bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial lipases and their industrial applications: a comprehensive review
Authors: Chandra Prem , Enespa  , Singh Ranjan , Arora Pankaj Kumar
Published: August 2020

Lipases are very versatile enzymes, and produced the attention of the several industrial processes. Lipase can be achieved from several sources, animal, vegetable, and microbiological. The uses of microbial lipase market is estimated to be USD 425.0 Million in 2018 and it is projected to reach USD 590.2 Million by 2023, growing at a CAGR of 6.8% from 2018. Microbial lipases (EC 3.1.1.3) catalyze the hydrolysis of long chain triglycerides. The microbial origins of lipase enzymes are logically dynamic and proficient also have an extensive range of industrial uses with the manufacturing of altered molecules. The unique lipase (triacylglycerol acyl hydrolase) enzymes catalyzed the hydrolysis, esterification and alcoholysis reactions. Immobilization has made the use of microbial lipases accomplish its best performance and hence suitable for several reactions and need to enhance aroma to the immobilization processes. Immobilized enzymes depend on the immobilization technique and the carrier type. The choice of the carrier concerns usually the biocompatibility, chemical and thermal stability, and insolubility under reaction conditions, capability of easy rejuvenation and reusability, as well as cost proficiency.Bacillusspp.,Achromobacterspp.,Alcaligenesspp.,Arthrobacterspp.,Pseudomonosspp., of bacteria andPenicilliumspp.,Fusariumspp.,Aspergillusspp., of fungi are screened large scale for lipase production. Lipases as multipurpose biological catalyst has given a favorable vision in meeting the needs for several industries such as biodiesel, foods and drinks, leather, textile, detergents, pharmaceuticals and medicals. This review represents a discussion on microbial sources of lipases, immobilization methods increased productivity at market profitability and reduce logistical liability on the environment and user.
RETRACTED ARTICLE: Long non-coding RNA LBX2-AS1 enhances glioma proliferation through downregulating microRNA-491-5p
Authors: Chen Qunbang , Gao Jian , Zhao Yingjia , Hou Ruizhe
Published: August 2020

Background

Dysregulation of lncRNAs is frequent in glioma and has emerged as an important mechanism involved in tumorigenesis. Previous analysis of Chinese Glioma Genome Atlas (CGGA) database indicated that LBX2-AS1 expression is one of differentially expression lncRNA between lower grade glioma (LGG) (grade II and III) and glioblastoma multiforme (GBM). However, the function and mechanism of LBX2-AS1 in glioma has not been evaluated yet.

Methods

Here, we analyzed the expression of LBX2-AS1 in GTEx data (normal brain), TCGA-LGG and TCGA-GBM. RT-PCR was performed to detect LBX2-AS1 in surgery obtained normal brain and glioma. CCK-8 kit and Annexin V-FITC-PI Apoptosis Detection Kit were used to study the function of LBX2-AS1 on glioma proliferation and apoptosis. Bioinformatic analysis, RNA immunoprecipitation, RT-PCR, western blotting and dual luciferase reporter assay were carried out to investigate the target miRNA of LBX2-AS1. The discovered mechanism was validated by the rescue assay.

Results

Following study of GTEx and TCGA data, LBX2-AS1 was significantly elevated in glioma compared with normal brain and in GBM compared with LGG. Higher expression of LBX2-AS1 was associated with poor prognosis of patients with glioma. Expression of LBX2-AS1 was positively correlated with pathology classification of glioma. Knockdown of LBX2-AS1 inhibited cell proliferation and induced cell apoptosis in glioma. LBX2-AS1 have complimentary binding site for tumor suppressor miR-491-5p and we showed that LBX2-AS1 sponged miR-491-5p to upregulate TRIM28 expression in glioma cells. TRIM28 overexpression attenuated the effect of LBX2-AS1 knockdown on glioma cells.

Conclusions

In conclusion, LBX2-AS1 was an increased lncRNA in glioma. Mechanistically, LBX2-AS1 promoted glioma cell proliferation and resistance to cell apoptosis via sponging miR-491-5p.
Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review
Authors: Tian Shengri , Lei Zhen , Gong Zuo , Sun Zhonghai , Xu Dongyuan , Piao Minhu
Published: August 2020

Background

Diagnosis of metastatic castrate resistant prostate cancer (mCRPC) with current biomarkers is difficult and often results in unnecessary invasive procedures as well as over-diagnosis and over-treatment. There are a number of prognostic biomarkers for CRPC, but there are no validated predictive biomarkers to guide in clinical decision-making. Specific biomarkers are needed that enable to understand the natural history and complex biology of this heterogeneous malignancy, identify early response to treatment outcomes and to identify the population of men most likely to benefit from the treatment. In this systematic review, we discuss the existing literature for the role of biomarkers in CRPC and how they aid in the prognosis, treatment selection and survival outcomes.

Methods

We performed a literature search on PubMed and EMBASE databases from January 2015 through February 2020 in accordance to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Articles were assessed to identify relevant observational studies and randomized controlled trials regarding biomarkers which aid in identifying progression to mCRPC as well as predictive biomarkers which help in treatment selection.

Results

We identified 3640 number of hits of which 58 articles were found to be relevant. Here we addressed biomarkers in the context of prognosis, prediction and patient selection of therapy. These biomarkers were found to be effective as prognostic or predictive factors under variety of conditions. The higher levels for all these biomarkers were associated with shorter median OS and sometimes PFS. Lower amounts of biomarkers in serum or urine were associated with prolonged survival outcomes, longer time to CRPC development or CRPC progression and longer median follow-up irrespective of any therapy.

Conclusion

We observed that the biomarkers included in our study predicted clinically relevant survival outcomes and treatment exposure. Though the current biomarkers are prognostic when measured prior to initiating treatment, not all are validated as predictive markers in post treatment setting. A greater understanding of biomarkers in CRPC is need of the hour for development of more personalized approach to maximize benefit and minimize harm in men with CRPC.
Disease experiences of female patients with Hansen’s disease residing in settlement in Korea
Authors: Jung Ho Gi , Yang Ya Ki
Published: August 2020

Purpose

The purpose of this study was to identify female Hansen’s disease experience in settlement village in Korea.

Method

For this study, 11 participants in settlement village were purposively chosen. Data were collected through in-depth individual interviews from July to December 2015. Verbatim transcripts were analyzed following Colaizzi’s phenomenological analysis to uncover the meaning of the experiences of the participants.

Results

The study results showed that female Hansen’s disease experience in settlement village consisted of 9 theme and 4 theme clusters: 1) Inescapable shackles; 2) Suffered as if being in prison,; 3) In no position to be a woman or a mother; 4) Another hometown.

Conclusion

The findings of this study recommends that health care professionals should pay attention not only to leprosy patients to reduce their physical and psychological suffering but also to the community and public culture to promote integration of Hansenin in the community, continued promotion and reform are needed to overcome the stigma. The results of the present study can help us in a better understanding of various aspects of female patients with Hansen’s disease residing in settlement.
The effect of exposure to particulate matter during pregnancy on lower respiratory tract infection hospitalizations during first year of life
Authors: Goshen Sharon , Novack Lena , Erez Offer , Yitshak-Sade Maayan , Kloog Itai , Shtein Alexandra , Shany Eilon
Published: August 2020

Background

Lower respiratory tract infections (LRTI) in early life, including pneumonia, bronchitis and bronchiolitis, can lead to decreased lung function, persistent lung damage and increased susceptibility to various respiratory diseases such as asthma. In-utero exposure to particulate matter (PM) during pregnancy may disrupt biological mechanisms that regulate fetal growth, maturation and development. We aimed to estimate the association between intrauterine exposure to PM of size < 2.5 μm in diameter (PM2.5) and incidence of LRTIs during the first year of life.

Methods

A retrospective population-based cohort study in a population of mothers and infants born in Soroka University Medical Center (SUMC) in the years 2004–2012. All infants < 1 year old that were hospitalized due to LRTIs were included. The main exposure assessment was based on a hybrid model incorporating daily satellite-based predictions at 1 km2spatial resolution. Data from monitoring stations was used for imputation of main exposure and other pollutants. Levels of environmental exposures were assigned to subjects based on their residential addresses and averaged for each trimester. Analysis was conducted by a multivariable generalized estimating equation (GEE) Poisson regression. Data was analyzed separately for the two main ethnic groups in the region, Jewish and Arab-Bedouin.

Results

The study cohort included 57,331 deliveries that met the inclusion criteria. Overall, 1871 hospitalizations of infants < 1 year old due to pneumonia or bronchiolitis were documented. In a multivariable analysis, intrauterine exposure to high levels of PM2.5(> 24 μg/m3) in the first and second trimesters was found to be adversely associated with LRTIs in the Arab-Bedouin population (1st trimester, RR = 1.31, CI 95% 1.08–1.60; 2nd trimester: RR = 1.34, CI 95% 1.09–1.66).

Conclusion

Intrauterine exposure to high levels of PM2.5is associated with a higher risk of hospitalizations due to lower respiratory tract infections in Arab-Bedouin infants.
Synergistic inhibition of metastatic breast cancer by dual-chemotherapy with excipient-free rhein/DOX nanodispersions
Authors: Wang Ruoning , Yang Yujie , Yang Mengmeng , Yuan Dandan , Huang Jinyu , Chen Rui , Wang Honglan , Hu Lihong , Di Liuqing , Li Junsong
Published: August 2020

Background

The management of metastatic cancer remains a major challenge in cancer therapy worldwide. The targeted delivery of chemotherapeutic drugs through rationally designed formulations is one potential therapeutic option. Notably, excipient-free nanodispersions that are entirely composed of pharmaceutically active molecules have been evaluated as promising candidates for the next generation of drug formulations. Formulated from the self-assembly of drug molecules, these nanodispersions enable the safe and effective delivery of therapeutic drugs to local disease lesions. Here, we developed a novel and green approach for preparing nanoparticles via the self-assembly of rhein (RHE) and doxorubicin (DOX) molecules, named RHE/DOX nanoparticles (RD NPs); this assembly was associated with the interaction force and did not involve any organic solvents.

Results

According to molecular dynamics (MD) simulations, DOX molecules tend to assemble around RHE molecules through intermolecular forces. This intermolecular retention of DOX was further improved by the nanosizing effect of RD NPs. Compared to free DOX, RD NPs exerted a slightly stronger inhibitory effect on 4T1 cells in the scratch healing assay. As a dual drug-loaded nanoformulation, the efficacy of RD NPs against tumor cells in vitro was synergistically enhanced. Compared to free DOX, the combination of DOX and RHE in nanoparticles exerted a synergistic effect with a combination index (CI) value of 0.51 and showed a stronger ability to induce cell apoptosis. Furthermore, the RD NP treatment not only effectively suppressed primary tumor growth but also significantly inhibited tumor metastasis both in vitro and in vivo, with a better safety profile.

Conclusions

The generation of pure nanodrugs via a self-assembly approach might hold promise for the development of more efficient and novel excipient-free nanodispersions, particularly for two small molecular antitumor drugs that potentially exert synergistic antiproliferative effects on metastatic breast cancer.
Cross-cultural adaptation and validation of the European Portuguese version of the heartland forgiveness scale
Authors: Ikedo Fabio , Castro Luisa , Fraguas Sofia , Rego Francisca , Nunes Rui
Published: August 2020

Background

Forgiveness is linked with well-being, and social and health research has focused on the role and aspects of forgiveness that has been recently suggested as a phenomenon of public health importance. The Heartland Forgiveness Scale (HFS) was developed gathering three subscales to assess the forgiveness of others, forgiveness of self, and forgiveness of situation. The present study aimed to adapt the HFS into European Portuguese, and investigate its reliability and validity.

Methods

Translation and cross-cultural adaptation were conducted using a multistep forward-back translation process. Internal consistency was assessed by Cronbach’s alpha. Confirmatory factor analysis was conducted to verify that the factor structure is the same as in the original HFS. The short version of the Ruminative Response Scale (RRS) and the Satisfaction with Life Scale (SWLS) were used to examine convergent validity.

Results

A sample of 222 university students, selected through convenience sampling, was used to access the validity of the European Portuguese version of the HFS (EPHFS). Cronbach’s alpha for the European Portuguese HFS subscales were 0.777, 0.814 and 0.816 for Self, Others and Situation, respectively, indicating acceptable reliability. The 3-factor model of the original HFS was replicated in confirmatory factor analysis. As expected by evidence in the literature, positive and statistically significant correlations were found between SWLS and HFS and subscales. RRS showed negative and statistically significant correlations with HFS and subscales.

Conclusions

The European Portuguese version of the HFS presented acceptable internal consistency, construct validity and confirmed the three-factor structure of the original HFS.
Unstructured regions of large enzymatic complexes control the availability of metabolites with signaling functions
Authors: Skalidis Ioannis , Tüting Christian , Kastritis Panagiotis L.
Published: August 2020

Metabolites produced via traditional biochemical processes affect intracellular communication, inflammation, and malignancy. Unexpectedly, acetyl-CoA, α-ketoglutarate and palmitic acid, which are chemical species of reactions catalyzed by highly abundant, gigantic enzymatic complexes, dubbed as “metabolons”, have broad “nonmetabolic” signaling functions. Conserved unstructured regions within metabolons determine the yield of these metabolites. Unstructured regions tether functional protein domains, act as spatial constraints to confine constituent enzyme communication, and, in the case of acetyl-CoA production, tend to be regulated by intricate phosphorylation patterns. This review presents the multifaceted roles of these three significant metabolites and describes how their perturbation leads to altered or transformed cellular function. Their dedicated enzymatic systems are then introduced, namely, the pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH) complexes, and the fatty acid synthase (FAS), with a particular focus on their structural characterization and the localization of unstructured regions. Finally, upstream metabolite regulation, in which spatial occupancy of unstructured regions within dedicated metabolons may affect metabolite availability and subsequently alter cell functions, is discussed.

Graphical abstract
Dose–response relationship between physical activity and mortality in adults with noncommunicable diseases: a systematic review and meta-analysis of prospective observational studies
Authors: Geidl Wolfgang , Schlesinger Sabrina , Mino Eriselda , Miranda Lorena , Pfeifer Klaus
Published: August 2020

Background

This study aims to investigate the relationship between post-diagnosis physical activity and mortality in patients with selected noncommunicable diseases, including breast cancer, lung cancer, type 2 diabetes, ischemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), osteoarthritis, low back pain and major depressive disorder.

Methods

A systematic search was conducted of PubMed, Scopus and the Web of Science from their inception to August 2018. Additionally, the search was updated in August 2019. Eligibility criteria included prospective observational studies examining the relationship between at least three physical activity categories (e.g. low, moderate, high) and all-cause mortality as the primary outcome.

Results

In total, 28 studies were included in the meta-analysis: 12 for breast cancer, 6 for type 2 diabetes, 8 for ischemic heart disease and 2 for COPD. The linear meta-analysis revealed that each 10 metabolic equivalent task hours increase of physical activity per week was associated with a 22% lower mortality rate in breast cancer patients (Summary Hazard Ratio [HR], 0.78; 95% CI: 0.71, 0.86; I2: 90.1%), 12% in ischemic heart disease patients (HR, 0.88; 95% CI: 0.83, 0.93; I2: 86.5%), 30% in COPD patients (HR, 0.70; 95% CI: 0.45, 1.09; I2: 94%) and 4% in type 2 diabetes patients (HR, 0.96; 95% CI: 0.93, 0.99; I2: 71.8%). There was indication of a non-linear association with mortality risk reductions even for low levels of activity, as well as a flattening of the curve at higher levels of activity. The certainty of evidence was low for breast cancer, type 2 diabetes and ischemic heart disease but only very low for COPD.

Conclusion

Higher levels of post-diagnosis physical activity are associated with lower mortality rates in breast cancer, type 2 diabetes, ischemic heart disease and COPD patients, with indication of a no-threshold and non-linear dose–response pattern.
Strengthening research capacity through regional partners: the HRP Alliance at the World Health Organization
Authors: Adanu Richard , Bahamondes Luis , Brizuela Vanessa , Gitau Evelyn , Kouanda Seni , Lumbiganon Pisake , Nguyen Thi Thuy Hanh , Saleem Sarah , Thorson Anna , Torpey Kwasi
Published: August 2020

Background

Improvements in health cannot occur without cutting-edge research informing the design and implementation of health programmes and policies, highlighting the need for qualified and capable researchers and institutions in countries where disease burden is high and resources are limited.

Main body

Research capacity strengthening efforts in low- and middle-income countries have included provision of training scholarships for postgraduate degrees, often in high-income countries, internships at research universities/centres, short courses, as well as involvement with research groups for hands-on experience, among others. The HRP Alliance provides opportunities for developing local research capacity in sexual and reproductive health and rights through institutions based in low- and middle-income countries linked with ongoing and past collaborative studies. It is a network of HRP research partner institutions, World Health Organization (WHO) country and regional offices, WHO special programmes and partnerships, and WHO collaborating centres.

Conclusion

It is through the HRP Alliance that HRP seeks to improve population health by strengthening local research capacity in sexual and reproductive health across the globe, with focus in low- and middle-income countries, in alignment with WHO’s quest of promoting healthier populations.
Self-selected step length asymmetry is not explained by energy cost minimization in individuals with chronic stroke
Authors: Nguyen Thu M. , Jackson Rachel W. , Aucie Yashar , de Kam Digna , Collins Steven H. , Torres-Oviedo Gelsy
Published: August 2020

Background

Asymmetric gait post-stroke is associated with decreased mobility, yet individuals with chronic stroke often self-select an asymmetric gait despite being capable of walking more symmetrically. The purpose of this study was to test whether self-selected asymmetry could be explained by energy cost minimization. We hypothesized that short-term deviations from self-selected asymmetry would result in increased metabolic energy consumption, despite being associated with long-term rehabilitation benefits. Other studies have found no difference in metabolic rate across different levels of enforced asymmetry among individuals with chronic stroke, but used methods that left some uncertainty to be resolved.

Methods

In this study, ten individuals with chronic stroke walked on a treadmill at participant-specific speeds while voluntarily altering step length asymmetry. We included only participants with clinically relevant self-selected asymmetry who were able to significantly alter asymmetry using visual biofeedback. Conditions included targeting zero asymmetry, self-selected asymmetry, and double the self-selected asymmetry. Participants were trained with the biofeedback system in one session, and data were collected in three subsequent sessions with repeated measures. Self-selected asymmetry was consistent across sessions. A similar protocol was conducted among unimpaired participants.

Results

Participants with chronic stroke substantially altered step length asymmetry using biofeedback, but this did not affect metabolic rate (ANOVA, p = 0.68). In unimpaired participants, self-selected step length asymmetry was close to zero and corresponded to the lowest metabolic energy cost (ANOVA, p = 6e-4). While the symmetry of unimpaired gait may be the result of energy cost minimization, self-selected step length asymmetry in individuals with chronic stroke cannot be explained by a similar least-effort drive.

Conclusions

Interventions that encourage changes in step length asymmetry by manipulating metabolic energy consumption may be effective because these therapies would not have to overcome a metabolic penalty for altering asymmetry.
Systemic vitamin intake impacting tissue proteomes
Authors: Jeong Heesoo , Vacanti Nathaniel M.
Published: August 2020

The kinetics and localization of the reactions of metabolism are coordinated by the enzymes that catalyze them. These enzymes are controlled via a myriad of mechanisms including inhibition/activation by metabolites, compartmentalization, thermodynamics, and nutrient sensing-based transcriptional or post-translational regulation; all of which are influenced as a network by the activities of metabolic enzymes and have downstream potential to exert direct or indirect control over protein abundances. Considering many of these enzymes are active only when one or more vitamin cofactors are present; the availability of vitamin cofactors likely yields a systems-influence over tissue proteomes. Furthermore, vitamins may influence protein abundances as nuclear receptor agonists, antioxidants, substrates for post-translational modifications, molecular signal transducers, and regulators of electrolyte homeostasis. Herein, studies of vitamin intake are explored for their contribution to unraveling vitamin influence over protein expression. As a body of work, these studies establish vitamin intake as a regulator of protein abundance; with the most powerful demonstrations reporting regulation of proteins directly related to the vitamin of interest. However, as a whole, the field has not kept pace with advances in proteomic platforms and analytical methodologies, and has not moved to validate mechanisms of regulation or potential for clinical application.
Comparison of targeted percutaneous vertebroplasty and traditional percutaneous vertebroplasty for the treatment of osteoporotic vertebral compression fractures in the elderly
Authors: Yuan Lingli , Bai Jianzhong , Geng Chunhui , Han Guansheng , Xu Wendi , Zhang Zhongchuan , Luo Hong , Zhu Xunbing
Published: August 2020

Objective

To investigate the clinical effect of precise puncture and low-dose bone cement in percutaneous vertebroplasty (PVP).

Methods

Sixty patients with osteoporotic vertebral compression fracture (OVCFs) who were treated with PVP in our hospital from July 2018 to June 2019. These included patients were divided into group A (N = 30) and group B (N = 30). Group A has punctured to the fracture area accurately and injected with a small dose of bone cement, the group B was injected with a conventional dose of bone cement. The operation time, the amount of bone cement injection, the number of X-rays, the VAS scores, the leakage rate of bone cement, and the incidence of adjacent vertebral fractures were compared between the two groups.

Result

The operation time, fluoroscopic times, and bone cement volume in group A are less than that in group B (P < 0.05). Patients in group A had a lower incidence of cement leakage and adjacent vertebral fracture than that in patients in group B. There was no significant difference in postoperative pain relief between the two groups.

Conclusions

Precise puncture and injection of small doses of bone cement can reduce the number of X-ray fluoroscopy, operation time, amount of bone cement injection, reduce the rate of bone cement leakage and the incidence of adjacent vertebral fractures, which is a safe and effective surgical approach for the treatment for the aged with OVCFs.
SAP30BP gene is associated with the susceptibility of rotator cuff tear: a case-control study based on Han Chinese population
Authors: Tian Bin , Kang Xin , Zhang Liang , Zheng Jiang , Zhao Zandong
Published: August 2020

Background

Multiple studies have indicated that genetic components contribute significantly to the risk of rotator cuff tears. Previous studies have suggested that theSAP30BPgene may play an essential role in the development of rotator cuff tears. The aim of this study was to evaluate the potential association of theSAP30BPgene with the susceptibility to rotator cuff tears in a Han Chinese population.

Methods

A total of 394 patients with rotator cuff tears and 998 healthy controls were included in the study. Twelve tag single nucleotide polymorphisms (SNPs) located in the region of theSAP30BPgene were selected for genotyping. Genetic association analyses were performed usingχ2tests for each SNP. Significant associations were searched in the GTEx database for their functional consequences.

Results

SNP rs820218 was significantly associated with rotator cuff tears (χ2= 9.49,P= 0.0021, OR [95% CI] = 0.67 [0.52–0.87]). In addition, SNP rs820218 was found to be significantly associated with the gene expression level ofSAP30BPin whole blood (NES = 0.12,P= 1.00 × 10−6).

Conclusion

Our study has shown that the genetic polymorphism ofSAP30BPcontributes to the risk of rotator cuff tears in Chinese Han people. Individuals with theAallele for SNP rs820218 were less susceptible to developing rotator cuff tears.
Hormonal determinants of mammographic density and density change
Authors: Gabrielson Marike , Azam Shadi , Hardell Elina , Holm Madeleine , Ubhayasekera Kumari A. , Eriksson Mikael , Bäcklund Magnus , Bergquist Jonas , Czene Kamila , Hall Per
Published: August 2020

Background

Mammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm2) and annual MD change (cm2/year).

Methods

This study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time.

Results

Greater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm2per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm2), oesterone sulphate (+ 1.42 cm2), prolactin (+ 2.11 cm2) and SHBG (+ 4.18 cm2), and inversely associated with 11-deoxycortisol (− 1.33 cm2). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was − 0.8 cm2. Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was − 0.96 cm2and − 1.16 cm2lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations.

Conclusions

Our results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.
The ORVAC trial: a phase IV, double-blind, randomised, placebo-controlled clinical trial of a third scheduled dose of Rotarix rotavirus vaccine in Australian Indigenous infants to improve protection against gastroenteritis: a statistical analysis plan
Authors: Jones Mark A , Graves Todd , Middleton Bianca , Totterdell James , Snelling Thomas L , Marsh Julie A
Published: August 2020

Objective

The purpose of this double-blind, randomised, placebo-controlled, adaptive design trial with frequent interim analyses is to determine if Australian Indigenous children, who receive an additional (third) dose of human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to < 12 months, would improve protection against clinically significant all-cause gastroenteritis.

Participants

Up to 1000 Australian Aboriginal and Torres Strait Islander (hereafter Indigenous) infants aged 6 to < 12 months will be recruited from all regions of the Northern Territory.

Interventions

The intervention is the addition of a third scheduled dose of human monovalent rotavirus vaccine.

Co-primary and secondary outcome measures

ORVAC has two co-primary outcomes: (1) anti-rotavirus IgA seroconversion, defined as serum anti-rotavirus IgA ≥ 20 U/ml 28 to 55 days post Rotarix/placebo, and (2) time from randomisation to medical attendance for which the primary reason for presentation is acute gastroenteritis or acute diarrhoea illness before age 36 months. Secondary outcomes include (1) change in anti-rotavirus IgA log titre, (2) time from randomisation to hospitalisation with primary admission code presumed or confirmed acute diarrhoea illness before age 36 months, (3) time from randomisation to hospitalisation for which the admission is rotavirus confirmed diarrhoea illness before age 36 months and (4) time from randomisation to rotavirus infection (not necessarily requiring hospitalisation) meeting the jurisdictional definition before age 36 months.

Discussion

A detailed, prospective statistical analysis plan is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptative elements, decision thresholds, statistical methods and the simulations used to evaluate the operating characteristics of the trial. As at August 2020, four interim analyses have been run, but no stopping rules have been triggered. Application of this SAP will minimise bias and supports transparent and reproducible research.

Trial registration

Clinicaltrials.gov NCT02941107. Registered on 21 October 2016

Original protocol for the study

10.1136/bmjopen-2019-032549
Ultrasound assessment of skin thickness and stiffness: the correlation with histology and clinical score in systemic sclerosis
Authors: Chen Chen , Cheng Yi , Zhu Xiaoxia , Cai Yehua , Xue Yu , Kong Ning , Yu Yiyun , Xuan Dandan , Zheng Shucong , Yang Xue , Zhu Zaihua , Zhao Tianyi , Wan Weiguo , Zou Hejian , Liang Minrui
Published: August 2020

Abstracts

Background

Ultrasound is a useful tool to evaluate and quantify skin lesions. Few studies have assessed the criterion validity of skin ultrasound in systemic sclerosis (SSc). The aims of the study were to investigate skin thickness and stiffness using ultrasound and shear wave elastography (SWE) in SSc and to validate skin ultrasound measurements against histological skin thickness.

Methods

A total of 22 patients with diffuse cutaneous SSc (dcSSc), 22 with limited cutaneous SSc (lcSSc), and 22 age- and gender-matched healthy controls were enrolled. Skin thickness and stiffness were measured by B-mode ultrasound with SWE imaging on the bilateral fingers and hands. Additional ultrasound evaluation was carried out in 13 patients (9 dcSSc and 4 lcSSc) on their dorsal forearms, followed by skin biopsy conducted in the same skin areas. Correlations between ultrasound measurements and histological skin thickness and modified Rodnan skin score (mRSS) were investigated using Spearman’s correlation.

Results

Compared with controls, ultrasound-measured skin thickness and skin stiffness were significantly higher in patients with SSc (p < 0.001) and even higher in those with dcSSc. No clear correlation could be established between ultrasound-determined skin thickness and stiffness at the same site. Ultrasound-measured skin thickness correlated well with histological skin thickness (r = 0.6926, p = 0.009). A weaker association was also observed between histological skin thickness and local mRSS (r = 0.5867, p = 0.050).

Conclusions

Ultrasound is a reliable tool for quantifying skin involvement in SSc. Ultrasound-measured skin thickness showed good agreement with histological skin thickness.
Does photobiomodulation therapy combined to static magnetic field (PBMT-sMF) promote ergogenic effects even when the exercised muscle group is not irradiated? A randomized, triple-blind, placebo-controlled trial
Authors: Machado Caroline dos Santos Monteiro , Casalechi Heliodora Leão , Vanin Adriane Aver , de Azevedo Jônatas Bezerra , de Carvalho Paulo de Tarso Camillo , Leal-Junior Ernesto Cesar Pinto
Published: August 2020

Background

The direct application of photobiomodulation therapy (PBMT) using low-level laser therapy (LLLT) and light emitting diodes (LEDs) combined with a static magnetic field (sMF) (PBMT-sMF) to target tissues is shown to improve muscle performance and recovery. Studies have reported possible PBMT effects when a local distant to the target tissue is irradiated. Notably, the extent of these effects on musculoskeletal performance and the optimal site of irradiation remain unclear, although this information is clinically important since these aspects could directly affect the magnitude of the effect. Therefore, we investigated the effects of local and non-local PBMT-sMF irradiations on musculoskeletal performance and post-exercise recovery before an eccentric exercise protocol.

Methods

This randomized, triple-blind (participants, therapists and assessors), placebo-controlled trial included 30 healthy male volunteers randomly assigned to the placebo, local, and non-local groups. Active or placebo PBMT-sMF was applied to 6 sites of the quadriceps muscle of both legs. An eccentric exercise protocol was used to induce fatigue. The primary outcome was peak torque assessed by maximal voluntary contraction (MVC). The secondary outcomes were delayed onset muscle soreness (DOMS) measured by visual analogue scale (VAS), muscle injury assessed by serum creatine kinase activity (CK), and blood lactate levels. Evaluations were performed before the eccentric exercise protocol (baseline), as well as immediately after and 1, 24, 48, and 72 h upon protocol completion.

Results

Ten volunteers were randomized per group and analysed for all outcomes. Compared to the placebo and non-local groups, irradiation with PBMT-SMF led to statistically significant improvement (p < 0.05) with regard to all variables in the local group. The outcomes observed in the non-local group were similar to those in the placebo group with regard to all variables.

The volunteers did not report any adverse effects.

Conclusion

Our results support the current evidence that local irradiation of all exercised muscles promotes ergogenic effects. PBMT-sMF improved performance and reduced muscle fatigue only when applied locally to muscles involved in physical activity.

Trial registration

NCT03695458. Registered October 04th 2018.
Triboelectric touch sensor for position mapping during total hip arthroplasty
Authors: Jeong Jae Bum , Kim Hyeok , Yoo Jun-Il
Published: August 2020

Objective

In this research, a triboelectric nanogenerator (TENG) was utilized to determine if a pressure-based sensor could detect bearing friction in a total hip arthroplasty (THA) and detect the contact of specific areas during ROM checks.

Results

The pressure-based sensor shows capability to sense bearing friction. In more detail, the TENG embedded in four different sides of the trial exhibits up to 1 V from peak-to-peak. Moreover, these flexible touch sensors with TENG describes a peak signal in output voltage which should lead to extremely sensitive detection of bearing friction induced by the THA.
Colorectal liver metastases: radiopathological correlation
Authors: Paulatto Luisa , Dioguardi Burgio Marco , Sartoris Riccardo , Beaufrère Aurélie , Cauchy François , Paradis Valérie , Vilgrain Valérie , Ronot Maxime
Published: August 2020

With the development of chemotherapy regimens, targeted therapies, and hepatic surgery, the survival of patients with colorectal liver metastases (CRLM) has dramatically improved. Imaging plays a central role for the diagnosis, staging, and treatment allocation in these patients. To interpret CRLM on imaging, radiologists must be familiar with the main imaging features of untreated tumors as well as the modifications induced by systemic therapies, and their meaning in relation to pathological tumor response and tumor biology. CRLM have the same histological features as the primary tumor. Most are “non-otherwise specified” (NOS) adenocarcinomas. The mucinous tumor is the most common of the rare subtypes. In NOS tumors, imaging usually differentiates central areas of necrosis from peripheral proliferating tumors and desmoplastic reaction. Areas of mucin mixed with fibrosis are seen in mucinous subtypes to help differentiate the metastases from other tumors cysts or hemangiomas. After treatment, the viable tumor is gradually replaced by ischemic-like necrosis and fibrosis, and remnants cells are mainly located on the periphery of tumors. Imaging can help predict the degree of tumor response, but changes can be difficult to differentiate from the pretherapeutic appearance. When chemotherapy is interrupted or in case of resistance to treatment, a peripheral infiltrating halo of tumor growth may appear. The purpose of the article is to illustrate the significance of the imaging features of colorectal liver metastases during systemic therapy, using radiopathological correlations.
Hypogonadal hypertension in male Sprague-Dawley rats is renin-angiotensin system-dependent: role of endogenous androgens
Authors: Hanson Andrea E. , Perusquia Mercedes , Stallone John N.
Published: August 2020

Background

Acutely, testosterone (TES) and other androgens are efficacious vasodilators, both in vitro and in vivo; however, their long-term effects on arterial blood pressure (BP) remain unclear. It was hypothesized that endogenous androgens exert long-term anti-hypertensive effects on systemic BP through a combination of genomic and nongenomic effects to enhance vasodilation of the systemic vasculature.

Methods

The long-term effects of endogenous TES and exogenous TES replacement therapy (TRT) on BP were studied in intact (InT) and castrated (CsX) male Sprague-Dawley (SD) and testicular-feminized male (Tfm, androgen receptor defective) rats (12 weeks old). Systolic BP (tail-cuff plethysmography) was determined weekly for 15 weeks in InT-control and CsX rats. Some CsX-SD rats received androgen replacement therapy at 10-15 weeks with TES-enanthate (TRT; 1.75 mg/kg, 2x/week) or DHT-enanthate (DRT; 1.00 mg/kg. 2x/week) and a separate group of CsX-SD rats received losartan-potassium in drinking water (LST, 250 mg/L) for the entire 15 week period. Expression of renin, angiotensinogen (Agt), angiotensin converting enzyme (ACE), and angiotensin II type I receptor (AT1R) mRNA in kidney and aorta were determined by real-time PCR (rt-PCR) and plasma renin levels were determined by radioimmunoassay.

Results

There was a progressive rise in BP over 10 weeks in CsX (109 ± 3.3 vs. 143 ± 3.5 mmHg), while BP remained stable in InT-control (109 ± 3.0 vs. 113 ± 0.3). BP gradually declined to normal in CsX-TRT rats (113 ± 1.3), while BP remained elevated in CsX (140 ± 1.2) and normal in InT-control (113 ± 0.3). LST prevented the development of hypertension in CsX at 10 weeks (100 ± 1.5 in CsX + LST vs. 143 ± 3.5 in CsX). During the next 5 weeks with TES-RT, BP declined in CsX-TRT (113 ± 1.3) and remained lower in CsX + LST (99 ± 0.4). DHT-RT reduced BP in CxS to a similar extent. In Tfm, CsX resulted in a similar rise in BP (109 ± 0.7 vs. 139 ± 0.4 mmHg), but TRT reduced BP more rapidly and to a greater extent (106 ± 2.8). rt-PCR of the kidney revealed that CsX increased expression of mRNA for renin (92%), ACE (58%), and AT1R (80%) compared to InT, while TES RT normalized expression of renin, AT1R, and ACE mRNA to levels of InT rats. Plasma renin levels exhibited changes similar to those observed for renin mRNA expression.

Conclusions

This is the first study to examine the long-term effects of endogenous and exogenous androgens on BP in male SD and Tfm rats. These data reveal that endogenous androgens (TES) exert anti-hypertensive effects that appear to involve non-genomic and possibly genomic mechanism(s), resulting in reductions in RAS expression in the kidney and enhanced systemic vasodilation.
Epidemiology of tuberculosis in Sabah, Malaysia, 2012–2018
Authors: Goroh Michelle May D. , Rajahram Giri Shan , Avoi Richard , Van Den Boogaard Christel H. A. , William Timothy , Ralph Anna P. , Lowbridge Christopher
Published: August 2020

Background

Tuberculosis (TB) is of high public health importance in Malaysia. Sabah State, located on the island of Borneo, has previously reported a particularly high burden of disease and faces unique contextual challenges compared with peninsular Malaysia. The aim of this study is to describe the epidemiology of TB in Sabah to identify risk groups and hotspots of TB transmission.

Methods

We conducted a retrospective review of TB cases notified in Sabah, Malaysia, between 2012 and 2018. Using data from the state’s ‘myTB’ notification database, we calculated the case notification rate and described trends in the epidemiology, diagnostic practices and treatment outcomes of TB in Sabah within this period. The Chi-squared test was used for determining the difference between two proportions.

Results

Between 2012 and 2018 there were 33 193 cases of TB reported in Sabah (128 cases per 100 000 population). We identified several geographic hotspots, including districts with > 200 cases per 100 000 population per year. TB rates increased with age and were highest in older males. Children < 15 years accounted for only 4.6% of cases. Moderate or advanced disease on chest X-ray and sputum smear positivity was high (58 and 81% of cases respectively), suggesting frequent late diagnosis. Multi-drug resistant (MDR) TB prevalence was low (0.3% of TB cases), however, rapid diagnostic test coverage was low (1.2%) and only 18% of all cases had a positive culture result. Treatment success was 83% (range: 81–85%) in those with drug-sensitive TB and 36% (range: 25–45%) in cases of MDR-TB.

Conclusion

Between 2012 and 2018, TB notifications in Sabah State equated to 20% of Malaysia’s total TB notifications, despite Sabah representing only 10% of Malaysia’s population. We found hotspots of TB in urbanised population hubs and points of migration, as well as evidence of late presentation and diagnosis. Ensuring universal health coverage and expansion of GeneXpert® coverage is recommended to reduce barriers to care and early diagnosis and treatment for TB.
A genetic predictive model for precision treatment of diffuse large B-cell lymphoma with early progression
Authors: Ma Jialin , Yan Zheng , Zhang Jiuyang , Zhou Wenping , Yao Zhihua , Wang Haiying , Chu Junfeng , Yao Shuna , Zhao Shuang , Zhang Peipei , Xu Yuanlin , Xia Qingxin , Ma Jie , Wei Bing , Yang Shujun , Liu Kangdong , Guo Yongjun , Liu Yanyan
Published: August 2020

Background

Early progression after the first-line R-CHOP treatment leads to a very dismal outcome and necessitates alternative treatment for patients with diffuse large B-cell lymphoma (DLBCL). This study aimed to develop a genetic predictive model for early progression and evaluate its potential in advancing alternative treatment.

Methods

Thirty-two hotspot driver genes were examined in 145 DLBCL patients and 5 DLBCL cell lines using next-generation sequencing. The association of clinical features, cell-of-origin, double expression, positive p53 protein, and gene alterations with early progression was analyzed, and the genetic predictive model was developed based on the related independent variables and assessed by the area under receiver operating characteristic. The potential of novel treatment based on the modeling was investigated in in-vitro DLBCL cell lines and in vivo xenograft mouse models.

Results

The frequency of CD79B (42.86% vs 9.38%, p = 0.000) and PIM1 mutations (38.78% vs 17.71%, p = 0.005) showed a significant increase in patients with early progression. CD79B and PIM1 mutations were associated with complex genetic events, double expression, non-GCB subtype, advance stage and unfavorable prognosis. A powerful genetic predictive model (AUROC = 0.771, 95% CI: 0.689–0.853) incorporating lactate dehydrogenase levels (OR = 2.990, p = 0.018), CD79B mutations (OR = 5.970, p = 0.001), and PIM1 mutations (OR = 3.021, p = 0.026) was created and verified in the other cohort. This modeling for early progression outperformed the prediction accuracy of conventional International Prognostic Index, and new molecular subtypes of MCD and Cluster 5. CD79B and PIM1 mutations indicated a better response to inhibitors of BTK (ibrutinib) and pan-PIM kinase (AZD 1208) through repressing activated oncogenic signaling. Since the two inhibitors failed to decrease BCL2 level, BCL2 inhibitor (venetoclax) was added and demonstrated to enhance their apoptosis-inducing activity in mutant cells with double expression.

Conclusions

The genetic predictive model provides a robust tool to identify early progression and determine precision treatment. These findings warrant the development of optimal alternative treatment in clinical trials.