bluuebunny/crossref_metadata_2025 huggingface dataset:
Genofunc: genome annotation and identification of genome features for automated pipelining analysis of virus whole genome sequences
Authors: Yu Xiaoyu
Published: May 2023

Background

Viral genomics and epidemiology have been increasingly important tools for analysing the spread of key pathogens affecting daily lives of individuals worldwide. With the rapidly expanding scale of pathogen genome sequencing efforts for epidemics and outbreaks efficient workflows in extracting genomic information are becoming increasingly important for answering key research questions.

Results

Here we present Genofunc, a toolkit offering a range of command line orientated functions for processing of raw virus genome sequences into aligned and annotated data ready for analysis. The tool contains functions such as genome annotation, feature extraction etc. for processing of large genomic datasets both manual or as part of pipeline such as Snakemake or Nextflow ready for down-stream phylogenetic analysis. Originally designed for a large-scale HIV sequencing project, Genofunc has been benchmarked against annotated sequence gene coordinates from the Los Alamos HIV database as validation with downstream phylogenetic analysis result comparable to past literature as case study.

Conclusion

Genofunc is implemented fully in Python and licensed under the MIT license. Source code and documentation is available at: https://github.com/xiaoyu518/genofunc.
Enhancement of feather degrading keratinase of Streptomyces swerraensis KN23, applying mutagenesis and statistical optimization to improve keratinase activity
Authors: Abd El-Aziz Nagwa M. , Khalil Bigad E. , Ibrahim Hayam Fouad
Published: May 2023

In this study, 25 actinomyces isolates were obtained from 10 different poultry farms and tested for their keratinase activity. The isolate with the highest keratinase activity was identified through molecular identification by PCR and sequencing of the 16S rRNA gene to be Streptomyces spp. and was named Streptomyces werraensis KN23 with an accession number of OK086273 in the NCBI database. Sequential mutagenesis was then applied to this strain using UV, H2O2, and SA, resulting in several mutants. The best keratinolytic efficiency mutant was designated as SA-27 and exhibited a keratinase activity of 106.92 U/ml. To optimize the keratinase expression of mutant SA-27, the Response Surface Methodology was applied using different parameters such as incubation time, pH, carbon, and nitrogen sources. The optimized culture conditions resulted in a maximum keratinase specific activity of 129.60 U/ml. The genetic diversity of Streptomyces werraensis KN23 wild type compared with five mutants was studied using Inter-simple sequence repeat (ISSR). The highest total and polymorphic unique bands were revealed in the S. werraensis KN23 and SA-18 mutant, with 51 and 41 bands, respectively. The dendrogram based on combined molecular data grouped the Streptomyces werraensis and mutants into two clusters. Cluster I included SA-31 only, while cluster II contained two sub-clusters. Sub-cluster one included SA-27, and sub-cluster two included SA-26. The sub-cluster two divided into two sub-sub clusters. Sub-sub cluster one included SA-18, while sub-sub cluster two included one group (SA-14 and S. werraensis KN23).
Recognition and management of hemorrhaging in combination with emerging enterogenic sepsis during a hepatectomy: a case report
Authors: Chen Yingjie , Liao Yanling , Chen Xiaoying , Fan Hanliang , Lin Daoyi , Zheng Ting , Chen Xiaohui , Gong Cansheng , Gao Fei , Jiang Jundan , Zheng Xiaochun
Published: May 2023

Background

Patients with hemorrhagic shock may develop emerging enterogenic sepsis due to damage to the intestinal mucosal barrier and translocation of intestinal bacteria and endotoxins caused by ischemic injury. Because of the dual effects of anesthesia state and hemorrhagic shock, perioperative emerging enterogenic sepsis is even more rare and insidious.

Case presentation

We reported a case of 56-year-old man who underwent right hepatectomy for intrahepatic bile duct stones. Severe hemorrhage occurred during the procedure and the hemodynamics neither improved nor worsened after rehydration therapy and vasoactive drug administration. Based on the patient’s history and clinical presentation, a possible enterogenic sepsis was considered. After anti-infective treatment and hormone supplementation, the patient’s circulation improved significantly and he had an uneventful recovery.

Conclusion

The possibility of emerging enterogenic sepsis in hemorrhagic shock must always be taken into consideration. Familiarity with the risk factors and pathophysiological alterations of enterogenic sepsis is a prerequisite for early recognition and sound clinical decision making.
MRI-based radiomics model and nomogram for predicting the outcome of locoregional treatment in patients with hepatocellular carcinoma
Authors: Wang Yuxin , Liu Zhenhao , Xu Hui , Yang Dawei , Jiang Jiahui , Asayo Himeko , Yang Zhenghan
Published: May 2023

Background

Prediction of locoregional treatment response is important for further therapeutic strategy in patients with hepatocellular carcinoma. This study aimed to investigate the role of MRI-based radiomics and nomogram for predicting the outcome of locoregional treatment in patients with hepatocellular carcinoma.

Methods

The initial postoperative MRI after locoregional treatment in 100 patients with hepatocellular carcinoma was retrospectively analysed. The outcome was evaluated according to mRECIST at 6 months. We delineated the tumour volume of interest on arterial phase, portal venous phase and T2WI. The radiomics features were selected by using the independent sample t test or nonparametric Mann‒Whitney U test and the least absolute shrinkage and selection operator. The clinical variables were selected by using univariate analysis and multivariate analysis. The radiomics model and combined model were constructed via multivariate logistic regression analysis. A nomogram was constructed that incorporated the Rad score and selected clinical variables.

Results

Fifty patients had an objective response, and fifty patients had a nonresponse. Nine radiomics features in the arterial phase were selected, but none of the portal venous phase or T2WI radiomics features were predictive of the treatment response. The best radiomics model showed an AUC of 0.833. Two clinical variables (hCRP and therapy method) were selected. The AUC of the combined model was 0.867. There was no significant difference in the AUC between the combined model and the best radiomics model (P = 0.573). Decision curve analysis demonstrated the nomogram has satisfactory predictive value.

Conclusions

MRI-based radiomics analysis may serve as a promising and noninvasive tool to predict outcome of locoregional treatment in HCC patients, which will facilitate the individualized follow-up and further therapeutic strategies guidance.
Optimal sequencing of the first- and second-line target therapies in metastatic renal cell carcinoma: based on nationally representative data analysis from the Korean National Health Insurance System
Authors: Kang Dong Hyuk , Lee Joo Yong , Lee Yunhee , Ha U-Syn
Published: May 2023

Background

The authors intend to compare the effects of each targeted therapy (TT) in the treatment of patients with metastatic renal cell carcinoma (mRCC) using big data based on the Korean National Health Insurance System (NHIS) and determine the optimal treatment sequence.

Methods

Data on the medical use of patients with kidney cancer were obtained from the NHIS database from January 1, 2002, to December 31, 2020. Patient variables included age, sex, income level, place of residence, prescribing department, and duration from diagnosis to the prescription date. The primary outcome was overall survival (OS) for each drug and sequencing. We performed propensity score matching (PSM) according to age, sex, and Charlson Comorbidity Index based on the primary TTs.

Results

After 1:1 PSM, the sunitinib (SUN) (n = 1,214) and pazopanib (PAZ) (n = 1,214) groups showed a well-matched distribution across the entire cohort. In the primary treatment group, PAZ had lower OS than SUN (HR, 1.167; p = 0.0015). In the secondary treatment group, axitinib (AXI) had more favorable OS than cabozantinib (CAB) (HR, 0.735; p = 0.0118), and everolimus had more adverse outcomes than CAB (HR, 1.544; p < 0.0001). In the first to second TT sequencing, SUN–AXI had the highest OS; however, there was no statistically significant difference when compared with PAZ–AXI, which was the second highest (HR, 0.876; p = 0.3312). The 5-year survival rate was calculated in the following order: SUN–AXI (51.44%), PAZ–AXI (47.12%), SUN–CAB (43.59%), and PAZ–CAB (34.28%). When the four sequencing methods were compared, only SUN–AXI versus PAZ–CAB (p = 0.003) and PAZ–AXI versus PAZ–CAB (p = 0.017) were statistically significant.

Conclusions

In a population-based RWD analysis of Korean patients with mRCC, SUN-AXI sequencing was shown to be the most effective among the first to second TT sequencing methods in treatment, with a relative survival advantage over other sequencing combinations. To further support the results of this study, risk-stratified analysis is needed.
Identification of urgent gaps in public and policymaker knowledge of heart failure: Results of a global survey
Authors: Lam Carolyn S. P. , Harding Ed , Bains Marc , Chin Alex , Kanumilli Naresh , Petrie Mark C. , Pohja-Hutchison Paula , Yang Jiefu , Butler Javed
Published: May 2023

Background

Despite advances in the treatment of heart failure (HF) with reduced ejection fraction, people with HF continue to have a high risk of mortality and hospitalisation. Patients also suffer from poor quality of life, with reduced societal and economic participation. The burden of HF on patients and healthcare systems is extraordinary, yet awareness remains low. This survey was conducted to identify gaps in general public and policymaker knowledge around HF.

Methods

A closed-question web-based survey of the general public and policymakers was conducted between February and October 2020. Study outcomes assessed the participants’ awareness and understanding of HF symptoms, risk factors and mortality, and views around hospital admissions in their country. Responses were collected using multiple-choice questions.

Results

The survey was completed by 26,272 general public respondents in 13 countries and 281 government and public sector policymakers in nine countries. While 99% of general public respondents had heard of HF, their understanding of the condition and its symptoms was poor, and only 6% identified that shortness of breath, fatigue, and leg swelling were the main symptoms of HF. Of policymaker respondents, 14% identified HF as the leading cause of avoidable hospitalisations, and only 4% recognised that ~ 87% of government spending on HF is related to hospitalisations.

Conclusions

Major gaps were identified in the understanding of HF and the burden it places on patients and their caregivers, healthcare systems and society. This study confirms an ongoing need for national policy strategies and investment to raise awareness of the importance of HF prevention, early diagnosis, and implementation of effective treatments to reduce hospitalisations and death.
Hurricanes Irma and Maria and Diabetes incidence in Puerto Rico
Authors: Martínez-Lozano Marijulie , Noboa Carlamarie , Alvarado-González Gerardo , Joshipura Kaumudi J.
Published: May 2023

Objective

To evaluate the impact of Hurricanes Irma/Maria on diabetes incidence in Puerto Rico. Mortality increased substantially after the hurricanes, but morbidity was not assessed.

Methods

We recruited 364 participants from the San Juan Overweight Adults Longitudinal Study (SOALS) aged 40–65 years who completed a three-year follow-up and were free of diabetes. We conducted additional questionnaires 1.7–2.5 years after hurricanes. Glycosylated hemoglobin (HbA1c), fasting glucose and insulin were assessed at all three visits. We compared diabetes incidence between pre-hurricane visits and between visits spanning the hurricanes using Generalized Estimating Equation (GEE) adjusting for within person repeated measures, age, and body mass index (BMI).

Results

Diabetes incidence was significantly higher spanning the hurricanes than pre-hurricane (multivariate GEE model: IRR = 2.1; 95% CI: 1.4–3.1). There was a significantly higher increase spanning the hurricanes compared to pre-hurricanes for Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (median: 0.3 uIU/mL vs. 0.2 uIU/mL). HbA1c levels increased by 0.4% spanning the hurricanes.

Conclusion

Increases in diabetes incidence, HOMA-IR and HbA1c were higher spanning the hurricanes compared to the pre-hurricanes period. The increase in diabetes incidence remains significant after adjusting for age and BMI.
Cross-sectional survey of attitudes and beliefs towards dementia risk reduction among Australian older adults
Authors: Siette Joyce , Dodds Laura , Deckers Kay , Köhler Sebastian , Armitage Christopher J.
Published: May 2023

Background

Little is known about what drives older adults’ motivation to change their behaviour and whether that is associated with their personal dementia risk profile. Our aims were to (i) understand what sociodemographic factors are associated with older Australians’ motivation to change behaviour to reduce their dementia risk, and (ii) explore the relationship between socio-demographic factors and motivation to reduce dementia risk with health- and lifestyle-based dementia risk scores in older adults.

Methods

A cross-sectional online postal or telephone survey was administered to community-dwelling older adults in New South Wales, Australia between January and March 2021. Measures included socioeconomic status, locality, and health status, the Motivation to Change Lifestyle and Health Behaviours for Dementia Risk Reduction (MCLHB-DRR) scale and the lifestyle-based dementia risk score (LIBRA index). Multiple linear regression analyses were used to explore the associations for (i) sociodemographic factors and motivation to reduce dementia risk (MCLHB-DRR scales) and (ii) sociodemographic factors and motivation to reduce dementia risk with health- and lifestyle-based dementia risk (LIBRA index).

Results

A total of 857 older adults (mean age 73.3 years, SD = 6.0, range 65–94; 70% women; 34.6% less than grade 6 education) completed the survey. Respondents reported high levels of motivation to adopt behaviour changes, agreeing on the importance of good health. Individuals who were younger were more likely to have greater motivation to modify lifestyle to reduce dementia risk and had higher perceived benefits to gain by adopting a healthy lifestyle. Dementia risk scores were moderately low (mean LIBRA index =− 2.8 [SD = 2.0], range − 5.9–3.8), indicating relatively moderate-to-good brain health. Men with low socioeconomic status and higher perceived barriers to lifestyle change had higher dementia risk scores.

Conclusions

Public health campaigns need to overcome motivational barriers to support reductions in dementia risk. A multifaceted and inclusive approach targeting both sociodemographic differences and impediments to brain healthy lifestyles is required to achieve genuine change.

Trial registration

ACTRN12621000165886, Date of registration: 17/02/2021.
Translation, cultural adaptation and validity assessment of the Dutch version of the eHealth Literacy Questionnaire: a mixed-method approach
Authors: Poot Charlotte C. , Meijer Eline , Fokkema Marjolein , Chavannes Niels H. , Osborne Richard H. , Kayser Lars
Published: May 2023

Background

The digitalization of healthcare requires users to have sufficient competence in using digital health technologies. In the Netherlands, as well as in other countries, there is a need for a comprehensive, person-centered assessment of eHealth literacy to understand and address eHealth literacy related needs, to improve equitable uptake and use of digital health technologies.

Objective

We aimed to translate and culturally adapt the original eHealth Literacy Questionnaire (eHLQ) to Dutch and to collect initial validity evidence.

Methods

The eHLQ was translated using a systematic approach with forward translation, an item intent matrix, back translation, and consensus meetings with the developer. A validity-driven and multi-study approach was used to collect validity evidence on 1) test content, 2) response processes and 3) internal structure. Cognitive interviews (n = 14) were held to assess test content and response processes (Study 1). A pre-final eHLQ version was completed by 1650 people participating in an eHealth study (Study 2). A seven-factor Confirmatory Factor Analysis (CFA) model was fitted to the data to assess the internal structure of the eHLQ. Invariance testing was performed across gender, age, education and current diagnosis.

Results

Cognitive interviews showed some problems in wording, phrasing and resonance with individual’s world views. CFA demonstrated an equivalent internal structure to the hypothesized (original) eHLQ with acceptable fit indices. All items loaded substantially on their corresponding latent factors (range 0.51–0.81). The model was partially metric invariant across all subgroups. Comparison of scores between groups showed that people who were younger, higher educated and who had a current diagnosis generally scored higher across domains, however effect sizes were small. Data from both studies were triangulated, resulting in minor refinements to eight items and recommendations on use, score interpretation and reporting.

Conclusion

The Dutch version of the eHLQ showed strong properties for assessing eHealth literacy in the Dutch context. While ongoing collection of validity evidence is recommended, the evidence presented indicate that the eHLQ can be used by researchers, eHealth developers and policy makers to identify eHealth literacy needs and inform the development of eHealth interventions to ensure that people with limited digital access and skills are not left behind.
Supporting intersecting cultural needs of gender and age by increasing cultural safety and humility for Housing First initiatives
Authors: Fang Mei Lan , Canham Sarah L. , Battersby Lupin
Published: May 2023

Background

To sufficiently house and support persons experiencing homelessness (PEH), deeper understandings of the cultural appropriateness and responsiveness of community resources and the service delivery system is essential. In the case of Metro Vancouver, Canada, the cultural appropriateness and responsiveness of Housing First as a service model for supporting PEH was explored.

Methods

Local service providers and stakeholders (n = 52) participated in three full day service-mapping workshops to identify Housing First supports for older adults, youth, and women experiencing homelessness, as part of a municipal-wide participatory and action-oriented study. Data were analyzed using a structured framework thematic analysis approach and cultural safety and humility lenses.

Results

We generated three key themes: (i) insufficient built environments create challenges across gender and age, (ii) cultural safety and humility concerns at the intersection of gender and age, and (iii) implications for a culturally-responsive Housing First implementation.

Conclusions

Findings informed the development of a Culturally-Responsive Planning resource to support housing, health, and social service providers who are implementing Housing First initiatives.
Between guidelines and clinical trials: evidence-based advice on the pharmacological management of non-specific chronic low back pain
Authors: Migliorini Filippo , Vaishya Raju , Pappalardo Gaetano , Schneider Marco , Bell Andreas , Maffulli Nicola
Published: May 2023

The pharmacological management of nonspecific chronic low back pain (NCLBP) aims to restore patients’ daily activities and improve their quality of life. The management of NCLBP is not well codified and extremely heterogeneous, and residual symptoms are common. Pharmacological management should be considered as co-adjuvant to non-pharmacological therapy, and should be guided by the symptoms reported by the patients. Depending on the individual severity of NCLPB, pharmacological management may range from nonopioid to opioid analgesics. It is important to identify patients with generalized sensory hypersensitivity, who may benefit from dedicated therapy. This article provides an evidence-based overview of the principles of pharmacological management of NCLPB.
A solitary osteolytic lesion with pathological fracture in the cervical spine - a case report
Authors: Kuang Guan-Ming , Loo Nga-Nuen , Gao Qingpeng , Li Jishi , Luo Lin , Chen Shuang , Cheung Jason Pui Yin , Cheung Kenneth M.C.
Published: May 2023

Background

Langerhans cell histiocytosis (LCH) is a rare disorder. The treatment options vary depending on how many organs are involved and how extensive the disease is. In this report, a case of LCH with isolated 6th cervical vertebra (C6) collapse was presented. This case was treated with anterior corpectomy and instrumented fusion, followed by local radiotherapy (RT), with a good clinical outcome up to postoperative six months.

Case presentation

This was a 47-year-old female patient with a complaint of neck pain and bilateral shoulder pain for two months before consultation. She was initially treated with analgesics, but the pain was persistent. Further radiological evaluations revealed an osteolytic lesion within the C6 vertebral body with a pathological fracture. Magnetic resonance imaging (MRI) with contrast of the cervical spine revealed diffused hypointense signal changes on the T1-weighted images and hyperintense signal changes on the T2-weighted images in the C6 vertebral body, with significant contrast-enhanced infiltration signals. Furthermore, in positron emission tomography-computed tomography (PET-CT), focal hypermetabolism and abnormal uptake signals were seen only in the C6 vertebral body. The patient underwent an anterior cervical corpectomy with instrumented fusion. The histopathological results confirmed the diagnosis of LCH. The patient reported significant pain relief on postoperative day one. Moreover, she was treated by local RT at postoperative one month. Good clinical outcomes were achieved in the form of no pain and recovery in neck mobility up to postoperative six months. No evidence of recurrence was observed at the final follow-up.

Conclusions

This case report describes a treatment option for a solitary C6 collapse with LCH managed by anterior corpectomy and instrumented fusion, followed by local RT, with a good clinical outcome at postoperative six months. More studies are needed to elucidate whether such a treatment strategy is superior to surgery or RT alone.
Knowledge of Saudi dental students and interns towards luting cements and their applications in fixed prosthodontics
Authors: Ellakany Passent , Abualsaud Reem , Gad Mohammed M. , Atteya Sara , El Meligy Omar A. , Qutub Osama A. , Mahrous Amr A.
Published: May 2023

Background

Enhancement of students’ knowledge is essential in improving their clinical skills and performance. Thus, the curriculum should be prepared to achieve a better outcome. The current study aimed to determine the dental students’ and interns’ basic knowledge towards dental luting cements and their application in dental practice to improve the theoretical and clinical training sections.

Materials and methods

A cross–sectional study was conducted among dental students and interns at three Colleges of Dentistry in the Kingdom of Saudi Arabia between September 2019–June 2020. An online questionnaire was used which included demographic data, questions about luting cement usage, cementation techniques, and commonly used cements in dental clinics. Descriptive analysis and chi–square test were used to show the association between level of dental education and the use of dental cements using SPSS software. The significance level was set at 5%.

Results

The total respondents were 626 dental students/interns of whom 78.8% were undergraduate dental students. Participants who reported undergraduate studies as the source of information were 79.7%. The type of restoration was the main factor in luting cement selection (62.6%). Concerning the isolation technique in cementing laminate veneers, 49.7% used dri–angles, cotton rolls and saliva ejectors. Dual–cure resin cement was the most common cement used in all the mentioned restorations except in pressed porcelain laminate veneers and cement–retained implant–supported restorations.

Conclusions

Students’ knowledge and practice in managing dental implants and porcelain laminate veneers need to be improved. The selection of a luting agent for a given restoration by students and interns was based on the basic knowledge, available cement, and the type of restoration. Awareness towards the management of short prepared teeth and custom-made cast posts and cores is also limited.
Association between quality antenatal care and low birth weight in Rwanda: a cross-sectional study design using the Rwanda demographic and health surveys data
Authors: Uwimana Gérard , Elhoumed Mohamed , Gebremedhin Mitslal Abrha , Azalati Mougni Mohamed , Nan Lin , Zeng Lingxia
Published: May 2023

Background

Low birth weight (LBW) is an important factor influencing infant morbidity and mortality. Pregnant women should receive a variety of interventions during antenatal care (ANC) that are crucial in improving birth weight. ANC visits alone do not promise that women have received all recommended antenatal services. However, there are limited evidence of the relationship between ANC quality and LBW in Rwanda. Therefore, the purpose of this study was to assess the association between quality ANC and LBW along with the factors influencing LBW and how quality ANC affects LBW in Rwandan pregnant women.

Methods

The Demographic and Health Surveys (DHS) are cross-sectional, nationally representative household surveys that collect population, health, and nutrition. In this Study we used three waves of Rwanda Demographic and Health Surveys 2010,2014-5 and 2019-20. A total of 16,144 women aged 15 to 49 years who had live births in the five years preceding each survey were included in this study. A stratified two-stage sampling methods was used to select the participants. The first stage involves selecting clusters (villages) from a list of all clusters in the country. The second stage involves selecting households within each cluster. A survey adjusted for clusters at multiple level and a bivariate and multivariable logistic regression was used to estimate adjusted odds ratios(aOR) and 95% confidence intervals to assess the association between the outcome and independent variables.

Results

The utilization of a high-quality ANC increased slightly over the three survey years and LBW had a slow decline. Out of 5813 women;201(3.45%) had high-quality ANC in the 2010 survey, and out of 5813 newborns,180(3.10%) were LBW. Out of 5404 women;492(9.11%) had high-quality ANC in 2015, and out of 5404 newborns,151(2.79% were LBW). Out of 5203 women,776(14.92%) had high-quality ANC in the 2020 survey year, and out of the 5206 newborns,139(2.67%) were LBW. In multivariable analysis, at a borderline limit high quality ANC was negatively associated with LBW(aOR:0.67;95%CI:0.43,1.05) compared to low-quality ANC. Higher birth orders of the newborn were negatively associated with LBW (aOR:0.63;95%CI:0.49,0.82 and aOR:0.44;95%CI:0.32,0.61 for 2nd -3rd and 4th and above respectively) compared to 1st orders newborn. Newborns from rich households were less likely to experience LBW than those from poor households (aOR:0.71;95%CI:0.55,0.91). Female newborns were associated with an increase of LBW (aOR:1.43;95% CI:1.18,1.73) than male newborns.

Conclusion

The findings confirm the fundamental importance of a high-quality ANC on LBW. The findings could be utilized to develop monitoring strategies and assess pregnancy health assistance programs with a focus on LBW reduction.
A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer
Authors: Kendzia Sandra , Franke Susanne , Kröhler Tarek , Golob-Schwarzl Nicole , Schweiger Caroline , Toeglhofer Anna M. , Skofler Christina , Uranitsch Stefan , El-Heliebi Amin , Fuchs Julia , Punschart Andreas , Stiegler Philipp , Keil Marlen , Hoffmann Jens , Henderson David , Lehrach Hans , Yaspo Marie-Laure , Reinhard Christoph , Schäfer Reinhold , Keilholz Ulrich , Regenbrecht Christian , Schicho Rudolf , Fickert Peter , Lax Sigurd F. , Erdmann Frank , Schulz Marcel H. , Kiemer Alexandra K. , Haybaeck Johannes , Kessler Sonja M.
Published: May 2023

Aim

Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches.

Methods

Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses.

Results

We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells.

Conclusions

IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance.
Conservative management following patellar dislocation: a level I systematic review
Authors: Flores Gustavo Wickert , de Oliveira Deise Ferreira , Ramos Ana Paula Silveira , Sanada Luciana Sayuri , Migliorini Filippo , Maffulli Nicola , Okubo Rodrigo
Published: May 2023

Background

Patellar instability is a common and disabling clinical condition. Treatment of acute primary patellar dislocation aims to reduce the risk of recurrence or painful subluxation and improve function. However, the actual clinical efficacy of any management modality following an acute dislocation has never been demonstrated in prospective or retrospective studies, and the optimal way in which the various management modalities should be used is at best unclear.

Methods

A search was conducted in PubMed, Bireme and Embase databases. Inclusion criteria followed the acronym PICOS, (P) subjects with patellar instability, (I) therapeutic interventions, (C) placebo or control or surgical treatments, (O) rate of dislocations and function, and (S) clinical trials. The Medical Subject Headings (MeSH) terms used were: ((“patellar instability”) OR (“patellar dislocation”)) AND ((physiotherapy) OR (rehabilitation) OR (“conservative treatment”) OR (therapy) OR (therapeutic)). The risk of bias was analysed using the PeDRO scale.

Results

Seven randomized controlled trials including 282 patients were considered. The quality of studies detailing the results of conservative treatment was higher than that of surgical procedures, but all studies have relatively low methodological quality. Four studies compared physiotherapeutic interventions with surgical procedures, and three studies compared conservative intervention techniques.

Conclusion

An unstructured lower limb physical therapy programme evidences similar outcomes to specific exercises. Surgical management is associated with a lower rate of re-dislocation; however, whether surgery produces greater functional outcomes than conservative management is still unclear. The use of a knee brace with a limited range of motion, stretching and neuromuscular exercises are the most commonly recommended physiotherapy methodologies.
Progesterone from ovulatory menstrual cycles is an important cause of breast cancer
Authors: Coelingh Bennink Herjan J. T. , Schultz Iman J. , Schmidt Marcus , Jordan V. Craig , Briggs Paula , Egberts Jan F. M. , Gemzell-Danielsson Kristina , Kiesel Ludwig , Kluivers Kirsten , Krijgh Jan , Simoncini Tommaso , Stanczyk Frank Z. , Langer Robert D.
Published: May 2023

Many factors, including reproductive hormones, have been linked to a woman’s risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting an essential role of P4. During the MC, P4 has a strong proliferative effect on normal breast epithelium, whereas estradiol (E2) has only a minimal effect. The origin of BC has been strongly linked to proliferation associated DNA replication errors, and the repeated stimulation of the breast epithelium by P4 with each MC is likely to impact the epithelial mutational burden. Long-lived cells, such as stem cells, present in the breast epithelium, can carry mutations forward for an extended period of time, and studies show that breast tumors tend to take decades to develop before detection. We therefore postulate that P4 is an important factor in a woman’s lifetime risk of developing BC, and that breast tumors arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.
Breast metastatic tumors in lung can be substituted by lung-derived malignant cells transformed by alternative splicing H19 lncRNA
Authors: Xu Jin Biao , Cao Jun , Xia Jin , Zhu Ying , He Yi , Cao Ming Guo , Fang Bing Mu , Thiery Jean Paul , Zhou Wu
Published: May 2023

Metastasis accounts for most cancer-associated deaths; yet, this complex process remains poorly understood, particularly the relationship between distant metastasis and primary site-derived cells. Here, we modified the classical MMTV–PyMT breast carcinoma model to trace the fate of mammary-derived carcinoma cells. We show that within the lung, when the metastatic breast carcinoma cells are conditionally depleted, transformed lung epithelial cells generate new metastases. Metastatic breast carcinoma cells transmit H19 long noncoding (lnc) RNA to lung epithelial cells through exosomes. SF3B1 bearing mutations at arginine-625 alternatively splices H19 lncRNA in lung epithelial cells, which selectively acts like a molecular sponge to sequester let-7a and induces Myc upregulation. Under the conditional elimination of primary site-derived breast carcinoma cells, lung malignant cells expressing the mutated SF3B1 splice variant dominate the newly created tumors. Our study suggests that these new carcinoma cells originating from within the colonized organ can replace the primary site-derived malignant cells whenever their expansion is abrogated using an inducible diphtheria toxin receptor in our designed system. These findings should call for a better understanding of metastatic tumors with the specific origin during cancer metastasis.
ZNF330/NOA36 interacts with HSPA1 and HSPA8 and modulates cell cycle and proliferation in response to heat shock in HEK293 cells
Authors: Sanchez-Briñas Alejandra , Duran-Ruiz Carmen , Astola Antonio , Arroyo Marta Marina , Raposo Fátima G. , Valle Antonio , Bolivar Jorge
Published: May 2023

Background

The human genome contains nearly 20.000 protein-coding genes, but there are still more than 6,000 proteins poorly characterized. Among them, ZNF330/NOA36 stand out because it is a highly evolutionarily conserved nucleolar zinc-finger protein found in the genome of ancient animal phyla like sponges or cnidarians, up to humans. Firstly described as a human autoantigen, NOA36 is expressed in all tissues and human cell lines, and it has been related to apoptosis in human cells as well as in muscle morphogenesis and hematopoiesis in Drosophila. Nevertheless, further research is required to better understand the roles of this highly conserved protein.

Results

Here, we have investigated possible interactors of human ZNF330/NOA36 through affinity-purification mass spectrometry (AP-MS). Among them, NOA36 interaction with HSPA1 and HSPA8 heat shock proteins was disclosed and further validated by co-immunoprecipitation. Also, “Enhancer of Rudimentary Homolog” (ERH), a protein involved in cell cycle regulation, was detected in the AP-MS approach. Furthermore, we developed a NOA36 knockout cell line using CRISPR/Cas9n in HEK293, and we found that the cell cycle profile was modified, and proliferation decreased after heat shock in the knocked-out cells. These differences were not due to a different expression of the HSPs genes detected in the AP-MS after inducing stress.

Conclusions

Our results indicate that NOA36 is necessary for proliferation recovery in response to thermal stress to achieve a regular cell cycle profile, likely by interaction with HSPA1 and HSPA8. Further studies would be required to disclose the relevance of NOA36-EHR interaction in this context.
Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study
Authors: Schoenbuchner Simon M. , Huang Chao , Waldron Cherry-Ann , Thomas-Jones Emma , Hood Kerenza , Carrol Enitan D. , Pallmann Philip
Published: May 2023

Introduction

The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study.

Methods

The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up.

Results

Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age.

Conclusion

We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up.

Trial registration

BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832.

PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.
Association of triglyceride-glucose index with early neurological deterioration events in patients with acute ischemic stroke
Authors: Wang Jia , Tang Hao , Wang Xiaokun , Wu Jiarong , Gao Jiaqi , Diao Shuang , Wu Yun
Published: May 2023

Background

The Triglyceride and Glucose (TyG) index has been found to have a strong correlation with the recurrence of acute ischemic stroke (AIS) and poor patient outcomes. Nevertheless, the relationship between the TyG index and early neurological deterioration (END) has not been fully explored. Therefore, the present study aims to investigate the potential association between the TyG index and END.

Methods

A retrospective analysis of 2129 patients diagnosed with AIS between January 2019 and December 2022 at the Second Affiliated Hospital of Harbin Medical University. Patients were divided into END and non-END groups based on changes in National Institutes of Health Stroke Scale scores within 7 days of admission, and the differences in the indicators between the two groups were examined using univariate analysis. The patients were then divided into three groups based on the tertile of the TyG index (T1: TyG index < 8.662; T2: 8.662 ≤ TyG index < 9.401; T3: TyG index ≥ 9.401), and logistic regression analysis was used to examine the association between the TyG index and END. Finally, the predictive ability of the TyG index was evaluated using the receiver operating characteristic (ROC) curve.

Results

A total of 724 patients experienced END. The results of the analysis showed that the TyG index was significantly higher in the END group compared to the non-END group. Furthermore, the TyG index was found to be an independent risk factor for the development of END (OR, 1.561; 95% 1.166–2.090, P = 0.003). After adjusting for confounders, the risk of END was 3.953 (95% CI 2.793–5.595; P < 0.001) and 5.906 (95% CI 3.676–9.488; P < 0.001) times higher in the T2 and T3 groups, respectively, in contrast to the T1 group. The area under the ROC curve of the TyG index was 0.711 (0.688–0.733), indicating an excellent predictive indicator.

Conclusions

Our study uncovered that higher TyG index levels were associated with END development in AIS patients.
The gut microbiome modifies the associations of short- and long-term physical activity with body weight changes
Authors: Wang Kai , Mehta Raaj S. , Ma Wenjie , Nguyen Long H. , Wang Dong D. , Ghazi Andrew R. , Yan Yan , Al-Shaar Laila , Wang Yiqing , Hang Dong , Fu Benjamin C. , Ogino Shuji , Rimm Eric B. , Hu Frank B. , Carmody Rachel N. , Garrett Wendy S. , Sun Qi , Chan Andrew T. , Huttenhower Curtis , Song Mingyang
Published: May 2023

Background

The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA).

Methods

Nested in the Health Professionals Follow-up Study, a subcohort of 307 healthy men (mean[SD] age, 70[4] years) provided stool and blood samples in 2012–2013. Data from cohort long-term follow-ups and from the accelerometer, doubly labeled water, and plasma biomarker measurements during the time of stool collection were used to assess long-term and short-term associations of PA with adiposity. The gut microbiome was profiled by shotgun metagenomics and metatranscriptomics. A subcohort of 209 healthy women from the Nurses’ Health Study II was used for validation.

Results

The microbial species Alistipes putredinis was found to modify the association between PA and body weight. Specifically, in individuals with higher abundance of A. putredinis, each 15-MET-hour/week increment in long-term PA was associated with 2.26 kg (95% CI, 1.53–2.98 kg) less weight gain from age 21 to the time of stool collection, whereas those with lower abundance of A. putredinis only had 1.01 kg (95% CI, 0.41–1.61 kg) less weight gain (pinteraction = 0.019). Consistent modification associated with A. putredinis was observed for short-term PA in relation to BMI, fat mass%, plasma HbA1c, and 6-month weight change. This modification effect might be partly attributable to four metabolic pathways encoded by A. putredinis, including folate transformation, fatty acid β-oxidation, gluconeogenesis, and stearate biosynthesis.

Conclusions

A greater abundance of A. putredinis may strengthen the beneficial association of PA with body weight change, suggesting the potential of gut microbial intervention to improve the efficacy of PA in body weight management.
Factor structure and psychometric properties of the german version chronic uncertainty scale (CU-20)
Authors: Schmalbach Ileana , Bastianon Christina Diane , Afifi Walid A. , Franke Gabriele Helga , Hinz Andreas , Petrowski Katja
Published: May 2023

Background

The experience of uncertainty is ubiquitous and universal across the globe. Many available tools measuring uncertainty are focused on one aspect of uncertainty, e.g., patients with life-threatening illnesses, hence a measure considering (chronic) uncertainty as an integral experience reflect ongoing uncertainties from a socio-cultural perspective is missing. Additionally, current tools do not account for an extended timeframe to measure chronic forms of uncertainty. The objective of this study is to validate a translated German version of the 20 item Chronic Uncertainty Scale (CU-20).

Methods

The full sample comprised N = 462 participants. Most of the participants were young German citizens and the sex distribution was relatively balanced (60% females; age in average: M = 24.56; SD = 4.78). Using equally split samples, an exploratory factor analysis (EFA) evaluated the CU-20 factor structure, followed by a confirmatory factor analysis (CFA) to test the established factor structure. Measurement invariance between male and female groups was evaluated. Internal consistency of the six-factor model was shown and scale discrimination was shown against chronic stress.

Results

The EFA results showed decent model fit for the five-factor structure, however based on the CFA results, the theoretically established six-factor model fits the data significantly better. Measurement invariance between male and female groups was shown to be clearly scalar invariant. Cronbach’s alpha, omega and lambda all support internal consistency and reliability of CU-20.

Conclusions

The CU-20 is a valid and reliable measure of one’s state of chronic uncertainty reflecting the individuals’ experiences of macrosocial forms of uncertainty, compared to the existing ones. This scale is especially useful in the context of migration, refugees or during global crises. Further psychometric testing is required in more diverse samples and a deeper look into measurement invariance is recommended.