bluuebunny/crossref_metadata_2025 huggingface dataset:
Update of the ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage (ULTRA) trial: statistical analysis plan
Authors: Post René , Germans Menno R. , Coert Bert A. , Rinkel Gabriël J. E. , Vandertop W. Peter , Verbaan Dagmar
Published: February 2020

Background

Recurrent bleeding from an intracranial aneurysm after subarachnoid hemorrhage (SAH) is associated with unfavorable outcome. Recurrent bleeding before aneurysm occlusion can be performed occurs in up to one in five patients and most often happens within the first 6 h after the primary hemorrhage. Reducing the rate of recurrent bleeding could be a major factor in improving clinical outcome after SAH. Tranexamic acid (TXA) reduces the risk of recurrent bleeding but has thus far not been shown to improve functional outcome, probably because of a higher risk of delayed cerebral ischemia (DCI). To reduce the risk of ultraearly recurrent bleeding, TXA should be administered as soon as possible after diagnosis and before transportation to a tertiary care center. If TXA is administered for a short duration (i.e., < 24 h), it may not increase the risk of DCI. The aim of this paper is to present in detail the statistical analysis plan (SAP) of the ULTRA trial (ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage), which is currently enrolling patients and investigating whether ultraearly and short-term TXA treatment in patients with aneurysmal SAH improves clinical outcome at 6 months.

Methods/design

The ULTRA trial is a multicenter, prospective, randomized, open, blinded endpoint, parallel-group trial currently ongoing at 8 tertiary care centers and 16 of their referral centers in the Netherlands. Participants are randomized to standard care or to receive TXA at a loading dose of 1 g, immediately followed by 1 g every 8 h for a maximum of 24 h, in addition to standard care, as soon as SAH is diagnosed. In the TXA group, TXA administration is stopped immediately prior to treatment (coil or clip) of the causative aneurysm. Primary outcome is the modified Rankin Scale (mRS) score at 6 months after SAH, dichotomized into good (mRS 0–3) and poor (mRS 4–6) outcomes, assessed blind to treatment allocation. Secondary outcomes include case fatalities at 30 days and at 6 months and causes of poor clinical outcome. Safety outcomes are recurrent bleeding, DCI, hydrocephalus, per-procedural complications, and other complications such as infections occurring during hospitalization. Data analyses will be according to this prespecified SAP.

Trial registration

Netherlands Trial Register, NTR3272. Registered on 25 January 2012.

ClinicalTrials.gov, NCT02684812. Registered on 17 February 2016.
A prospective double-blinded randomised control trial comparing robotic arm-assisted functionally aligned total knee arthroplasty versus robotic arm-assisted mechanically aligned total knee arthroplasty
Authors: Kayani Babar , Konan Sujith , Tahmassebi Jenni , Oussedik Sam , Moriarty Peter D. , Haddad Fares S.
Published: February 2020

Background

Total knee arthroplasty (TKA) with mechanical alignment (MA) aims to achieve neutral limb alignment in all patients, whereas TKA with functional alignment (FA) aims to restore native, patient-specific anatomy and knee kinematics by manipulating bone resections and fine-tuning implant positioning. The objective of this study is to determine the optimal alignment technique in TKA by comparing patient satisfaction, functional outcomes, implant survivorship, complications, and cost-effectiveness in MA TKA versus FA TKA. Robotic technology will be used to execute the planned implant positioning and limb alignment with high-levels of accuracy in all study patients.

Methods and analysis

This prospective double-blinded randomised control trial will include 100 patients with symptomatic knee osteoarthritis undergoing primary robotic arm-assisted TKA. Following informed consent, patients will be randomised to MA TKA (the control group) or FA TKA (the investigation group) at a ratio of 1:1 using an online random number generator. Blinded observers will review patients at regular intervals for 2 years after surgery to record predefined study outcomes relating to postoperative rehabilitation, clinical progress, functional outcomes, accuracy of implant positioning and limb alignment, gait, implant stability, cost-effectiveness, and complications. A superiority study design will be used to evaluate whether FA TKA provides superior outcomes compared to MA TKA. Primary and secondary objectives will be used to quantify and draw inferences on differences in the efficacy of treatment between the two groups. Intention-to-treat and per-protocol population analysis will be undertaken. The following statistical methods will be employed to analyse the data: descriptive statistics, independentttest, pairedttest, analysis of variance, Fisher exact test, chi-square test, and graphical displays. Ethical approval was obtained from the London-Surrey Research Ethics Committee, UK. The study is sponsored by University College London, UK.

Discussion

This is the first study to describe the use of robotic technology to achieve FA TKA, and the only existing clinical trial comparing robotic MA TKA versus robotic FA TKA. The findings of this study will enable an improved understanding of the optimal alignment technique in TKA for achieving high-levels of patient satisfaction, improving functional outcomes, increasing implant survivorship, improving cost-effectiveness, and reducing complications.

Registration

ClinicalTrials.gov,NCT04092153. Registered on 17 September 2019.
Identification of proteins from the secretory/excretory products (SEPs) of the branchiuran ectoparasite Argulus foliaceus (Linnaeus, 1758) reveals unique secreted proteins amongst haematophagous ecdysozoa
Authors: AmbuAli Aisha , Monaghan Sean J. , McLean Kevin , Inglis Neil F. , Bekaert Michaël , Wehner Stefanie , Bron James E.
Published: February 2020

Background

It is hypothesised that being a blood-feeding ectoparasite, Argulus foliaceus (Linnaeus, 1758), uses similar mechanisms for digestion and host immune evasion to those used by other haematophagous ecdysozoa, including caligid copepods (e.g. sea louse). We recently described and characterised glands associated with the feeding appendages of A. foliaceus using histological techniques. The work described in the present study is the first undertaken with the objective of identifying and partially characterising the components secreted from these glands using a proteomic approach.

Methods

Argulus foliaceus parasites were sampled from the skin of rainbow trout (Oncorhynchus mykiss), from Loch Fad on the Isle of Bute, Scotland, UK. The proteins from A. foliaceus secretory/excretory products (SEPs) were collected from the supernatant of artificial freshwater conditioned with active adult parasites (n = 5–9 per ml; n = 560 total). Proteins within the SEPs were identified and characterised using LC-ESI-MS/MS analysis. Data are available via ProteomeXchange with identifier PXD016226.

Results

Data mining of a protein database translated from an A. foliaceus dataset using ProteinScape allowed identification of 27 predicted protein sequences from the A. foliaceus SEPs, each protein matching the criteria of 2 peptides with at least 4 contiguous amino acids. Nine proteins had no matching sequence through OmicsBox (Blast2GO) analysis searches suggesting that Argulus spp. may additionally have unique proteins present in their SEPs. SignalP 5.0 software, identified 13 proteins with a signal sequence suggestive of signal peptides and supportive of secreted proteins being identified. Notably, the functional characteristics of identified A. foliaceus proteins/domains have also been described from the salivary glands and saliva of other blood-feeding arthropods such as ticks. Identified proteins included: transporters, peroxidases, metalloproteases, proteases and serine protease inhibitors which are known to play roles in parasite immune evasion/induction (e.g. astacin), immunomodulation (e.g. serpin) and digestion (e.g. trypsin).

Conclusions

To our knowledge, the present study represents the first proteomic analysis undertaken for SEPs from any branchiuran fish louse. Here we reveal possible functional roles of A. foliaceus SEPs in digestion and immunomodulation, with a number of protein families shared with other haematophagous ectoparasites. A number of apparently unique secreted proteins were identified compared to other haematophagous ecdysozoa.
Transcriptional changes in Toxoplasma gondii in response to treatment with monensin
Authors: Zhai Bintao , He Jun-Jun , Elsheikha Hany M. , Li Jie-Xi , Zhu Xing-Quan , Yang Xiaoye
Published: February 2020

Background

Infection with the apicomplexan protozoan parasite T. gondii can cause severe and potentially fatal cerebral and ocular disease, especially in immunocompromised individuals. The anticoccidial ionophore drug monensin has been shown to have anti-Toxoplasma gondii properties. However, the comprehensive molecular mechanisms that underlie the effect of monensin on T. gondii are still largely unknown. We hypothesized that analysis of T. gondii transcriptional changes induced by monensin treatment can reveal new aspects of the mechanism of action of monensin against T. gondii.

Methods

Porcine kidney (PK)-15 cells were infected with tachyzoites of T. gondii RH strain. Three hours post-infection, PK-15 cells were treated with 0.1 μM monensin, while control cells were treated with medium only. PK-15 cells containing intracellular tachyzoites were harvested at 6 and 24 h post-treatment, and the transcriptomic profiles of T. gondii-infected PK-15 cells were examined using high-throughput RNA sequencing (RNA-seq). Quantitative real-time PCR was used to verify the expression of 15 differentially expressed genes (DEGs) identified by RNA-seq analysis.

Results

A total of 4868 downregulated genes and three upregulated genes were identified in monensin-treated T. gondii, indicating that most of T. gondii genes were suppressed by monensin. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of T. gondii DEGs showed that T. gondii metabolic and cellular pathways were significantly downregulated. Spliceosome, ribosome, and protein processing in endoplasmic reticulum were the top three most significantly enriched pathways out of the 30 highly enriched pathways detected in T. gondii. This result suggests that monensin, via down-regulation of protein biosynthesis in T. gondii, can limit the parasite growth and proliferation.

Conclusions

Our findings provide a comprehensive insight into T. gondii genes and pathways with altered expression following monensin treatment. These data can be further explored to achieve better understanding of the specific mechanism of action of monensin against T. gondii.
The paradox of cancer genes in non-malignant conditions: implications for precision medicine
Authors: Adashek Jacob J. , Kato Shumei , Lippman Scott M. , Kurzrock Razelle
Published: February 2020

Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activatingKRASmutations are discerned in endometriosis and in brain arteriovenous malformations, inactivatingTP53tumor suppressor mutations in rheumatoid arthritis synovium, andAKT,MAPK, andAMPKpathway gene alterations in the brains of Alzheimer’s disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation ofPIK3CAmutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate non-malignant illnesses and/or to prevent the emergence of cancer.
Helicobacter pylori in early childhood and asthma in adolescence
Authors: Melby Kjetil K. , Carlsen Karin L. , Håland Geir , Samdal Helvi H. , Carlsen Kai-Håkon
Published: February 2020

Objective

An inverse effect of Helicobacter pylori (H. pylori) on the occurrence of asthma is debated and early acquisition of H. pylori may be important. We analyzed sera from 197 children from Environment and Childhood Asthma (ECA) study in Oslo for Helicobacter pylori (H. pylori) at 2 and 10 years, and symptoms and signs of asthma at 16 years of age.

Results

While 16.4% of children who were H. pylori negative at 2 and 10 years had current asthma at 16 years, none of the 12 children who were H. pylori positive at 2 years of age had asthma at the age of 16 years, regardless of H. pylori status at 10 years. This trend for less current asthma in children who were H. pylori positive at 2 years compared to persistent or transient negative status at 10 years was not statistically significant, probably due to low number of H. pylori positive children at 2 years of age. Acquisition of H. pylori in school age did not appear to influence the risk of current asthma. Much larger prospective studies are probably required to document whether or not early H. pylori infection may be involved in the risk of asthma development in later childhood.
Paraneoplastic syndrome in undifferentiated embryonic sarcoma of the liver
Authors: Perl Regine Mariette , Häring Almut , Horger Marius Stefan , Pfannenberg Christina , Gatidis Sergios
Published: February 2020

Background

The undifferentiated embryonic sarcoma of the liver (UESL) is a rare, aggressive tumor mainly affecting children. Since UESL has no specific clinical symptoms or imaging characteristics, many cases of UESL are diagnosed late. The paraneoplastic leukemoid reaction (PLR) is a very rare concomitant of oncological patients associated with poor prognosis. This report describes the clinical course of a patient combining these two rare entities and describes the diagnostic challenges and dynamics of paraneoplastic syndrome.

Case presentation

We report a case of UESL in a 46-year-old male who became clinically conspicuous due to pronounced B symptoms. CT and MRI showed a suspicious unifocal liver lesion. As the histological analysis of a tissue sample did not reveal a clear result, an 18F-FDG-PET-CT examination was performed. In addition to a high glucose metabolism of the liver lesion, an increased glucose metabolism in the entire bone marrow was observed. This finding was considered as pronounced paraneoplasia and laparotomy with liver segment resection followed. Immediately after resection of the tumor the paraneoplastic symptoms completely declined and the patient showed no signs of recurrence in the 1-year follow-up.

Conclusions

Although UESL is rare and predominantly affects children, this diagnosis should always be considered for unclear unifocal cystic liver lesions, regardless of the patient’s age, as appropriate treatment has a good prognosis.
Statistical evaluation of growth parameters in biofuel waste as a culture medium for improved production of single cell protein and amino acids by Yarrowia lipolytica
Authors: Jach Monika Elżbieta , Baj Tomasz , Juda Marek , Świder Robert , Mickowska Barbara , Malm Anna
Published: February 2020

Yarrowia lipolytica is an oleaginous yeast species with the ability to grow on a number of substrates types, especially industrial wastes. This paper concerns the statistical optimization of fermentation parameters and media to ensure consistent and improved Y. lipolytica protein production. A strain of Y. lipolytica A-101 was observed to be proficient in producing single cell protein, amino acids, and vitamin B12 while utilizing biofuel waste instead of a complete YPD medium for yeast growth. A fractional fractal design experiment was then applied, and the two fermentation parameters of temperature and pH were recognized to have a significant effect on the protein and amino acid production. Subsequently, the response surface methodology with a three-level complete factorial design was employed to optimize these influential parameters. Therefore, five different measuring systems were utilized to construct a quadratic model and a second-order polynomial equation. Optimal levels of parameters were then obtained by analysis of the model and the numerical optimization method. When the Y. lipolytica A-101 was cultivated at optimized pH (5.0) using biofuel waste as a medium, the protein concentration was increased to 8.28—a 44% enhancement as compared to the original (3.65). This study has thus demonstrated a beneficial way to cultivate Y. lipolytica A-101 on biofuel waste for enhanced production of single cell protein and amino acids for use in human diet and in animal feed.
Commentary to: TDOA versus ATDOA for wide area multilateration system
Authors: Frisch Daniel , Hanebeck Uwe D.
Published: February 2020

The paper (Stefanski and Sadowski, EURASIP J. Wirel. Commun. Netw. 2018, Article 179) introduces a multilateration algorithm for unsynchronized sensor networks. However, a very similar method has been proposed before that is not cited. Furthermore, in the measurement model of Stefanski and Sadowski (EURASIP J. Wirel. Commun. Netw. 2018, Article 179), an incorrect covariance matrix (Eq. (11) in Stefanski and Sadowski (EURASIP J. Wirel. Commun. Netw. 2018, Article 179)) has been used that leads to inferior results. We summarize the context and explain the measurement methodology proposed in Stefanski and Sadowski (EURASIP J. Wirel. Commun. Netw. 2018, Article 179), while referring to the missing citation. Finally, we derive the correct covariance matrix of the measurement error and demonstrate that the covariance matrix proposed in Stefanski and Sadowski (EURASIP J. Wirel. Commun. Netw. 2018, Article 179) is incorrect.
Characterization of two leaf rust-resistant Aegilops tauschii accessions for the synthetic wheat development
Authors: Lee Aro , Trinh Cao Son , Lee Won Je , Kim Minseo , Lee Hyeri , Pathiraja Duleepa , Choi In-Geol , Chung Namhyun , Choi Changhyun , Lee Byung Cheon , Lee Hojoung
Published: February 2020

Aegilops tauschii (Ae. tauschii) is a diploid (2n = 2x = 14) wild grass species, which has been reported as the progenitor of hexaploid wheat (Triticum aestivum) with D-genome. In this study, 68 Ae. tauschii accessions with diverse geographical backgrounds were investigated for their resistance to infection by the leaf rust fungi Puccinia triticina. Two Ae. tauschii accessions that exhibited hyper-resistance to leaf rust at both seedling and adult stages were identified. Utilizing two susceptible Ae. tauschii ecotypes and keumkang, a common Korean wheat cultivar known to be susceptible to leaf rust, as the negative control, further investigations were conducted for understanding the mechanism underlying immunity to leaf rust disease of these two resistant accessions. Resistant accessions displayed the increased β-1,3-glucanase activity to prevent fungal penetration and the better peroxidase activity to cope with leaf rust-induced oxidative stress. Moreover, transcriptional analyses reveal the important role of the LRR receptor-like serine/threonine-protein kinase FLS2 (lrr) to the disease resistance of the two ecotypes. Ae. tauschii is a remarkable genetic source, especially for abiotic and biotic stress resistance genes, as the plant is known for its wide-ranging geographical habitat and adaptability to different environments. This, combined with the fact that Ae. tauschii and wheat share a close evolutionary relationship, is indicative of the immense benefit of using Ae. tauschii as a material for improving the quality of synthetic wheat. Our aim was to identify and evaluate the strongest Ae. tauschii contenders for breeding leaf rust-resistant synthetic wheat.
Single-nucleus RNA-seq identifies Huntington disease astrocyte states
Authors: Al-Dalahmah Osama , Sosunov Alexander A. , Shaik A. , Ofori Kenneth , Liu Yang , Vonsattel Jean Paul , Adorjan Istvan , Menon Vilas , Goldman James E.
Published: February 2020

Huntington Disease (HD) is an inherited movement disorder caused by expanded CAG repeats in the Huntingtin gene. We have used single nucleus RNASeq (snRNASeq) to uncover cellular phenotypes that change in the disease, investigating single cell gene expression in cingulate cortex of patients with HD and comparing the gene expression to that of patients with no neurological disease. In this study, we focused on astrocytes, although we found significant gene expression differences in neurons, oligodendrocytes, and microglia as well. In particular, the gene expression profiles of astrocytes in HD showed multiple signatures, varying in phenotype from cells that had markedly upregulated metallothionein and heat shock genes, but had not completely lost the expression of genes associated with normal protoplasmic astrocytes, to astrocytes that had substantially upregulated glial fibrillary acidic protein (GFAP) and had lost expression of many normal protoplasmic astrocyte genes as well as metallothionein genes. When compared to astrocytes in control samples, astrocyte signatures in HD also showed downregulated expression of a number of genes, including several associated with protoplasmic astrocyte function and lipid synthesis. Thus, HD astrocytes appeared in variable transcriptional phenotypes, and could be divided into several different “states”, defined by patterns of gene expression. Ultimately, this study begins to fill the knowledge gap of single cell gene expression in HD and provide a more detailed understanding of the variation in changes in gene expression during astrocyte “reactions” to the disease.
Verbal guidance for sit-to-stand support system
Authors: Takeda Mizuki , Hirata Yasuhisa , Weng Yueh-Hsuan , Katayama Takahiro , Mizuta Yasuhide , Koujina Atsushi
Published: February 2020

Artificial intelligence (AI)-based robots have become popular in various fields, thereby increasing the demand for care robots. Such care robots recognize or estimate factors such as human states and then perform actions depending on the estimation results. If the humans cooperating with robots do not understand robot functions well, the task will not be performed appropriately. Additionally, it is possible that the estimation may be incorrect. Robots may make mistakes, and there is a risk that these mistakes may not be understood by humans. In such cases, robots are not useful, and this may hinder the cooperation between humans and robots. There are several ways to deal with this issue including improving estimation and information representation. We can know what is important to design care robots by analyzing the influence of factors including accurate estimation and contents and timing of information representation. We developed a robot for analysis that can support a human during standing, by raising its armrest. The developed robot raises its armrest when the user leans on it. In the nursing-care field, verbal communication is important. Hence, we also adopt a verbal guidance for information representation. Verbal guidance to encourage a user to stand up and countdown timer representations are adopted. Initially, an experiment is conducted to validate the usability of the system that acts according to considerably accurate estimations. The experimental results show that system without verbal guidance causes anxiety to humans and the system becomes not useful, even if the human state is detected accurately. Furthermore, we determine the appropriate content and timing of verbal guidance based on the results. Subsequently, we conduct an experiment to confirm that the proposed method is applicable under imperfect estimations.
Chlorhexidine locking device for central line infection prevention in ICU patients: protocol for an open-label pilot and feasibility randomized controlled trial
Authors: Zamir Nasim , Pook Makena , McDonald Ellen , Fox-Robichaud Alison E.
Published: February 2020

Background

Critically ill patients in the intensive care unit (ICU) are at risk for central line-associated bloodstream infection (CLABSI) with an incidence up to 6.9 per 1000 catheter days. CLABSI has a significant attributable mortality and increases in-hospital length of stay, readmissions, and costs. Chlorhexidine gluconate (CHG), a broad-spectrum biocide, has been shown to effectively reduce infections including CLABSI; however, few trials have utilized CHG for prevention of central line infections. Our preclinical work has demonstrated a device that diffuses CHG into the intravenous lock solution of central venous catheters and decreases bacterial growth on the catheter lumen. We designed a clinical trial to test the feasibility of using a CHG device in an ICU patient population.

Methods

The proposed pilot trial will be a single centre, open-label, two-arm, parallel group feasibility randomized controlled trial (RCT). Participants will have a central line in situ and will be enrolled within 72 h of admittance to 3 ICUs at a single academic hospital. Exclusion criteria will include suspected infection, chronic indwelling catheters, and CHG allergy. Informed consent will be obtained from eligible participants or their substitute decision maker prior to randomization. Participants will be randomized to receive either usual care or the CHG locking device. Blood cultures will be drawn from all participants every 48 h. The primary objective of this study will be to determine the feasibility of using this protocol to conduct a larger trial. Feasibility will be assessed through the following outcomes: (1) consent rate, (2) recruitment rate, (3) protocol adherence, and (4) comfort level with the device. The secondary objective of this study will be to establish the preliminary efficacy of the device.

Discussion

This study will be the first human RCT to investigate a CHG locking device for the prevention of central line infections. Findings from this trial will inform the feasibility of conducting a large RCT and provide preliminary data on the efficacy of a CHG locking device.

Trial registration

ClinicalTrials.gov, NCT03309137, registered on October 13, 2017.
Examining the influence of native and non-native English-speaking teachers on Korean EFL writing
Authors: Schenck Andrew
Published: February 2020

Both Native English-Speaking Teachers (NESTs) and Non-Native English-Speaking Teachers (NNESTs) may have advantages as writing instructors, yet little is known about how they actually influence writing in EFL contexts like South Korea. To address this issue, 76 high proficiency Korean EFL university students from the International Corpus Network of Asian Learners of English (ICNALE) were separated into a group that received extensive native English speaker instruction (n = 57) and a group that did not (n = 19) using a self-survey. Analysis of essay content revealed that words used by Korean EFL writers with more NEST instruction are similar in difficulty and variety to native English writers. Concerning style, Korean EFL learners with more NEST instruction used stances to evaluate, validate, and state personal opinions, while learners with less NEST instruction used speech formulas and more unbiased logical arguments. Regarding grammar, Korean EFL learners with extensive NEST instruction used more sophisticated vocabulary, word forms, and verb tenses to create a novel argument using personal experience, whereas Korean EFL learners with low NEST instruction tended to use formulaic and logical arguments with more accuracy. Overall, results suggest that NEST instruction in Korea promotes more creativity and sophistication in composition, while NNEST instruction encourages more accurate use of language. In accordance with the findings, curricula or teacher training may be developed to ensure that each type of instruction shares the strengths of its counterpart.
Does time to loss to follow-up differ among adult tuberculosis patients initiated on tuberculosis treatment and care between general hospital and health centers? A retrospective cohort study
Authors: Shaweno Tamrat , Getnet Masrie , Fikru Chaltu
Published: February 2020

Background

Patients’ loss to follow-up (LTFU) from tuberculosis treatment and care is a growing worry in Ethiopia. But, available information is inadequate in assessing the time to tuberculosis patient loss to follow-up difference between health centers and a general hospital in Ethiopia. We aimed to assess time to LTFU difference between health centers and a general hospital in rural Ethiopia.

Methods

We conducted a retrospective cohort study from September 2008 to August 2015 and collected data from September 1 to October 02, 2016. A total of 1341 TB patients with known treatment outcomes were included into the study. Log rank test was used to compare the difference in time to TB patient loss to follow-up between health centers and a general hospital, whereas Cox proportional hazard model was used to assess factors associated with time to loss to follow-up in both settings.

Results

We reviewed a total of 1341 patient records, and the overall follow-up time was 3074.7 and 3974 person months of observation (PMOs) for TB patients followed at health centers and a general hospital, respectively. The incidence of loss to follow-up rate was 27.3 per 1000 PMOs and 9.6 per 1000 PMOs, at health centers and a general hospital, respectively. From the overall loss to follow-ups that occurred, 55 (65.5%) and 33 (86.8%) of LTFUs occurred during the intensive phase and grew to 78 (92.9%) and 38 (100%) at health center and a general hospital, respectively, at the end of 6-month observation period. Older age (AOR = 1.7, 95%CI, 1.2–2.5, P < 0.001), being a rural resident (AHR = 2.7, 95%CI, 1.6–4.6), HIV reactive (AHR = 2.2, 95%CI, 1.5–3.2), following treatment and care in health center (AHR = 3.38, 95%CI, 2.06–5.53), and living at more than 10 km away from the health facility (AHR = 3.4, 95%CI, 2.1–5.7) were predictors for time to loss to follow-up among TB patients on treatment and care.

Conclusion

Time to TB patient loss to follow-up between health centers and a general hospital was significant. Loss to follow-up was high in patients with older age, rural residence, sero positive for HIV, living further from the health facilities, and following treatment and care at health centers. Strengthening the DOTs program with special emphasis on health centers is highly recommended.
Development and content validation of two new patient-reported outcome measures for endometriosis: the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS)
Authors: Gater Adam , Taylor Fiona , Seitz Christian , Gerlinger Christoph , Wichmann Kamonthip , Haberland Claudia
Published: February 2020

Background

Endometriosis is a common, chronic, impactful condition in women of reproductive age. In the absence of established sensitive and specific biomarkers, disease severity is determined by patient-reported symptoms and impacts. This article details the development of two new patient-reported outcome (PRO) measures designed to assess efficacy endpoints in clinical studies: The Endometriosis Symptom Diary (ESD) and the Endometriosis Impact Scale (EIS).

Methods

The ESD and EIS were developed according to best practice and scientific standards (including the Food and Drug Administration (FDA) PRO Guidance) and with extensive input from women with surgically-confirmed endometriosis. Research included: a review of published qualitative literature; concept elicitation interviews in the US, Germany and France (n = 45) to explore the experiences of women with endometriosis and to inform ESD and EIS development; and cognitive interviews in the US and Germany (n = 31) to assess relevance and understanding of the ESD and EIS and usability of administration using an electronic handheld device. The FDA and the European Medicines Agency (EMA) as well as PRO and clinical experts were consulted throughout the process.

Results

Pelvic pain was identified as the most frequent, severe and bothersome symptom for women with endometriosis. Pain was reported to be greatest during menstruation (dysmenorrhea) and during or after sexual intercourse (dyspareunia). Pain resulted in significant impairments in physical activities, work/study, social/leisure activities, household activities and sexual functioning. All women highlighted the emotional impact of endometriosis. Descriptions of pain and associated impacts were largely consistent across participants from the US and Europe, with the most notable differences being the words used to describe the location of pain (e.g., ‘pelvis’ vs. ‘abdomen’). Testing during cognitive interviews indicated that the ESD and EIS were well understood and consistently interpreted. Furthermore, all participants found the ePRO devices easy to use and no issues regarding visual presentation, selection of responses or navigation were identified.

Conclusions

Evidence from extensive qualitative research supports the content validity of the ESD and EIS as patient-reported measures of the disease-defining symptoms of endometriosis and the associated impact on women’s lives. Future research will seek to establish the measurement properties of the measures.
Aphid’s parasitoid fauna and their trophic associations in the oasis ecosystems of Zibans (Biskra, Algeria)
Authors: Hemidi Widad , Laamari Malik
Published: February 2020

A study on the fauna of aphids’ parasitoids was carried out in the oasis ecosystems of the Ziban in the region of Biskra, Algeria. Eighteen primary parasitoids species belong to 2 subfamilies; Aphidiinae (Hymenoptera: Ichneumonoidea, Braconidae), represented by 17 species and 6 genera (Aphidius, Diaeretiella, Ephedrus, Lysiphlebus, Praon,andBinodoxys) and the subfamily Aphelininae (Hymenoptera: Chalcidoidea, Aphelinidae), represented by only one species of the genusAphelinuswas listed. The parasitoid species were collected and identified in association with 22 species of aphids infesting 29 host plant species belonging to 13 botanical families. A number of 83 tri-trophic plant-aphid-parasitoid associations were presented. The two parasitoid species,Aphidius matricariae(Hal.) andLysiphlebus testaceipes(Cress.), were the most abundant species. The present study dealt only with primary parasitoids, while hyperparasitoids will be presented in another publication.
Compensatory role of C3 convertase on the strain difference for C3 protein expression in FVB/N, C3H/HeN and C57BL/6N mice
Authors: Park Ji Won , Kim Ji Eun , Kang Mi Ju , Choi Hyeon Jun , Bae Su Ji , Hwang Dae Youn
Published: February 2020

To investigate the role of complement C3 (C3) convertase on the strain difference for C3 protein expression in three inbred mice strains, we compared the levels of C2, C3 and C4 mRNA, as well as C3 protein and C3 convertase activity in the serum and liver tissue of FVB/N, C3H/HeN and C57BL/6N mice. The level of mRNA, inactive form (InACF) and active form (ACF) for C3 showed a regular pattern, which they were higher in the FVB/N and C57BL/6N mice than C3H/HeN mice. However, the level of C3b fragments (C3bα and β) derived from C3 protein were constantly maintained in the liver of FVB/N, C3H/HeN and C57BL/6N mice in spite of the strain difference on the transcriptional and translation level of C3. Especially, a reverse pattern of the level of mRNA, InACF and ACF for C3 was observed on the activity level of C3 convertase activity. The highest level of C3 convertase activity was measured in C3H/HeN mice, followed by C57BL/6N and FVB/N mice. In case of C3 convertase components, the level of C2 mRNA was higher in C3H/HeN mice than FVB/N and C57BL/6 N mice, while levels of C4 mRNA were higher in FVB/N and C57BL/6N mice than C3H/HeN mice. The current study results provide the first scientific evidence that C3 convertase may play complementary role to overcome the strain difference on the C3 protein expression in FVB/N, C3H/HeN and C57BL/6N mice.
Molecular and environmental characterization of Noonan syndrome in Morocco reveals a significant association with consanguinity and advanced parental age
Authors: El Bouchikhi Ihssane , Bouguenouch Laila , Moufid Fatima Zohra , Samri Imane , Abdouss Fatima , Melhouf Moulay Abdelilah , Iraqui Houssaini Mohammed , Belhassan Khadija , Atmani Samir , Ouldim Karim
Published: February 2020

Background

Noonan syndrome (NS) is one of the most common RASopathies, with an autosomal dominant inheritance. This disorder is caused by a range of genes belonging to the RAS-MAP kinase (rat sarcoma viral oncogene homolog/mitogen-activated protein kinases) pathway, with PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) being the most involved genetic factor.

The aim of this study is to report PTPN11 mutations found in a cohort of Moroccans with Noonan syndrome, compare the mutation rate with various studies, and statistically assess involvement of prominent risk factors in manifestation of this disorder.

Thirty-one NS patients were screened for PTPN11 mutations using PCR-Sanger sequencing method. Pathogenic effect prediction, for detected variants, was carried out using PROVEAN, MutationTaster2, and HSF programs. Statistical tests were performed with R software. Chi-square and Fisher’s exact tests were used in percentage comparisons, while Student’s test was used in average comparisons.

Results

We detected five pathogenic mutations, one synonymous variant with a potential altering effect on splicing function, and three novel intronic duplications. PTPN11 mutation rate in our cohort is around 16.13%. Comparison of this rate with the corresponding rates in various populations shows notably significant differences across continents.

Conclusions

Besides genetic factors, the present study suggests involvement of additional environmental factors. Statistical assessment of clinical data confirms particularly the association of NS manifestation with consanguinity and advanced paternal age, and suggests an eventual implication of advanced maternal age as well.
Changes in glomerular filtration rate and clinical course after sequential doses of carboplatin in children with embryonal brain tumors undergoing autologous stem cell transplantation
Authors: Elborai Yasser , Almutereen Mohammad , Maher Ossama M. , Hafez Hanafy , Lee Michelle A. , Lehmann Leslie
Published: February 2020

Background

Treatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n = 15) / atypical teratoid/rhabdoid tumor (AT/RT, n = 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose.

Results

In this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM.

Conclusion

Daily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.
Total anomalous pulmonary venous drainage repair: the effect of anatomical type and pulmonary vein stenosis on outcomes
Authors: Al-Radi Osman O. , Elmahrouk Ahmed , Ismail Mohamed , Helal Abdelmonem , Hamouda Tamer
Published: February 2020

Background

Surgical repair of total anomalous venous drainage (TAPVD) is lifesaving. The operative mortality is reported between 4 and 35%. Anatomical type, obstructed presentation, associated single ventricle, and heterotaxy syndromes are thought to influence short- and long-term outcomes. The effect of simple versus sutureless repair for primary surgery is unclear. This study reports the outcomes of the surgical repair and the effect of these variables in a contemporary setting.

Results

Between 2011 and 2019, all patients undergoing surgical repair for TAPVD were included. Operative mortality, length of hospital stay, and long-term survival were reported. The effect of anatomical type, surgical technique, obstruction, and associated lesions was assessed. Pearson’s test, Wilcoxson’s test, and generalized linear regression with Poisson distribution were used.

Forty-nine patients from two centers underwent TAPVD repair. The operative mortality was 4%. Postoperative pulmonary vein stenosis occurred in three patients, and reoperation was done in one patient. Survival free from reoperation was 98%, 98%, and 90% at 1, 24, and 60 months in the absence of pulmonary vein stenosis. However, all three patients who developed pulmonary vein stenosis died, at 0.5, 2.7, and 6.3 months of follow-up, respectively. We were unable to detect a significant effect of anatomical type, preoperative obstruction, associated single ventricle, or heterodoxy syndrome on operative mortality or long-term freedom from death or reoperation. Patients who presented with obstruction and infracardiac or supracardiac TAPVD had longer hospital stay.

Conclusion

TAPVD repair outcomes are excellent except for patients who develop postoperative pulmonary venous stenosis. Anatomical type, obstructed presentation, associated single ventricle, or heterotaxy are not significant predictors of survival.
Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties: Case Study—Hypromellose (HPMC)
Authors: Zarmpi P. , Flanagan T. , Meehan E. , Mann J. , Fotaki N.
Published: February 2020

Identification of the biopharmaceutical risks of excipients and excipient variability on oral drug performance can be beneficial for the development of robust oral drug formulations. The current study investigated the impact of Hypromellose (HPMC) presence and varying viscosity type, when used as a binder in immediate release formulations, on the apparent solubility of drugs with wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). The role of physiological conditions on the impact of excipients on drug apparent solubility was assessed with the use of pharmacopoeia (compendial) and biorelevant media. Presence of HPMC affected drug solubility according to the physicochemical properties of studied compounds. The possible combined effects of polymer adsorption (drug shielding effect) or the formation of a polymeric viscous layer around drug particles may have retarded drug dissolution leading to reduced apparent solubility of highly soluble and/or highly ionized compounds and were pronounced mainly at early time points. Increase in the apparent solubility of poorly soluble low ionized drugs containing a neutral amine group was observed which may relate to enhanced drug solubilization or reduced drug precipitation. The use of multivariate data analysis confirmed the importance of drug physicochemical properties on the impact of excipients on drug apparent solubility and revealed that changes in HPMC material properties or amount may not be critical for oral drug performance when HPMC is used as a binder. The construction of a roadmap combining drug, excipient, and medium characteristics allowed the identification of the cases where HPMC presence may present risks in oral drug performance and bioavailability.
Elastic turbulence in two-dimensional cross-slot viscoelastic flows
Authors: Canossi D. O. , Mompean G. , Berti S.
Published: February 2020

We report evidence of irregular unsteady flow of two-dimensional polymer solutions in the absence of inertia in cross-slot geometry using numerical simulations of Oldroyd-B model. By exploring the transition to time-dependent flow vs. both the fluid elasticity and the polymer concentration, we find a periodic behaviour close to the instability threshold and more complex flows at larger elasticity, in agreement with experimental findings. For high enough elasticity we obtain dynamics pointing to elastic turbulence, with temporal spectra of velocity fluctuations showing a power-law decay, of exponent between –3 and –2, and probability density functions of velocity fluctuations that weakly deviate from Gaussianity while high non-Gaussian tails characterise those of local accelerations.
In Vitro Impact of FSH Glycosylation Variants on FSH Receptor-stimulated Signal Transduction and Functional Selectivity
Authors: Zariñán Teresa , Butnev Viktor Y , Gutiérrez-Sagal Rubén , Maravillas-Montero José Luis , Martínez-Luis Iván , Mejía-Domínguez Nancy R , Juárez-Vega Guillermo , Bousfield George R , Ulloa-Aguirre Alfredo
Published: February 2020

FSH exists as different glycoforms that differ in glycosylation of the hormone-specific β-subunit. Tetra-glycosylated FSH (FSH24) and hypo-glycosylated FSH (FSH18/21) are the most abundant glycoforms found in humans. Employing distinct readouts in HEK293 cells expressing the FSH receptor, we compared signaling triggered by human pituitary FSH preparations (FSH18/21 and FSH24) as well as by equine FSH (eFSH), and human recombinant FSH (recFSH), each exhibiting distinct glycosylation patterns. The potency in eliciting cAMP production was greater for eFSH than for FSH18/21, FSH24, and recFSH, whereas in the ERK1/2 activation readout, potency was highest for FSH18/21 followed by eFSH, recFSH, and FSH24. In β-arrestin1/2 CRISPR/Cas9 HEK293-KO cells, FSH18/21 exhibited a preference toward β-arrestin-mediated ERK1/2 activation as revealed by a drastic decrease in pERK during the first 15-minute exposure to this glycoform. Exposure of β-arrestin1/2 KO cells to H89 additionally decreased pERK1/2, albeit to a significantly lower extent in response to FSH18/21. Concurrent silencing of β-arrestin and PKA signaling, incompletely suppressed pERK response to FSH glycoforms, suggesting that pathways other than those dependent on Gs-protein and β-arrestins also contribute to FSH-stimulated pERK1/2. All FSH glycoforms stimulated intracellular Ca2+ (iCa2+) accumulation through both influx from Ca2+ channels and release from intracellular stores; however, iCa2+ in response to FSH18/21 depended more on the latter, suggesting differences in mechanisms through which glycoforms promote iCa2+ accumulation. These data indicate that FSH glycosylation plays an important role in defining not only the intensity but also the functional selectivity for the mechanisms leading to activation of distinct signaling cascades.