bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes, hypertension, and cardiovascular disease development
Authors: Yen Fu-Shun , Wei James Cheng-Chung , Chiu Lu-Ting , Hsu Chih-Cheng , Hwu Chii-Min
Published: January 2022

Background

We aimed to compare cardiovascular risks among participants with T2DM with and without subsequent HTN and participants with HTN with and without subsequent T2DM.

Methods

From January 1, 2000, to December 31, 2018, we identified 16,236 matched pairs of T2DM participants with and without HTN (T2DM cohorts), 53,509 pairs of HTN participants with and without T2DM (HTN cohorts), and 21,158 pairs of comorbid HTN and T2DM participants with T2DM history or HTN history (comorbid cohorts) from Taiwan’s National Health Insurance Research Database. Cox proportional-hazard models were used to calculate the risk of cardiovascular disease.

Results

The mean follow-up time of this study was 6.75 years. Mean incident rates of coronary artery disease for T2DM cohorts, HTN cohorts, and comorbid cohorts were 16.80, 23.18, and 31.53 per 1000 person-years, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [95% CIs]) for incident coronary artery disease, stroke, and heart failure in T2DM participants with versus without HTN were 2.22 (2.07–2.37), 1.19 (1.16–1.23), and 0.92 (0.82–1.02), respectively; the adjusted HRs for HTN participants with versus without T2DM were 1.69 (1.55–1.84), 1.25 (1.21–1.30), and 0.98 (0.93–1.05), respectively; the adjusted HRs for comorbid T2DM and HTN participants with previous T2DM versus previous HTN were 2.78 (2.37–3.27), 1.20 (1.13–1.28), and 0.95 (0.88–1.03), respectively.

Conclusions

This nationwide cohort study demonstrated that both T2DM with subsequent HTN and HTN with subsequent diabetes were associated with higher cardiovascular disease risks.
Health service providers’ perspectives on the influence of modern health systems on adolescents’ sexual health practices in Umguza and Mberengwa districts of Zimbabwe
Authors: Nunu Wilfred Njabulo , Makhado Lufuno , Mabunda Jabu Tsakani , Lebese Rachel Tsakani
Published: January 2022

Background

Health service providers play a significant role in crafting and implementing health policies and programs that manage adolescent sexual health-related issues at different health system levels. These influence adolescent sexual behaviours and practices.

Aim

This study explored the roles of health service providers in managing adolescent sexual issues and how this impacts their sexual behaviours and practices. The study further probed the health service providers on how the indigenous health system could be integrated into the modern health system for effective management of adolescent sexual health related issues.

Methods

A qualitative cross-sectional survey was conducted on purposively selected health service providers in health facilities in Mberengwa and Umguza districts. Data was collected using unstructured interviews that were recorded, transcribed verbatim, and thematically analysed. Findings were presented as clearly defined as superordinate and subordinate themes.

Results

A total of five superordinate themes and 19 subordinate themes emerged from the interrogated data. The superordinate themes were: overview of adolescent sexual health issues, role of modern health system in adolescent sexual health issues, challenges encountered, indigenous health system factors that could be factored into modern health systems, and strategies to foster the integration of indigenous health system and modern health system. The subordinate themes explored in-depth the findings of the key stakeholders under the five superordinate themes.

Conclusions

From the findings, it can be concluded that health service providers play an essential role in shaping and providing adolescent sexual health services that adolescents utilise despite challenges that have reduced demand for these services. Therefore, there is a need to point out that there is a window of opportunity to foster collaborations between the indigenous health system and the modern health system as they strive to serve the adolescents to the best of their ability though in different contextual settings.
Knockdown of lncRNA BDNF-AS inhibited the progression of multiple myeloma by targeting the miR-125a/b-5p-BCL2 axis
Authors: Chu Min , Fan Yingchao , Wu Liting , Ma Xiaoyan , Sao Jinfeng , Yao Yonghua , Zhuang Wenfang , Zhang Cui
Published: January 2022

Purpose

This study aimed to explore the role of long non-coding RNA (lncRNA) BDNF-AS in the progression of multiple myeloma (MM).

Methods

The expression of BDNF-AS, miR-125a-5p, and miR-125b-5p in MM serum and cell lines were detected by quantitative reverse transcriptase PCR (qRT-PCR). The binding relationships between miR-125a/b-5p and BDNF-AS or Bcl-2 were predicted by Starbase and verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2′-deoxyuridine (EdU) staining assay. Cell migration was evaluated by wound healing assay. The expression levels of apoptosis-related proteins were evaluated by Western blot analysis. The role of BDNF-AS was also investigated in a xenograft tumor model in vivo.

Results

BDNF-AS was significantly upregulated, while miR-125a-5p and miR-125b-5p were downregulated in MM serum and corresponding cancer cell lines. Knockdown of BDNF-AS effectively inhibited the proliferation and migration of MM.1S and U266 cells, and co-transfection of miR-125a-5p or miR-125b-5p inhibitor and sh-BDNF-AS enhanced cell proliferation and migration compared with that in sh-BDNF-AS group. Knockdown of miR-125a-5p or miR-125b-5p significantly enhanced the proliferation and migration of MM.1S and U266 cells, and co-transfection of sh-Bcl-2 and miR-125a/b-5p inhibitor inhibited cell proliferation compared with that in miR-125a/b-5p inhibitor group. Moreover, knockdown of BDNF-AS increased the expression levels of apoptosis-related proteins (cleaved caspase 3 and cleaved PARP), while knockdown of miR-125a-5p or miR-125b-5p reduced the expression levels of these apoptosis-related proteins compared with knockdown of BDNF-AS. Furthermore, knockdown of BDNF-AS effectively suppressed MM tumor growth in vivo.

Conclusion

Our findings revealed that knockdown of BDNF-AS inhibited the progression of MM by targeting the miR-125a/b-5p-Bcl-2 axis, indicating that BDNF-AS might serve as a novel drug target for MM.
Expression profiles of hsa-miR-148a-3p and hsa-miR-125b-5p in human breast milk and infant formulae
Authors: Chiba Takeshi , Kooka Aya , Kowatari Kiyoko , Yoshizawa Megumi , Chiba Naoko , Takaguri Akira , Fukushi Yoshiyuki , Hongo Fuminori , Sato Hideki , Wada Shinichiro
Published: January 2022

Background

Milk-derived microRNAs (miRNAs), including hsa-miR-148a-3p (miR-148a) and hsa-miR-125b-5p (miR-125b), have been shown to be beneficial to the gastrointestinal function in infants. Here, we investigated their expression during lactation in humans and determined whether the infant formulae available in Japan contain these miRNAs.

Methods

Healthy Japanese women (n = 16) who gave birth vaginally or by cesarean section at the Teine Keijinkai Hospital between 1 September 2020, and 31 April 2021 were included in this study. Breast milk was collected by nurses on days 4 or 5 after delivery (hereinafter, transition milk) and on day 30 of postpartum (hereinafter, mature milk). The levels of miR-148a and miR-125b in breastmilk and six commercially available infant formulae were compared and evaluated using quantitative reverse transcription-polymerase chain reaction.

Results

In all participants, the miR-148a level in mature breastmilk was significantly lower than that in the transition milk. The changes in miR-125b expression during lactation showed similar trends to the changes in miR-148a expression. The miR-148a and miR-125b levels in all analyzed infant formulae were lower than 1/500th and 1/100th of those in mature breastmilk, respectively.

Conclusions

The levels of both miR-148a and miR-125b in human breast milk decreased on day 30 postpartum compared with those in the transition milk. Additionally, the expression of these miRNAs in infant formulae available in Japan was very low. Further studies with larger populations are required to understand precisely the lactational changes in the expression of miR148a and miR-125b in breast milk.
Client satisfaction to methadone maintenance treatment program in Myanmar
Authors: Tun Sun , Vicknasingam Balasingam , Singh Darshan , Wai Nyunt
Published: January 2022

Background

To tackle the long-standing opioid misuse problem, Myanmar introduced the methadone maintenance treatment (MMT) program in 2006, starting with 260 clients. Since then, the program has been expanded across different geographical sites in the country. This study was done in 2017 to explore the treatment satisfaction of the clients towards the MMT program.

Method

A total of 210 clients with a minimum of six-month treatment history enrolled in five MMT program sites across Myanmar were recruited through stratified random sampling. Administering the Verona Service Satisfaction Scale for Methadone-Treatment (VSSS-MT), this study assessed the satisfactory responses under three categories viz., 1) clinic staff professional skills; 2) basic drug intervention; 3) specific intervention (individual rehabilitation and psychotherapy).

Results

The majority (89%, n = 186) of the respondents were satisfied with the current MMT program. Specifically, 89.5% (n = 187) were satisfied with the clinic staff professional skills category, 91.9% (n = 192) with the basic program intervention and 74.6% (n = 156) with specific interventions. Among the respondents, treatment satisfaction with the MMT program was higher (p < 0.05) in those (i) with a higher quality of life score in physical, psychological, social and environmental categories, ii) who were satisfied with their current marital and leisure status, and those iii) who consumed alcohol. Results from stepwise binary logistic regression showed alcohol consumption and physical health status had a significant association with MMT treatment satisfaction.

Conclusion

Treatment satisfaction of the clients, in general is high. However, the lower percentage of satisfied clients (74.6%) for the specific interventions category compared with 89.5 and 91.9% respectively for staff and basic drug management categories highlights the need for improvement in this category for overall enhancement of the MMT program.
Gastric side effects and the stomach dosimetric analysis in left-sided breast cancer radiotherapy in free-breathing and deep inspiration breath-hold technique
Authors: Yang Dong , Piao Ying , Yuan Fengshun , Chen Hongtao , Zhang Ding , Li Xianming
Published: January 2022

Background

Adjuvant radiotherapy following surgery reduces the local recurrence and improves the prognosis. However, a considerable part of patients developed digestive reaction in daily treatment. In order to explore the correlation between breast radiotherapy and gastric toxicity, we investigated the clinic symptoms and stomach dose during DIBH or FB mode while left-sided breast cancer patients (LSBCP) receiving radiotherapy.

Methods

In the study, 124 LSBCP received adjuvant radiotherapy after surgery at our department were analyzed clinical characteristics and enquired about gastrointestinal side effects after treatment. Moreover, dosimetric parameters were assessed.

Results

There was no statistically significant difference between the two groups in age, T staging, N staging, hormone receptors, human epidermal receptor-2 (HER2), surgical methods, fractionated regimen, and chemotherapy conditions. However, larger stomach volumes and higher fractionated dose (Dmax/F) were associated with a statistically significantly greater risk for acute radiotherapy toxicity. In addition, the use of the DIBH gating technique (FB/DIBH) reduced the incidence of digestive reactions.

Conclusion

In order to cut down gastric side effects after breast radiotherapy, large meals should be avoided before treatment. DIBH treatment should be implemented in centers where conditions are satisfied to reduce radiotherapy side effects. Furthermore, dose limitation in stomach should be considered when the radiotherapy plan was formulated, especially for the patients treated with hypofractionated radiotherapy.
Evaluation of plan robustness on the dosimetry of volumetric arc radiotherapy (VMAT) with set-up uncertainty in Nasopharyngeal carcinoma (NPC) radiotherapy
Authors: Ding Zhen , Xiang Xiaoyong , Zeng Qi , Ma Jun , Dai Zhitao , Kang Kailian , Bi Suyan
Published: January 2022

Purpose

To evaluate the sensitivity to set up the uncertainty of VMAT plans in Nasopharyngeal carcinoma (NPC) treatment by proposing a plan robustness evaluation method.

Methods

10 patients were selected for this study. A 2-arc volumetric-modulated arc therapy (VMAT) plan was generated for each patient using Varian Eclipse (13.6 Version) treatment planning system (TPS). 5 uncertainty plans (U-plans) were recalculated based on the first 5 times set-up errors acquired from cone-beam computer tomography (CBCT). The dose differences of the original plan and perturbed plan corresponded to the plan robustness for the structure. Tumor control probability (TCP) and normal tissues complication probability (NTCP) were calculated for biological evaluation.

Results

The mean dose differences of D98% and D95% (ΔD98% and ΔD95%) of PTVp were respectively 3.30 Gy and 2.02 Gy. The ΔD98% and ΔD95% of CTVp were 1.12 Gy and 0.58 Gy. The ΔD98% and ΔD95% of CTVn were 1.39 Gy and 1.03 Gy, distinctively lower than those in PTVn (2.8 Gy and 2.0 Gy). The CTV-to-PTV margin increased the robustness of CTVs. The ΔD98% and ΔD95% of GTVp were 0.56 Gy and 0.33 Gy. GTVn exhibited strong robustness with little variation of D98% (0.64 Gy) and D95% (0.39 Gy). No marked mean dose variations of Dmean were seen. The mean reduction of TCP (ΔTCP) in GTVp and CTVp were respectively 0.4% and 0.3%. The mean ΔTCPs of GTVn and CTVn were 0.92% and 1.3% respectively. The CTV exhibited the largest ΔTCP (2.2%). In OARs, the brain stem exhibited weak robustness due to their locations in the vicinity of PTV. Bilateral parotid glands were sensitive to set-up uncertainty with a mean reduction of NTCP (ΔNTCP) of 6.17% (left) and 7.70% (right). The Dmax of optical nerves and lens varied slightly.

Conclusion

VMAT plans had a strong sensitivity to set-up uncertainty in NPC radiotherapy, with increasing risk of underdose of tumor and overdose of vicinal OARs. We proposed an effective method to evaluate the plan robustness of VMAT plans. Plan robustness and complexity should be taken into account in photon radiotherapy.
I don't leave my people; They need me: Qualitative research of local health care professionals' working motivations in Syria
Authors: Kallström Agneta , Al-Abdulla Orwa , Parkki Jan , Häkkinen Mikko , Juusola Hannu , Kauhanen Jussi
Published: January 2022

Background

The Syrian conflict has endured for a decade, causing one of the most significant humanitarian crises since World War II. The conflict has inflicted massive damage to civil infrastructure, and not even the health care sector has been spared. On the contrary, health care has been targeted, and as a result, many health professionals have left the country. Despite the life-threatening condition, many health professionals continued to work inside Syria even in the middle of the acute crisis. This qualitative study aims to determine the factors that have motivated Syrian health professionals to work in a conflict-affected country.

Methods

The research is based on 20 semi-structured interviews of Syrian health care workers. Interviews were conducted in 2016–2017 in Gaziantep, Turkey. A thematic inductive content analysis examined the motivational factors Syrian health care workers expressed for their work in the conflict area.

Results

Motivating factors for health care workers were intrinsic and extrinsic. Intrinsic reasons included humanitarian principles and medical ethics. Also, different ideological reasons, patriotic, political and religious, were mentioned. Economic and professional reasons were named as extrinsic reasons for continuing work in the war-torn country.

Conclusions

The study adds information on the effects of the Syrian crisis on health care—from healthcare workers' perspective. It provides a unique insight on motivations why health care workers are continuing their work in Syria. This research underlines that the health care system would collapse totally without local professionals and leave the population without adequate health care.
RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner
Authors: Yu Dan , Pan Min , Li Yanshi , Lu Tao , Wang Zhihai , Liu Chuan , Hu Guohua
Published: January 2022

Background

Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined.

Methods

The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC.

Results

We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability.

Conclusions

Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.
Down-regulation of ZNF252P-AS1 alleviates ovarian cancer progression by binding miR-324-3p to downregulate LY6K
Authors: Geng Li , Wang Zhongqiu , Tian Yongju
Published: January 2022

Background

Ovarian cancer is a common gynecological malignant disease in women. Our work aimed to study the specific functions of ZNF252P antisense RNA 1 (ZNF252P-AS1) in ovarian cancer.

Methods

ZNF252P-AS1, miR-324-3p, and lymphocyte antigen 6 family member K (LY6K) expression were analyzed by bioinformatics tools in ovarian cancer tissues and was quantified by qRT-PCR in ovarian cancer cells. The effect of ZNF252P-AS1 knockdown, miR-324-3p suppression, and LY6K over-expression on apoptosis, cell viability, invasion, migration, and epithelial to mesenchymal transition (EMT) was determined in vitro by using colony formation and EdU assays, flow cytometry, transwell assay, and Western blot. The interactions between ZNF252P-AS1 and miR-324-3p and between miR-324-3p and LY6K were validated by luciferase assays. The effects of restraining ZNF252P-AS1 in vivo were studied using BALB/c male nude mice.

Results

ZNF252P-AS1 and LY6K levels were up-regulated, while miR-324-3p was declined in ovarian cancer tissues and cells. ZNF252P-AS1 knockdown reduced ovarian cancer cell proliferation, invasion, migration, and EMT, whereas promoted its apoptosis. Besides, ZNF252P-AS1 interacted with miR-324-3p and reversely regulated its level, and miR-324-3p was directly bound to LY6K and negatively regulated its expression. Moreover, ZNF252P-AS1 knockdown reversed the effect of miR-324-3p on cancer cell apoptosis, growth, migration, invasion, and EMT. Similar results were discovered in the rescue experiments between miR-324-3p and LY6K. Additionally, mouse models in vivo experiments further validated that ZNF252P-AS1 knockdown distinctly inhibited tumor growth.

Conclusion

ZNF252P-AS1 mediated miR-324-3p/LY6K signaling to facilitate progression of ovarian cancer.
Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial
Authors: Santamarina Mario G. , Beddings Ignacio , Lomakin Felipe Martinez , Boisier Riscal Dominique , Gutiérrez Claveria Mónica , Vidal Marambio Jaime , Retamal Báez Nicole , Pavez Novoa Cristian , Reyes Allende César , Ferreira Perey Paulina , Gutiérrez Torres Miguel , Villalobos Mazza Camila , Vergara Sagredo Constanza , Ahumada Bermejo Sebastian , Labarca Mellado Eduardo , Barthel Munchmeyer Elizabeth , Marchant Ramos Solange , Volpacchio Mariano , Vega Jorge
Published: January 2022

Background

SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation–perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA.

Methods

Triple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO2/FiO2 ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis.

Results

Totally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41–68] years. No significant differences in mean PaO2/FiO2 ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7–12 days vs. 12 IQR 9–21 days, p = 0.04).

Conclusions

No statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results.

Trial Registration: Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial, NCT04489446, Registered 28 July 2020, https://clinicaltrials.gov/ct2/show/NCT04489446.
Robust normalization and transformation techniques for constructing gene coexpression networks from RNA-seq data
Authors: Johnson Kayla A. , Krishnan Arjun
Published: January 2022

Background

Constructing gene coexpression networks is a powerful approach for analyzing high-throughput gene expression data towards module identification, gene function prediction, and disease-gene prioritization. While optimal workflows for constructing coexpression networks, including good choices for data pre-processing, normalization, and network transformation, have been developed for microarray-based expression data, such well-tested choices do not exist for RNA-seq data. Almost all studies that compare data processing and normalization methods for RNA-seq focus on the end goal of determining differential gene expression.

Results

Here, we present a comprehensive benchmarking and analysis of 36 different workflows, each with a unique set of normalization and network transformation methods, for constructing coexpression networks from RNA-seq datasets. We test these workflows on both large, homogenous datasets and small, heterogeneous datasets from various labs. We analyze the workflows in terms of aggregate performance, individual method choices, and the impact of multiple dataset experimental factors. Our results demonstrate that between-sample normalization has the biggest impact, with counts adjusted by size factors producing networks that most accurately recapitulate known tissue-naive and tissue-aware gene functional relationships.

Conclusions

Based on this work, we provide concrete recommendations on robust procedures for building an accurate coexpression network from an RNA-seq dataset. In addition, researchers can examine all the results in great detail athttps://krishnanlab.github.io/RNAseq_coexpressionto make appropriate choices for coexpression analysis based on the experimental factors of their RNA-seq dataset.
Assessing reproducibility of inherited variants detected with short-read whole genome sequencing
Authors: Pan Bohu , Ren Luyao , Onuchic Vitor , Guan Meijian , Kusko Rebecca , Bruinsma Steve , Trigg Len , Scherer Andreas , Ning Baitang , Zhang Chaoyang , Glidewell-Kenney Christine , Xiao Chunlin , Donaldson Eric , Sedlazeck Fritz J. , Schroth Gary , Yavas Gokhan , Grunenwald Haiying , Chen Haodong , Meinholz Heather , Meehan Joe , Wang Jing , Yang Jingcheng , Foox Jonathan , Shang Jun , Miclaus Kelci , Dong Lianhua , Shi Leming , Mohiyuddin Marghoob , Pirooznia Mehdi , Gong Ping , Golshani Rooz , Wolfinger Russ , Lababidi Samir , Sahraeian Sayed Mohammad Ebrahim , Sherry Steve , Han Tao , Chen Tao , Shi Tieliu , Hou Wanwan , Ge Weigong , Zou Wen , Guo Wenjing , Bao Wenjun , Xiao Wenzhong , Fan Xiaohui , Gondo Yoichi , Yu Ying , Zhao Yongmei , Su Zhenqiang , Liu Zhichao , Tong Weida , Xiao Wenming , Zook Justin M. , Zheng Yuanting , Hong Huixiao
Published: January 2022

Background

Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS.

Results

To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×.

Conclusions

Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.
Low-dose corticosteroid therapy for cardiogenic shock in adults (COCCA): study protocol for a randomized controlled trial
Authors: Mekontso Dessap Armand , Bagate François , Delmas Clément , Morichau-Beauchant Tristan , Cholley Bernard , Cariou Alain , Lattuca Benoit , Moussa Mouhamed , Mongardon Nicolas , Fard Damien , Schmidt Matthieu , Bouglé Adrien , Kerneis Mathieu , Vivier Emmanuel , Roubille François , Duprey Matthieu , Decalf Véronique , Genet Thibaud , Merzoug Messaouda , Audureau Etienne , Squara Pierre
Published: January 2022

Background

Cardiogenic shock (CS) is a life-threatening condition characterized by circulatory insufficiency caused by an acute dysfunction of the heart pump. The pathophysiological approach to CS has recently been enriched by the tissue consequences of low flow, including inflammation, endothelial dysfunction, and alteration of the hypothalamic-pituitary-adrenal axis. The aim of the present trial is to evaluate the impact of early low-dose corticosteroid therapy on shock reversal in adults with CS.

Method/design

This is a multicentered randomized, double-blind, placebo-controlled trial with two parallel arms in adult patients with CS recruited from medical, cardiac, and polyvalent intensive care units (ICU) in France. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 380 patients (190 per group). For the treatment group, hydrocortisone (50 mg intravenous bolus every 6 h) and fludrocortisone (50 μg once a day enterally) will be administered for 7 days or until discharge from the ICU. The primary endpoint is catecholamine-free days at day 7. Secondary endpoints include morbidity and all-cause mortality at 28 and 90 days post-randomization. Pre-defined subgroups analyses are planned, including: postcardiotomy, myocardial infarction, etomidate use, vasopressor use, and adrenal profiles according the short corticotropin stimulation test. Each patient will be followed for 90 days. All analyses will be conducted on an intention-to-treat basis.

Discussion

This trial will provide valuable evidence about the effectiveness of low dose of corticosteroid therapy for CS. If effective, this therapy might improve outcome and become a therapeutic adjunct for patients with CS.

Trial registration

ClinicalTrials.gov, NCT03773822. Registered on 12 December 2018
Efficacy of Chinese herbal medicine Jiangniaosuan formula for treatment of hyperuricemia: study protocol for a double-blinded non-inferiority randomized controlled clinical trial
Authors: Guo Yafang , Lu Hong , Gan Jing , Li Dongdong , Gao Jiandong , Zhang Changming
Published: January 2022

Background

Jiangniaosuan formula (JNSF) is commonly used in China for treating hyperuricemia, but there is little research-based evidence to support its use. This randomized controlled trial aims to assess the efficacy and safety of JNSF.

Methods

A total of 72 patients with hyperuricemia will be selected and randomly assigned in a ratio of 1:2 to receive either Western medicine, i.e., febuxostat 40 mg (WG group; n = 24), or Chinese herbal medicine, i.e., Jiangniaosuan formula + febuxostat 20 mg (WJNSG group; n = 48). After 12 weeks, the WJNSG will be randomly divided into two groups of 24 patients each; one group (WJNSG; n = 24) still will receive febuxostat 20 mg + Jiangniaosuan formula, and the other group (JNSG; n = 24) will continue to receive Jiangniaosuan formula + placebo. Participants will be followed up at 4-week intervals. The primary outcome will be the change in serum uric acid level, and the secondary outcome will be the change in traditional Chinese medicine (TCM) syndrome scores. Serum creatinine, blood glucose, and insulin levels will also be measured.

Discussion

We hypothesize that patients with hyperuricemia will benefit from JNSF. This study will provide evidence-based recommendations for clinicians.

Dissemination

The results will be published in a peer-reviewed journal and disseminated by academic conferences. The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Trial registration

Chinese Clinical Trials Register ChiCTR2000041083. Registered on 3 May 2021. The protocol version number is V3.0, 20210301.
Nutritional support and prophylaxis of azithromycin for pregnant women to improve birth outcomes in peri-urban slums of Karachi, Pakistan—a protocol of multi-arm assessor-blinded randomized controlled trial (Mumta PW trial)
Authors: Muhammad Ameer , Fazal Zoha Zahid , Baloch Benazir , Nisar Imran , Jehan Fyezah , Shafiq Yasir
Published: January 2022

Background

Maternal undernutrition is critical in the etiology of poor perinatal outcomes and accounts for 20% of small-for-gestational-age (SGA) births. High levels of food insecurity, antenatal undernourishment, and childhood undernutrition necessitate the supplementation of fortified balanced energy protein (BEP) during pregnancy in low-income settings especially with scarce literature available in this subject. Hence, this paper extensively covers the protocol of such a trial conducted in an urban slum of Karachi, Pakistan.

Methods

The trial is community-based, open-labelled, four-arm, and randomized controlled that will include parallel group assignments with a 1:1:1:1 allocation ratio in low-income squatter settlements in urban Karachi, Pakistan. All pregnant women (PW), if identified between > 8 and < 19 weeks of gestation based on ultrasound, will be offered routine antenatal care (ANC) counseling and voluntary participation in the trial after written informed consent. A total number of 1836 PW will be enrolled with informed consent and randomly allocated to one of the four arms receiving: (1) ANC counseling only (control group), (2) ANC counseling plus BEP supplement (intervention arm 1), (3) ANC counseling plus BEP supplement plus 2 doses azithromycin (intervention arm 2), or (4) ANC counseling plus BEP supplement plus daily single dose of nicotinamide and choline (intervention arm 3).

Trial registration

ClinicalTrials.govNCT04012177. Registered on July 9, 2019.
Loss of Neuropilin2a/b or Sema3fa alters olfactory sensory axon dynamics and protoglomerular targeting
Authors: Cheng Ryan P. , Dang Puneet , Taku Alemji A. , Moon Yoon Ji , Pham Vi , Sun Xiaohe , Zhao Ethan , Raper Jonathan A.
Published: January 2022

Background

Olfactory Sensory Neuron (OSN) axons project from the zebrafish olfactory epithelium to reproducible intermediate target locations in the olfactory bulb called protoglomeruli at early stages in development. Two classes of OSNs expressing either OMP or TRPC2 exclusively target distinct, complementary protoglomeruli. Using RNAseq, we identified axon guidance receptors nrp2a and nrp2b, and their ligand sema3fa, as potential guidance factors that are differentially expressed between these two classes of OSNs.

Methods

To investigate their role in OSN axon guidance, we assessed the protoglomerular targeting fidelity of OSNs labeled by OMP:RFP and TRPC2:Venus transgenes in nrp2a, nrp2b, or sema3fa mutants. We used double mutant and genetic interaction experiments to interrogate the relationship between the three genes. We used live time-lapse imaging to compare the dynamic behaviors of OSN growth cones during protoglomerular targeting in heterozygous and mutant larvae.

Results

The fidelity of protoglomerular targeting of TRPC2-class OSNs is degraded in nrp2a, nrp2b, or sema3fa mutants, as axons misproject into OMP-specific protoglomeruli and other ectopic locations in the bulb. These misprojections are further enhanced in nrp2a;nrp2b double mutants suggesting that nrp2s work at least partially in parallel in the same guidance process. Results from genetic interaction experiments are consistent with sema3fa acting in the same biological pathway as both nrp2a and nrp2b. Live time-lapse imaging was used to examine the dynamic behavior of TRPC2-class growth cones in nrp2a mutants compared to heterozygous siblings. Some TRPC2-class growth cones ectopically enter the dorsal-medial region of the bulb in both groups, but in fully mutant embryos, they are less likely to correct the error through retraction. The same result was observed when TRPC2-class growth cone behavior was compared between sema3fa heterozygous and sema3fa mutant larvae.

Conclusions

Our results suggest that nrp2a and nrp2b expressed in TRPC2-class OSNs help prevent their mixing with axon projections in OMP-specific protoglomeruli, and further, that sema3fa helps to exclude TRPC2-class axons by repulsion from the dorsal-medial bulb.
Validation of an algorithm to identify incident interstitial lung disease in patients with rheumatoid arthritis
Authors: Meehan M. , Shah A. , Lobo J. , Oates J. , Clinton C. , Annapureddy N. , Xie F. , Zhuo J. , Danila M. I. , England B. R. , Curtis J. R.
Published: January 2022

Background/purpose

Interstitial lung disease (ILD) is an important problem for patients with rheumatoid arthritis (RA). However, current approaches to ILD case finding in real-world data have been evaluated only in limited settings and identify only prevalent ILD and not new-onset disease. Our objective was to develop, refine, and validate a claims-based algorithm to identify both prevalent and incident ILD in RA patients compared to the gold standard of medical record review.

Methods

We used administrative claims data 2006–2015 from Medicare to derive a cohort of RA patients. We then identified suspected ILD using variations of ILD algorithms to classify both prevalent and incident ILD based on features of the data that included hospitalization vs. outpatient setting, physician specialty, pulmonary-related diagnosis codes, and exclusions for potentially mimicking pulmonary conditions. Positive predictive values (PPV) of several ILD algorithm variants for both prevalent and incident ILD were evaluated.

Results

We identified 234 linkable RA patients with sufficient data to evaluate for ILD. Overall, 108 (46.2%) of suspected cases were confirmed as ILD. Most cases (64%) were diagnosed in the outpatient setting. The best performing algorithm for prevalent ILD had a PPV of 77% (95% CI 67–84%) and for incident ILD was 96% (95% CI 85–100%).

Conclusion

Case finding in administrative data for both prevalent and incident interstitial lung disease in RA patients is feasible and has reasonable accuracy to support population-based research and real-world evidence generation.
Preterm birth is strongly affected by the glucocorticoid dose during pregnancy in women complicated by systemic lupus erythematosus
Authors: Shimada Hiromi , Wakiya Risa , Kanenishi Kenji , Miyatake Nobuyuki , Nakashima Shusaku , Mansour Mai Mahmoud Fahmy , Kato Mikiya , Miyagi Taichi , Sugihara Koichi , Ushio Yusuke , Mino Rina , Mizusaki Mao , Kameda Tomohiro , Kadowaki Norimitsu , Dobashi Hiroaki
Published: January 2022

Background

This study aimed to investigate the effect of glucocorticoid doses on adverse pregnancy outcomes (APOs) in women complicated by systemic lupus erythematosus (SLE).

Methods

We investigated 74 pregnancies complicated by SLE or SLE-dominant mixed connective tissue disease. The pregnancies were managed from conception to delivery in our institution. We retrospectively evaluated whether the mean glucocorticoid dose during pregnancy is associated with APOs, including preterm birth (PB), low birth weight (LBW), and light-for-date (LFD). We also calculated the cut-off dose of glucocorticoid that affected APOs.

Results

All APOs occurred in 35 (50.7%) patients, with 14 cases of PB, 23 cases of LBW, and 10 cases of LFD. Patients with all APOs or PB had a higher dose of glucocorticoid during pregnancy than patients without all APOs or with full-term birth (P = 0.03, P <  0.01, respectively). Logistic regression analysis for all APOs and PB showed that the cut-off values of the mean glucocorticoid dose were 6.5 and 10.0 mg/day, respectively. Patients who delivered LBW or LFD newborns showed no significant difference in the glucocorticoid dose used during pregnancy than patients without LBW or LFD newborns. Patients who delivered LBW newborns were more likely to have used glucocorticoids during pregnancy (P <  0.01).

Conclusions

In pregnancies complicated by SLE, a relatively lower dose of glucocorticoid than previously reported is significantly related to APOs, especially PB. Therefore, the disease activity of patients with SLE should be managed with the appropriate lower dose of glucocorticoid during pregnancy.
Comment on “the IS6 family, a clinically important group of insertion sequences including IS26” by Varani and co-authors
Authors: Hall Ruth M.
Published: January 2022

The insertion sequence IS26 has long been known to play a major role in the recruitment of antibiotic resistance genes into the mobile resistance gene pool of Gram-negative bacteria and IS26 also plays a major role in their subsequent broad dissemination. Related IS, IS431/257 and IS1216 are important in the same roles in Gram positive bacteria. However, until recently the properties of IS26 movement that could potentially explain this ability had not been explored. A much needed insight has come from our recent demonstration that IS26 uses a novel targeted mechanism that is conservative. The targeted conservative mechanism is much more efficient than the known replicative mechanism, which is now more accurately called copy-in. A recent review “The IS6 family, a clinically important group of insertion sequences including IS26” by Varani, He, Siguier, Ross and Chandler published in Mobile DNA has substantially misrepresented the recent studies on the targeted conservative mechanism and at the same time incorrectly implied that any mechanism established for IS26 can be assumed to apply to a range of IS that are at best very distantly related. A few of the most important issues are examined in this comment. Readers are advised to consult the original literature to check facts before drawing firm conclusions.
Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer
Authors: Beynon Rhona A. , Ingle Suzanne M. , Langdon Ryan , May Margaret , Ness Andy , Martin Richard M. , Suderman Matthew , Ingarfield Kate , Marioni Riccardo E. , McCartney Daniel L. , Waterboer Tim , Pawlita Michael , Relton Caroline , Smith George Davey , Richmond Rebecca C.
Published: January 2022

Background

Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed “epigenetic age acceleration”, has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvathandIEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated.

Results

IEAAHannumandAgeAccelGrimwere associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57;p = 0.007] and 1.40 [95% CI 1.06, 1.83;p = 0.016], respectively). There was weak evidence that the addition ofAgeAccelGrimto the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77;pvalue for difference = 0.069).

Conclusion

In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.
Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline
Authors: González-Domínguez Raúl , Castellano-Escuder Pol , Lefèvre-Arbogast Sophie , Low Dorrain Y. , Du Preez Andrea , Ruigrok Silvie R. , Lee Hyunah , Helmer Catherine , Pallàs Mercè , Urpi-Sarda Mireia , Sánchez-Pla Alex , Korosi Aniko , Lucassen Paul J. , Aigner Ludwig , Manach Claudine , Thuret Sandrine , Samieri Cécilia , Andres-Lacueva Cristina
Published: January 2022

Background

Fatty acids play prominent roles in brain function as they participate in structural, metabolic and signaling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) gene and sex, remains elusive.

Methods

In order to investigate early alterations associated with cognitive decline in the fatty acid-related serum metabolome, we here applied targeted metabolomics analysis on a nested case-control study (N=368), part of a prospective population cohort on dementia.

Results

When considering the entire study population, circulating levels of free fatty acids, acyl-carnitines and pantothenic acid were found to be increased among those participants who had greater odds of cognitive decline over a 12-year follow-up. Interestingly, stratified analyses indicated that these metabolomic alterations were specific for ApoE-ɛ4 non-carriers and women.

Conclusions

Altogether, our results highlight that the regulation of fatty acids and related metabolic pathways during ageing and cognitive decline depends on complex inter-relationships between the ApoE-ε4 genotype and sex. A better understanding of the ApoE-ɛ4 and sex dependent modulation of metabolism is essential to elucidate the individual variability in the onset of cognitive decline, which would help develop personalized therapeutic approaches.