bluuebunny/crossref_metadata_2025 huggingface dataset:
Inspiratory flow profile and usability of the NEXThaler, a multidose dry powder inhaler, in asthma and COPD
Authors: Chetta Alfredo , Yorgancioglu Arzu , Scuri Mario , Barile Sara , Guastalla Daniele , Dekhuijzen P. N. Richard
Published: February 2021

Background

Inhaler selection is important when managing respiratory conditions; a patient’s inhalation technique should be appropriate for the selected device, and patients should ideally be able to use a device successfully regardless of disease severity. The NEXThaler is a multidose dry-powder inhaler with a breath-actuated mechanism (BAM) and dose counter that activates only following inhalation, so effectively an ‘inhalation counter’. We assessed inspiratory flow through the NEXThaler in two studies and examined whether inhalation triggered the BAM.

Methods

The two studies were open-label, single-arm, and single visit. One study recruited patients with asthma aged ≥ 18 years; the other recruited patients with chronic obstructive pulmonary disease (COPD) aged ≥ 40 years. All patients inhaled twice through a placebo NEXThaler. The inspiratory profile through the device was assessed for each inhalation using acoustic monitoring, with flow at and time to BAM firing, peak inspiratory flow (PIF), and total inhalation time assessed.

Results

A total of 40 patients were enrolled in the asthma study: 20 with controlled asthma and 20 with partly controlled/uncontrolled asthma. All patients were able to trigger the BAM, as evidenced by the inhalation counter activating on closing the device. Mean flow at BAM firing following first inhalation was 35.0 (range 16.3–52.3) L/min; mean PIF was 64.6 (35.0–123.9) L/min. A total of 72 patients were enrolled in the COPD study, with data analysed for 69 (mean forced expiratory volume in 1 s 48.7% predicted [17–92%]). As with the asthma study, all patients, regardless of airflow limitation, were able to trigger the BAM. Mean flow at BAM firing following first inhalation was 41.9 (26.6–57.1) L/min; mean PIF was 68.0 (31.5–125.4) L/min. Device usability was rated highly in both studies, with 5 min sufficient to train the patients, and a click heard shortly after inhalation in all cases (providing feedback on BAM firing).

Conclusions

Inhalation flows triggering the BAM in the NEXThaler were similar between patients with controlled and partly controlled/uncontrolled asthma, and were similar across COPD airflow limitation. All enrolled patients were able to activate the device.
Dual-section versus conventional archwire for en-masse retraction of anterior teeth with direct skeletal anchorage: a finite element analysis
Authors: Hamanaka Ryo , Cantarella Daniele , Lombardo Luca , Karanxha Lorena , Del Fabbro Massimo , Siciliani Giuseppe , Yoshida Noriaki
Published: February 2021

Background

The aim of this study is to compare the biomechanical effects of the conventional 0.019 × 0.025-in stainless steel archwire with the dual-section archwire when en-masse retraction is performed with sliding mechanics and skeletal anchorage.

Methods

Models of maxillary dentition equipped with the 0.019 × 0.025-in archwire and the dual-section archwire, whose anterior portion is 0.021 × 0.025-in and posterior portion is 0.018 × 0.025-in were constructed. Then, long-term tooth movement during en-masse retraction was simulated using the finite element method. Power arms of 8, 10, 12 and 14 mm length were employed to control anterior torque, and retraction forces of 2 N were applied with a direct skeletal anchorage.

Results

For achieving bodily movement of the incisors, power arms longer than 14 mm were required for the 0.019 × 0.025-in archwire, while between 8 and 10 mm for the dual-section archwire. The longer the power arms, the greater the counter-clockwise rotation of the occlusal plane was produced. Frictional resistance generated between the archwire and brackets and tubes on the posterior teeth was smaller than 5% of the retraction force of 2 N.

Conclusions

The use of dual-section archwire might bring some biomechanical advantages as it allows to apply retraction force at a considerable lower height, and with a reduced occlusal plane rotation, compared to the conventional archwire. Clinical studies are needed to confirm the present results.
Essential oils from Syzygium aromaticum and Zingiber officinale, administered alone or in combination with benznidazole, reduce the parasite load in mice orally inoculated with Trypanosoma cruzi II
Authors: Sarto Marcella Paula Mansano , Lucas da Silva Hevillyn Fernanda , de Souza Fernandes Nilma , de Abreu Ana Paula , Zanusso Junior Gerson , de Ornelas Toledo Max Jean
Published: February 2021

Background

Trypanosoma cruzi is the etiological agent of Chagas disease (CD) or American trypanosomiasis, an important public health problem in Latin America. Benznidazole (BZ), a drug available for its treatment, has limited efficacy and significant side effects. Essential oils (EOs) have demonstrated trypanocidal activity and may constitute a therapeutic alternative. Our aim was to evaluate the efficacy of the EOs of clove (CEO - Syzygium aromaticum) and ginger (GEO - Zingiber officinale), administered alone and in combination with BZ, in Swiss mice infected with T. cruzi.

Methods

The animals were inoculated with 10,000 blood trypomastigotes of the Y strain of T. cruzi II by gavage and divided into four groups (n = 12 to 15): 1) untreated control (NT); 2) treated with BZ; 3) treated with CEO or GEO; and 4) treated with BZ + CEO or GEO. The treatments consisted of oral administration of 100 mg/kg/day, from the 5th day after parasite inoculation, for 20 consecutive days. All groups were submitted to fresh blood examination (FBE), blood culture (BC), conventional PCR (cPCR) and real-time PCR (qPCR), before and after immunosuppression with cyclophosphamide.

Results

Clove and ginger EOs, administered alone and in combination with BZ, promoted suppression of parasitemia (p < 0.0001), except for the animals treated with CEO alone, which presented a parasitemia curve similar to NT animals. However, there was a decrease in the BC positivity rate (p < 0.05) and parasite load (< 0.0001) in this group. Treatment with GEO alone, on the other hand, besides promoting a decrease in the BC positivity rate (p < 0.05) and parasite load (p < 0.01), this EO also resulted in a decrease in mortality rate (p < 0.05) of treated mice.

Conclusions

Decreased parasite load, as detected by qPCR, was observed in all treatment groups (BZ, CEO, GEO and BZ + EOs), demonstrating benefits even in the absence of parasitological cure, thus opening perspectives for further studies.
A method to determine a personalized set of online exercises for improving the positive mental health of a caregiver of a chronically ill patient
Authors: Ferré-Bergadà Maria , Valls Aida , Raigal-Aran Laia , Lorca-Cabrera Jael , Albacar-Riobóo Núria , Lluch-Canut Teresa , Ferré-Grau Carme
Published: February 2021

Background

Taking care of chronic or long-term patients at home is an arduous task. Non-professional caregivers suffer the consequences of doing so, especially in terms of their mental health. Performing some simple activities through a mobile phone app may improve their mindset and consequently increase their positivity. However, each caregiver may need support in different aspects of positive mental health. In this paper, a method is defined to calculate the utility of a set of activities for a particular caregiver in order to personalize the intervention plan proposed in the app.

Methods

Based on the caregivers’ answers to a questionnaire, a modular averaging method is used to calculate the personal level of competence in each positive mental health factor. A reward-penalty scoring procedure then assigns an overall impact value to each activity. Finally, the app ranks the activities using this impact value.

Results

The results of this new personalization method are provided based on a pilot test conducted on 111 caregivers. The results indicate that a conjunctive average is appropriate at the first stage and that reward should be greater than penalty in the second stage.

Conclusions

The method presented is able to personalize the intervention plan by determining the best order of carrying out the activities for each caregiver, with the aim of avoiding a high level of deterioration in any factor.
Digi-Do: a digital information tool to support patients with breast cancer before, during, and after start of radiotherapy treatment: an RCT study protocol
Authors: Fristedt Sofi , Smith Frida , Grynne Annika , Browall Maria
Published: February 2021

Background

Radiation Therapy (RT) is a common treatment after breast cancer surgery and a complex process using high energy X-rays to eradicate cancer cells, important in reducing the risk of local recurrence. The high-tech environment and unfamiliar nature of RT can affect the patient’s experience of the treatment. Misconceptions or lack of knowledge about RT processes can increase levels of anxiety and enhance feelings of being unprepared at the beginning of treatment. Moreover, the waiting time is often quite long. The primary aim of this study will be to evaluate whether a digital information tool with VR-technology and preparatory information can decrease distress as well as enhance the self-efficacy and health literacy of patients affected by breast cancer before, during, and after RT. A secondary aim will be to explore whether the digital information tool increase patient flow while maintaining or increasing the quality of care.

Method

The study is a prospective and longitudinal RCT study with an Action Research participatory design approach including mixed-methods data collection, i.e., standardised instruments, qualitative interviews (face-to-face and telephone) with a phenomenological hermeneutical approach, diaries, observations, and time measurements, and scheduled to take place from autumn 2020 to spring 2022. The intervention group (n = 80), will receive standard care and information (oral and written) and the digital information tool; and the control group (n = 80), will receive standard care and information (oral and written). Study recruitment and randomisation will be completed at two centres in the west of Sweden.

Discussion

Research in this area is scarce and, to our knowledge, only few previous studies examine VR as a tool for increasing preparedness for patients with breast cancer about to undergo RT that also includes follow-ups six months after completed treatment. The participatory approach and design will safeguard the possibilities to capture the patient perspective throughout the development process, and the RCT design supports high research quality. Digitalisation brings new possibilities to provide safe, person-centred information that also displays a realistic picture of RT treatment and its contexts. The planned study will generate generalisable knowledge of relevance in similar health care contexts.

Trial registration: ClinicalTrials.gov Identifier: NCT04394325. Registered May 19, 2020. Prospectively registered.
The practice environment’s influence on patient participation in intermediate healthcare services – the perspectives of patients, relatives and healthcare professionals
Authors: Kvæl Linda Aimée Hartford , Bergland Astrid
Published: February 2021

Background

Intermediate care (IC) bridges the clinical pathway of older patients transitioning from the hospital to home. Currently, there is a strong consensus that the practice environment is an important factor in helping older people overcome their limitations and regain function after illness or injury. Regardless of the arising attention related to person-centred care, the practice environment is yet to be recognised as a vital part of care, and a small extent of focus has been given the environmental dimensions of IC services. Thus, more research is required regarding the complex relationships between older people and the practice environment. This study explores the perspectives of older patients, their relatives and healthcare professionals related to the practice environment’s influence on patient participation among older people in the context of intermediate healthcare services.

Methods

Using purposive sampling and theoretical approaches, including frameworks of patient participation, the practices environment and person-centred care, semi-structured interviews were conducted with 15 older patients, 12 relatives and 18 healthcare professionals from three different IC institutions in Norway to discuss their experiences and preferences regarding patient participation. A thematic analysis was used to explore patterns across the interviews.

Results

Three main themes were identified: ‘location and access to physical facilities’, ‘symbolic expression of patients’ and professionals’ possibilities’ and ‘participating in meaningful activities’. The findings show that both the physical and the psychosocial environments influenced older patients’ various types of participation in IC services.

Conclusions

To optimise rehabilitation care for older people, the ward configuration should focus on supportive environments that facilitate patient participation and provide options for the patients and relatives to independently access the facilities, balancing the personal capabilities with the environmental demands. To foster patient participation, the practice environment should thus align with the model of person-centred rehabilitation.
20E-mediated regulation of BmKr-h1 by BmKRP promotes oocyte maturation
Authors: Zhu Zidan , Tong Chunmei , Qiu Binbin , Yang Hongguang , Xu Jiahui , Zheng Sichun , Song Qisheng , Feng Qili , Deng Huimin
Published: February 2021

Background

Krüppel homolog 1 (Kr-h1) is a critical transcription factor for juvenile hormone (JH) signaling, known to play a key role in regulating metamorphosis and adult reproduction in insects. Kr-h1 can also be induced by molting hormone 20-hydroxyecdysone (20E), however, the underlying mechanism of 20E-induced Kr-h1 expression remains unclear. In the present study, we investigated the molecular mechanism of Kr-h1 induction by 20E in the reproductive system of a model lepidopteran insect, Bombyx mori.

Results

Developmental and tissue-specific expression analysis revealed that BmKr-h1 was highly expressed in ovaries during the late pupal and adult stages and the expression was induced by 20E. RNA interference (RNAi)-mediated depletion of BmKr-h1 in female pupae severely repressed the transcription of vitellogenin receptor (VgR), resulting in the reduction in vitellogenin (Vg) deposition in oocytes. BmKr-h1 specifically bound the Kr-h1 binding site (KBS) between − 2818 and − 2805 nt upstream of BmVgR and enhanced the transcription of BmVgR. A 20E cis-regulatory element (CRE) was identified in the promoter of BmKr-h1 and functionally verified using luciferase reporter assay, EMSA and DNA-ChIP. Using pull-down assays, we identified a novel transcription factor B. mori Kr-h1 regulatory protein (BmKRP) that specifically bound the BmKr-h1 CRE and activated its transcription. CRISPR/Cas9-mediated knockout of BmKRP in female pupae suppressed the transcription of BmKr-h1 and BmVgR, resulting in arrested oogenesis.

Conclusion

We identified BmKRP as a new transcription factor mediating 20E regulation of B. mori oogenesis. Our data suggests that induction of BmKRP by 20E regulates BmKr-h1 expression, which in turn induces BmVgR expression to facilitate Vg uptake and oogenesis.
Glycolysis-associated lncRNAs identify a subgroup of cancer patients with poor prognoses and a high-infiltration immune microenvironment
Authors: Ho Kuo-Hao , Huang Tzu-Wen , Shih Chwen-Ming , Lee Yi-Ting , Liu Ann-Jeng , Chen Peng-Hsu , Chen Ku-Chung
Published: February 2021

Background

Long noncoding (lnc)RNAs and glycolysis are both recognized as key regulators of cancers. Some lncRNAs are also reportedly involved in regulating glycolysis metabolism. However, glycolysis-associated lncRNA signatures and their clinical relevance in cancers remain unclear. We investigated the roles of glycolysis-associated lncRNAs in cancers.

Methods

Glycolysis scores and glycolysis-associated lncRNA signatures were established using a single-sample gene set enrichment analysis (GSEA) of The Cancer Genome Atlas pan-cancer data. Consensus clustering assays and genomic classifiers were used to stratify patient subtypes and for validation. Fisher’s exact test was performed to investigate genomic mutations and molecular subtypes. A differentially expressed gene analysis, with GSEA, transcription factor (TF) activity scoring, cellular distributions, and immune cell infiltration, was conducted to explore the functions of glycolysis-associated lncRNAs.

Results

Glycolysis-associated lncRNA signatures across 33 cancer types were generated and used to stratify patients into distinct clusters. Patients in cluster 3 had high glycolysis scores and poor survival, especially in bladder carcinoma, low-grade gliomas, mesotheliomas, pancreatic adenocarcinomas, and uveal melanomas. The clinical significance of lncRNA-defined groups was validated using external datasets and genomic classifiers. Gene mutations, molecular subtypes associated with poor prognoses, TFs, oncogenic signaling such as the epithelial-to-mesenchymal transition (EMT), and high immune cell infiltration demonstrated significant associations with cluster 3 patients. Furthermore, five lncRNAs, namely MIR4435-2HG, AC078846.1, AL157392.3, AP001273.1, and RAD51-AS1, exhibited significant correlations with glycolysis across the five cancers. Except MIR4435-2HG, the lncRNAs were distributed in nuclei. MIR4435-2HG was connected to glycolysis, EMT, and immune infiltrations in cancers.

Conclusions

We identified a subgroup of cancer patients stratified by glycolysis-associated lncRNAs with poor prognoses, high immune infiltration, and EMT activation, thus providing new directions for cancer therapy.
A CTSA One Health Alliance (COHA) survey of clinical trial infrastructure in North American veterinary institutions
Authors: Moore Sarah A. , McCleary-Wheeler Angela , Coates Joan R , Olby Natasha , London Cheryl
Published: February 2021

While a necessary step toward enhancing rigor and reproducibility of veterinary clinical trials conducted on the translational spectrum includes understanding the current state of the field, no broad assessment of existing veterinary clinical trial resources has been previously conducted. Funded by a CTSA One Health Alliance (COHA) pilot award, the goal of this project was to conduct an electronic survey of North American Veterinary Colleges regarding practices in veterinary clinical trial review, approval, conduct, and support in order to identify opportunities to leverage existing resources and develop new ones to enhance the impact of veterinary and translational health research.

A total of 30 institutions were invited to participate in the survey and the survey response rate was 73 %. The most common source of funding noted for veterinary clinical research was industry (33 %); however, respondents reported that only 5 % (3.7–11.0) of studies were FDA-regulated. Respondents indicated that most studies (80 %); conducted at their institution were single site studies. Study review and approval involved the IACUC either solely, or in combination with a hospital review board, at 95.5 % of institutions. Workforce training related to clinical research best practices was variable across institutions.

Opportunities were identified to strengthen infrastructure through harmonization of clinical research review and approval practices. This might naturally lead to expansion of multi-site studies. Based on respondent feedback, future workforce development initiatives might center on training in the specifics of conducting FDA-sponsored research, Good Clinical Practice (GCP), clinical study budget design, grants management, adverse event reporting, study monitoring and use of electronic data capture platforms.
Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism
Authors: Ma Na , Xi Hui , Chen Jing , Peng Ying , Jia Zhengjun , Yang Shuting , Hu Jiancheng , Pang Jialun , Zhang Yanan , Hu Rong , Wang Hua , Liu Jing
Published: February 2021

Background

Emerging studies suggest that low‐coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted.

Methods

A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements.

Results

Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%.

Conclusion

In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.
Airway gene-expression classifiers for respiratory syncytial virus (RSV) disease severity in infants
Authors: Wang Lu , Chu Chin-Yi , McCall Matthew N. , Slaunwhite Christopher , Holden-Wiltse Jeanne , Corbett Anthony , Falsey Ann R. , Topham David J. , Caserta Mary T. , Mariani Thomas J. , Walsh Edward E. , Qiu Xing
Published: February 2021

Background

A substantial number of infants infected with RSV develop severe symptoms requiring hospitalization. We currently lack accurate biomarkers that are associated with severe illness.

Method

We defined airway gene expression profiles based on RNA sequencing from nasal brush samples from 106 full-tem previously healthy RSV infected subjects during acute infection (day 1–10 of illness) and convalescence stage (day 28 of illness). All subjects were assigned a clinical illness severity score (GRSS). Using AIC-based model selection, we built a sparse linear correlate of GRSS based on 41 genes (NGSS1). We also built an alternate model based upon 13 genes associated with severe infection acutely but displaying stable expression over time (NGSS2).

Results

NGSS1 is strongly correlated with the disease severity, demonstrating a naïve correlation (ρ) of ρ = 0.935 and cross-validated correlation of 0.813. As a binary classifier (mild versus severe), NGSS1 correctly classifies disease severity in 89.6% of the subjects following cross-validation. NGSS2 has slightly less, but comparable, accuracy with a cross-validated correlation of 0.741 and classification accuracy of 84.0%.

Conclusion

Airway gene expression patterns, obtained following a minimally-invasive procedure, have potential utility for development of clinically useful biomarkers that correlate with disease severity in primary RSV infection.
Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer
Authors: Liang Li , Liu Mengling , Sun Xun , Yuan Yitao , Peng Ke , Rashid Khalid , Yu Yiyi , Cui Yuehong , Chen Yanjie , Liu Tianshu
Published: February 2021

Background

The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.

Methods

A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.

Results

We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4+ T cell, CD8+ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression.

Conclusions

SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.
Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer
Authors: Chen Jihui , Wang Zhipeng , Gao Shouhong , Wu Kejin , Bai Fang , Zhang Qiqiang , Wang Hongyu , Ye Qin , Xu Fengjing , Sun Hong , Lu Yunshu , Liu Yan
Published: February 2021

Aim

Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen.

Methods

First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer.

Results

The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC50, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC50 values of 0.06 and 0.20 μg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold).

Conclusions

Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.
Genetic characterization of Plasmodium vivax isolates from Pakistan using circumsporozoite protein (pvcsp) and merozoite surface protein-1 (pvmsp-1) genes as genetic markers
Authors: Bibi Zainab , Fatima Anam , Rani Rehana , Maqbool Ayesha , Khan Samea , Naz Shumaila , Waseem Shahid
Published: February 2021

Background

Plasmodium vivax contributes to over 70% malaria burden in Pakistan, but limited data exists on various aspects including genetic diversity of the parasite as compared to other parts of the world. Since the information about the genetic diversity of P. vivax assists to understand the population dynamics of the parasite, the current study was designed to understand population divergence of P. vivax in Pakistan using circumsporozoite protein (pvcsp) and merozoite surface protein-1 (pvmsp-1) genes as molecular markers.

Methods

The PCR for pvcsp and pvmsp-1 genes was carried out for 150 P. vivax isolates, followed by DNA sequencing of 35 and 30, respectively. Genetic diversity and polymorphism were analysed using ChromasPro, ClustalW, MEGA7, DnaSP v.5 and WebLogo programs.

Results

The PCR for pvcsp and pvmsp-1 genes was carried out for 150 P. vivax isolates and resulting the PCR products of 1100 bp for pvcsp and ~ 400 bp for pvmsp-1 genes, respectively. In the central-repeat region (CRR) of pvcsp gene, sequences comprised of four variable repeats of PRMs, out of which GDRADGQPA (PRM1), GDRAAGQPA (PRM2) were more extensively dispersed among the P. vivax isolates. Partial sequences (~ 400 bp) of block 2 of pvmsp-1 gene depicted high level of diversity.

Conclusion

The results revealed the polymorphism and genetic diversity especially at the CRR of pvcsp and block 2 of pvmsp-1 genes, respectively. The base-line data presented here warrants future studies to investigate more into the genetic diversity of P. vivax with large sample size from across the country for better understanding of population dynamics of P. vivax that will help to control malaria at individual and community level.
Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice
Authors: Osei Silas Acheampong , Biney Robert Peter , Obese Ernest , Agbenyeku Mary Atta-Panyi , Attah Isaac Yaw , Ameyaw Elvis Ofori , Boampong Johnson Nyarko
Published: February 2021

Background

Evidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect.

Methods

Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg−1), artesunate (ART: 1, 2, 4, 8, 16 mg kg−1), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg−1) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED50s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Bodyweight and 30-day survival post-treatment were additionally recorded.

Results

ED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg−1, respectively. The Zadd, Zexp, and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Zexp for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss.

Conclusion

Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.
The effect of temperature on the stability of PCSK-9 monoclonal antibody: an experimental study
Authors: Kongmalai Tanawan , Chuanchaiyakul Nalinee , Sripatumtong Chattip , Tansit Tunsuda , Srinoulprasert Yuttana , Klinsukon Nareerak , Thongtang Nuntakorn
Published: February 2021

Background

PCSK9 monoclonal antibody lowers plasma PCSK9 and LDL-cholesterol levels. The manufacturers recommend drug storage at 2–8 °C, and not above 25 °C. This study aimed to investigate drug stability at various temperatures that this drug could be exposed to during medication handling and transportation in tropical countries.

Methods

Alirocumab and evolocumab were tested in 3 study conditions: room temperature (RT), cooler device with cold pack, and freeze-thaw for 9 and 18 h. Heated drugs were used as negative control. Free plasma PCSK9 levels from 9 hyperlipidemia subjects were measured with ELISA.

Results

Average subject age was 49.2 ± 18.4 years. Percent PCSK9 inhibition significantly declined in heated drugs compared to baseline. Average RT during the study period was 30.4 ±2.6 °C. Change in percent PCSK9 inhibition of PCSK9 mAb at RT from baseline was − 5.8 ± 4.4% (P = 0.005) and − 11.0 ± 8.9% (P = 0.006) for alirocumab at 9 h and 18 h, and − 9.7 ± 11.8% (P = 0.04) and − 15.1 ± 14.3% (P = 0.01) for evolocumab at 9 and 18 h, respectively. In contrast, there were no significant changes in percent PCSK9 inhibition from baseline when PCSK9 mAb was stored in a cooler. In freeze-thaw condition, changes in percent PCSK9 inhibition from baseline to 9 and 18 h were − 5.2 ± 2.9% (P = 0.001) and − 2.6 ± 4.9% (P = 0.16) for alirocumab, and − 1.8 ± 4.2% (P = 0.24) and 0.4 ± 6.1% (P = 0.83) for evolocumab.

Conclusion

Proper drug storage according to manufacturer’s recommendation is essential. Drug storage at RT in tropical climate for longer than 9 h significantly decreased drug efficacy; however, storage in a cooler device with cold pack for up to 18 h is safe.
Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles
Authors: Gong Chunai , Yu Xiaoyan , Zhang Wei , Han Lu , Wang Rong , Wang Yujie , Gao Shen , Yuan Yongfang
Published: February 2021

The combination of an immuno-metabolic adjuvant and immune checkpoint inhibitors holds great promise for effective suppression of tumor growth and invasion. In this study, a pH-responsive co-delivery platform was developed for metformin (Met), a known immuno-metabolic modulator, and short interfering RNA (siRNA) targeting fibrinogen-like protein 1 mRNA (siFGL1), using a hybrid biomimetic membrane (from macrophages and cancer cells)-camouflaged poly (lactic-co-glycolic acid) nanoparticles. To improve the endo-lysosomal escape of siRNA for effective cytosolic siRNA delivery, a pH-triggered CO2gas-generating nanoplatform was developed using the guanidine group of Met. It can react reversibly with CO2to form Met-CO2for the pH-dependent capture/release of CO2. The introduction of Met, a conventional anti-diabetic drug, promotes programmed death-ligand 1 (PD-L1) degradation by activating adenosine monophosphate-activated protein kinase, subsequently blocking the inhibitory signals of PD-L1. As a result, siFGL1 delivery by the camouflaged nanoparticles of the hybrid biomimetic membrane can effectively silence the FGL1 gene, promoting T-cell-mediated immune responses and enhancing antitumor immunity. We found that a combination of PD-L1/programmed death 1 signaling blockade and FGL1 gene silencing exhibited high synergistic therapeutic efficacy against breast cancer in vitro and in vivo. Additionally, Met alleviated tumor hypoxia by reducing oxygen consumption and inducing M1-type differentiation of tumor-related macrophages, which improved the tumor immunosuppressive microenvironment. Our results indicate the potential of hybrid biomimetic membrane-camouflaged nanoparticles and combined Met-FGL1 blockade in breast cancer immunotherapy.
Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers
Authors: Nooraei Saghi , Bahrulolum Howra , Hoseini Zakieh Sadat , Katalani Camellia , Hajizade Abbas , Easton Andrew J. , Ahmadian Gholamreza
Published: February 2021

Virus-like particles (VLPs) are virus-derived structures made up of one or more different molecules with the ability to self-assemble, mimicking the form and size of a virus particle but lacking the genetic material so they are not capable of infecting the host cell. Expression and self-assembly of the viral structural proteins can take place in various living or cell-free expression systems after which the viral structures can be assembled and reconstructed. VLPs are gaining in popularity in the field of preventive medicine and to date, a wide range of VLP-based candidate vaccines have been developed for immunization against various infectious agents, the latest of which is the vaccine against SARS-CoV-2, the efficacy of which is being evaluated. VLPs are highly immunogenic and are able to elicit both the antibody- and cell-mediated immune responses by pathways different from those elicited by conventional inactivated viral vaccines. However, there are still many challenges to this surface display system that need to be addressed in the future. VLPs that are classified as subunit vaccines are subdivided into enveloped and non- enveloped subtypes both of which are discussed in this review article. VLPs have also recently received attention for their successful applications in targeted drug delivery and for use in gene therapy. The development of more effective and targeted forms of VLP by modification of the surface of the particles in such a way that they can be introduced into specific cells or tissues or increase their half-life in the host is likely to expand their use in the future. Recent advances in the production and fabrication of VLPs including the exploration of different types of expression systems for their development, as well as their applications as vaccines in the prevention of infectious diseases and cancers resulting from their interaction with, and mechanism of activation of, the humoral and cellular immune systems are discussed in this review.
Health-related quality of life and self-reported cognitive function in patients with delayed neurocognitive recovery after radical prostatectomy: a prospective follow-up study
Authors: Kahl Ursula , Callsen Sarah , Beck Stefanie , Pinnschmidt Hans , von Breunig Franziska , Haese Alexander , Graefen Markus , Zöllner Christian , Fischer Marlene
Published: February 2021

Background

Delayed neurocognitive recovery (DNCR) is a common and serious complication after radical prostatectomy. We hypothesized that patients with DNCR in the early postoperative period would report reduced health-related quality of life (HRQoL) and more cognitive failures 12 months after surgery, compared with patients without DNCR.

Methods

We performed a 12-month follow-up on 367 patients who had been enrolled in a prospective observational trial to study the incidence of DNCR after radical prostatectomy. Patients were screened for preoperative cognitive impairment and depression. We defined DNCR as a decline in cognitive function between days 3 and 5 after surgery, compared with baseline assessments. We evaluated HRQoL and cognitive failures 12 months after surgery with the 36-item Short Form Health Survey and the Cognitive Failures Questionnaire. General linear models were used to analyze associations of DNCR with HRQoL and cognitive failures.

Results

Delayed neurocognitive recovery in the early postoperative period was significantly associated with self-reported cognitive failures (B for no DNCR =  − 0.411 [95% CI: − 0.798;0.024], p = 0.038), but not with physical (B = 0.082 [95% CI: − 0.021;0.186], p = 0.118) or mental HRQoL (B =  − 0.044 [95% CI: − 0.149;0.062], p = 0.417) 12 months after surgery. Preoperative depression screening scores were significantly associated with self-reported cognitive failures and both physical and mental HRQoL 12 months after surgery.

Conclusions

Delayed neurocognitive recovery in the early period after radical prostatectomy has a long-term impact on patients’ daily lives by impairing memory, attention, action, and perception. Therefore, prevention of DNCR must be a priority for physicians and researchers. Consequent preoperative screening for depressive symptoms may facilitate early psycho-oncological intervention to improve postoperative HRQoL.

Trials registrationDRKS00010014, date of registration: 21.03.2016, retrospectively registered.
On the way home: a BCI-FES hand therapy self-managed by sub-acute SCI participants and their caregivers: a usability study
Authors: Zulauf-Czaja Anna , Al-Taleb Manaf K. H. , Purcell Mariel , Petric-Gray Nina , Cloughley Jennifer , Vuckovic Aleksandra
Published: February 2021

Background

Regaining hand function is the top priority for people with tetraplegia, however access to specialised therapy outwith clinics is limited. Here we present a system for hand therapy based on brain-computer interface (BCI) which uses a consumer grade electroencephalography (EEG) device combined with functional electrical stimulation (FES), and evaluate its usability among occupational therapists (OTs) and people with spinal cord injury (SCI) and their family members.

Methods

Users: Eight people with sub-acute SCI (6 M, 2F, age 55.4 ± 15.6) and their caregivers (3 M, 5F, age 45.3 ± 14.3); four OTs (4F, age 42.3 ± 9.8). User Activity: Researchers trained OTs; OTs subsequently taught caregivers to set up the system for the people with SCI to perform hand therapy. Hand therapy consisted of attempted movement (AM) of one hand to lower the power of EEG sensory-motor rhythm in the 8-12 Hz band and thereby activate FES which induced wrist flexion and extension. Technology: Consumer grade wearable EEG, multichannel FES, custom made BCI application. Location: Research space within hospital. Evaluation: donning times, BCI accuracy, BCI and FES parameter repeatability, questionnaires, focus groups and interviews.

Results

Effectiveness: The BCI accuracy was 70–90%. Efficiency: Median donning times decreased from 40.5 min for initial session to 27 min during last training session (N = 7), dropping to 14 min on the last self-managed session (N = 3). BCI and FES parameters were stable from session to session. Satisfaction: Mean satisfaction with the system among SCI users and caregivers was 3.68 ± 0.81 (max 5) as measured by QUEST questionnaire. Main facilitators for implementing BCI-FES technology were “seeing hand moving”, “doing something useful for the loved ones”, good level of computer literacy (people with SCI and caregivers), “active engagement in therapy” (OT), while main barriers were technical complexity of setup (all groups) and “lack of clinical evidence” (OT).

Conclusion

BCI-FES has potential to be used as at home hand therapy by people with SCI or stroke, provided it is easy to use and support is provided. Transfer of knowledge of operating BCI is possible from researchers to therapists to users and caregivers.

Trial registration Registered with NHS GG&C on December 6th 2017; clinicaltrials.gov reference number NCT03257982, url: https://clinicaltrials.gov/ct2/show/NCT03257982.
The occurrence rate and clinical application of Osteo-line on the femur neck
Authors: Zou Mingchen , Wu Haotian , Yao Shuangquan , Ren Dong , Liu Song , Liu Yueju , Song Zhaohui
Published: February 2021

Background

This study was done to observe the incidence of Osteo-line on the femur neck and to explore the clinical application of Osteo-line in osteotomy.

Methods

Eighty-nine adult femur specimens were selected to observe the incidence of Osteo-line on the femur neck. From August 2015 to January 2019, a total of 278 patients who completed unilateral hip arthroplasty at the Third Hospital of Hebei Medical University were retrospectively included. Patients who accepted osteotomy via Osteo-line on the femur neck were defined as the experimental group (n = 139), and patients who accepted osteotomy via traditional method (The femoral distance 1.5 cm above the trochanter was retained for osteotomy by visual inspection.) were defined as the control group (n = 139). According to the postoperative pelvic X-ray, Photoshop was used to evaluate the leg length discrepancy (LLD) by the CFR-T-LT method.

Results

Among the 89 specimens, the incidence of anterior Osteo-line was 75.28%, and the incidence of posterior Osteo-line was 100%. According to the clinical application results, the incidence of anterior Osteo-line on the femur neck was 80%, and the incidence of posterior Osteo-line was 100%. The Osteo-line was clearer than those on the femoral specimens. Twenty-six cases had LLD greater than 1 cm (9.29%), including 2 cases in the experimental group and 24 cases in the control group. The average postoperative LLD in the experimental group (0.19 ± 0.38 mm) was significantly shorter than in the control group (0.54 ± 0.51 mm)(P = 0.005).

Conclusion

The incidence of Osteo-line on the femur neck was high, and patients who accepted osteotomy via Osteo-line on the femur neck can achieve shorter postoperative LLD than the control group.
Inter-rater variability of three-dimensional fracture reduction planning according to the educational background
Authors: Zindel Christoph , Fürnstahl Philipp , Hoch Armando , Götschi Tobias , Schweizer Andreas , Nagy Ladislav , Roner Simon
Published: February 2021

Background

Computer-assisted three-dimensional (3D) planning is increasingly delegated to biomedical engineers. So far, the described fracture reduction approaches rely strongly on the performance of the users. The goal of our study was to analyze the influence of the two different professional backgrounds (technical and medical) and skill levels regarding the reliability of the proposed planning method. Finally, a new fragment displacement measurement method was introduced due to the lack of consistent methods in the literature.

Methods

3D bone models of 20 distal radius fractures were presented to nine raters with different educational backgrounds (medical and technical) and various levels of experience in 3D operation planning (0 to 10 years) and clinical experience (1.5 to 24 years). Each rater was asked to perform the fracture reduction on 3D planning software.

Results

No difference was demonstrated in reduction accuracy regarding rotational (p= 1.000) and translational (p= 0.263) misalignment of the fragments between biomedical engineers and senior orthopedic residents. However, a significantly more accurate planning was performed in these two groups compared with junior orthopedic residents with less clinical experience and no 3D planning experience (p< 0.05).

Conclusion

Experience in 3D operation planning and clinical experience are relevant factors to plan an intra-articular fragment reduction of the distal radius. However, no difference was observed regarding the educational background (medical vs. technical) between biomedical engineers and senior orthopedic residents. Therefore, our results support the further development of computer-assisted surgery planning by biomedical engineers. Additionally, the introduced fragment displacement measure proves to be a feasible and reliable method.

Level of Evidence

Diagnostic Level II