microbiota in biliary tract cancer patients and healthy adults by metagenome analysis and evaluate its potential values as biomarkers for biliary tract cancer.

Methods

Patients who were diagnosed with biliary tract cancer or benign inflammation were enrolled in this study. The control group consisted of healthy adults who presented with no history of significant medical issues. We isolated bacteria-derived extracellular vesicles in the plasma. The microbiome composition was investigated with 16S rDNA metagenome analysis. We evaluated each microbiome to ensure suitability for the biliary tract cancer prediction model.

Results

A total of 155 patients were included in this study: 24 patients with diagnosed biliary tract cancers, 43 diagnosed with cholecystitis or cholangitis, and 88 healthy adults. The microbiome composition pattern of the biliary tract cancer differed from the microbiome composition pattern seen in healthy adult group in beta diversity analysis. The percent composition of microbiota was found to be different from the phylum to genus level. Differences in the composition of the Bifidobacteriaceae and Pseudomonaceae families and Corynebacteriaceae Corynebacterium, Oxalobacteraceae Ralstonia and Comamonadaceae Comamonas species may be used to develop predictive models for biliary tract cancer.

Conclusion

Biliary tract cancer patients have altered microbiome composition, which represents a promising biomarker to differentiate malignant biliary tract disease from normal control group.
Cancer-associated fibroblasts promote prostate tumor growth and progression through upregulation of cholesterol and steroid biosynthesis
Authors: Neuwirt Hannes , Bouchal Jan , Kharaishvili Gvantsa , Ploner Christian , Jöhrer Karin , Pitterl Florian , Weber Anja , Klocker Helmut , Eder Iris E.
Published: January 2020

Background

Androgen receptor targeted therapies have emerged as an effective tool to manage advanced prostate cancer (PCa). Nevertheless, frequent occurrence of therapy resistance represents a major challenge in the clinical management of patients, also because the molecular mechanisms behind therapy resistance are not yet fully understood. In the present study, we therefore aimed to identify novel targets to intervene with therapy resistance using gene expression analysis of PCa co-culture spheroids where PCa cells are grown in the presence of cancer-associated fibroblasts (CAFs) and which have been previously shown to be a reliable model for antiandrogen resistance.

Methods

Gene expression changes of co-culture spheroids (LNCaP and DuCaP seeded together with CAFs) were identified by Illumina microarray profiling. Real-time PCR, Western blotting, immunohistochemistry and cell viability assays in 2D and 3D culture were performed to validate the expression of selected targets in vitro and in vivo. Cytokine profiling was conducted to analyze CAF-conditioned medium.

Results

Gene expression analysis of co-culture spheroids revealed that CAFs induced a significant upregulation of cholesterol and steroid biosynthesis pathways in PCa cells. Cytokine profiling revealed high amounts of pro-inflammatory, pro-migratory and pro-angiogenic factors in the CAF supernatant. In particular, two genes, 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (HMGCS2) and aldo-keto reductase family 1 member C3 (AKR1C3), were significantly upregulated in PCa cells upon co-culture with CAFs. Both enzymes were also significantly increased in human PCa compared to benign tissue with AKR1C3 expression even being associated with Gleason score and metastatic status. Inhibiting HMGCS2 and AKR1C3 resulted in significant growth retardation of co-culture spheroids as well as of various castration and enzalutamide resistant cell lines in 2D and 3D culture, underscoring their putative role in PCa. Importantly, dual targeting of cholesterol and steroid biosynthesis with simvastatin, a commonly prescribed cholesterol synthesis inhibitor, and an inhibitor against AKR1C3 had the strongest growth inhibitory effect.

Conclusions

From our results we conclude that CAFs induce an upregulation of cholesterol and steroid biosynthesis in PCa cells, driving them into AR targeted therapy resistance. Blocking both pathways with simvastatin and an AKR1C3 inhibitor may therefore be a promising approach to overcome resistances to AR targeted therapies in PCa.
Crosstalk between stressed brain cells: direct and indirect effects of ischemia and aglycemia on microglia
Authors: Rabenstein Monika , Vay Sabine Ulrike , Blaschke Stefan , Walter Helene Luise , Ladwig Anne , Fink Gereon Rudolf , Rueger Maria Adele , Schroeter Michael
Published: January 2020

Background

In cerebral ischemia, microglia have a dichotomous role in keeping the balance between pro- and anti-inflammatory mediators to avoid deleterious chronic inflammation and to leverage repair processes.

Methods

We examined functional and inflammatory markers in primary rat microglia in vitro after oxygen-glucose deprivation (OGD) or glucose deprivation (aglycemia). We then investigated the preconditioning effect of OGD or aglycemia upon a subsequent strong inflammatory stimulus, here lipopolysaccharides (LPS). Moreover, an “in vitro brain model” of neurons and glia, differentiated from primary rat neural stem cells, was exposed to OGD or aglycemia. Conditioned medium (CM) of this neuronal/glial co-culture was then used to condition microglia, followed by LPS as a “second hit.”

Results

OGD or aglycemia at sublethal doses did not significantly affect microglia function, including the expression of inflammatory markers. However, preconditioning with either OGD or aglycemia led to a decreased pro-inflammatory response to a subsequent stimulus with LPS. Interestingly, the anti-inflammatory markers IGF-1 and IL-10 were additionally reduced after such preconditioning, while expression of CD206 remained unaffected. Treatment with CM from the neuronal/glial co-culture alone did not affect the expression of inflammatory markers in microglia. In contrast, treatment with CM increased the expression of both pro- and anti-inflammatory markers in microglia upon a second hit with LPS. Interestingly, this effect could be attenuated in microglia treated with CM from neuronal/glia co-cultures preconditioned with OGD or aglycemia.

Conclusions

Data suggest specific and distinct microglia signatures in response to metabolic stress. While metabolic stress directly and indirectly applied to microglia did not mitigate their subsequent response to inflammation, preconditioning with metabolic stress factors such as OGD and aglycemia elicited a decreased inflammatory response to a subsequent inflammation stimulus.
Hypomethylation of nerve growth factor (NGF) promotes binding of C/EBPα and contributes to inflammatory hyperalgesia in rats
Authors: Yuan Hongjie , Du Shibin , Chen Liping , Xu Xiaoqing , Wang Yufeng , Ji Fuhai
Published: January 2020

Background

Chronic pain usually accompanied by tissue damage and inflammation. However, the pathogenesis of chronic pain remains unclear.

Methods

We investigated the role of nerve growth factor (NGF) in chronic inflammatory pain induced by complete Freund’s adjuvant (CFA), explored the methylation status of CpG islands in the promoter region of the NGF gene, and clarified the function and mechanism of C/EBPα-NGF signaling pathway from epigenetic perspective in the chronic inflammatory pain model.

Results

CFA induced significant hyperalgesia and continuous upregulation of NGF mRNA and protein levels in the L4–6 dorsal root ganglions (DRGs) in rats. Hypomethylation of CpG islands occurred in the NGF gene promoter region after CFA treatment. At the same time, the miR-29b expression level was significantly increased, while the DNA methyltransferase 3b (DNMT3b) level reduced significantly. Moreover, CFA treatment promoted binding of C/EBPα to the NGF gene promoter region and C/EBPα siRNA treatment obviously decreased expression of NGF levels and also alleviate inflammatory hyperalgesia significantly in rats.

Conclusion

Collectively, the results indicated that CFA leads to the upregulation of miR-29b level, which represses the expression of DNMT3b, enhances the demethylation of the NGF gene promoter region, and promotes the binding of C/EBPα with the NGF gene promoter, thus results in the upregulation of NGF gene expression and maintenance of chronic inflammatory pain.
scMAGeCK links genotypes with multiple phenotypes in single-cell CRISPR screens
Authors: Yang Lin , Zhu Yuqing , Yu Hua , Cheng Xiaolong , Chen Sitong , Chu Yulan , Huang He , Zhang Jin , Li Wei
Published: January 2020

We present scMAGeCK, a computational framework to identify genomic elements associated with multiple expression-based phenotypes in CRISPR/Cas9 functional screening that uses single-cell RNA-seq as readout. scMAGeCK outperforms existing methods, identifies genes and enhancers with known and novel functions in cell proliferation, and enables an unbiased construction of genotype-phenotype network. Single-cell CRISPR screening on mouse embryonic stem cells identifies key genes associated with different pluripotency states. Applying scMAGeCK on multiple datasets, we identify key factors that improve the power of single-cell CRISPR screening. Collectively, scMAGeCK is a novel tool to study genotype-phenotype relationships at a single-cell level.
CUBIC: an atlas of genetic architecture promises directed maize improvement
Authors: Liu Hai-Jun , Wang Xiaqing , Xiao Yingjie , Luo Jingyun , Qiao Feng , Yang Wenyu , Zhang Ruyang , Meng Yijiang , Sun Jiamin , Yan Shijuan , Peng Yong , Niu Luyao , Jian Liumei , Song Wei , Yan Jiali , Li Chunhui , Zhao Yanxin , Liu Ya , Warburton Marilyn L. , Zhao Jiuran , Yan Jianbing
Published: January 2020

Background

Identifying genotype-phenotype links and causative genes from quantitative trait loci (QTL) is challenging for complex agronomically important traits. To accelerate maize gene discovery and breeding, we present the Complete-diallel design plus Unbalanced Breeding-like Inter-Cross (CUBIC) population, consisting of 1404 individuals created by extensively inter-crossing 24 widely used Chinese maize founders.

Results

Hundreds of QTL for 23 agronomic traits are uncovered with 14 million high-quality SNPs and a high-resolution identity-by-descent map, which account for an average of 75% of the heritability for each trait. We find epistasis contributes to phenotypic variance widely. Integrative cross-population analysis and cross-omics mapping allow effective and rapid discovery of underlying genes, validated here with a case study on leaf width.

Conclusions

Through the integration of experimental genetics and genomics, our study provides useful resources and gene mining strategies to explore complex quantitative traits.
Waardenburg-Shah syndrome (WS type IV): a rare case from Pakistan
Authors: Khan Taimoor Ashraf , Safdar C. Aqeel , Zameer Shehryar , Khushdil Arshad
Published: January 2020

Waardenburg-Shah syndrome is a rare autosomal recessive [AR] inherited disorder characterized by the presence of Hirschsprung’s disease with a high likelihood of aganglionic megacolon, due to which the mortality is high. The management of the condition involves surgical intervention for the removal of the aganglionic segment of the colon. Here, we report a neonate that presented with a white forelock, white eyelashes, iris hypopigmentation, and sensorineural deafness associated with bilious vomiting, refusal to feed, and failure to pass meconium indicating intestinal obstruction.
Random X chromosome inactivation in patients with Klinefelter syndrome
Authors: Kinjo Kenichi , Yoshida Tomoko , Kobori Yoshitomo , Okada Hiroshi , Suzuki Erina , Ogata Tsutomu , Miyado Mami , Fukami Maki
Published: January 2020

Background

X chromosome inactivation (XCI) is an indispensable process in the development of human female embryos. Reportedly, XCI occurs when a blastocyst contains 10–12 embryonic progenitor cells. To date, it remains unclear whether XCI ratios are normally preserved in Klinefelter syndrome (KS) patients with 47,XXY karyotype.

Methods

We examined XCI ratios in 18 KS patients through DNA methylation analysis for the polymorphic trinucleotide locus in the AR gene. The results of the KS patients were compared to previous data from healthy young women.

Results

XCI ratios in KS patients followed a normal distribution. Skewed XCI was observed in two patients, one of whom exhibited extremely skewed XCI. The frequencies of skewed and extremely skewed XCI in the KS cohort were comparable to those in healthy women.

Conclusion

This study confirmed the rarity of skewed XCI in KS patients. These results indicate that the presence of a supernumerary X chromosome during the cleavage and early blastocyst stages does not affect the developmental tempo of embryos. Our data deserve further validation.
Astaxanthin accumulation difference between non-motile cells and akinetes of Haematococcus pluvialis was affected by pyruvate metabolism
Authors: Fang Lei , Zhang Jingkui , Fei Zhongnan , Wan Minxi
Published: January 2020

Background

Haematococcus pluvialis is the best source of natural astaxanthin, known as the king of antioxidants. H. pluvialis have four cell forms: spore, motile cell, non-motile cell and akinete. Spores and motile cells are susceptible to photoinhibition and would die under photoinduction conditions. Photoinduction using non-motile cells as seeds could result in a higher astaxanthin production than that using akinetes. However, the mechanism of this phenomenon has not been clarified.

Results

Transcriptome was sequenced and annotated to illustrate the mechanism of this phenomenon. All differentially expressed genes involved in astaxanthin biosynthesis were up-regulated. Particularly, chyb gene was up-regulated by 16-fold, improving the conversion of β-carotene into astaxanthin. Pyruvate was the precursor of carotenoids biosynthesis. Pyruvate kinase gene expression level was increased by 2.0-fold at the early stage of akinetes formation. More changes of gene transcription occurred at the early stage of akinetes formation, 52.7% and 51.9% of total DEGs in control group and treatment group, respectively.

Conclusions

Genes transcription network was constructed and the synthesis mechanism of astaxanthin was clarified. The results are expected to further guide the in-depth optimization of the astaxanthin production process in H. pluvialis by improving pyruvate metabolism.
High frequencies of PMN-MDSCs are associated with low suppressive capacity in advanced stages of HIV-1 infection
Authors: Grützner Eva M. , Neizert Ashley , Stirner Renate , Conca Raffaele , Andrä Immanuel , Wolff Lisa , Schiemann Matthias , Holdt Lesca M. , Klein Christoph , Bogner Johannes R. , Draenert Rika
Published: January 2020

Background

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are an immature cell type that inhibits the effector functions of T lymphocytes in chronic HIV infection. A well-known immunological feature of the disease course is the development of immune exhaustion, which is correlated with excessive immune activation in late-stage disease. Here, we hypothesized that immune exhaustion would also affect PMN-MDSCs in late-stage HIV-1 infection.

Methods

We evaluated untreated chronically HIV-infected patients (progressors,n = 10) and control groups (controllers, patients with non-small cell lung carcinoma and healthy controls,n = 16) with regard to levels of PMN-MDSCs and their inhibitory potential. Additionally, we studied CD8 T cell effector functions (interferon-gamma, TNF alpha, IL-2 and CD107) and parameters of CD8 T cell activation (CD38 and HLA-DR) and exhaustion (PD-1 and LAG-3) by flow cytometry. Plasma inflammation markers analyzed here were IL-6, IL-8, soluble CD14, highly sensitive CRP, and cystatin C.

Results

Coincubation experiments with isolated PMN-MDSCs led to a significant inhibition of CD8 T cell proliferation (p < 0.0001), with a significant correlation between PMN-MDSC frequency and suppressive capacity: the higher the frequency of PMN-MDSCs was, the lower the suppressive capacity (rho = 0.51,p = 0.0082). Stratifying all study subjects into subgroups with PMN-MDSC frequencies above or below 2.5% resulted in a significantly increased suppressive capacity in patients with frequencies below 2.5% (p = 0.021). While there was no correlation with the cellular activation markers CD38 and HLA-DR, high IL-8 levels were significantly associated with high PMN-MDSC frequencies (rho = 0.52,p = 0.0074) and low suppressive capacity (rho = 0.47,p = 0.019).

Conclusions

In this study, we demonstrate for the first time that PMN-MDSCs show limited effector functions in advanced disease stages of HIV infection. The hyperactive immune state is associated with this loss of function. However, we show an association with the proinflammatory cytokine IL-8, which is an important factor for the migration and adhesion of polymorphonuclear cells.