bluuebunny/crossref_metadata_2025 huggingface dataset:
Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death
Authors: Hu Zhaoyang , Ju Feng , Du Lei , Abbott Geoffrey W.
Published: October 2021

Background

Empagliflozin is a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor used to lower blood sugar in adults with type 2 diabetes. Empagliflozin also exerts cardioprotective effects independent from glucose control, but its benefits on arrhythmogenesis and sudden cardiac death are not known. The purpose of this study was to examine the effect of empagliflozin on myocardial ischemia/reperfusion-provoked cardiac arrhythmia and sudden cardiac death in vivo.

Methods

Male Sprague Dawley rats were randomly assigned to sham-operated, control or empagliflozin groups. All except for the sham-operated rats were subjected to 5-min left main coronary artery ligation followed by 20-min reperfusion. A standard limb lead II electrocardiogram was continuously measured throughout the experiment. Coronary artery reperfusion-induced ventricular arrhythmogenesis and empagliflozin therapy were evaluated. The hearts were used for protein phosphorylation analysis and immunohistological assessment.

Results

Empagliflozin did not alter baseline cardiac normal conduction activity. However, empagliflozin eliminated myocardial vulnerability to sudden cardiac death (from 69.2% mortality rate in the control group to 0% in the empagliflozin group) and reduced the susceptibility to reperfusion-induced arrhythmias post I/R injury. Empagliflozin increased phosphorylation of cardiac ERK1/2 after reperfusion injury. Furthermore, inhibition of ERK1/2 using U0126 abolished the anti-arrhythmic action of empagliflozin and ERK1/2 phosphorylation.

Conclusions

Pretreatment with empagliflozin protects the heart from subsequent severe lethal ventricular arrhythmia induced by myocardial ischemia and reperfusion injury. These protective benefits may occur as a consequence of activation of the ERK1/2-dependent cell-survival signaling pathway in a glucose-independent manner.
Genome mining of novel rubiginones from Streptomyces sp. CB02414 and characterization of the post-PKS modification steps in rubiginone biosynthesis
Authors: Zhang Jingyan , Sun Ying , Wang Yeji , Chen Xin , Xue Lu , Zhang Jingjing , Zhu Xiangcheng , Duan Yanwen , Yan Xiaohui
Published: October 2021

Background

Rubiginones belong to the angucycline family of aromatic polyketides, and they have been shown to potentiate the vincristine (VCR)-induced cytotoxicity against VCR-resistant cancer cell lines. However, the biosynthetic gene clusters (BGCs) and biosynthetic pathways for rubiginones have not been reported yet.

Results

In this study, based on bioinformatics analysis of the genome of Streptomyces sp. CB02414, we predicted the functions of the two type II polyketide synthases (PKSs) BGCs. The rub gene cluster was predicted to encode metabolites of the angucycline family. Scale-up fermentation of the CB02414 wild-type strain led to the discovery of eight rubiginones, including five new ones (rubiginones J, K, L, M, and N). Rubiginone J was proposed to be the final product of the rub gene cluster, which features extensive oxidation on the A-ring of the angucycline skeleton. Based on the production profiles of the CB02414 wild-type and the mutant strains, we proposed a biosynthetic pathway for the rubiginones in CB02414.

Conclusions

A genome mining strategy enabled the efficient discovery of new rubiginones from Streptomyces sp. CB02414. Based on the isolated biosynthetic intermediates, a plausible biosynthetic pathway for the rubiginones was proposed. Our research lays the foundation for further studies on the mechanism of the cytochrome P450-catalyzed oxidation of angucyclines and for the generation of novel angucyclines using combinatorial biosynthesis strategies.
Multivalent poultry vaccine development using Protein Glycan Coupling Technology
Authors: Mauri Marta , Sannasiddappa Thippeswamy H. , Vohra Prerna , Corona-Torres Ricardo , Smith Alexander A. , Chintoan-Uta Cosmin , Bremner Abi , Terra Vanessa S. , Abouelhadid Sherif , Stevens Mark P. , Grant Andrew J. , Cuccui Jon , Wren Brendan W. ,   the Glycoengineering of Veterinary Vaccines Consortium
Published: October 2021

Background

Poultry is the world's most popular animal-based food and global production has tripled in the past 20 years alone. Low-cost vaccines that can be combined to protect poultry against multiple infections are a current global imperative. Glycoconjugate vaccines, which consist of an immunogenic protein covalently coupled to glycan antigens of the targeted pathogen, have a proven track record in human vaccinology, but have yet to be used for livestock due to prohibitively high manufacturing costs. To overcome this, we use Protein Glycan Coupling Technology (PGCT), which enables the production of glycoconjugates in bacterial cells at considerably reduced costs, to generate a candidate glycan-based live vaccine intended to simultaneously protect against Campylobacter jejuni, avian pathogenic Escherichia coli (APEC) and Clostridium perfringens. Campylobacter is the most common cause of food poisoning, whereas colibacillosis and necrotic enteritis are widespread and devastating infectious diseases in poultry.

Results

We demonstrate the functional transfer of C. jejuni protein glycosylation (pgl) locus into the genome of APEC χ7122 serotype O78:H9. The integration caused mild attenuation of the χ7122 strain following oral inoculation of chickens without impairing its ability to colonise the respiratory tract. We exploit the χ7122 pgl integrant as bacterial vectors delivering a glycoprotein decorated with the C. jejuni heptasaccharide glycan antigen. To this end we engineered χ7122 pgl to express glycosylated NetB toxoid from C. perfringens and tested its ability to reduce caecal colonisation of chickens by C. jejuni and protect against intra-air sac challenge with the homologous APEC strain.

Conclusions

We generated a candidate glycan-based multivalent live vaccine with the potential to induce protection against key avian and zoonotic pathogens (C. jejuni, APEC, C. perfringens). The live vaccine failed to significantly reduce Campylobacter colonisation under the conditions tested but was protective against homologous APEC challenge. Nevertheless, we present a strategy towards the production of low-cost “live-attenuated multivalent vaccine factories” with the ability to express glycoconjugates in poultry.
Changes in retinal multilayer thickness and vascular network of patients with Alzheimer’s disease
Authors: Mei Xi , Qiu Conglong , Zhou Qi , Chen Zhongming , Chen Yang , Xu Zemin , Zou Chenjun
Published: October 2021

Background

Retinal biomarkers of Alzheimer’s disease (AD) have been extensively investigated in recent decades. Retinal nervous and vascular parameters can reflect brain conditions, and they can facilitate early diagnosis of AD.

Objective

Our study aimed to evaluate the difference in retinal neuro-layer thickness and vascular parameters of patients with AD and healthy controls (HCs).

Methods

Non-invasive optical coherence tomography angiography (OCTA) was used to determine the combined thickness of the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), as well as the full retinal thickness (FRT). The vascular branching (VB), vascular curvature (VC), and vascular density (VD) for AD and HC groups were also obtained. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive performance of all the participants. After obtaining all the parameters, two-way analysis of variance (ANOVA) was used to compare the mean values of all the retinal parameters of the patients with AD and the HCs. Pearson's correlation was used to test the association between retinal parameters, MMSE scores, and vascular parameters.

Results

Seventy-eight eyes from 39 participants (19 AD and 20 HC; male, 52.6% in AD and 45.0% in HC; mean [standard deviation] age of 73.79 [7.22] years in AD and 74.35 [6.07] years in HC) were included for the analysis. The average RNFL + GCL thickness (106.32 ± 7.34 μm), FRTs of the four quadrants (290.35 ± 13.05 μm of inferior quadrant, 294.68 ± 9.37 μm of superior quadrant, 302.97 ± 6.52 μm of nasal quadrant, 286.02 ± 13.74 μm of temporal quadrant), and retinal VD (0.0148 ± 0.003) of patients with AD, compared with the HCs, were significantly reduced (p < 0.05). Retinal thickness was significantly correlated with the MMSE scores (p < 0.05). Meanwhile, retinal VD was significantly correlated with the average RNFL + GCL thickness (r2 = 0.2146, p < 0.01). When the vascular parameters were considered, the sensitivity of the AD diagnosis was increased from 0.874 to 0.892.

Conclusion

Our study suggested that the patients with AD, compared with age-matched HCs, had significantly reduced RNFL + GCL thickness and vascular density. These reductions correlated with the cognitive performance of the participants. By combining nerve and vessel parameters, the diagnosis of AD can be improved using OCTA technology.

Trail registration Name of the registry: Chinese Clinical Trail Registry, Trial registration number: ChiCTR2000035243, Date of registration: Aug. 5, 2020. URL of trial registry record: http://www.chictr.org.cn/index.aspx
Structural geometries and mechanical properties of vertebral implant with honeycomb sandwich structure for vertebral compression fractures: a finite element analysis
Authors: Guo Yuan , Liu Jing , Zhang Xushu , Xing Zejun , Chen Weiyi , Huang Di
Published: October 2021

Background

Because of osteoporosis, traffic accidents, falling from high places, and other reasons, the vertebral body can be compressed and even collapse. Vertebral implants can be used for clinical treatment. Because of the advantages of honeycomb sandwich structures, such as low cost, less material, light weight, high strength, and good cushioning performance. In this paper, the honeycomb sandwich structure was used as the basic structure of vertebral implants.

Methods

The orthogonal experiment method is applied to analyse the size effect of honeycomb sandwich structures by the finite element method. Based on the minimum requirements of three indexes of peak stress, axial deformation, and anterior–posterior deformation, the optimal structure size was determined. Furthermore, through local optimization of the overall structure of the implant, a better honeycomb sandwich structure vertebral implant was designed.

Results

The optimal structure size combination was determined as a panel thickness of 1 mm, wall thickness if 0.49 mm, cell side length of 1 mm, and height of 6 mm. Through local optimization, the peak stress was further reduced, the overall stress distribution was uniform, and the deformation was reduced. The optimized peak stress decreased to 1.041 MPa, the axial deformation was 0.1110%, and the anterior–posterior deformation was 0.0145%. A vertebral implant with good mechanical performance was designed.

Conclusions

This paper is the first to investigate vertebral implants with honeycomb sandwich structures. The design and analysis of the vertebral implant with a honeycomb sandwich structure were processed by the finite element method. This research can provide a feasible way to analyse and design clinical implants based on biomechanical principles.
Overexpression of lncRNAs with endogenous lengths and functions using a lncRNA delivery system based on transposon
Authors: Zhang Yin , Huang Yong-Xin , Jin Xin , Chen Jie , Peng Li , Wang Dan-Lan , Li Yun , Yao Xin-Yi , Liao Jian-You , He Jie-Hua , Hu KaiShun , Lu Daning , Guo Yabin , Yin Dong
Published: October 2021

Background

Long noncoding RNAs (lncRNAs) play important roles in many physiological and pathological processes, this indicates that lncRNAs can serve as potential targets for gene therapy. Stable expression is a fundamental technology in the study of lncRNAs. The lentivirus is one of the most widely used delivery systems for stable expression. However, it was initially designed for mRNAs, and the applicability of lentiviral vectors for lncRNAs is largely unknown.

Results

We found that the lentiviral vector produces lncRNAs with improper termination, appending an extra fragment of ~ 2 kb to the 3ʹ-end. Consequently, the secondary structures were changed, the RNA–protein interactions were blocked, and the functions were impaired in certain lncRNAs, which indicated that lentiviral vectors are not ideal delivery systems of lncRNAs. Here, we developed a novel lncRNA delivery method called the Expression of LncRNAs with Endogenous Characteristics using the Transposon System (ELECTS). By inserting a termination signal after the lncRNA sequence, ELECTS produces transcripts without 3ʹ-flanking sequences and retains the native features and function of lncRNAs, which cannot be achieved by lentiviral vectors. Moreover, ELECTS presents no potential risk of infection for the operators and it takes much less time. ELECTS provides a reliable, convenient, safe, and efficient delivery method for stable expression of lncRNAs.

Conclusions

Our study demonstrated that improper transcriptional termination from lentiviral vectors have fundamental effects on molecular action and cellular function of lncRNAs. The ELECTS system developed in this study will provide a convenient and reliable method for the lncRNA study.

Graphic Abstract
Dizziness and health-related quality of life among older adults in an urban population: a cross-sectional study
Authors: Lindell Ellen , Kollén Lena , Johansson Mia , Karlsson Therese , Rydén Lina , Fässberg Madeleine Mellqvist , Erhag Hanna Falk , Skoog Ingmar , Finizia Caterina
Published: October 2021

Background

Dizziness is a common complaint among older adults and may affect quality of life in a negative way. The aim of this study was to assess health-related quality of life (HRQL), sense of coherence (SOC), self-rated health (SRH) and comorbidity in relation to dizziness, among older persons from an urban population.

Methods

The study is part of the Gothenburg H70 Birth Cohort Studies (H70). A cross-sectional population-based sample including 662 79-years-olds (404 women, 258 men, 62% response rate) were surveyed with questions regarding dizziness, imbalance, comorbidities and general health. HRQL was assessed using the 36-item Short Form-36 Health Survey (SF-36) and SOC with the 13-items questionnaire Sense of Coherence (SOC-13).

Results

Half of the participants reported problems with dizziness (54%). Dizziness was negatively associated with HRQL, including after adjusting for comorbidities, especially in the physical domains of SF-36. Having dizziness was also associated with poorer SRH, tiredness and comorbidity among both men and women. SOC (mean total score), however, did not differ between dizzy and non-dizzy participants.

Conclusions

Dizziness was negatively associated with HRQL, also after adjusting for comorbidities. Identification and treatment of dizziness, when possible, are important because reduction of dizziness symptoms may potentially help to enhance overall well-being in this age group.
Bleeding risks with novel oral anticoagulants especially rivaroxaban versus aspirin: a meta-analysis
Authors: Chen Xiehui , Huang Weichao , Sun Aimei , Wang Lili , Mo Fanrui , Guo Wenqin
Published: October 2021

Background

This pairwise meta-analysis determines the difference in bleeding risks associated with the use of novel oral anticoagulants (NOACs) and aspirin.

Methods

PubMed, the Cochrane Library database, clinicaltrial.gov, and related studies were searched for randomized control trials (RCTs) comparing NOAC and aspirin published between January 1, 2000 and May 10, 2021. The primary endpoint was intracranial hemorrhage (ICH).

Results

Eleven studies involving 57,645 patients were included. Compared to aspirin, rivaroxaban (5 mg/day) had a similar risk of ICH, major bleeding, and fatal bleeding; rivaroxaban (10 mg/day) had higher risks of gastrointestinal hemorrhage (OR: 1.41; 95% CI: 1.03–1.94; P = 0.032; I2 = 0%) and a similar risk of ICH, major bleeding, and fatal bleeding; and rivaroxaban (15–20 mg/day) had higher risks of ICH (OR: 3.21; 95% CI: 1.36–7.60; P = 0.008; I2 = 0%), major bleeding (OR: 2.64; 95% CI: 1.68–4.16; P < 0.001; I2 = 0%), and fatal bleeding (OR: 2.26; 95% CI: 1.25–4.08; P = 0.007; I2 = 0%) and a similar risk of gastrointestinal hemorrhage. Bleeding outcomes between other NOACs (apixaban and dabigatran etexilate) and aspirin were not different.

Conclusions

The bleeding risks associated with NOACs depend on drug type and dosage. For ≥15 mg/day of rivaroxaban, the risk of ICH was significantly higher than that with aspirin. However, further studies comparing dabigatran etexilate and apixaban versus aspirin are warranted to draw a definite conclusion.
Mortality trends in chronic liver disease and cirrhosis from 1981 to 2015 in Taiwan
Authors: Su Shih-Yung , Lee Long-Teng , Lee Wen-Chung
Published: October 2021

Background

Globally, the morbidity and mortality rates for chronic liver disease and cirrhosis are increasing. The National Viral Hepatitis Therapy Program in Taiwan was implemented in 2003, but evidence regarding the program’s effect on the trends of mortality for chronic liver disease and cirrhosis is limited.

Methods

We analyzed mortality rates for chronic liver disease and cirrhosis in Taiwan for the period from 1981 to 2015. An autoregressive age–period–cohort model was used to estimate age, period, and cohort effects.

Results

Age-adjusted mortality rates for chronic liver disease and cirrhosis all displayed a flat but variable trend from 1981 to 2004 and a decreasing trend thereafter for both sexes. The age–period–cohort model revealed differential age gradients between the two sexes; mortality rates in the oldest age group (90–94 years) were 12 and 66 times higher than those in the youngest age group (30–34 years) for men and women, respectively. The period effects indicated that mortality rates declined after 2004 in both sexes. Mortality rates decreased in men but increased in women in the 1891–1940 birth cohorts and increased in both sexes in the birth cohorts from 1950 onward.

Conclusions

The National Viral Hepatitis Therapy Program in Taiwan may have contributed to the decrease in mortality rates for chronic liver disease and cirrhosis in adulthood.
Knowledge about juvenile idiopathic arthritis-associated uveitis: more frequent reminders are associated with higher patient and family uveitis knowledge
Authors: Cooper Ashley M. , Flanagan Elaine R. , Ronis Tova , Goldberg Baruch , Sherman Ashley K. , Smith Chelsey , Holland Gary N. ,   for the CARRA Uveitis Workgroup
Published: October 2021

Background

Chronic anterior uveitis is a sight-threatening complication of juvenile idiopathic arthritis (JIA) and a primary contributor to long-term morbidity in people with JIA. Levels of knowledge about uveitis among JIA patients and their parents are unknown. A survey of JIA patients and parents was conducted to assess knowledge about uveitis complications and recommended screening.

Methods

A survey was developed consisting of six demographic questions, six arthritis/uveitis history questions, and nine uveitis knowledge questions. The survey was administered to JIA patients age 14 and older and parents of patients with JIA at three pediatric rheumatology practices and online through the Patients, Advocates, and Rheumatology Teams Network for Research and Service (PARTNERS) network. ANOVA, chi-square and Fisher’s exact tests were used to look for relationships between survey questions and demographic variables.

Results

Thirty-three patients and 111 parents completed the survey. Overall, 17.4% reported a history of uveitis, and 89.6% had heard of uveitis. The mean composite knowledge score was 6.46 ± 2.6 out of 9. Patients and parents with a history of uveitis had higher composite knowledge scores than their counterparts without a uveitis history (p = 0.01 andp < 0.01, respectively). Parents whose rheumatologist reminded them about eye exams at every visit had higher knowledge of the risk of blindness (p = 0.04), the risk for uveitis when arthritis is controlled (p = 0.02), the need for ongoing eye exams when off of medications (p = 0.01), and had a higher overall score (p = 0.02) than those who were reminded at some visits or not at all.

Conclusions

JIA patients and parents report variable levels of knowledge regarding uveitis complications and recommended screening. Frequent discussion between the rheumatology provider and family about uveitis screening is associated with higher uveitis knowledge. Incorporating detailed and frequent education about uveitis into rheumatology clinic appointments may improve early uveitis detection and visual outcomes.
Differential chemokine alteration in the variants of primary progressive aphasia—a role for neuroinflammation
Authors: Sogorb-Esteve Aitana , Swift Imogen J. , Woollacott Ione O. C. , Warren Jason D. , Zetterberg Henrik , Rohrer Jonathan D.
Published: October 2021

Background

The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer’s disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF)

Methods

Thirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11.

Results

In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13).

Conclusion

Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.
Next generation sequencing based in-house HIV genotyping method: validation report
Authors: Ayitewala Alisen , Ssewanyana Isaac , Kiyaga Charles
Published: October 2021

Background

HIV genotyping has had a significant impact on the care and treatment of HIV/AIDS. At a clinical level, the test guides physicians on the choice of treatment regimens. At the surveillance level, it informs policy on consolidated treatment guidelines and microbial resistance control strategies. Until recently, the conventional test has utilized the Sanger sequencing (SS) method. Unlike Next Generation Sequencing (NGS), SS is limited by low data throughput and the inability of detecting low abundant drug-resistant variants. NGS can improve sensitivity and quantitatively identify low-abundance variants; in addition, it has the potential to improve efficiency as well as lowering costs when samples are batched. Despite the NGS benefits, its utilization in clinical drug resistance profiling is faced with mixed reactions. These are largely based on a lack of a consensus regarding the quality control strategy. Nonetheless, transitional views suggest validating the method against the gold-standard SS. Therefore, we present a validation report of an NGS-based in-house HIV genotyping method against the SS method in Uganda.

Results

Since there were no established proficiency test panels for NGS-based HIV genotyping, 15 clinical plasma samples for routine care were utilized. The use of clinical samples allowed for accuracy and precision studies. The workflow involved four main steps; viral RNA extraction, targeted amplicon generation, amplicon sequencing and data analysis. Accuracy of 98% with an average percentage error of 3% was reported for the NGS based assay against the SS platform demonstrating similar performance. The coefficient of variation (CV) findings for both the inter-run and inter-personnel precision showed no variability (CV ≤ 0%) at the relative abundance of ≥ 20%. For both inter-run and inter-personnel, a variation that affected the precision was observed at 1% frequency. Overall, for all the frequencies, CV registered a small range of (0–2%).

Conclusion

The NGS-based in-house HIV genotyping method fulfilled the minimum requirements that support its utilization for drug resistance profiling in a clinical setting of a low-income country. For more inclusive quality control studies, well-characterized wet panels need to be established.
The pharmaceuticalisation of life? A fictional case report of insomnia with a thought experiment
Authors: Bäckryd Emmanuel
Published: October 2021

Background

The safety of sleeping pills has increased dramatically during the last 100 years, from barbiturates to bensodiazepines to modern day so-called Z-drugs.

Methods

The circumstances of prescribing sleeping pills in the early 20th century are illustrated by summarizing the main storyline of a novel by Swedish writer Vilhelm Moberg. This is followed by a thought experiment and a theoretical discussion.

Results

In his 1937 novel Sömnlös (Swedish for sleepless) Vilhelm Moberg portrayed existential and relational distress in relation to insomnia. In a thought experiment, past progresses in sleeping pills safety are projected into the future. Thereby, it is claimed that important issues in the area of philosophy of medicine come to the fore. This leads to a theoretical discussion about broader questions concerning the role of the physician, the goals of medicine (as described by Lennart Nordenfelt), the concept of pharmaceuticalisation (as described notably by sociologist of sleep Simon J. Williams and co-workers), and health enhancement (c.f. Carl Elliott and the alleged wish to be better than well).

Conclusion

Insomnia is a prism through which important philosophical and sociological questions related to the practice of medicine can be asked.
The susceptibility of the aortic root: porcine aortic rupture testing under cardiopulmonary bypass
Authors: Surman Timothy Luke , Abrahams John Matthew , Manavis Jim , Finnie John , Christou Chris , Williams Georgia Kate , Walls Angela , Frantzis Peter , Adams Mark , Edwards James , Worthington Michael George , Beltrame John
Published: October 2021

Background

In our earlier study on the functional limits of the aneurysmal aortic root we determined the pig root is susceptible to failure at high aortic pressures levels. We established a pig rupture model using cardiopulmonary bypass to determine the most susceptible region of the aortic root under the highest pressures achievable using continuous flow, and what changes occur in these regions on a macroscopic and histological level. This information may help guide clinical management of aortic root and ascending aorta pathology.

Methods

Five pigs underwent 4D flow MRI imaging pre surgery to determine vasopressor induced wall sheer stress and flow parameters. All pigs were then placed on cardiopulmonary bypass (CPB) via median sternotomy, and maximal aortic root and ascending aorta flows were initiated until rupture or failure, to determine the most susceptible region of the aorta. The heart was explanted and analysed histologically to determine if histological changes mirror the macroscopic observations.

Results

The magnetic resonance imaging (MRI) aortic flow and wall sheer stress (WSS) increased significantly in all regions of the aorta, and the median maximal pressures obtained during cardiopulmonary bypass was 497 mmHg and median maximal flows was 3.96 L/m. The area of failure in all experiments was the non-coronary cusp of the aortic valve. Collagen and elastin composition (%) was greatest in the proximal regions of the aorta. Collagen I and III showed greatest content in the inner aortic root and ascending aorta regions.

Conclusions

This unique porcine model shows that the aortic root is most susceptible to failure at high continuous aortic pressures, supported histologically by different changes in collagen content and subtypes in the aortic root. With further analysis, this information could guide management of the aortic root in disease.
Neurobehavioral alternations of the female offspring born to polycystic ovary syndrome model rats administered by Chinese herbal medicine
Authors: Zhang Xian , You Lifang , Zhang Xiaohui , Wang Fangfang , Wang Yi , Zhou Jue , Liu Chang , Qu Fan
Published: October 2021

Background

Chinese herbal medicine (CHM) has significant effects that improve the reproductive functions of patients with polycystic ovary syndrome (PCOS). However, the intergenerational effects of CHM on offspring and the underlying mechanism of CHM remain unclear. This study aimed to explore the effects and the underlying mechanism of CHM, specifically the Bu-Shen-Tian-Jing formula (BSTJF), on model rats with polycystic ovary syndrome (PCOS) and the neurobehavioral alterations of female offspring born to PCOS rats administered BSTJF.

Methods

High-performance liquid chromatography-mass spectrometry (HPLC–MS) and network pharmacology analysis were performed to identify the active ingredients and potential targets of BSTJF. Moreover, PCOS model rats were used to validate the role of BSTJF in reproduction and progeny neural development and to confirm the network pharmacological targets.

Results

A total of 91 constituents were characterized from BSTJF. The 20 most significant KEGG pathways and the high-frequency genes of these pathways were predicted to be putative targets of these molecules. The rat experiment showed that the downregulation of FOS protein expression in the ovarian granulosa cells of the PCOS group was reversed by BSTJF. The target residence time of the 5-week-old female offspring of the BSTJF group was higher than that of the PCOS group in the water maze experiment. Compared to the PCOS group, the changes in dendritic spine density, ultrastructure of neurons and synapses, and Gabrb1 and Grin2b protein expression levels in the hippocampus of female offspring were partially reversed in the BSTJF group.

Conclusions

BSTJF can effectively improve ovarian follicle development in PCOS rats and has positive effects on pubertal neurobehavioral alterations in the female offspring of these rats by reversing dendritic spine density, the ultrastructure of neurons and synapses, and the Gabrb1 and Grin2b protein expression levels in the hippocampus.
Cognitive–behavioral therapy for management of mental health and stress-related disorders: Recent advances in techniques and technologies
Authors: Nakao Mutsuhiro , Shirotsuki Kentaro , Sugaya Nagisa
Published: October 2021

Cognitive–behavioral therapy (CBT) helps individuals to eliminate avoidant and safety-seeking behaviors that prevent self-correction of faulty beliefs, thereby facilitating stress management to reduce stress-related disorders and enhance mental health. The present review evaluated the effectiveness of CBT in stressful conditions among clinical and general populations, and identified recent advances in CBT-related techniques. A search of the literature for studies conducted during 1987–2021 identified 345 articles relating to biopsychosocial medicine; 154 (45%) were review articles, including 14 systemic reviews, and 53 (15%) were clinical trials including 45 randomized controlled trials. The results of several randomized controlled trials indicated that CBT was effective for a variety of mental problems (e.g., anxiety disorder, attention deficit hypersensitivity disorder, bulimia nervosa, depression, hypochondriasis), physical conditions (e.g., chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, breast cancer), and behavioral problems (e.g., antisocial behaviors, drug abuse, gambling, overweight, smoking), at least in the short term; more follow-up observations are needed to assess the long-term effects of CBT. Mental and physical problems can likely be managed effectively with online CBT or self-help CBT using a mobile app, but these should be applied with care, considering their cost-effectiveness and applicability to a given population.
Humans and machines in biomedical knowledge curation: hypertrophic cardiomyopathy molecular mechanisms’ representation
Authors: Glavaški Mila , Velicki Lazar
Published: October 2021

Background

Biomedical knowledge is dispersed in scientific literature and is growing constantly. Curation is the extraction of knowledge from unstructured data into a computable form and could be done manually or automatically. Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, with genotype–phenotype associations still incompletely understood. We compared human- and machine-curated HCM molecular mechanisms’ models and examined the performance of different machine approaches for that task.

Results

We created six models representing HCM molecular mechanisms using different approaches and made them publicly available, analyzed them as networks, and tried to explain the models’ differences by the analysis of factors that affect the quality of machine-curated models (query constraints and reading systems’ performance). A result of this work is also the Interactive HCM map, the only publicly available knowledge resource dedicated to HCM. Sizes and topological parameters of the networks differed notably, and a low consensus was found in terms of centrality measures between networks. Consensus about the most important nodes was achieved only with respect to one element (calcium). Models with a reduced level of noise were generated and cooperatively working elements were detected. REACH and TRIPS reading systems showed much higher accuracy than Sparser, but at the cost of extraction performance. TRIPS proved to be the best single reading system for text segments about HCM, in terms of the compromise between accuracy and extraction performance.

Conclusions

Different approaches in curation can produce models of the same disease with diverse characteristics, and they give rise to utterly different conclusions in subsequent analysis. The final purpose of the model should direct the choice of curation techniques. Manual curation represents the gold standard for information extraction in biomedical research and is most suitable when only high-quality elements for models are required. Automated curation provides more substance, but high level of noise is expected. Different curation strategies can reduce the level of human input needed. Biomedical knowledge would benefit overwhelmingly, especially as to its rapid growth, if computers were to be able to assist in analysis on a larger scale.
Epigenetic dynamics shaping melanophore and iridophore cell fate in zebrafish
Authors: Jang Hyo Sik , Chen Yujie , Ge Jiaxin , Wilkening Alicia N. , Hou Yiran , Lee Hyung Joo , Choi You Rim , Lowdon Rebecca F. , Xing Xiaoyun , Li Daofeng , Kaufman Charles K. , Johnson Stephen L. , Wang Ting
Published: October 2021

Background

Zebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood.

Results

We chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validatealx4aas a necessary and sufficient transcription factor for iridophore differentiation and present evidence onalx4a’s potential regulatory role in guanine synthesis pathway.

Conclusions

Pigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specificalx4atranscription factor.
A phase I/II dose-escalation multi-center study to evaluate the safety of infusion of natural killer cells or memory T cells as adoptive therapy in coronavirus pneumonia and/or lymphopenia: RELEASE study protocol
Authors: García-García I. , Guerra-García P. , Ferreras C. , Borobia A. M. , Carcas A. J. , Queiruga-Parada J. , Vicario J. L. , Mirones I. , Solano C. , Eguizabal C. , Soria B. , Pérez-Martínez A.
Published: October 2021

Background

Moderate/severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state.

This is a study protocol of an open-label, multi-center, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the safety, tolerability, alloreactivity, and efficacy of the administration of allogeneic memory T cells and natural killer (NK) cells in COVID-19 patients with lymphopenia and/or pneumonia. The aim of the study is to determine the safety and the efficacy of the recommended phase 2 dose (RP2D) of this treatment for patients with moderate/severe COVID-19.

Methods

In the phase I trial, 18 patients with COVID-19-related pneumonia and/or lymphopenia with no oxygen requirement or with an oxygen need of ≤ 2.5 liters per minute (lpm) in nasal cannula will be assigned to two arms, based on the biology of the donor and the patient. Treatment of arm A consists of the administration of escalating doses of memory T cells, plus standard of care (SoC). Treatment of arm B consists of the administration of escalating doses of NK cells, plus SoC.

In the phase II trial, a total of 182 patients with COVID-19-related pneumonia and/or lymphopenia requiring or not oxygen supplementation but without mechanical ventilation will be allocated to arm A or B, considering HLA typing. Within each arm, they will be randomized in a 1:1 ratio. In arm A, patients will receive SoC or RP2D for memory T cells plus the SoC. In arm B, patients will receive SoC or RP2D for NK cells plus the SoC.

Discussion

We hypothesized that SARS-CoV-2-specific memory T-lymphocytes obtained from convalescent donors recovered from COVID-19 can be used as a passive cell immunotherapy to treat pneumonia and lymphopenia in moderate/severe patients. The lymphopenia induced by COVID-19 constitutes a therapeutic window that may facilitate donor engraftment and viral protection until recovery.

Trial registration

ClinicalTrials.govNCT04578210. First Posted : October 8, 2020
Immunomodulation for primary prevention of urinary tract infections in patients with spinal cord injury during primary rehabilitation: protocol for a randomized placebo-controlled pilot trial (UROVAXOM-pilot)
Authors: Krebs Jörg , Stoyanov Jivko , Wöllner Jens , Valido Ezra , Pannek Jürgen
Published: October 2021

Background

Urinary tract infections (UTIs) are common in individuals with neurogenic lower urinary tract dysfunction (NLUTD) following spinal cord injury (SCI). They are not only a great burden for affected individuals, but also cause considerable health costs. Furthermore, recurrent antibiotic treatments of UTIs contribute to the growing problem of bacterial resistance to antimicrobial compounds. Even though there is a multitude of different measures to prevent UTIs in individuals with NLUTD, no clear evidence exists for any of these. Oral immunomodulation with UTI-relevant Escherichia coli lysate may be a promising preventative measure with a good safety profile in individuals with NLUTD. However, currently available data are sparse.

Methods

This is a randomized, quasi-blinded, placebo-controlled, mono-centric pilot trial investigating the feasibility of a main trial regarding the effects of a lyophilized lysate of E. coli strains for oral application (Uro-Vaxom®, OM Pharma SA, Meyrin, Switzerland). There will be two parallel groups of 12 participants each. Individuals with acute SCI (duration SCI ≤ 56 days) from 18 to 70 years of age admitted for primary rehabilitation will be eligible. Blood and urine samples will be taken prior to intervention start, at the end of the intervention, and 3 months after intervention termination. The trial intervention will last 90 days. The participants will not be informed regarding the treatment allocation (quasi-blinded). The nursing staff will prepare the daily dose of the allocated treatment from the original packaging. The trial personnel and the biostatistician will be blinded. Feasibility (e.g., recruitment rate, patient attrition), clinical (e.g., number of symptomatic UTIs), and laboratory parameters (e.g., urinary culture, urinary proteo- and microbiome, blood cell counts) as well as adverse events will be collected.

Discussion

Effective and efficient measures for the prevention of UTIs in individuals with NLUTD are urgently needed. If the conclusion of this pilot is positive regarding feasibility, the effects of oral immunomodulation with a E. coli lysate will be investigated in a larger, sufficiently powered, multi-center trial.

Trial registration

ClinicalTrials.govNCT04049994. Registered on 8 August 2019
Analysis of septal spacing and septal crowding in Devonian and Carboniferous ammonoids
Authors: Beck Sophie Marie , De Baets Kenneth , Klug Christian , Korn Dieter
Published: October 2021

Septal crowding is widely known as a sign of maturity in conchs of ammonoids and nautiloids. However, reduced septal spacing may also occur as a consequence of adverse ecological conditions. Here, we address the question how septal spacing varied through ontogeny in representatives of some of the major clades of Devonian and Carboniferous ammonoids. We found that the degree of ontogenetic variation is similar between clades and that variation is only weakly linked with conch form. The results show that septal crowding alone is insufficient to identify adulthood in ammonoids; intermediate septal crowding is a common phenomenon and occurs in various growth stages. Changes in septal distances during ontogeny were, in addition to adulthood of the individuals, a passive reaction likely caused by fluctuating environmental conditions.
Long-term survival of mechanically ventilated patients with severe COVID-19: an observational cohort study
Authors: Peñuelas Oscar , del Campo-Albendea Laura , de Aledo Amanda Lesmes González , Añón José Manuel , Rodríguez-Solís Carmen , Mancebo Jordi , Vera Paula , Ballesteros Daniel , Jiménez Jorge , Maseda Emilio , Figueira Juan Carlos , Franco Nieves , Algaba Ángela , Avilés Juan Pablo , Díaz Ricardo , Abad Beatriz , Canabal Alfonso , Abella Ana , Gordo Federico , García Javier , Suarez Jessica García , Cedeño Jamil , Martínez-Palacios Basilia , Manteiga Eva , Martínez Óscar , Blancas Rafael , Bardi Tommaso , Pestaña David , Lorente José Ángel , Muriel Alfonso , Esteban Andrés , Frutos-Vivar Fernando
Published: October 2021

Background

Information is lacking regarding long-term survival and predictive factors for mortality in patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19) and undergoing invasive mechanical ventilation. We aimed to estimate 180-day mortality of patients with COVID-19 requiring invasive ventilation, and to develop a predictive model for long-term mortality.

Methods

Retrospective, multicentre, national cohort study between March 8 and April 30, 2020 in 16 intensive care units (ICU) in Spain. Participants were consecutive adults who received invasive mechanical ventilation for COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection detected in positive testing of a nasopharyngeal sample and confirmed by real time reverse-transcriptase polymerase chain reaction (rt-PCR). The primary outcomes was 180-day survival after hospital admission. Secondary outcomes were length of ICU and hospital stay, and ICU and in-hospital mortality. A predictive model was developed to estimate the probability of 180-day mortality.

Results

868 patients were included (median age, 64 years [interquartile range [IQR], 56–71 years]; 72% male). Severity at ICU admission, estimated by SAPS3, was 56 points [IQR 50–63]. Prior to intubation, 26% received some type of noninvasive respiratory support. The unadjusted overall 180-day survival rates was 59% (95% CI 56–62%). The predictive factors measured during ICU stay, and associated with 180-day mortality were: age [Odds Ratio [OR] per 1-year increase 1.051, 95% CI 1.033–1.068)), SAPS3 (OR per 1-point increase 1.027, 95% CI 1.011–1.044), diabetes (OR 1.546, 95% CI 1.085–2.204), neutrophils to lymphocytes ratio (OR per 1-unit increase 1.008, 95% CI 1.001–1.016), failed attempt of noninvasive positive pressure ventilation prior to orotracheal intubation (OR 1.878 (95% CI 1.124–3.140), use of selective digestive decontamination strategy during ICU stay (OR 0.590 (95% CI 0.358–0.972) and administration of low dosage of corticosteroids (methylprednisolone 1 mg/kg) (OR 2.042 (95% CI 1.205–3.460).

Conclusion

The long-term survival of mechanically ventilated patients with severe COVID-19 reaches more than 50% and may help to provide individualized risk stratification and potential treatments.

Trial registration: ClinicalTrials.gov Identifier: NCT04379258. Registered 10 April 2020 (retrospectively registered)
Deep learning-based optimal placement of a mobile HAP for common throughput maximization in wireless powered communication networks
Authors: Kim Hong-Sik , Joe Inwhee
Published: October 2021

Hybrid access point (HAP) is a node in wireless powered communication networks (WPCN) that can distribute energy to each wireless device and also can receive information from these devices. Recently, mobile HAPs have emerged for efficient network use, and the throughput of the network depends on their location. There are two kinds of metrics for throughput, that is, sum throughput and common throughput; each is the sum and minimum value of throughput between a HAP and each wireless device, respectively. Likewise, two types of throughput maximization problems can be considered, sum throughput maximization and common throughput maximization. In this paper, we focus on the latter to propose a deep learning-based methodology for common throughput maximization by optimally placing a mobile HAP for WPCN. Our study implies that deep learning can be applied to optimize a complex function of common throughput maximization, which is a convex function or a combination of a few convex functions. The experimental results show that our approach provides better performance than mathematical methods for smaller maps.