bluuebunny/crossref_metadata_2025 huggingface dataset:
Views, knowledge, and practices of hospital pharmacists about using clinical pharmacokinetics to optimize pharmaceutical care services: a cross-sectional study
Authors: Shawahna Ramzi , Shraim Naser , Aqel Rafeef
Published: March 2022

Background

Pharmacokinetics (PK) is often used to optimize individualized dosing regimens of some drugs. This study was conducted to determine views, knowledge, and practices of hospital pharmacists in Palestine about using clinical PK to optimize pharmaceutical care services.

Method

This study was conducted in a cross-sectional design using a questionnaire. The questionnaire collected information about the nature of PK courses taught to hospital pharmacists, importance, relevance, effectiveness, adequacy, and depth of these courses, adequacy of PK skills, implementing PK knowledge/skills in current practice, and barriers limiting the implementation of PK to optimize pharmaceutical care services for hospitalized patients. The hospital pharmacists were visited in their places of work and were asked to complete the questionnaire in privacy. Categorical data were compared using Kruskal-Wallis test or Mann-WhitneyUtests.

Results

The questionnaire was completed by 145 hospital pharmacists. Of the pharmacists, 84 (57.9%) received basic PK courses, 79 (54.5%) were taught integrated PK courses, and 94 (64.8%) agreed that the PK courses were important to their current practice. Similarly, 85 (57.9%) of the pharmacists were not satisfied with the teaching methods and contents of the PK courses. Pharmacists who obtained their degrees from Palestine were less satisfied with the methods of teaching compared to those who obtained their degrees from foreign countries (p-value = 0.006). Only 25 (17.2%) pharmacists reported frequent use of PK knowledge in their current practice. Lack of practical knowledge and continuing education, poor understanding of PK by pharmacists and other healthcare professionals were identified as barriers limiting the implementation of PK in optimizing pharmaceutical care services to hospitalized patients.

Conclusion

The hospital pharmacists were generally not satisfied with the way PK courses were taught and expressed difficulty in implementing PK knowledge and skills to improve pharmaceutical care services to hospitalized patients. Integrating PK topics within other relevant courses and adopting more clinically oriented learning methods could improve understanding and implementing PK knowledge and skills in optimizing pharmaceutical services to hospitalized patients. Further studies are still needed to determine the optimal teaching/learning methods that can improve knowledge and skill acquisitions of pharmacists in the area of PK.
Navigating the care between two distinct cultures: a qualitative study of the experiences of Arabic-speaking immigrants in Norwegian hospitals
Authors: Alkhaled Tariq , Rohde Gudrun , Lie Birgit , Johannessen Berit
Published: March 2022

Background

During the past decades, there has been an increase in the number of immigrants to European and Scandinavian countries. This has challenged the health-care systems, which cater to the needs of patients despite their cultural and linguistic barriers, in these countries. Most studies on this topic have focused on the perspectives of health-care providers in delivering their service. The purpose of this qualitative study was to explore how hospitalized Arabic-speaking patients experienced their interaction with the Norwegian health-care system.

Methods

In-depth interviews with 20 participants and researcher’s participant observation were conducted to explore the idiosyncratic details and ascribed meanings that foreign-born patients attach to their everyday experience of the Norwegian health-care system. Thematic analysis was performed on the transcribed and translated versions of the in-depth interviews.

Results

The findings of this study indicated three interrelated core themes. Firstly, there exist challenges in understanding and being understood because of linguistic and cultural differences of newly migrated patients. Secondly, some patients missed the holistic and direct care available in their home countries. Finally, patients were satisfied with the Norwegian health-care system because of its compassion, care, and respect toward them as well as advanced health-care equipment.

Conclusion

Arabic-speaking patients in Norwegian hospitals experienced long waiting times and linguistic problems. Hence, a better and specialized interpreter service may resolve problems emanating from communication within the system and the subsequent delays in treatment. Compassionate care and the feeling of respect and love is the core strength of the Norwegian system as perceived by the patients.
A method for ultrafast tissue clearing that preserves fluorescence for multimodal and longitudinal brain imaging
Authors: Shan Qing-Hong , Qin Xin-Ya , Zhou Nan , Huang Chuan , Wang Yu , Chen Peng , Zhou Jiang-Ning
Published: March 2022

Background

Tissue-clearing techniques have recently been developed to make tissues transparent for three-dimensional (3D) imaging at different scales, including single-cell resolution. However, current tissue-clearing workflows have several disadvantages, including complex protocols, time-consuming application, and fluorescence quenching. Additionally, they can be used mainly for clearing larger-volume samples, preventing wide and easy applicability in conventional experimental approaches. In this study, we aimed to develop a versatile, fast, and convenient method for clearing thin and semi-thick samples, which can be used for three-dimensional imaging of experimental or even clinical samples.

Results

We developed an alkaline solution (AKS) containing a combination of 2,2′-thiodiethanol (TDE), DMSO, D-sorbitol, and Tris for tissue clearing, as the alkaline environment is suitable for maintaining the fluorescence of most commonly used fluorescence protein GFP and its variants, and tested its clearing effect on samples from mice and human brains. We assessed the clearing speed, the preservation of fluorescence protein and dyes, and the imaging depth and quality. The results showed that AKS treatment rapidly cleared 300-μm-thick brain slices and 1-mm-thick slices from different organs within 5 min and 1 h, respectively. Moreover, AKS was compatible with a variety of fluorescence proteins and dyes. Most importantly, AKS enhanced the fluorescence of YFP, in contrast to the majority of existing tissue-clearing methods which reduce the fluorescence intensity of fluorescent proteins. Using AKS, we performed long-time high-resolution imaging of weak fluorescent protein-labelled tissues, long-distance fibre tracking, larger-scale 3D imaging and cell counting of the entire brain area, neural circuit tracing, 3D neuromorphic reconstruction, and 3D histopathology imaging.

Conclusions

AKS can be used for simple and rapid clearing of samples from mice and human brains and is widely compatible with a variety of fluorescent dyes. Therefore, AKS has great potential to be used as a broad tissue-clearing reagent for biological optical imaging, especially for time-sensitive experiments.
Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients
Authors: Toscano-Guerra Emily , Martínez-Gallo Mónica , Arrese-Muñoz Iria , Giné Anna , Díaz-Troyano Noelia , Gabriel-Medina Pablo , Riveiro-Barciela Mar , Labrador-Horrillo Moisés , Martinez-Valle Fernando , Montalvá Adrián Sánchez , Hernández-González Manuel , Borrell Ricardo Pujol , Rodríguez-Frias Francisco , Ferrer Roser , Thomson Timothy M. , Paciucci Rosanna
Published: March 2022

Background

SARS-CoV-2 infection portends a broad range of outcomes, from a majority of asymptomatic cases to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty, and co-morbidities such as obesity, diabetes, and cardiovascular disease. A precise knowledge of the molecular and biological mechanisms that may explain the association of severe disease with male sex is still lacking. Here, we analyzed the relationship of serum testosterone levels and the immune cell skewing with disease severity in male COVID-19 patients.

Methods

Biochemical and hematological parameters of admission samples in 497 hospitalized male and female COVID-19 patients, analyzed for associations with outcome and sex. Longitudinal (in-hospital course) analyses of a subcohort of 114 male patients were analyzed for associations with outcome. Longitudinal analyses of immune populations by flow cytometry in 24 male patients were studied for associations with outcome.

Results

We have found quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients identified serum testosterone trajectories as the strongest predictor of survival (AUC of ROC = 92.8%, p < 0.0001) in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. In lethal cases, longitudinal determinations of serum luteinizing hormone (LH) and androstenedione levels did not follow physiological feedback patterns. Failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes.

Conclusions

Recovery or failure to reinstate testosterone levels is strongly associated with survival or death, respectively, from COVID-19 in male patients. Our data suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by full recovery in survivors or a peripheral failure in lethal cases. These observations are suggestive of a significant role of testosterone status in the immune responses to COVID-19 and warrant future experimental explorations of mechanistic relationships between testosterone status and SARS-CoV-2 infection outcomes, with potential prophylactic or therapeutic implications.
Integrative analyses of biomarkers and pathways for heart failure
Authors: Fan Shaowei , Hu Yuanhui
Published: March 2022

Background

Heart failure (HF) is the most common potential cause of death, causing a huge health and economic burden all over the world. So far, some impressive progress has been made in the study of pathogenesis. However, the underlying molecular mechanisms leading to this disease remain to be fully elucidated.

Methods

The microarray data sets of GSE76701, GSE21610 and GSE8331 were retrieved from the gene expression comprehensive database (GEO). After merging all microarray data and adjusting batch effects, differentially expressed genes (DEG) were determined. Functional enrichment analysis was performed based on Gene Ontology (GO) resources, Kyoto Encyclopedia of Genes and Genomes (KEGG) resources, gene set enrichment analysis (GSEA), response pathway database and Disease Ontology (DO). Protein protein interaction (PPI) network was constructed using string database. Combined with the above important bioinformatics information, the potential key genes were selected. The comparative toxicological genomics database (CTD) is used to explore the interaction between potential key genes and HF.

Results

We identified 38 patients with heart failure and 16 normal controls. There were 315 DEGs among HF samples, including 278 up-regulated genes and 37 down-regulated genes. Pathway enrichment analysis showed that most DEGs were significantly enriched in BMP signal pathway, transmembrane receptor protein serine/threonine kinase signal pathway, extracellular matrix, basement membrane, glycosaminoglycan binding, sulfur compound binding and so on. Similarly, GSEA enrichment analysis showed that DEGs were mainly enriched in extracellular matrix and extracellular matrix related proteins. BBS9, CHRD, BMP4, MYH6, NPPA and CCL5 are central genes in PPI networks and modules.

Conclusions

The enrichment pathway of DEGs and GO may reveal the molecular mechanism of HF. Among them, target genes EIF1AY, RPS4Y1, USP9Y, KDM5D, DDX3Y, NPPA, HBB, TSIX, LOC28556 and XIST are expected to become new targets for heart failure. Our findings provide potential biomarkers or therapeutic targets for the further study of heart failure and contribute to the development of advanced prediction, diagnosis and treatment strategies.
Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM
Authors: Liu Bao , Ji Qifeng , Cheng Ying , Liu Miao , Zhang Bangle , Mei Qibing , Liu Daozhou , Zhou Siyuan
Published: March 2022

Background

Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM.

Results

Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2.

Conclusion

The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice.

Graphical Abstract
Service utilization patterns and characteristics among clients of integrated supervised consumption sites in Toronto, Canada
Authors: Nassau Tanner , Kolla Gillian , Mason Kate , Hopkins Shaun , Tookey Paula , McLean Elizabeth , Werb Dan , Scheim Ayden
Published: March 2022

Introduction

Supervised consumption services (SCS), intended to reduce morbidity and mortality among people who inject drugs, have been implemented in a variety of delivery models. We describe and compare access to and uptake of co-located and external services among clients accessing harm reduction-embedded (HR-embedded) and community health center-embedded (CHC-embedded) SCS models.

Methods

Cross-sectional baseline data were collected between November 2018 and March 2020 as part of a cohort of people who inject drugs in Toronto, Canada designed to evaluate one HR-embedded and two CHC-embedded SCS. This analysis was restricted to clients who reported accessing these SCS more than once in the previous 6 months. Participants were classified as HR-embedded or CHC-embedded SCS clients based on self-reported usage patterns. Client characteristics, as well as access to onsite services and referral and uptake of external services, were compared by SCS model.

Results

Among 469 SCS clients, 305 (65.0%) primarily used HR-embedded SCS and 164 (35.0%) primarily used CHC-embedded SCS. Compared to clients accessing CHC-embedded SCS, clients accessing HR-embedded SCS were somewhat younger (37.6 vs. 41.4, p < 0.001), more likely to report fentanyl as their primary injected drug (62.6% vs. 42.7%, p < 0.001), and visited SCS more often (49.5% vs. 25.6% ≥ daily, p < 0.001). HR-embedded SCS clients were more likely to access harm reduction services onsite compared to CHC-embedded SCS clients (94.8% vs. 89.6%, p = 0.04), while CHC-embedded SCS clients were more likely to access non-harm reduction services onsite (57.3% vs. 26.6%, p < 0.001). For external services, HR-embedded SCS clients were more likely to receive a referral (p = 0.03) but less likely to report referral uptake (p = 0.009).

Conclusions

Clients accessing HR-embedded and CHC-embedded SCS were largely demographically similar but had different drug and SCS use patterns, with CHC-embedded SCS clients using the site less frequently. While clients of CHC-embedded SCS reported greater access to ancillary health services onsite, external service use remained moderate overall, underscoring the importance of co-location and support for clients with system navigation. Importantly, lack of capacity in services across the system may impact ability of staff to make referrals and/or the ability of clients to take up a referral.
Identification of blood-based key biomarker and immune infiltration in Immunoglobulin A nephropathy by comprehensive bioinformatics analysis and a cohort validation
Authors: Xu Jie , Shen Xiahong , Wei Xing , Ding Jie , Yuan Jiaojiao , Weng Zhen , He Yang
Published: March 2022

Background

To identify the critical genes in the onset and progression of Immunoglobulin A nephropathy (IgAN) and to explore its immune cell infiltration feature.

Methods

Differentially expressed genes (DEGs) were firstly screened from 1 blood-derived dataset GSE73953 and a glomerulus derived dataset GSE93798 through limma analysis, overlap genes omitting and weighted gene correlation network analysis (WGCNA) and further reduced according to expression pattern and correlation with the clinical features: eGFR and proteinuria, followed by external validation using the GSE37460 dataset and an IgAN cohort. In addition, the CIBERSORT tool for immune cell infiltration analysis, ceRNA network construction and Connectivity Map (CMAP) were also performed.

Results

A total of 195 DEGs were found, and among them, 3 upregulated (ORMDL2, NRP1, and COL4A1) and 3 downregulated genes (ST13, HSPA8 and PKP4) are verified to correlate clinically, and finally ORMDL2, NRP1 and COL4A1 were validated in patient cohort and with the ability of IgAN discrimination (highest AUC was COL4A1: 97.14%). The immune cell infiltration results revealed that significant differences could be found on resting memory CD4 T cells, activated NK cells, and M2 macrophages between control and IgAN.

Conclusions

Our results demonstrated here that significantly upregulated DEGs: ORMDL2, NRP1 and COL4A1, could be served as the diagnostic marker for IgAN, and dysregulated immune cell infiltration hinted possible the immune system intervention point in the setting of IgAN.
Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control
Authors: Moyano Ana , Blanch-Lombarte Oscar , Tarancon-Diez Laura , Pedreño-Lopez Nuria , Arenas Miguel , Alvaro Tamara , Casado Concepción , Olivares Isabel , Vera Mar , Rodriguez Carmen , del Romero Jorge , López-Galíndez Cecilio , Ruiz-Mateos Ezequiel , Prado Julia G. , Pernas María
Published: March 2022

Background

Long-Term Non-Progressors (LTNPs) are untreated Human Immunodeficiency virus type 1 (HIV-1) infected individuals able to control disease progression for prolonged periods. However, the LTNPs status is temporary, as viral load increases followed by decreases in CD4 + T-cell counts. Control of HIV-1 infection in LTNPs viremic controllers, have been associated with effective immunodominant HIV-1 Gag-CD8 + T-cell responses restricted by protective HLA-B alleles. Individuals carrying HLA-B*14:02 control HIV-1 infection is related to an immunodominant Env-CD8 + T-cell response. Limited data are available on the contribution of HLA-B*14:02 CD8 + T -cells in LTNPs.

Results

In this study, we performed a virological and immunological detailed analysis of an HLA-B*14:02 LNTP individual that lost viral control (LVC) 27 years after HIV-1 diagnosis. We analysed viral evolution and immune escape in HLA-B*14:02 restricted CD8 + T -cell epitopes and identified viral evolution at the Env-EL9 epitope selecting the L592R mutation. By IFN-γ ELISpot and immune phenotype, we characterized HLA- B*14:02 HIV-1 CD8 + T cell responses targeting, Gag-DA9 and Env-EL9 epitopes before and after LVC. We observed an immunodominant response against the Env-EL9 epitope and a decreased of the CD8 T + cell response over time with LVC. Loss of Env-EL9 responses was concomitant with selecting K588R + L592R mutations at Env-EL9. Finally, we evaluated the impact of Env-EL9 escape mutations on HIV-1 infectivity and Env protein structure. The K588R + L592R escape variant was directly related to HIV-1 increase replicative capacity and stability of Env at the LVC.

Conclusions

These findings support the contribution of immunodominant Env-EL9 CD8 + T-cell responses and the imposition of immune escape variants with higher replicative capacity associated with LVC in this LNTP. These data highlight the importance of Env-EL9 specific-CD8 + T-cell responses restricted by the HLA-B*14:02 and brings new insights into understanding long-term HIV-1 control mediated by Env mediated CD8 + T-cell responses.
Characteristics of lymphocyte subsets and cytokine profiles of patients with COVID-19
Authors: Pan Pengfei , Du Xinxin , Zhou Qilong , Cui Yong , Deng Xiaochun , Liu Chao , Hu Zongjun , Chen Jianguo , Yu Xiangyou , Shi Weihua
Published: March 2022

Background

Abnormalities of lymphocyte subsets and cytokine profiles have been observed in most patients with coronavirus disease (COVID-19). Here, we explore the role of lymphocyte subsets and cytokines on hospital admission in predicting the severity of COVID-19.

Methods

This study included 214 patients with COVID-19 who were treated at Chongqing University Three Gorges Hospital from January 19, 2020 to April 30, 2020. Any mutants were not detected in the studied patients. Patients were divided into non-intensive care unit (ICU) (mild/moderate) group and ICU (severe/critical) group, according to the severity of the disease. Clinical and laboratory data, including peripheral lymphocyte subsets and cytokines, were analyzed and compared. Logistic regression was used to analyze the predictive factors for ICU admission. Receiver operating characteristic (ROC) curves were drawn to evaluate the predictive value of selected indicators for the severity of COVID-19.

Results

Of the 214 patients enrolled, 161 were non-ICU patients and 53 were ICU patients. Lymphopenia was observed in nearly all of ICU patients (96.2%) and 84.5% of non-ICU patients on hospital admission. The absolute number of lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and natural killer (NK) cells were lower in ICU group (659.00 × 106/L, 417.00 × 106/L, 261.00 × 106/L, 140.00 × 106/L, 109.00 × 106/L, 102.00 × 106/L, respectively) than in non-ICU group (1063.00 × 109/L, 717.00 × 106/L, 432.00 × 106/L, 271.00 × 106/L, 133.00 × 106/L, 143.00 × 106/L, respectively). Interleukin (IL)-6 was significantly higher in ICU patients than in non-ICU patients (18.08 pg/mL vs. 3.13 pg/mL, P < 0.001). Multivariate logistic regression analysis showed that age (odds ratio: 1.067 [1.034–1.101]), diabetes mellitus (odds ratio: 9.154 [2.710–30.926]), CD3+ T cells (odds ratio: 0.996 [0.994–0.997]), and IL-6 (odds ratio: 1.006 [1.000–1.013]) were independent predictors for the development of severe disease. ROC curve analysis showed that the area under the ROC curve (AUC) of CD3+ T cells and IL-6 was 0.806 (0.737–0.874) and 0.785 (0.705–0.864), respectively, and the cutoff values were 510.50 × 106/L (sensitivity, 71.7%; specificity, 79.5%) and 6.58 pg/mL (77.4%, 74.5%), respectively. There were no statistical differences among all tested indicators of lymphocyte subsets and cytokines between severe group (n = 38) and critical group (n = 15) on hospital admission or ICU admission, respectively.

Conclusions

The levels of lymphocyte subsets decreased and the level of IL-6 increased significantly in ICU COVID-19 patients compared with non-ICU COVID-19 patients. Therefore, the number of CD3+ T cells and the level of IL-6 on hospital admission may serve as predictive factors for identifying patients with wild-type virus infection who will have severe disease.
Indigenous farmers’ perceptions of problems in the rice field agroecosystems in the upper Baram, Malaysia
Authors: Hollaus Alexander , Schunko Christoph , Weisshaidinger Rainer , Bala Poline , Vogl Christian R.
Published: March 2022

Background

Rice field agroecosystems produce food for more than half of the world’s population and deliver important services supporting farmers’ livelihoods. However, traditional rice field agroecosystems are facing a variety of problems, including pests or markets that are hard to access. This research explored indigenous farmers’ perceptions of the problems, their causes and consequences, and the solutions applied to address them in the rice field agroecosystem. Furthermore, the study investigated how indigenous farmers related these problems to the surrounding landscape elements and to microzones in the fields.

Methods

Data were collected in two villages in the upper Baram, Sarawak using a qualitative approach that included sketch drawings and face-to-face interviews. Forty-three indigenous farmers of the Kenyah, Penan and Sa’ban ethnic groups were interviewed in their rice fields. The sketch drawings were used to identify the perceived landscape elements, while the oral interviews were employed to identify perceived microzones. Furthermore, the interviews elicited the perceived problems in the rice field agroecosystem and their relations to landscape elements and microzones.

Results

The findings identified a total of nine environmental problems, e.g. animal disturbance, six social problems, e.g. difficult to access farm inputs, and eight agricultural technology system problems, e.g. poor soil quality, with some found to be rooted in complex causes and affecting agricultural productivity. While some problems were perceived at field level, microzones were frequently used as sub-field indicators of the problems. The surrounding landscape elements were perceived as both a source of the problems and as a means of avoiding them. To solve the problems, farmers applied preventive and reactive strategies based on traditional knowledge and scientific knowledge, resulting in a hybridisation of knowledge systems.

Conclusions

By including environmental, social, agricultural technology system problems and different spatial scales, this research contributes to addressing issues that can be overlooked when focusing on only one dimension of the problems. These results contribute to a better understanding of how indigenous farmers perceive, cope with and adapt to problems in rice field agroecosystems, which is important for landscape management.
Reduction malarplasty using a simulated surgical guide for asymmetric/prominent zygoma
Authors: Kang Sang-Hoon , Tak Hye-Jin , Kim Hak-Jin , Lee Sang-Hwy
Published: March 2022

Background

The present study introduces a reduction malarplasty using a three-dimensional (3D)-printed surgical guide and evaluates the guide’s technical applicability.

Methods

Twenty malarplasties were performed for 12 subjects with zygomatic asymmetry/prominency using the current method. 3D reconstruction of the craniomaxillofacial region and fine dental occlusion was made with image data from computed tomograpy and dental scanning. A computer-assisted surgical simulation was performed for reduction malarplasty and a surgical guide was designed for later 3D printing. The manufactured surgical guide was introduced to the operation field to guide the surgery; its surgical accuracy was confirmed by comparing five corresponding points from preoperative simulation and postoperative data.

Results

We successfully performed the reduction malarplasty with the surgical guide. The accuracy level of surgery fell to 0.93 mm of total median difference for the corresponding zygoma points of preoperative simulations and postoperative zygoma. The anterior and upper points showed less error level (0.59 and 0.73 mm difference, respectively) than did other points.

Conclusions

We developed a computer-assisted surgical technique using a surgical guide for asymmetrical/prominent zygoma which proved to be simple, practical, and accurate; it is expected to help surgeons perform reduction malarplasty with ease and accuracy.
Efficacy and safety of re-irradiation for locoregional esophageal squamous cell carcinoma recurrence after radiotherapy: a systematic review and meta-analysis
Authors: Lan Kuntian , Chen Jiaohong
Published: March 2022

Background

There is currently no standard treatment for locoregional recurrence of esophageal squamous cell carcinoma (ESCC) previously treated with radiotherapy. This study aimed to assess the efficacy and safety of re-irradiation for ESCC patients with locoregional recurrence.

Methods

The PubMed, EmBase, and Cochrane library databases were systematically searched for eligible studies published before January 2021. The pooled effect estimates were calculated using the random effects model. Subgroup analyses were conducted to assess the treatment effectiveness of re-irradiation based on specific characteristics.

Results

Nine retrospective studies including 573 ESCC patients with locoregional recurrence were selected. The pooled incidences of the 1-year, 2-year, 3-year, and 5-year survival for patients after re-irradiation were 59% (95% confidence interval [CI]: 35–83; P < 0.001), 25% (95% CI: 16–33; P < 0.001), 25% (95% CI: 4–45; P = 0.017), and 15% (95% CI: 2–27; P = 0.024), respectively. The rates of complete response and local re-recurrence after re-irradiation were 54% (95% CI: 21–88; P = 0.001) and 62% (95% CI: 55–70; P < 0.001), respectively. The median overall survival and local failure-free survival for patients after re-irradiation were 13.94 months (95% CI: 4.18–46.51; P < 0.001) and 11.01 months (95% CI: 5.99–20.22; P < 0.001), respectively. Grade ≥ 3 adverse events of esophageal perforation, tracheoesophageal fistula, and radiation pneumonitis were significantly more common after re-irradiation.

Conclusions

This study found that re-irradiation for ESCC patients with locoregional recurrence after previous radiotherapy was feasible. However, patients should be carefully observed in order to treat associated adverse events, including esophageal perforation, tracheoesophageal fistula, and radiation pneumonitis.
Anti-inflammatory effects of anemonin on acute ulcerative colitis via targeted regulation of protein kinase C-θ
Authors: Jiang Lu , Chi Chunhua , Yuan Fang , Lu Meiqi , Hu Dongqing , Wang Lin , Liu Xiaoming
Published: March 2022

Background

Ulcerative colitis (UC) is an inflammatory bowel disease that causes continuous mucosal inflammation. Anemonin is a natural molecule from the Ranunculaceae and Gramineae plants that exerts anti-inflammatory properties. This study aimed to explore the effects and mechanisms of anemonin on UC.

Methods

C57BL/6 mice were administered dextran sulphate sodium (DSS; 3% [w/v]) to establish an animal model of UC. Mice were treated with an intraperitoneal injection of anemonin. Body weight and the disease activity index (DAI) were recorded. Haematoxylin and eosin staining, RT-qPCR, ELISA, and western blotting were performed to evaluate the histopathological changes and tissue inflammation. HT-29 cells were treated with lipopolysaccharide (LPS) and anemonin. Cell inflammation was evaluated using RT-qPCR and western blotting. The target proteins of anemonin were predicted using bioinformatics analysis and confirmed in vitro and in vivo.

Results

Anemonin improved DSS-induced body weight loss, shortened colon length, increased DAI, and induced pathological changes in the colon tissue of mice. Anemonin inhibited DSS-induced colon tissue inflammation as the release of IL-1β, TNF-α, and IL-6 was significantly suppressed. Additionally, anemonin attenuated LPS-induced cytokine production in HT-29 cells. PKC-θ was predicted as a target protein of anemonin. Anemonin did not affect PRKCQ gene transcription, but inhibited its translation. PRKCQ overexpression partially reversed the protective effects of anemonin on HT-29 cells. Adeno-associated virus delivery of the PRKCQ vector significantly reversed the protective effects of anemonin on the mouse colon.

Conclusions

Anemonin has the potential to treat UC. The anti-inflammatory effects of anemonin may be mediated through targeting PKC-θ.
Nationwide comprehensive epidemiological study of rare diseases in Japan using a health insurance claims database
Authors: Ninomiya Kota , Okura Masahiro
Published: March 2022

Background

There are more than 7000 rare diseases, most of which have no specific treatment. Disease profiles, such as prevalence and natural history, among the population of a specific country are essential in determining for which disease to research and develop drugs. In Japan, disease profiles of fewer than 2000 rare diseases, called Nanbyo, have been investigated. However, non-Nanbyo rare diseases remain largely uninvestigated. Accordingly, we revealed the prevalence and natural history of rare diseases among the Japanese population. This cross-disease study is the first to analyze rare-disease epidemiology in Japan with high accuracy, disease coverage, and granularity.

Method

We applied for permission to use the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which covered 99.9% of public health insurance claims from hospitals and 97.9% from clinics as of May 2015. Then, we obtained 10 years of data on the number of patients of approx. 4500 rare diseases, by sex and age. We translated disease names and established correspondences between rare diseases in NDB and those in Orphanet. Accordingly, we compared the prevalence and natural history between them.

Results

About 3000 diseases in NDB are included in Orphanet and other medical databases. The data indicates that even if the Nanbyo systems do not cover a rare disease, its patients survive in many cases. Regarding natural history, genetic diseases tend to be diagnosed later in Japan than in the West. The data shown in this research are available in the Additional file 1 and the website of NanbyoData.

Conclusions

Our research revealed the basic epidemiology and natural history of Japanese patients with some rare diseases using a health insurance claims database. The results imply that the coverage of the present Nanbyo systems is inadequate for rare diseases. Therefore, fundamental reform might be needed to reduce unfairness between rare diseases. Most diseases in Japan follow a tendency of natural history similar to those reported in Orphanet. However, some are detected later, partly because fewer clinical genetic tests are available in Japan than in the West. Finally, we hope that our data and analysis accelerate drug discovery for rare diseases in Japan.
Survival of children with rare structural congenital anomalies: a multi-registry cohort study
Authors: Coi Alessio , Santoro Michele , Pierini Anna , Rankin Judith , Glinianaia Svetlana V. , Tan Joachim , Reid Abigail-Kate , Garne Ester , Loane Maria , Given Joanne , Ballardini Elisa , Cavero-Carbonell Clara , de Walle Hermien E. K. , Gatt Miriam , García-Villodre Laura , Gissler Mika , Jordan Sue , Kiuru-Kuhlefelt Sonja , Kjaer Urhoj Stine , Klungsøyr Kari , Lelong Nathalie , Lutke L. Renée , Neville Amanda J. , Rahshenas Makan , Scanlon Ieuan , Wellesley Diana , Morris Joan K.
Published: March 2022

Background

Congenital anomalies are the leading cause of perinatal, neonatal and infant mortality in developed countries. Large long-term follow-up studies investigating survival beyond the first year of life in children with rare congenital anomalies are costly and sufficiently large standardized cohorts are difficult to obtain due to the rarity of some anomalies. This study aimed to investigate the survival up to 10 years of age of children born with a rare structural congenital anomaly in the period 1995–2014 in Western Europe.

Methods

Live births from thirteen EUROCAT (European network for the epidemiological surveillance of congenital anomalies) population-based registries were linked to mortality records. Survival for 12,685 live births with one of the 31 investigated rare structural congenital anomalies (CAs) was estimated at 1 week, 4 weeks and 1, 5 and 10 years of age within each registry and combined across Europe using random effects meta-analyses. Differences between registries were evaluated for the eight rare CAs with at least 500 live births.

Results

Amongst the investigated CAs, arhinencephaly/holoprosencephaly had the lowest survival at all ages (58.1%, 95% Confidence Interval (CI): 44.3–76.2% at 1 week; 47.4%, CI: 36.4–61.6% at 1 year; 35.6%, CI: 22.2–56.9% at 10 years). Overall, children with rare CAs of the digestive system had the highest survival (> 95% at 1 week, > 84% at 10 years). Most deaths occurred within the first four weeks of life, resulting in a 10-year survival conditional on surviving 4 weeks of over 95% for 17 out of 31 rare CAs. A moderate variability in survival between participating registries was observed for the eight selected rare CAs.

Conclusions

Pooling standardised data across 13 European CA registries and the linkage to mortality data enabled reliable survival estimates to be obtained at five ages up to ten years. Such estimates are useful for clinical practice and parental counselling.
Delineation of dual molecular diagnosis in patients with skeletal deformity
Authors: Liu Lian , Sun Liying , Chen Yujun , Wang Muchuan , Yu Chenxi , Huang Yingzhao , Zhao Sen , Du Huakang , Chen Shaoke , Fan Xin , Tian Wen , Wu Zhihong ,   Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group, Qiu Guixing , Zhang Terry Jianguo , Wu Nan
Published: March 2022

Background

Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities.

Results

From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700).

Conclusions

This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.
Multi-omics analysis dissects the genetic architecture of seed coat content in Brassica napus
Authors: Zhang Yuting , Zhang Hui , Zhao Hu , Xia Yefan , Zheng Xiangbo , Fan Ruyi , Tan Zengdong , Duan Chenhua , Fu Yansong , Li Long , Ye Jiang , Tang Shan , Hu Honghong , Xie Weibo , Yao Xuan , Guo Liang
Published: March 2022

Background

Brassica napus is an important vegetable oil source worldwide. Seed coat content is a complex quantitative trait that negatively correlates with the seed oil content in B. napus.

Results

Here we provide insights into the genetic basis of natural variation of seed coat content by transcriptome-wide association studies (TWAS) and genome-wide association studies (GWAS) using 382 B. napus accessions. By population transcriptomic analysis, we identify more than 700 genes and four gene modules that are significantly associated with seed coat content. We also characterize three reliable quantitative trait loci (QTLs) controlling seed coat content by GWAS. Combining TWAS and correlation networks of seed coat content-related gene modules, we find that BnaC07.CCR-LIKE (CCRL) and BnaTT8s play key roles in the determination of the trait by modulating lignin biosynthesis. By expression GWAS analysis, we identify a regulatory hotspot on chromosome A09, which is involved in controlling seed coat content through BnaC07.CCRL and BnaTT8s. We then predict the downstream genes regulated by BnaTT8s using multi-omics datasets. We further experimentally validate that BnaCCRL and BnaTT8 positively regulate seed coat content and lignin content. BnaCCRL represents a novel identified gene involved in seed coat development. Furthermore, we also predict the key genes regulating carbon allocation between phenylpropane compounds and oil during seed development in B. napus.

Conclusions

This study helps us to better understand the complex machinery of seed coat development and provides a genetic resource for genetic improvement of seed coat content in B. napus breeding.
Developing a core outcome set for assessing clinical safety outcomes of cardiovascular diseases in clinical trials of integrated traditional Chinese medicine and Western medicine: study protocol
Authors: Qiu Ruijin , Zhong Changming , Wan Siqi , Zhang Yao , Wei Xuxu , Li Min , Hu Jiayuan , Chen Shiqi , Zhao Chen , Chen Zhao , Chen Jing , Shang Hongcai
Published: March 2022

Background

Integrative medicine is commonly used in China. Researchers prefer to report efficacy outcomes rather than safety outcomes in clinical trials; thus, evidence regarding safety in integrative medicine is unclear. Developing a core outcome set (COS) for safety outcomes is necessary. In this study, a representative example of the methodology for developing COS to assess safety outcomes of cardiovascular diseases in clinical trials investigating integrated medicine will be developed.

Methods and analysis

Safety information will be extracted from package inserts and through systematic reviews of treatments for cardiovascular diseases (including angina pectoris, myocardial infarction, heart failure, arrhythmia, and hypertension) to develop an extensive list of safety outcomes, which will then be categorized according to whether subjective or objective outcomes. Questionnaires for clinician-reported safety outcomes and patient-reported safety outcomes will be developed. Two rounds of the Delphi survey will then be conducted for different stakeholders (traditional Chinese medicine clinicians and researchers in cardiovascular diseases, Western medicine clinicians and researchers in cardiovascular diseases, integrated medicine clinicians and researchers of cardiovascular diseases, pharmacologists, methodologists of evidence-based medicine, and patients). After round 2 of the Delphi analysis, a face-to-face consensus meeting will be held to determine the final COS for assessing safety outcomes in cardiovascular diseases.

Discussion

A COS for safety outcomes in cardiovascular diseases may improve the consistency of reporting results and will help identify potential bias of selective reporting in the future.

Trial registration

This study was registered in the Core Outcome Measures in Effectiveness Trials database as study 1564.
The clinical efficacy and safety of dapagliflozin in patients with diabetic nephropathy
Authors: Huang Ying , Lu Wen , Lu Hongyun
Published: March 2022

Objective

To investigate the clinical efficacy and safety of dapagliflozin in the treatment of diabetic nephropathy (DN).

Methods

A total of 120 DN patients admitted to our hospital from June 2017 to March 2020 were divided into control and experimental groups, with 60 cases in each group. The control group received valsartan, and the experimental group received dapagliflozin for 3 months. Body mass index (BMI), hemoglobin A1c (HbA1c), serum creatinine (sCr), uric acid (UA), urine microalbumin (uMA), urine creatinine (uCr), and bilateral kidney function were compared before and after treatment, and adverse reactions in both groups were observed. Serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were also evaluated.

Results

After treatment, except for BMI in the control group, all indexes in both groups were significantly improved. The BMI, HbA1c, sCr, UA, and uMA/uCr ratios of the experimental group were lower than those of the control group. Serum albumin (sAlb) levels were increased in both groups, and the experimental group showed a significant difference compared with the control group. Estimated glomerular filtration rate (eGFR) levels were increased in both groups, and the experimental group was higher than the control group, with no significant differences. Serum IL-6 and TNF-α levels in both groups were lower, and the experimental group was significantly lower than the control group. No serious adverse reactions were observed in either group.

Conclusion

The efficacy of dapagliflozin was demonstrated by its ability to improve diabetes, prevent nephropathy exacerbation, and reduce symptomatic reactions. The low rate of adverse reactions makes dapagliflozin a very safe medication.
Structure-based design and construction of a synthetic phage display nanobody library
Authors: Moreno Ernesto , Valdés-Tresanco Mario S. , Molina-Zapata Andrea , Sánchez-Ramos Oliberto
Published: March 2022

Objective

To design and construct a new synthetic nanobody library using a structure-based approach that seeks to maintain high protein stability and increase the number of functional variants within the combinatorial space of mutations.

Results

Synthetic nanobody (Nb) libraries are emerging as an attractive alternative to animal immunization for the selection of stable, high affinity Nbs. Two key features define a synthetic Nb library: framework selection and CDR design. We selected the universal VHH framework from the cAbBCII10 Nb. CDR1 and CDR2 were designed with the same fixed length as in cAbBCII10, while for CDR3 we chose a 14-long loop, which creates a convex binding site topology. Based on the analysis of the cAbBCII10 crystal structure, we carefully selected the positions to be randomized and tailored the codon usage at each position, keeping at particular places amino acids that guarantee stability, favoring properties like polarity at solvent-exposed positions and avoiding destabilizing amino acids. Gene synthesis and library construction were carried out by GenScript, using our own phagemid vector. The constructed library has an estimated size of 1.75 × 108. NGS showed that the amino acid diversity and frequency at each randomized position are the expected from the codon usage.