bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycobacterium bovis and M. caprae in Bulgaria: insight into transmission and phylogeography gained through whole-genome sequencing
Authors: Valcheva Violeta , Perea Claudia , Savova-Lalkovska Tanya , Dimitrova Albena , Radulski Lukasz , Mokrousov Igor , Marinov Krustyu , Najdenski Hristo , Bonovska Magdalena
Published: April 2022

Background

This study aimed to characterize recent Mycobacterium bovis/M. caprae isolates from Bulgaria by whole-genome sequencing (WGS) to gain a first insight into their molecular diversity, transmission, and position within the global phylogeography of this important zoonotic species.

Results

The isolates were obtained from cattle in diverse locations of Bulgaria in 2015-2020 and were identified by microbiological and PCR assays. WGS data were used for phylogenetic analysis that also included M. bovis global dataset. Thirty-seven M. bovis/caprae isolates from Bulgaria were studied and 34 of them were SNP genotyped. The isolates were subdivided into 3 major phylogenetic groups. Type Mbovis-13 (Eu2 complex [western Europe and northern Africa]) included one isolate. Mbovis-37 type included 5 isolates outside of known clonal complexes. The Bulgarian M. caprae isolates formed a sub-group within the Mcaprae-27B cluster which also included 22 M. caprae isolates from Poland, Spain, Germany, and the Republic of Congo. The Bulgarian M. caprae isolates share their latest common ancestors with Spanish isolates. The Mbovis-37 group shares a distant common ancestor (pairwise distance 22-29 SNPs) with an isolate from Poland but was very distant (> 200 SNPs) from the rest of the tree. The Mbovis-13 group shares a common ancestor with two human isolates from Germany. Phylogeographically, both M. bovis clades had limited circulation in northeastern Bulgaria while the majority of the studied isolates (M. caprae) were from central and western provinces. A phylogenetic network-based analysis demonstrated that 11 Bulgarian isolates were separated by 1 to 6 SNPs within four clusters, mostly forming pairs of isolates.

Conclusion

The obtained WGS analysis positioned the Bulgarian isolates within the global phylogeography of M. bovis/M. caprae. Hypothetically, the observed phylogenetic diversity may not have resulted from livestock trade routes, but instead may reflect the deeply rooted M. bovis/M. caprae phylogeography of Europe. A high level of genetic divergence between the majority of the studied isolates suggests limited active transmission of bTB in Bulgaria during the survey period. At the same time, a possibility of the endemic presence of circulating bTB strains in the form of the latent persistent disease cannot be ruled out.
Piezo1 promoted hepatocellular carcinoma progression and EMT through activating TGF-β signaling by recruiting Rab5c
Authors: Li Yi-ming , Xu Cong , Sun Bo , Zhong Fang-jing , Cao Momo , Yang Lian-yue
Published: April 2022

Background

Piezo1 has been revealed to play a regulatory role in vascular development and progression of variety tumors. However, whether and how the progression of hepatocellular carcinoma (HCC) regulated by Piezo1 remains elusive. This study aimed to elucidate the effect and mechanisms of Piezo1 in HCC.

Methods

The mRNA and protein expression level of Piezo1 in HCC samples and cell lines was determined by qRT-PCR, western blot and immunohistochemistry analyses. Two independent study cohorts containing 280 patients were analyzed to reveal the association between Piezo1 expression and clinicopathological characteristics. Series of in vitro and in vivo experiments were used to validate the function of Piezo1 in HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. Immunoprecipitation, immunofluorescence and in vitro and in vivo experiments were used to explore the molecular mechanism of Piezo1 in HCC progression.

Results

Our results demonstrated the Piezo1 expression was significantly upregulated in HCC tissues and cell lines, and upregulation of Piezo1 closely correlated with aggressive clinicopathological features and poor prognosis. Knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly restrained proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, metastasis, EMT in vivo. TGF-β signaling pathway was most significant enriched pathway in GSEA. Finally, tumor promotion effect of Piezo1 was found to exerted through recruiting and combining Rab5c to activating TGF-β signaling pathway.

Conclusions

Piezo1 significantly related to poor prognosis and promotes progression of hepatocellular carcinoma via activating TGF-β signaling, which suggesting that Piezo1 may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.
Exploring the potential for a new measure of socioeconomic deprivation status to monitor health inequality
Authors: Dirksen Jakob , Pinilla-Roncancio Monica , Wehrmeister Fernando C. , Ferreira Leonardo Z. , Vidaletti Luis Paulo , Kirkby Katherine , Koller Theadora Swift , Schlotheuber Anne , Tapia Heriberto , Vidal Fuertes Cecilia , Alkire Sabina , Barros Aluisio J. D. , Hosseinpoor Ahmad Reza
Published: April 2022

Background

Monitoring health inequalities is an important task for health research and policy, to uncover who is being left behind – and where – and to inform effective and equitable policies and programmes to tackle existing inequities. The choice of which measure to use to monitor and analyse health inequalities is thereby not trivial. This article explores a new measure of socioeconomic deprivation status (SDS) to monitor health inequalities.

Methods

The SDS measure was constructed using the Alkire-Foster method. It includes eight indicators across two equally weighted dimensions (education and living standards) and specifies a four-level gradient of socioeconomic deprivation at the household-level. We conducted four exercises to examine the value-added of the proposed SDS measure, using Demographic and Health Surveys data. First, we examined the discriminatory power of the new measure when applied to outcomes in four select reproductive, maternal, neonatal, and child health (RMNCH) indicators across six countries: skilled birth attendance, stunting, U5MR, and DTP3 immunisation. Then, we analysed the behaviour and association of the new SDS measure vis-à-vis the DHS Wealth Index, including chi-squared test and Pearson correlation coefficient. Third, we analysed the robustness of the SDS measure results to changes in its structure, using pairwise comparisons and Kendal Tau-b rank correlation. Finally, we illustrated some of the advantageous properties of the new measure, disaggregation and decomposition, on Haitian data.

Results

1) Higher levels of socioeconomic deprivation are generally consistently associated with lower levels of achievements in the RMNCH indicators across countries. 2) 87% of all pairwise rank comparisons across a range of SDS measure structures were robust. 3) SDS and DHS Wealth Index are associated, but with considerable cross-country variation, highlighting their complementarity. 4) Haitian households in rural areas experienced, on average, more severe socioeconomic deprivation as well as lower levels of RMNCH achievement than urban households.

Conclusions

The proposed SDS measure adds analytical possibilities to the health inequality monitoring literature, in line with ethically and conceptually well-founded notions of absolute, multidimensional disadvantage. In addition, it allows for breakdown by its dimensions and components, which may facilitate nuanced analyses of health inequality, its correlates, and determinants.
Targeting TGF-β signal transduction for fibrosis and cancer therapy
Authors: Peng Dandan , Fu Minyang , Wang Manni , Wei Yuquan , Wei Xiawei
Published: April 2022

Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
RNA-based therapy in the management of lipid disorders: a review
Authors: Blom Dirk Jacobus , Marais Adrian David , Moodley Rajen , van der Merwe Nico , van Tonder Alet , Raal Frederick Johan
Published: April 2022

This review focuses on antisense oligonucleotides and small interfering ribonucleic acid therapies approved or under development for the management of lipid disorders. Recent advances in RNA-based therapeutics allow tissue-specific targeting improving safety. Multiple potential target proteins have been identified and RNA-based therapeutics have the potential to significantly improve outcomes for patients with or at risk for atherosclerotic cardiovascular disease. The advantages of RNA-based lipid modifying therapies include the ability to reduce the concentration of almost any target protein highly selectively, allowing for more precise control of metabolic pathways than can often be achieved with small molecule-based drugs. RNA-based lipid modifying therapies also make it possible to reduce the expression of target proteins for which there are no small molecule inhibitors. RNA-based therapies can also reduce pill burden as their administration schedule typically varies from weekly to twice yearly injections. The safety profile of most current RNA-based lipid therapies is acceptable but adverse events associated with various therapies targeting lipid pathways have included injection site reactions, inflammatory reactions, hepatic steatosis and thrombocytopenia. While the body of evidence for these therapies is expanding, clinical experience with these therapies is currently limited in duration and the results of long-term studies are eagerly awaited.
Extraperitoneal laparoscopic radical cystectomy with intracorporeal neobladder: a comparison with transperitoneal approach
Authors: Zhang Ying , Zhou Huan , Tuo Zhou Ting , Wang Jinyou , Sun Chenyu , Bi Liangkuan
Published: April 2022

Background

Bladder cancer is one of the most common genitourinary cancers. Traditional transperitoneal radical cystectomy is the gold standard treatment for muscle-invasive bladder cancer. Our study was to compare the perioperative and oncological outcomes of extraperitoneal laparoscopic radical cystectomy (ELRC) with intracorporeal neobladder versus transperitoneal urinary diversion for bladder cancer.

Method

A total of 113 patients who underwent laparoscopic radical cystectomy performed at our center were included in this retrospective study. The perioperative data of the extraperitoneal laparoscopic radical cystectomy (ELRC) with intracorporeal urinary diversion (ICUD) and transperitoneal laparoscopic radical cystectomy (TLRC) with ICUD groups were compared. The demographic, perioperative, oncological, and complication data were collected and analyzed.

Results

In total, 113 patients were enrolled for the final analysis. The median follow-up period was 22 months. The ELRC group had shorter interval to flatus (p < 0.001), solid food (p < 0.001), shorter length of hospital stay (p < 0.01), and fewer early gastrointestinal complications (p < 0.05). Furthermore, urinary continence, recurrence-free, cancer-specific, and overall survival rates and recurrence patterns did not significantly differ.

Conclusions

Surgical technique of ELRC with ICUD can achieve the established oncologic criteria of TLRC, and such technique can improve perioperative and early postoperative outcomes.
Prognostic factors of BRAF V600E colorectal cancer with liver metastases: a retrospective multicentric study
Authors: Javed Sahir , Benoist Stéphane , Devos Patrick , Truant Stéphanie , Guimbaud Rosine , Lièvre Astrid , Sefrioui David , Cohen Romain , Artru Pascal , Dupré Aurélien , Bachet Jean-Baptiste , de la Fouchardière Christelle , Ploquin Anne , Turpin Anthony
Published: April 2022

Background

BRAF V600E-mutant colorectal cancers (CRCs) are associated with shorter survival than BRAF wild-type tumors. Therapeutic decision-making for colorectal liver metastases (CRLM) harboring this mutation remains difficult due to the scarce literature. The aim was to study a large cohort of BRAF V600E-mutant CRLM patients in order to see if surgery extend overall survival among others prognostic factors.

Methods

BRAF V600E-mutant CRCs diagnosed with liver-only metastases, resected or not, were retrospectively identified between April 2008 and December 2017, in 25 French centers. Clinical, molecular, pathological characteristics and treatment features were collected. Overall survival (OS) was defined as the time from CRLM diagnosis to death from any cause. Cox proportional hazard models were used for statistical analysis.

Results

Among the 105 patients included, 79 (75%) received chemotherapy, 18 (17%) underwent upfront CRLM surgery, and 8 (8%) received exclusive best supportive care. CRLM surgery was performed in 49 (46.7%) patients. CRLM were mainly synchronous (90%) with bilobar presentation (61%). The median OS was 34 months (range, 28.9–67.3 months) for resected patients and 10.6 (6.7–12.5) months for unresected patients (P < 0.0001). In multivariate analysis, primary tumor surgery (hazard ratio (HR) = 0.349; 95% confidence interval (CI) 0.164–0.744, P = 0.0064) and CRLM resection (HR = 0.169; 95% CI 0.082–0.348, P < 0.0001) were associated with significantly better OS.

Conclusions

In the era of systemic cytotoxic chemotherapies, liver surgery seems to extend OS in BRAF V600E-mutant CRCs with liver only metastases historical cohort.
ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFκB/NLRP3 pathway
Authors: Cai Lin , Gong Qiuyuan , Qi Lin , Xu Tongtong , Suo Qian , Li Xiang , Wang Wei , Jing Yao , Yang Dianxu , Xu Zhiming , Yuan Fang , Tang Yaohui , Yang Guoyuan , Ding Jun , Chen Hao , Tian Hengli
Published: April 2022

Background

Microglia-mediated neuroinflammatory response following traumatic brain injury (TBI) is considered as a vital secondary injury factor, which drives trauma-induced neurodegeneration and is lack of efficient treatment. ACT001, a sesquiterpene lactone derivative, is reportedly involved in alleviation of inflammatory response. However, little is known regarding its function in regulating innate immune response of central nervous system (CNS) after TBI. This study aimed to investigate the role and underlying mechanism of ACT001 in TBI.

Methods

Controlled cortical impact (CCI) models were used to establish model of TBI. Cresyl violet staining, evans blue extravasation, neurobehavioral function assessments, immunofluorescence and transmission electron microscopy were used to evaluate therapeutic effects of ACT001 in vivo. Microglial depletion was induced by administering mice with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Cell-cell interaction models were established as co-culture system to simulate TBI conditions in vitro. Cytotoxic effect of ACT001 on cell viability was assessed by cell counting kit-8 and activation of microglia cells were induced by Lipopolysaccharides (LPS). Pro-inflammatory cytokines expression was determined by Real-time PCR and nitric oxide production. Apoptotic cells were detected by TUNEL and flow cytometry assays. Tube formation was performed to evaluate cellular angiogenic ability. ELISA and western blot experiments were used to determine proteins expression. Pull-down assay was used to analyze proteins that bound ACT001.

Results

ACT001 relieved the extent of blood-brain barrier integrity damage and alleviated motor function deficits after TBI via reducing trauma-induced activation of microglia cells. Delayed depletion of microglia with PLX5622 hindered therapeutic effect of ACT001. Furthermore, ACT001 alleviated LPS-induced activation in mouse and rat primary microglia cells. Besides, ACT001 was effective in suppressing LPS-induced pro-inflammatory cytokines production in BV2 cells, resulting in reduction of neuronal apoptosis in HT22 cells and improvement of tube formation in bEnd.3 cells. Mechanism by which ACT001 functioned was related to AKT/NFκB/NLRP3 pathway. ACT001 restrained NFκB nuclear translocation in microglia cells through inhibiting AKT phosphorylation, resulting in decrease of NLRP3 inflammasome activation, and finally down-regulated microglial neuroinflammatory response.

Conclusions

Our study indicated that ACT001 played critical role in microglia-mediated neuroinflammatory response and might be a novel potential chemotherapeutic drug for TBI.
Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems
Authors: Quiroga I. Y. , Cruikshank A. E. , Bond M. L. , Reed K. S. M. , Evangelista B. A. , Tseng J. H. , Ragusa J. V. , Meeker R. B. , Won H. , Cohen S. , Cohen T. J. , Phanstiel D. H.
Published: April 2022

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aβ) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aβ is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e., microglia), which culminates in neuronal damage and cognitive decline. To test this hypothesis, many in vitro systems have been established to study Aβ-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale.

Methods

We used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aβ or LPS and INFγ.

Results

We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aβ does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aβ formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes that resemble many, but not all, aspects of the transcriptomic profiles of disease associated microglia (DAM) present in the AD brain.

Conclusions

These results suggest that synthetic Aβ treatment of innate immune cell cultures does not recapitulate transcriptional profiles observed in microglia from AD brains. In contrast, treating IMGL with LPS and INFγ induces transcriptional changes similar to those observed in microglia detected in AD brains.
The research output of rod-cone dystrophy genetics
Authors: Jaffal Lama , Mrad Zamzam , Ibrahim Mariam , Salami Ali , Audo Isabelle , Zeitz Christina , El Shamieh Said
Published: April 2022

Non-syndromic rod-cone dystrophy (RCD) is the most common condition in inherited retinal diseases. The aim of this study was to evaluate the research output and productivity related to RCD genetics per countries as classified by the human development index (HDI), by analyzing publication frequency and citations, the choice of journals and publishers, since 2000 to date. We have also analyzed the use of next-generation sequencing (NGS) in publications originating from countries with different HDIs. One thousand four hundred articles focusing on non-syndromic RCD were downloaded and analyzed. Citations and published articles were adjusted per one million individuals. The research output is significantly higher in very high HDI countries (86% of the total publications and 95% of the citations) than countries with lower HDIs in all aspects. High and medium HDI countries published together 13.6% of the total articles worldwide and received 4.6% of the citations. On the publication level, the USA (26%), United Kingdom (10%), and Japan (7%) were the top 3 among very high HDI countries, while China (6%) and India (2%) ranked first in high and medium HDI countries respectively. On the citation level, similar profiles were found. Following adjustment for population size, Switzerland (~14%), Jordan (~ 1%) and Morocco (<0.2%) showed the highest rates of publications in very high, high and medium HDI countries respectively. Very high HDI countries published 71% of their papers in first quartile journals (first quartile in Scimago journal rank; Q1), and 23% in Q2 journals. High and medium HDI countries showed a similar profile in quartiles with ~ 40% of their papers published in Q1 journals and ~ 30% in Q2 journals. The first publication using NGS was issued in 2009 in very high HDI countries, while it appeared in 2012 in high HDI countries, and in 2017 in medium HDI countries, with a respective lag of 3 to 8 years compared to very high HDI countries. A profound gap exists between very high HDI countries and the rest of the world. To fill it in, we propose implementing NGS, supporting international collaborations, building capacities and infrastructures, improving accessibility of patients to services, and increasing national and international funding.
Clinical overview and outcome of the Stuve-Wiedemann syndrome: a systematic review
Authors: Warnier Hélène , Barrea Christophe , Bethlen Sarah , Schrouff Isabelle , Harvengt Julie
Published: April 2022

Background

Stuve-Wiedemann syndrome (SWS) is a rare and severe genetic disease characterized by skeletal anomalies and dysautonomic disturbances requiring appropriate care. Peer support is mandatory to fill the lack of clinical recommendations in such rare diseases. We report a new case and provide the first systematic review of all previous published cases.

Objective

To better describe the timeline of SWS and to improve paediatric management.

Data sources

SWS English publications available on Pubmed until 31/03/2021.

Study selection

Case description combining typical osteo-articular and dysautonomic involvement (with 2 items by categories required for children < 2 years and 3 items > 2 years).

Data extraction

Demographic, clinical, genetics and outcome data.

Results

In our cohort of 69 patients, the median age at report was 32 months. Only 46% presented antenatal signs. Mortality rate is higher during the first 2 years (42% < 2 years; 10% > 2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%). After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%).

Conclusions

Natural history of SWS is marked by a high mortality rate before 2 years due to dysautonomic disturbances. A specialized multidisciplinary approach is needed to address these early mortality risks and then adapt to the specific, mainly orthopaedic, needs of patients after 2 years of age. Further research is required to provide clinical guidelines and improve pre-natal counselling.
Development of the Clinical Gestalt Assessment: a visual clinical global impression scale for Proteus syndrome
Authors: Ours Christopher A. , Hodges Mia B. , Oden Neal , Sapp Julie C. , Biesecker Leslie G.
Published: April 2022

Background

Clinical outcome assessments are important tools for measuring the natural history of disease and efficacy of an intervention. The heterogenous phenotype and difficult to quantity features of Proteus syndrome present challenges to measuring clinical outcomes. To address these, we designed a global clinical assessment for Proteus syndrome, a rare mosaic overgrowth disorder. The Clinical Gestalt Assessment (CGA) aims to evaluate change over time in this phenotypically diverse disorder.

Results

We gathered paired serial photographs and radiographs obtained at 12-to-36-month intervals from our natural history study of Proteus syndrome. The chronologic order of each set was blinded and presented to clinicians familiar with overgrowth disorders. They were asked to determine the chronologic order and, based on that response, rate global clinical change using a seven-point scale (Much Worse, Worse, Minimally Worse, No Change, Minimally Improved, Improved, Much Improved). Following a pilot, we tested the inter-rater reliability of the CGA using eight cases rated by eight clinicians. Raters identified the correct chronologic order in 53 of 64 (83%) of responses. There was low inter-rater variance and poor to moderate reliability with an intraclass correlation coefficient of 0.46 (95% CI 0.24–0.75). The overall estimate of global change was Minimally Worse over time, which is an accurate reflection of the natural history of Proteus syndrome.

Conclusions

The CGA is a tool to evaluate clinical change over time in Proteus syndrome and may be a useful adjunct to measure clinical outcomes in prospective therapeutic trials.
Administration of spruce bark (Picea abies) extracts in young lambs exhibits anticoccidial effects but reduces milk intake and body weight gain
Authors: Blomstrand Berit Marie , Enemark Heidi Larsen , Steinshamn Håvard , Aasen Inga Marie , Johanssen Juni Rosann Engelien , Athanasiadou Spiridoula , Thamsborg Stig Milan , Sørheim Kristin Marie
Published: April 2022

Background

Eimeria spp. are widespread apicomplexan parasites known to cause coccidiosis in livestock, resulting in reduced animal welfare and productivity, particularly in sheep. The treatment options are limited, and there is an emerging development of resistance against registered pharmaceuticals. Spruce bark is rich in plant secondary metabolites (PSM), such as condensed tannins, which are bioactive compounds previously shown to have antiparasitic activity. Here, we examined the anticoccidial properties of bark extract of Norway spruce (Picea abies) against a field isolate of ovine Eimeria spp. by treating Eimeria-infected pre-ruminant lambs with water-extracted bark daily for 12 days. We hypothesised that the bark extract would reduce the faecal oocyst excretion and, consequently, the severity of diarrhoea.

Results

Oral administration of spruce bark extract significantly reduced the excretion of Eimeria oocysts in milk-fed lambs post treatment till the end of the trial 22 days post infection. This difference in oocyst excretion between the treated and the untreated infected animals increased with time.

Compared to the untreated and the sham-infected control group, the group treated with bark extract had softer faeces and reduced milk intake during the treatment period. After discontinuing the treatment, the treated animals got a more solid and formed faeces compared to that of the untreated control group, and the milk intake increased to the level of the sham-infected, untreated control group. The bark extract treated animals had a lower body weight and a lower mean daily body weight gain throughout the whole duration of the experiment.

Conclusions

Bark extract from Norway spruce showed marked anticoccidial properties by reducing the faecal oocyst count and associated diarrhoea in young lambs. Simultaneously we experienced detrimental effects of the treatment, displayed as reduced feed intake and daily body weight gain. Therefore, we suggest conducting similar studies with lower bark extract dosage to explore the possibilities of a better trade-off to reduce the negative impact while maintaining the antiparasitic effect.
Colorectal cancer subtype identification from differential gene expression levels using minimalist deep learning
Authors: Li Shaochuan , Yang Yuning , Wang Xin , Li Jun , Yu Jun , Li Xiangtao , Wong Ka-Chun
Published: April 2022

Background

Cancer molecular subtyping plays a critical role in individualized patient treatment. In previous studies, high-throughput gene expression signature-based methods have been proposed to identify cancer subtypes. Unfortunately, the existing ones suffer from the curse of dimensionality, data sparsity, and computational deficiency.

Methods

To address those problems, we propose a computational framework for colorectal cancer subtyping without any exploitation in model complexity and generality. A supervised learning framework based on deep learning (DeepCSD) is proposed to identify cancer subtypes. Specifically, based on the differentially expressed genes under cancer consensus molecular subtyping, we design a minimalist feed-forward neural network to capture the distinct molecular features in different cancer subtypes. To mitigate the overfitting phenomenon of deep learning as much as possible,L1andL2regularization and dropout layers are added.

Results

For demonstrating the effectiveness of DeepCSD, we compared it with other methods including Random Forest (RF), Deep forest (gcForest), support vector machine (SVM), XGBoost, and DeepCC on eight independent colorectal cancer datasets. The results reflect that DeepCSD can achieve superior performance over other algorithms. In addition, gene ontology enrichment and pathology analysis are conducted to reveal novel insights into the cancer subtype identification and characterization mechanisms.

Conclusions

DeepCSD considers all subtype-specific genes as input, which is pathologically necessary for its completeness. At the same time, DeepCSD shows remarkable robustness in handling cross-platform gene expression data, achieving similar performance on both training and test data without significant model overfitting or exploitation of model complexity.
M2HepPrEP: study protocol for a multi-site multi-setting randomized controlled trial of integrated HIV prevention and HCV care for PWID
Authors: Martel-Laferrière Valérie , Feaster Daniel J. , Metsch Lisa R. , Schackman Bruce R. , Loignon Christine , Nosyk Bohdan , Tookes Hansel , Behrends Czarina N. , Arruda Nelson , Adigun Oluleye , Goyer Marie-Eve , Kolber Michael A. , Mary Jean-Francois , Rodriguez Allan E. , Yanez Iveth G. , Pan Yue , Khemiri Rania , Gooden Lauren , Sako Aïssata , Bruneau Julie
Published: April 2022

Background

Opioid use is escalating in North America and comes with a multitude of health consequences, including HIV and hepatitis C virus (HCV) outbreaks among persons who inject drugs (PWID). HIV pre-exposure prophylaxis (PrEP) and HCV treatment regimens have transformative potential to address these co-occurring epidemics. Evaluation of innovative multi-modal approaches, integrating harm reduction, opioid agonist therapy (OAT), PrEP, and HCV treatment is required. The aim of this study is to assess the effectiveness of an on-site integrated care model where delivery of PrEP and HCV treatment for PWID takes places at syringe service programs (SSP) and OAT programs compared with referring PWID to clinical services in the community through a patient navigation model and to examine how structural factors interact with HIV prevention adherence and HCV treatment outcomes.

Methods

The Miami-Montreal Hepatitis C and Pre-Exposure Prophylaxis trial (M2HepPrEP) is an open-label, multi-site, multi-center, randomized, controlled, superiority trial with two parallel treatment arms. A total of 500 persons who injected drugs in the prior 6 months and are eligible for PrEP will be recruited in OAT clinics and SSP in Miami, FL, and Montréal, Québec. Participants will be randomized to either on-site care, with adherence counseling, or referral to off-site clinics assisted by a patient navigator. PrEP will be offered to all participants and HCV treatment to those HCV-infected. Co-primary endpoints will be (1) adherence to pre-exposure prophylaxis medication at 6 months post-randomization and (2) HCV sustained virological response (SVR) 12 weeks post-treatment completion among participants who were randomized within the HCV stratum. Up to 100 participants will be invited to participate in a semi-structured interview regarding perceptions of adherence barriers and facilitators, after their 6-month assessment. A simulation model-based cost-effectiveness analysis will be performed to determine the comparative value of the strategies being evaluated.

Discussion

The results of this study have the potential to demonstrate the effectiveness and cost-effectiveness of offering PrEP and HCV treatment in healthcare venues frequently attended by PWID. Testing the intervention in two urban centers with high disease burden among PWID, but with different healthcare system dynamics, will increase generalizability of findings.

Trial registration

Clinicaltrials.gov NCT03981445. Trial registry name: Integrated HIV Prevention and HCV Care for PWID (M2HepPrEP). Registration date: June 10, 201.
Developing a theoretically informed education programme within the context of a complex implementation strategy in UK primary care: an exemplar from the IMP2ART trial
Authors: McClatchey Kirstie , Marsh Viv , Steed Liz , Holmes Steve , Taylor Stephanie J. C. , Wiener-Ogilvie Sharon , Neal Julia , Last Rhian , Saxon Ann , Pinnock Hilary ,   for the IMP2ART Programme Group
Published: April 2022

Background

IMPlementing IMProved Asthma self-management as RouTine (IMP2ART) is a programme of work developing and evaluating a strategy for implementing supported asthma self-management in UK primary care. The strategy encompasses patient-facing resources, professional education, and organisational approaches to embed supported self-management. This paper reports the development of a theoretically informed interprofessional education programme which aims to raise awareness of and enable healthcare professionals to deliver effective supported self-management.

Methods

Aligned with the Medical Research Council (MRC) Complex Intervention Framework, the multidisciplinary team developed educational content in three phases: (1) developmental phase, identifying educational and behaviour change theory to guide development, in consultation with a professional advisory group; (2) feasibility pilot phase, testing the education using a ‘think-aloud’ method; and (3) pre-pilot phase, delivering the education within the IMP2ART strategy.

Results

The developmental phase identified educational and behaviour change theory and the need to provide two education modules: (1) a team module to raise awareness of supported asthma self-management for the whole team and (2) an individual study module for those who conduct asthma reviews with patients. The feasibility pilot highlighted content and design features in need of refinement and the pre-pilot identified substantial changes to the delivery strategy for the education modules.

Conclusions

A multi-stage development process, aligned with the MRC Framework, contributed to the module design and delivery. Prior explorative work, multi-disciplinary team discussions, and professional advisory group consultation, informed the initial development, and in-practice testing and pre-pilot stages enabled refinement. In our experience, there were important benefits of working together as an educationalist/researcher team. The education programme, a core component of the implementation strategy, is now being tested in the IMP2ART UK-wide cluster randomised controlled trial.
Effects of Jianpi Lishi Jiedu granules on colorectal adenoma patients after endoscopic treatment: study protocol for a randomized, double-blinded, placebo-controlled clinical trial
Authors: Wu Hao , Huang Yuzhen , Yang Lu , Su Kunhan , Tian Shuo , Chen Xin , Li Siyu , Liu Wanli
Published: April 2022

Background

Colorectal adenomas (CRAs) are precancerous lesions of the large intestine presenting as colorectal polyps. At present, the conventional treatment methods for CRA mainly include high-frequency electrocoagulation and electroexcision, biopsy forceps polypectomy, cauterization by laser and microwave, and other endoscopic interventions. The principal advantages conferred by these treatment strategies include less trauma, quick postoperative recovery, and simplicity to perform. However, the higher recurrence rates and insignificant improvement of postoperative symptoms after endoscopic surgery are considerable drawbacks to this approach. Besides, there is currently no effective pharmacotherapy to prevent the recurrence of CRA. Jianpi Lishi Jiedu (JLJ) granules are a form of traditional Chinese medicine (TCM) used to manage postoperative patients with CRA, which has shown a certain degree of efficacy in clinical practice. However, its effectiveness and safety profile have not been convincingly evaluated. The purpose of this study is to evaluate the clinical efficacy and safety profile of JLJ granules in the management of postoperative patients with CRA and to observe the recurrence rate of adenoma in these patients.

Methods

A randomized, double-blind, and placebo-controlled clinical trial is performed in this study. A total of 80 postoperative patients with CRA will be randomly classified into the Jianpi Lishi Jiedu granules group or the placebo control group. Patients in both groups shall receive 3 months of intervention, after which medical follow-up and safety evaluation will be performed for all of the patients. The primary outcome is the recurrence rate of adenomas within 12 months. The secondary outcomes are the cardinal TCM symptom scores, minor TCM symptom scores, Bristol Stool Scale, efficacy of TCM symptoms, safety indicators, and blinding assessment.

Discussion

In this study, the impact on the recurrence of adenomas and the efficacy and safety of JLJ granules in terms of improving the clinical symptoms of postoperative patients with CRA will be evaluated.

Trial registration

Trial registration Chinese Clinical Trial Registry ChiCTR 2100044297. Registered on March 16, 2021
Efficacy and safety of scopolamine compared to placebo in individuals with bipolar disorder who are experiencing a depressive episode (SCOPE-BD): study protocol for a randomised double-blind placebo-controlled trial
Authors: Miravalles Cerena , Kane Ruán , McMahon Eimear , McDonald Colm , Cannon Dara M. , Hallahan Brian
Published: April 2022

Background

Current treatment options for the management of depressive episodes in bipolar disorder are often sub-optimal, with some treatments either noted to be only partially effective or to require long durations of treatment prior to a therapeutic response. Therefore, pharmaco-therapeutic options that reduce depressive symptoms in a more rapid manner might provide a viable therapeutic option for some people. Intravenous (IV) scopolamine, a pan muscarinic antagonist, has been demonstrated in a number of studies to confer a rapid antidepressant effect, albeit no study to date has exclusively evaluated its potential therapeutic effect in a cohort consisting solely of individuals with bipolar disorder.

Methods

Individuals with bipolar disorder who are currently experiencing a depressive episode of at least moderate severity will be included in this study. Eligible participants will undergo a screening and placebo-run in visit and will be randomised at visit 3 to the treatment or placebo group. Participants will receive the three blinded infusions over the course of 2 weeks, with two subsequent follow-up visits, 1 and 3 weeks after the last infusion visit. The total duration of the study will be approximately 6 weeks. Patients will continue their regular treatment regime in addition to study medication. Objective and subjective mood questionnaires, cognitive assessments and other psychometric instruments will be administered and recorded.

Discussion

To our knowledge, this is the first study to investigate the antidepressant effects of IV scopolamine in an exclusively bipolar disorder cohort. Trial findings will contribute to the evidence base regarding the cholinergic hypothesis of mood disorders and specifically might result in an additional safe therapeutic option for the management of depressive episodes in bipolar disorder.

Trial registration

ClinicalTrials.gov NCT04211961. December 26, 2019. EudraCT Number 2017-003112-39
Effect of antisecretory factor, given as a food supplement to adult patients with severe traumatic brain injury (SASAT): protocol for an exploratory randomized double blind placebo-controlled trial
Authors: Cederberg David , Harrington Bradley M. , Vlok Adriaan Johannes , Siesjö Peter
Published: April 2022

Background

Traumatic brain injury (TBI) constitutes a global epidemic. Overall outcome is poor, with mortality ranging from 10 to 70% and significant long-term morbidity. Several experimental reports have claimed effect on traumatic edema, but no clinical trials have shown effect on edema or outcome. Antisecretory factor, an endogenous protein, is commercially available as Salovum®, which is classified as a medical food by the European Union and has shown effect in experimental trauma models and feasibility with signs of effect in 2 pilot case series. The aim of this study is to assess the effect of antisecretory factor in adult patients with severe traumatic brain injury as measured by 30-day mortality, treatment intensity level (TIL), and intracranial pressure (ICP).

Methods/design

This is a single-center, double-blind, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement to adults with severe TBI (GCS < 9), presenting to the trauma unit at Tygerberg University Hospital, Cape Town, South Africa, that are planned for invasive ICP monitoring and neurointensive care, will be screened for eligibility, and assigned to either treatment group (n = 50) or placebo group (n = 50). In both groups, the primary outcome will be 30-day mortality, recorded via hospital charts, follow-up phone calls, and the population registry. Secondary outcomes will be treatment intensity level (TIL), scored from hospital charts, and ICP registered from hospital data monitoring.

Trial registration

ClinicalTrials.gov NCT03339505. Registered on September 17, 2017.

Protocol version 3.0 from November 13, 2020
Quality problems of clinical trials in China: evidence from quality related studies
Authors: Fan Jin , Liu Xiaobo , Li Yuxi , Xia Haisha , Yang Rong , Li Juan , Zhang Yonggang
Published: April 2022

Background

Recently, the quality of clinical trials conducted in China has made considerable progress. However, clinical trials conducted in China still fall below the global average standard. The aim of this systematic review was to assess studies that investigated the quality of clinical trials conducted in China, summarize the issues, and provide suggestions for conducting high-quality clinical trials in China.

Methods

We comprehensively searched studies that investigated the quality of clinical trials conducted in China in the following databases from inception to December 1, 2021: National Knowledge Infrastructure, the Chinese Science and Technology Periodical Database, WanFang Data, China Biology Medicine, PubMed, and Embase. We then analyzed the issues in clinical trial registration, ethics review, implementation, and reporting. SPSS 25.0 software was used for data analysis. The data synthesis was conducted using summary statistics and a narrative format.

Results

A total of 90 studies were analyzed, there were 50 studies with 0–5 citation counts (55.56%), 18 studies with 5–10 citation counts (20%), 9 studies with 10–15 citation counts (10%), and 13 studies with more than 15 citation counts (14.44%). Eight (8.89%) studies were conducted by a supervision department, 38 (42.22%) by organizations with GCP qualification, and 44 (48.89%) by third parties. Additionally, there were some problems in the ethical review process of clinical trials, clinical trial registration process, clinical trial implementation process, and clinical trial reporting process.

Conclusions

The current study shows that the quality problems of clinical trials in China still exist. The reported problems are related to the process of clinical trials, including ethical review, registration, implementation, reporting. Due to the limited quantity and quality of included studies, the conclusions of this study need to be verified by high-quality studies.

Review registration

Not registerated in  PROSPERO.
Effect of Automated Closed-loop ventilation versus convenTional VEntilation on duration and quality of ventilation in critically ill patients (ACTiVE) – study protocol of a randomized clinical trial
Authors: Botta Michela , Tsonas Anissa M. , Sinnige Jante S. , De Bie Ashley J. R. , Bindels Alexander J. G. H. , Ball Lorenzo , Battaglini Denise , Brunetti Iole , Buiteman–Kruizinga Laura A. , van der Heiden Pim L. J. , de Jonge Evert , Mojoli Francesco , Robba Chiara , Schoe Abraham , Paulus Frederique , Pelosi Paolo , Neto Ary Serpa , Horn Janneke , Schultz Marcus J. ,   The ACTiVE collaborative group, Botta Michela , Tsonas Anissa M. , Sinnige Jante S. , De Bie Ashley J. R. , Bindels Alexander J. G. H. , Ball Lorenzo , Battaglini Denise , Brunetti Iole , Buiteman–Kruizinga Laura A. , van der Heiden Pim L. J. , de Jonge Evert , Mojoli Francesco , Robba Chiara , Schoe Abraham , Paulus Frederique , Pelosi Paolo , Neto Ary Serpa , Horn Janneke , Schultz Marcus J.
Published: April 2022

Background

INTELLiVENT–Adaptive Support Ventilation (ASV) is a fully automated closed-loop mode of ventilation for use in critically ill patients. Evidence for benefit of INTELLiVENT–ASV in comparison to ventilation that is not fully automated with regard to duration of ventilation and quality of breathing is largely lacking. We test the hypothesis that INTELLiVENT–ASV shortens time spent on a ventilator and improves the quality of breathing.

Methods

The “Effects of Automated Closed–loop VenTilation versus Conventional Ventilation on Duration and Quality of Ventilation” (ACTiVE) study is an international, multicenter, two-group randomized clinical superiority trial. In total, 1200 intensive care unit (ICU) patients with an anticipated duration of ventilation of > 24 h will be randomly assigned to one of the two ventilation strategies. Investigators screen patients aged 18 years or older at start of invasive ventilation in the ICU. Patients either receive automated ventilation by means of INTELLiVENT–ASV, or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is the number of days free from ventilation and alive at day 28; secondary endpoints are quality of breathing using granular breath-by-breath analysis of ventilation parameters and variables in a time frame of 24 h early after the start of invasive ventilation, duration of ventilation in survivors, ICU and hospital length of stay (LOS), and mortality rates in the ICU and hospital, and at 28 and 90 days.

Discussion

ACTiVE is one of the first randomized clinical trials that is adequately powered to compare the effects of automated closed-loop ventilation versus conventional ventilation on duration of ventilation and quality of breathing in invasively ventilated critically ill patients. The results of ACTiVE will support intensivist in their choices regarding the use of automated ventilation.

Trial registration

ACTiVE is registered in clinicaltrials.gov (study identifier: NCT04593810) on 20 October 2020.