bluuebunny/crossref_metadata_2025 huggingface dataset:
SVAT: Secure outsourcing of variant annotation and genotype aggregation
Authors: Kim Miran , Wang Su , Jiang Xiaoqian , Harmanci Arif
Published: October 2022

Background

Sequencing of thousands of samples provides genetic variants with allele frequencies spanning a very large spectrum and gives invaluable insight into genetic determinants of diseases. Protecting the genetic privacy of participants is challenging as only a few rare variants can easily re-identify an individual among millions. In certain cases, there are policy barriers against sharing genetic data from indigenous populations and stigmatizing conditions.

Results

We present SVAT, a method for secure outsourcing of variant annotation and aggregation, which are two basic steps in variant interpretation and detection of causal variants. SVAT uses homomorphic encryption to encrypt the data at the client-side. The data always stays encrypted while it is stored, in-transit, and most importantly while it is analyzed. SVAT makes use of a vectorized data representation to convert annotation and aggregation into efficient vectorized operations in a single framework. Also, SVAT utilizes a secure re-encryption approach so that multiple disparate genotype datasets can be combined for federated aggregation and secure computation of allele frequencies on the aggregated dataset.

Conclusions

Overall, SVAT provides a secure, flexible, and practical framework for privacy-aware outsourcing of annotation, filtering, and aggregation of genetic variants. SVAT is publicly available for download from https://github.com/harmancilab/SVAT.
Psychometric validation of a chinese version of COVID-19 vaccine hesitancy scale: a cross-sectional study
Authors: Huang Yiman , Wu Yijin , Dai Zhenwei , Xiao Weijun , Wang Hao , Si Mingyu , Wang Wenjun , Gu Xiaofen , Ma Li , Li Li , Zhang Shaokai , Yang Chunxia , Yu Yanqin , Qiao Youlin , Su Xiaoyou
Published: October 2022

Background

COVID-19 vaccines have been administered in many countries; however, a sufficient vaccine coverage rate is not guaranteed due to vaccine hesitancy. To improve the uptake rate of COVID-19 vaccine, it is essential to evaluate the rate of vaccine hesitancy and explore relevant factors in different populations. An urgent need is to measure COVID-19 vaccine hesitancy among different population groups, hence a validated scale for measuring COVID-19 vaccine hesitancy is necessary. The present study aims to validate the COVID-19 vaccine hesitancy scale among different populations in China and to provide a scale measuring COVID-19 vaccine hesitancy with satisfactory reliability and validity.

Methods

Self-reported survey data were collected from different populations in China from January to March 2021. Based on the Parent Attitudes about Childhood Vaccines scale, 15 items were adapted to evaluate the COVID-19 vaccine hesitancy. Exploratory and confirmatory factor analysis were utilized to identify internal constructs of the COVID-19 vaccine hesitancy scale among two randomly split subsets of the overall sample. Reliability was analyzed with the internal consistency, composite reliability, and the test–retest reliability, and validity was analyzed with the criterion validity, convergent validity, and discriminant validity.

Results

A total of 4227 participants completed the survey, with 62.8% being medical workers, 17.8% being students, 10.3% being general population, and 9.1% being public health professionals. The exploratory factor analysis revealed a three-factor structure that explain 50.371% of the total variance. The confirmatory factor analysis showed that models consisting of three dimensions constructed in different populations had good or acceptable fit (CFI ranged from 0.902 to 0.929, RMSEA ranged from 0.061 to 0.069, and TLI ranged from 0.874 to 0.912). The Cronbach’s α for the total scale and the three subscales was 0.756, 0.813, 0.774 and 0.705, respectively. Moreover, the COVID-19 vaccine hesitancy scale had adequate test–retest reliability, criterion validity, convergent validity, and discriminant validity.

Conclusions

The COVID-19 vaccine hesitancy scale is a valid and reliable scale for identifying COVID-19 vaccine hesitancy among different population groups in China. Given the serious consequences of COVID-19 vaccine hesitancy, future studies should validate it across regions and time to better understand the application of the COVID-19 vaccine hesitancy scale.
LRIG2 regulates cell proliferation, migration and apoptosis of osteosarcoma
Authors: Li Zhi-Qiang , Liao Wei-Jie , Sun Bo-Lin , Luo Zhi-Wen , Zhong Nan-Shan , Wu Jia-Bao , Liu Zhi-Li , Liu Jia-Ming
Published: October 2022

Background

Osteosarcoma (OS) is one of the malignant bone tumors with strong aggressiveness and poor prognosis. Leucine-rich repeats and immunoglobulin-like domains2 (LRIG2) is closely associated with the poor prognosis of a variety of tumors, but the role of LRIG2 in osteosarcoma and the underlying molecular mechanism remains unclear.

Objective

The aim of this study was to determine the function of LRIG2 in OS and the related molecular mechanism on cell proliferation, apoptosis and migration of OS.

Methods

The mRNA and protein expression of LRIG2 in OS tissues and cells was detected by qRT-PCR, western blot (WB) assay and immunohistochemistry (IHC). The cell counting Kit-8 (CCK-8), clone formation, transwell, TdT-mediated dUTP Nick-End Labeling (TUNEL) and WB assay were applied to determine the proliferation, migration and apoptosis abilities of OS cells and its molecular mechanisms. Spontaneous metastasis xenografts were established to confirm the role of LRIG2 in vivo.

Results

LRIG2 exhibited high expression in OS tissues and OS cell lines and the expression of which was significantly correlated with Enneking stage of patients, knockdown LRIG2 expression significantly inhibited OS cell proliferation, migration and enhanced apoptosis. Silencing LRIG2 also suppressed the growth of subcutaneous transplanted tumor in nude mice. Further, the mechanism investigation revealed that the protein level of cell proapoptotic proteins (Bax, caspase9 and caspase3) all increased attributed to LRIG2 deficiency, whereas expression of anti-apoptotic protein BCL2 decreased. LRIG2 silencing led to the decrease phosphorylation of AKT signaling, a decrease expression of vimentin and N-cadherin. Additionally, silencing LRIG2 significantly decreased the rate of tumor growth and tumor size.

Conclusions

LRIG2 acts as an oncogene in osteosarcoma, and it might become a novel target in the treatment of human OS.
Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer
Authors: Lai Ming-Yu , Kang Shi-Yang , Sun Yu-Ting , Quan Ting-Ting , Lu Shi-Xun , He Cai-Yun , Zhou Zhi-Wei , Yang Li-Qiong , Luo Hui-Yan , Wang Feng-Hua , Li Yu-Hong , Xu Rui-Hua , Guan Wen-Long , Qiu Miao-Zhen
Published: October 2022

Background

Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values.

Methods

Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0–1 and 2–3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method.

Result

One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0–1 group and was 16.13 months in TRG 2–3 group. TRG 2–3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001).

Conclusion

TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy.
A cross-sectional national investigation of COVID-19 outbreaks in nurseries during rapid spread of the Alpha (B.1.1.7) variant of SARS-CoV-2 in England
Authors: Aiano Felicity , McOwat Kelsey , Obi Chinelo , Powell Annabel A. , Flood Jessica , Bhardwaj Shivraj , Stoker Kelly , Haskins Donna , Wong Brian , Bertran Marta , Zavala Maria , Bosowski Johanna , Jones Samuel E. I. , Amin-Chowdhury Zahin , Coughlan Laura , Sinnathamby Mary , Zaidi Asad , Merrick Rachel , Zhao Hongxin , Ismail Sharif , Ramsay Mary E. , Ladhani Shamez N. , Saliba Vanessa
Published: October 2022

Background

In England, the emergence the more transmissible SARS-CoV-2 variant Alpha (B.1.1.7) led to a third national lockdown from December 2020, including restricted attendance at schools. Nurseries, however, remained fully open. COVID-19 outbreaks (≥ 2 laboratory-confirmed cases within 14 days) in nurseries were investigated to assess the risk of SARS-CoV-2 infection and cumulative incidence in staff and children over a three-month period when community SARS-CoV-2 infections rates were high and the Alpha variant was spreading rapidly across England.

Methods

This was a cross-sectional national investigation of COVID-19 outbreaks in nurseries across England. Nurseries reporting a COVID-19 outbreak to PHE between November 2020 and January 2021 were requested to complete a questionnaire about their outbreak.

Results

Three hundred and twenty-four nurseries, comprising 1% (324/32,852) of nurseries in England, reported a COVID-19 outbreak. Of the 315 (97%) nurseries contacted, 173 (55%) reported 1,657 SARS-CoV-2 cases, including 510 (31%) children and 1,147 (69%) staff. A child was the index case in 45 outbreaks (26%) and staff in 125 (72%) outbreaks. Overall, children had an incidence rate of 3.50% (95%CI, 3.21–3.81%) and was similar irrespective of whether the index case was a child (3.55%; 95%CI, 3.01–4.19%) or staff (3.44%; 95%CI, 3.10–3.82%). Among staff, cumulative incidence was lower if the index case was a child (26.28%; 95%CI, 23.54–29.21%%) compared to a staff member (32.98%; 95%CI, 31.19–34.82%), with the highest cumulative incidence when the index case was also a staff member (37.52%; 95%CI, 35.39–39.70%). Compared to November 2020, outbreak sizes and cumulative incidence was higher in January 2021, when the Alpha variant predominated. Nationally, SARS-CoV-2 infection rates in < 5 year-olds remained low and followed trends in older age-groups, increasing during December 2020 and declining thereafter.

Conclusions

In this cross-sectional study of COVID-19 outbreaks in nurseries, one in three staff were affected compared to one in thirty children. There was some evidence of increased transmissibility and higher cumulative incidence associated with the Alpha variant, highlighting the importance of maintaining a low level of community infections.
Impact of refractory and unexplained chronic cough on disease burden: a qualitative study
Authors: Ueda Naoya , Yakushiji Anzu , Schelfhout Jonathan , Tokita Shigeru , Kubo Takekazu
Published: October 2022

Background

Chronic cough lasting for > 8 weeks is a common medical condition that burdens patients. This study aimed to qualitatively describe knowledge, awareness, experiences, and subtypes of burdens (physical, social, psychological) among Japanese patients with refractory chronic cough (refractory to treatment of underlying relevant medical conditions) and unexplained chronic cough (symptoms of unexplained origin).

Methods

This non-interventional, cross-sectional study was conducted between February and March 2021 among patients (aged ≥ 20 years) with self-reported refractory or unexplained chronic cough. Subjects with a history of comorbid respiratory conditions were excluded. Eligible subjects participated in a 60-min online semi-structured interview. Verbatim terms from interviews were qualitatively transcribed and generated into word clouds, followed by a clustering analysis in which meaningful clusters were chosen, manually coded, and utterances and burdens categorized.

Results

A total of 21 participants (95.2% with refractory chronic cough, mean age 53.5 years, and 76.2% being males) with Leicester Cough Questionnaire mean ± standard deviation scores of physical 4.8 ± 1.1, psychological 4.4 ± 1.3, social 4.9 ± 1.4, and total 14.1 ± 3.5 were included. The word cloud identified the most frequently used word (‘cough’); etiology (‘asthma’); and words associated with change in states (‘influence,’ ‘changing,’ ‘change’) and expressions (‘tough,’ ‘pain,’ ‘hard,’ ‘terrible,’ ‘unpleasant’). The patients experienced ‘mental/social burden,’ ‘physical burden,’ ‘impact on sleep and meals,’ ‘impact on work and housework,’ ‘impact on communication,’ ‘impact on hobbies and leisure,’ and ‘economic burden.’ By closed coding analysis, the situations or types of burden patients experienced from the cough were ordered sequentially as emotion, working style, acquaintanceship, hobbies and leisure, and sleeping pattern.

Conclusions

The present study indicated that there were two types of participant clusters, in which one showed mainly the burdens in the social communications such as work-related communication and another one showed the burdens of relationships with others. Also, some participants highlighted ‘mental burden,’ on social life due to the current pandemic. To relieve these burdens, disease awareness and knowledge should be improved for patients with refractory and unexplained chronic cough.

Trial registration The trial was registered under UMIN-CTR as UMIN000042772, on 17/12/2020. The study was approved by the Medical Corporation Toukeikai Kitamachi Clinic (IRB registration number: 11001110).
Morphological changes of TMJ disc in surgically treated ADDwoR patients: a retrospective study
Authors: Wang Ruiyu , Bi Ruiye , Liu Yao , Cao Pinyin , Abotaleb Bassam , Zhu Songsong
Published: October 2022

Background

This study aimed to quantify the morphological changes of temporomandibular joint (TMJ) discs after disc repositioning surgery using the three-dimensional (3D) modeling.

Methods

Thirty patients who diagnosed with unilateral ADDwoR were included to compare the morphological differences between ADDWoR discs and normal discs, and fifteen patients who experienced unilateral or bilateral disc repositioning surgery were included to analyze the morphological changes before and after disc repositioning surgery. Disc 3D reconstruction and analyses were performed using magnetic resonance imaging (MRI) data.

Results

In the unilateral ADDwoR patients, volume, superficial area, length, and maximum longitudinal-sectional area of the ADDwoR disc were significantly smaller compared with the non-affected discs. However, there was no significant difference in width and cross-sectional areas between ADDwoR discs and non-affected discs. In patients who subjected to disc repositioning surgery, disc volume, superficial area, length, width and maximum longitudinal-sectional area of TMJ discs were markedly increased 6 months after surgery.

Conclusions

This study demonstrated that the TMJ discs tended to be morphologically smaller in volume and shorter in length under ADDwoR status. Importantly, the ADDwoR discs tended to morphologically recover toward non-affected discs after 6 months follow-up following TMJ disc repositioning surgery.
Dealing with pluralism: the managerial work of CEOs in Italian public healthcare organizations
Authors: Lega Federico , Rotolo Andrea , Sartirana Marco
Published: October 2022

Background

Healthcare organizations are extremely complex. The work of their CEOs is particularly demanding, especially in the public sector, though little is known about how the managerial work of a healthcare organization CEO unfolds. Drawing from scholarship on managerial work and management in pluralistic organizations, we sought to answer the questions: What is the content of managerial work of CEOs in public healthcare in Italy? How do healthcare CEOs perform their managerial work in complex interactions with multiple stakeholders?

Methods

For this study we adopted a multi-method approach in which we conducted a survey to investigate CEO behaviors, tracked CEO working time for 4 weeks, and conducted semi-structured interviews with senior CEOs.

Results

CEOs in public healthcare devote most of their time to interaction, which half of which is perceived as being occupied with apparently mundane problems. Nonetheless, devoting time to such activities is functional to a CEO’s goals because change in pluralistic contexts can be achieved only if the CEO can handle the organization’s complexity. CEOs do this by engaging in routines and conversations with professionals, creating consensus, and establishing networks with external stakeholders.

Conclusions

CEOs are called to reduce fragmentation and foster cooperation across disciplines and professional groups, with the overarching aim to achieve integrated care. Using an analytical approach we were able to take into account the context and the relational dimension of the managerial work of healthcare CEOs and the specificities of this role.

Trial registration

This article does not report the results of a healthcare intervention on human participants, and the material used in the research did not require ethical approval according to Italian law.
A healthcare workers’ mHealth adoption instrument for the developing world
Authors: Addotey-Delove Michael , Scott Richard E. , Mars Maurice
Published: October 2022

Introduction

Healthcare workers’ adoption of mHealth is critical to the success or failure of clinician based mHealth services in the developing world. mHealth adoption is affected or promoted by certain factors, some of which are peculiar to the developing world. Identifying these factors and evaluating them will help develop a valid and reliable measuring instrument for more successful prediction of mHealth adoption in the future. The aim of this study was to design and develop such an instrument.

Method

A Healthcare workers’ mHealth Adoption Questionnaire (HmAQ) was developed based on five constructs identified through a prior literature review: multi-sectorial engagement and ownership; staffing and technical support; reliable infrastructure; usefulness and stewardship; and intention to adopt. After testing face and content validity, the questionnaire was administered to 104 nurses and midwives in the Ewutu-Senya district of the Central Region of Ghana who used a maternal mHealth intervention. After data collection confirmatory factor analysis and structural equation modelling were applied and the Healthcare Worker mHealth Adoption Impact Model (HmAIM) developed.

Results

Exploratory factor analysis showed the eigenvalue of all five components to be significant (cumulative total greater than 1.0). Bartlett’s Test of Sphericity was significant, the Kaiser-Meyer-Olkin value was 0.777, and the mean Cronbach’s α value was 0.82 (range 0.81–0.83). Confirmatory factor analysis showed that constructs for the HmAQ were within acceptable limits and valid. Structural equation modelling showed the causal relationships between components. This resulted in development of the HmAIM. A modified model was then developed using the averages of individual construct items. This model showed strong correlation among the constructs. Further research will be required to understand new dimensions of mHealth adoption as a result of emerging technology needs, new complexities in the healthcare work environment, and how different cadres of healthcare workers respond to it.

Conclusion

The study presents a valid and reliable instrument, the HmAIM, to serve as a tool for assessment of healthcare workers’ mHealth adoption in the developing world. Use of the instrument will enhance the likelihood of successful adoption of mHealth implementations.
Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC
Authors: Becker-Pelster Eva M. , Hahn Michael G. , Delbeck Martina , Dietz Lisa , Hüser Jörg , Kopf Johannes , Kraemer Thomas , Marquardt Tobias , Mondritzki Thomas , Nagelschmitz Johannes , Nikkho Sylvia M. , Pires Philippe V. , Tinel Hanna , Weimann Gerrit , Wunder Frank , Sandner Peter , Schuhmacher Joachim , Stasch Johannes-Peter , Truebel Hubert K. F.
Published: October 2022

Background

Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential.

Methods

We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592).

Results

Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model.

Conclusion

Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.
Human umbilical cord mesenchymal stem cells combined with pirfenidone upregulates the expression of RGS2 in the pulmonary fibrosis in mice
Authors: Wu Xian , Gou Hao , Zhou Ou , Qiu Huijun , Liu Hanmin , Fu Zhou , Chen Lina
Published: October 2022

Objective

The therapeutic effect of umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in combination with pirfenidone (PFD) on pulmonary fibrosis in mice and its possible mechanism were investigated.

Methods

C57BL/6 mice were randomly divided into six groups: control group, model group, P10 group, P30 group, P100 group, and P300 group. Modeled by tracheal intubation with 3 mg/kg bleomycin drip, each dose of PFD was administered daily by gavage from day 7 onwards. The mice were observed continuously for 21 days and survival was recorded. Lung tissues were collected on day 21, and hematoxylin–eosin (HE) and Masson staining were performed to assess morphological changes and collagen deposition in the lungs. Collagen content was measured by the Sircol method, and fibrosis marker levels were detected by PCR and Western blot. Another batch of C57BL/6 mice was then randomly divided into five groups: hUC-MSC control group, model group, P100 group, hUC-MSC treatment group, and hUC-MSCs + P30 group. On day 7, 5 × 105 hUC-MSCs were injected into the tail vein, the mice were administered PFD gavage daily from day 7 onwards, and their survival was recorded. Lung tissues were collected on day 21 to detect pathological changes, the collagen content, and the expression of regulator of G protein signaling 2 (RGS2). Pulmonary myofibroblasts (MFBs) were divided into an MFB group and an MFB + hUC-MSCs group; different doses of PFD were administered to each group, and the levels of RGS2, intracellular Ca2+, and fibrosis markers were recorded for each group.

Results

Compared with other PFD group doses, the P100 group had significantly improved mouse survival and lung pathology and significantly reduced collagen and fibrosis marker levels (p < 0.05). The hUC-MSCs + P30 group had significantly improved mouse survival and lung pathology, significantly reduced collagen content and fibrosis marker levels (p < 0.05), and the efficacy was better than that of the P100 and hUC-MSCs groups (p < 0.05). RGS2 expression was significantly higher in the MSCs + P30 group compared with the P100 and hUC-MSCs groups (p < 0.05). PFD increased RGS2 expression in MFBs (p < 0.05) in a dose-dependent manner. Compared with PFD and hUC-MSCs treatment alone, combination of hUC-MSCs and PFD increased RGS2 protein levels, significantly decreased intracellular Ca2+ concentration, and significantly reduced fibrosis markers.

Conclusion

The findings suggest that hUC-MSCs combined with low-dose PFD have a therapeutic effect better than that of the two treatments used separately. Its effect on attenuating bleomycin-induced pulmonary fibrosis in mice is related to the increase of RGS2.
Implication of asymptomatic and clinical Plasmodium falciparum infections on biomarkers of iron status among school-aged children in Malawi
Authors: Ntenda Peter A. M. , Chirambo Angeziwa C. , Nkoka Owen , El-Meidany Walaa M. , Goupeyou-Youmsi Jessy
Published: October 2022

Background

Iron status is considered as a continuum from an iron deficiency with anaemia, without anaemia, varying amounts of stored iron to iron overload. The burden ofPlasmodium falciparuminfections is typically high among school-aged children (SAC). Nonetheless, SAC are often less likely to be covered by malaria interventions, making them a group with an untreated reservoir of parasite transmission. This study aimed to assess the effects of asymptomatic and clinical malaria infections on biochemical markers of iron status among SAC in Malawi.

Methods

Data from the 2015–2016 Malawi Micronutrient Survey (MNS) was used and multivariable logistic regression models using a generalized estimating equation to account for the complex cluster survey design were constructed. Blood samples of 684 children aged 5 to 14 years old were evaluated for clinical and asymptomatic malaria infections. Furthermore, blood samples were used to estimate haemoglobin (Hb), serum ferritin (SF) and, soluble transferrin receptors (sTfR) concentrations.

Results

Of the 684 SAC analysed, approximately 42% had asymptomatic malaria, while 41.0% had clinical malaria. Anaemia (low Hb levels), iron deficiency (low SF concentration), and functional iron deficiency (high sTfR levels) were found in 20%, 5%, and 30% of the children, respectively. School-aged children with asymptomatic malaria had increased odds of being anaemic (adjusted odds ratio [aOR]: 3.71, 95% confidence interval [CI]: 2.29–5.99) and increased levels of sTfR (aOR: 3.00, 95% CI 2.01–4.47). Similarly, SAC with clinical malaria had increased odds of being anaemic (aOR: 3.54, 95% CI 2.19–5.72) and increased levels of sTfR (aOR: 3.02, 95% CI 2.02–4.52).

Conclusions

Both asymptomatic and clinical malaria were independent risk factors for anaemia and functional iron deficiency (FID). The notion that asymptomatic and clinical malaria were associated with both anaemia and FID underscores the need for public health programmers to consider adding mass screening and treatment for malaria to existing school-based health programmes.
β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression
Authors: Liu Yang , Song Nanshan , Yao Hang , Jiang Siyuan , Wang Yueping , Zheng Ying , Zhou Yuanzhang , Ding Jianhua , Hu Gang , Lu Ming
Published: October 2022

Background

Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation.

Methods

We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence.

Results

Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK–STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression.

Conclusions

Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.
Combination of long-term 13CO2 labeling and isotopolog profiling allows turnover analysis of photosynthetic pigments in Arabidopsis leaves
Authors: Banh Anh Thi-Mai , Thiele Björn , Chlubek Antonia , Hombach Thomas , Kleist Einhard , Matsubara Shizue
Published: October 2022

Background

Living cells maintain and adjust structural and functional integrity by continual synthesis and degradation of metabolites and macromolecules. The maintenance and adjustment of thylakoid membrane involve turnover of photosynthetic pigments along with subunits of protein complexes. Quantifying their turnover is essential to understand the mechanisms of homeostasis and long-term acclimation of photosynthetic apparatus. Here we report methods combining whole-plant long-term 13CO2 labeling and liquid chromatography - mass spectrometry (LC–MS) analysis to determine the size of non-labeled population (NLP) of carotenoids and chlorophylls (Chl) in leaf pigment extracts of partially 13C-labeled plants.

Results

The labeling chamber enabled parallel 13CO2 labeling of up to 15 plants of Arabidopsis thaliana with real-time environmental monitoring ([CO2], light intensity, temperature, relative air humidity and pressure) and recording. No significant difference in growth or photosynthetic pigment composition was found in leaves after 7-d exposure to normal CO2 (~ 400 ppm) or 13CO2 in the labeling chamber, or in ambient air outside the labeling chamber (control). Following chromatographic separation of the pigments and mass peak assignment by high-resolution Fourier-transform ion cyclotron resonance MS, mass spectra of photosynthetic pigments were analyzed by triple quadrupole MS to calculate NLP. The size of NLP remaining after the 7-d 13CO2 labeling was ~ 10.3% and ~ 11.5% for all-trans- and 9-cis-β-carotene, ~ 21.9% for lutein, ~ 18.8% for Chl a and 33.6% for Chl b, highlighting non-uniform turnover of these pigments in thylakoids. Comparable results were obtained in all replicate plants of the 13CO2 labeling experiment except for three that were showing anthocyanin accumulation and growth impairment due to insufficient water supply (leading to stomatal closure and less 13C incorporation).

Conclusions

Our methods allow 13CO2 labeling and estimation of NLP for photosynthetic pigments with high reproducibility despite potential variations in [13CO2] between the experiments. The results indicate distinct turnover rates of carotenoids and Chls in thylakoid membrane, which can be investigated in the future by time course experiments. Since 13C enrichment can be measured in a range of compounds, long-term 13CO2 labeling chamber, in combination with appropriate MS methods, facilitates turnover analysis of various metabolites and macromolecules in plants on a time scale of hours to days.
Randomized controlled trials in de-implementation research: a systematic scoping review
Authors: Raudasoja Aleksi J. , Falkenbach Petra , Vernooij Robin W. M. , Mustonen Jussi M. J. , Agarwal Arnav , Aoki Yoshitaka , Blanker Marco H. , Cartwright Rufus , Garcia-Perdomo Herney A. , Kilpeläinen Tuomas P. , Lainiala Olli , Lamberg Tiina , Nevalainen Olli P. O. , Raittio Eero , Richard Patrick O. , Violette Philippe D. , Komulainen Jorma , Sipilä Raija , Tikkinen Kari A. O.
Published: October 2022

Background

Healthcare costs are rising, and a substantial proportion of medical care is of little value. De-implementation of low-value practices is important for improving overall health outcomes and reducing costs. We aimed to identify and synthesize randomized controlled trials (RCTs) on de-implementation interventions and to provide guidance to improve future research.

Methods

MEDLINE and Scopus up to May 24, 2021, for individual and cluster RCTs comparing de-implementation interventions to usual care, another intervention, or placebo. We applied independent duplicate assessment of eligibility, study characteristics, outcomes, intervention categories, implementation theories, and risk of bias.

Results

Of the 227 eligible trials, 145 (64%) were cluster randomized trials (median 24 clusters; median follow-up time 305 days), and 82 (36%) were individually randomized trials (median follow-up time 274 days). Of the trials, 118 (52%) were published after 2010, 149 (66%) were conducted in a primary care setting, 163 (72%) aimed to reduce the use of drug treatment, 194 (85%) measured the total volume of care, and 64 (28%) low-value care use as outcomes. Of the trials, 48 (21%) described a theoretical basis for the intervention, and 40 (18%) had the study tailored by context-specific factors. Of the de-implementation interventions, 193 (85%) were targeted at physicians, 115 (51%) tested educational sessions, and 152 (67%) multicomponent interventions. Missing data led to high risk of bias in 137 (60%) trials, followed by baseline imbalances in 99 (44%), and deficiencies in allocation concealment in 56 (25%).

Conclusions

De-implementation trials were mainly conducted in primary care and typically aimed to reduce low-value drug treatments. Limitations of current de-implementation research may have led to unreliable effect estimates and decreased clinical applicability of studied de-implementation strategies. We identified potential research gaps, including de-implementation in secondary and tertiary care settings, and interventions targeted at other than physicians. Future trials could be improved by favoring simpler intervention designs, better control of potential confounders, larger number of clusters in cluster trials, considering context-specific factors when planning the intervention (tailoring), and using a theoretical basis in intervention design.

Registration

OSF Open Science Framework hk4b2
Prediction model for delirium in patients with cardiovascular surgery: development and validation
Authors: Xu Yanghui , Meng Yunjiao , Qian Xuan , Wu Honglei , Liu Yanmei , Ji Peipei , Chen Honglin
Published: October 2022

Background

The aim of this study was to construct a nomogram model for discriminating the risk of delirium in patients undergoing cardiovascular surgery.

Methods

From January 2017 to June 2020, we collected data from 838 patients who underwent cardiovascular surgery at the Affiliated Hospital of Nantong University. Patients were randomly divided into a training set and a validation set at a 5:5 ratio. A nomogram model was established based on logistic regression. Discrimination and calibration were used to evaluate the predictive performance of the model.

Results

The incidence of delirium was 48.3%. A total of 389 patients were in the modelling group, and 449 patients were in the verification group. Logistic regression analysis showed that CPB duration (OR $$=$$
=
1.004, 95% CI: 1.001–1.008, $$P=$$

P
=

0.018), postoperative serum sodium (OR $$=$$
=
1.112, 95% CI: 1.049–1.178, $$P<$$

P
<

0.001), age (OR $$=$$
=
1.027, 95% CI: 1.006–1.048, $$P=$$

P
=

0.011), and postoperative MV (OR $$=$$
=
1.019, 95% CI: 1.008–1.030, $$P<$$

P
<

0.001) were independent risk factors. The results showed that AUC$$^\text {ROC}$$

ROC

was 0.712 and that the 95% CI was 0.661–0.762. The Hosmer-Lemeshow goodness of fit test showed that the predicted results of the model were in good agreement with the actual situation ($$\chi ^{2}=$$

χ
2

=

6.200, $$P=$$

P
=

0.625). The results of verification showed that the AUC$$^\text {ROC}$$

ROC

was 0.705, and the 95% CI was 0.657–0.752. The Hosmer-Lemeshow goodness of fit test results were $$\chi ^{2}=$$

χ
2

=

8.653 and $$P=$$

P
=

0.372, indicating that the predictive effect of the model is good.

Conclusions

The establishment of the model provides accurate and objective assessment tools for medical staff to start preventing postoperative delirium in a purposeful and focused manner when a patient enters the CSICU after surgery.
Inflammatory aneurysm of ascending aorta and left anterior descending artery
Authors: Stella Amanda , Tuluca Alexandra , Arce Anastasia , Samuels Louis
Published: October 2022

Background

Inflammatory aortic aneurysms represent less than 5% of ascending aortic aneurysms and are mostly diagnosed intraoperatively. Furthermore, to our knowledge, a case of an accompanying inflammatory LAD aneurysm has not been previously reported.

Case presentation

We report an unusual case of a 42-year-old female with a symptomatic inflammatory aneurysm of the ascending aorta and the LAD. The patient underwent successful resection and replacement of the aneurysm as well as bypass of the LAD.

Conclusions

The underlying etiology of severe inflammatory ascending aortic aneurysms in a previously healthy individual remains unknown. The pre-operative diagnosis is difficult to obtain as it does not have a characteristic appearance on currently available imaging modalities.
Stents versus bypass surgery: 3-year mortality risk of patients with coronary interventions aged 50+ in Germany
Authors: Nestler Sophia , Kreft Daniel , Donndorf Peter , Ince Hüseyin , Doblhammer Gabriele
Published: October 2022

Objectives

Due to demographic aging, the prevalence of coronary artery disease (CAD) is expected to increase in the future, resulting in a growing demand for stent and bypass interventions. This study aims to investigate the mortality risk of patients following conventional coronary artery bypass grafting (CABG) or endovascular procedure by the implantation of bare-metal stents (BMS) or drug-eluting stents (DES).

Methods

Based on a random sample of 250,000 members of Germany’s largest health insurance ‘Allgemeine Ortskrankenkassen’ (AOK) from 2004 to 2015, incident CAD patients were analyzed by Cox Proportional-Hazard models. Risk adjustment was made for sex, age, other cardiac diseases, non-cardiovascular comorbidities and years since intervention. Due to later admission of DES and thus a shorter observation time, mortality was examined for 3 years since the intervention.

Results

BMS represented the most frequent procedure (48%). We found similar proportions of CABG (19%) and DES interventions (23%). After risk adjustment, the models showed a 21% (p = 0.004) lower mortality risk of patients with DES and also a 21% (p = 0.002) lower mortality risk of CABG patients compared to persons with BMS.

Conclusion

Based on a large-scale dataset, our study demonstrated survival advantages of CABG and DES interventions over BMS, with no differences between the DES and CABG groups. The results help to assess the risks of coronary interventions. Aspects of quality of life, severity of postoperative physical limitations, duration of rehabilitation, patients’ preferences, and aspects of cost-effectiveness for hospitals and society should be further considered.

Graphical abstract
Required displacement factors for evaluating and comparing climate impacts of intensive and extensive forestry in Germany
Authors: Christian Buschbeck , Stefan Pauliuk
Published: October 2022

Background

Forestry plays a major role in climate change mitigation. However, which intensity of logging is best suited for that task remains controversial. We contribute to the debate by quantitatively analyzing three different forest management scenarios in Germany—a baseline scenario which represents a continuation of current forest management practice as well as an intensive and an extensive logging scenario. We assess whether increased carbon storage in wood products and substitution of other emission-intensive materials can offset reduced carbon stocks in the forest due to increased harvesting. For that, we calculate annual required displacement factors (RDF)—a dimensionless quantity that indicates the minimal displacement factor (DF) so that intensive forestry outperforms extensive forestry from a climate perspective.

Results

If the intensive forest management scenario is included in the comparison, the RDF starts off with relatively high values (1 to 1.5) but declines over time and eventually even reaches negative values. Comparing the extensive scenario to a baseline yields RDF values between 0.1 and 0.9 with a slightly increasing trend. Compared to RDFs, expected future DFs are too low to favour the intensive forestry scenario and too high to favour the extensive forestry scenario, during the first 25 years of the modeling period. However, towards the end of the modeling period, the relationship between DFs and RDF is turned around in both comparisons. In the comparison between intensive and extensive forest management RDF values are very similar to future DF trajectories.

Conclusion

RDFs are a useful tool for comparing annual climate impacts of forest growth scenarios and can be used to benchmark material and energy substitution effects of wood. Our results indicate that the baseline scenario reflects an effective compromise between carbon stocks in the forest and carbon displacement by wood use. For a longer modeling period, however, this might not be the case. Which of the alternative scenarios would be best suited for climate change mitigation is heavily dependent on future DF trajectory. Hence, our findings highlight the necessity of robust projections of forest dynamics and industry decarbonization pathways.
EZCancerTarget: an open-access drug repurposing and data-collection tool to enhance target validation and optimize international research efforts against highly progressive cancers
Authors: Dora David , Dora Timea , Szegvari Gabor , Gerdán Csongor , Lohinai Zoltan
Published: October 2022

The expanding body of potential therapeutic targets requires easily accessible, structured, and transparent real-time interpretation of molecular data. Open-access genomic, proteomic and drug-repurposing databases transformed the landscape of cancer research, but most of them are difficult and time-consuming for casual users. Furthermore, to conduct systematic searches and data retrieval on multiple targets, researchers need the help of an expert bioinformatician, who is not always readily available for smaller research teams. We invite research teams to join and aim to enhance the cooperative work of more experienced groups to harmonize international efforts to overcome devastating malignancies. Here, we integrate available fundamental data and present a novel, open access, data-aggregating, drug repurposing platform, deriving our searches from the entries of Clue.io. We show how we integrated our previous expertise in small-cell lung cancer (SCLC) to initiate a new platform to overcome highly progressive cancers such as triple-negative breast and pancreatic cancer with data-aggregating approaches. Through the front end, the current content of the platform can be further expanded or replaced and users can create their drug-target list to select the clinically most relevant targets for further functional validation assays or drug trials. EZCancerTarget integrates searches from publicly available databases, such as PubChem, DrugBank, PubMed, and EMA, citing up-to-date and relevant literature of every target. Moreover, information on compounds is complemented with biological background information on eligible targets using entities like UniProt, String, and GeneCards, presenting relevant pathways, molecular- and biological function and subcellular localizations of these molecules. Cancer drug discovery requires a convergence of complex, often disparate fields. We present a simple, transparent, and user-friendly drug repurposing software to facilitate the efforts of research groups in the field of cancer research.