bluuebunny/crossref_metadata_2025 huggingface dataset:
The Validity and Efficacy of a Preventative Intervention Model for Reducing Ulcer Recurrence in Diabetic Patients in Indonesia
Authors: Jais Suriadi , Pratama Kharisma , Pradika Jaka , Haryanto Haryanto
Published: June 2023

Introduction

It is important to reduce foot problems by preventing the recurrence of ulcers in diabetes mellitus (DM) patients. In Indonesia, interventions for the prevention of ulcer recurrence remain scarce.

Objective

The present study aimed to evaluate the validity and efficacy of a proposed intervention model for preventing the recurrence of ulcers in DM patients.

Method

Sixty-four DM patients were selected to participate in this quasi-experimental study and divided into two groups: intervention ( n  =  32) and control ( n  =  32). The intervention group received preventive treatment while the control group received standard care. Two trained nurses supported this study.

Results

Of the 32 participants in the intervention group, 18 (56.20%) were male, 25 (78.10%) were non-smokers, 23 (71.90%) had neuropathy, 14 (43.80%) had foot deformities, four (12.50%) had recurring ulcers, and 20 (62.50%) had a previous ulcer  < 12 months ago. Of the 32 participants in the control group, 17 (53.10%) were male, 26 (81.25%) were non-smokers, 17 (46.90%) had neuropathy, 19 (69.40%) had foot deformities, 12 (37.50%) had recurring ulcers, and 24 (75.00%) had a previous ulcer < 12 months ago. The mean (SD) age [62 (11.28) and 59 (11.11) years], ankle-brachial index [1.19 (0.24) and 1.11 (0.17)], HbA1C [9.18 (2.14%) and 8.91 (2.75%)], and DM duration [10.22 (6.71) and 10.13 (7.54)] of the intervention and control groups did not differ significantly. The content validity of the proposed intervention model was strong (I-CVI > 0.78). When the proposed screening tool for predicting the risk of ulcer recurrence in DM patients (NASFoHSkin) was used in the intervention group, its predictive validity, sensitivity, and specificity were 4, 100%, and 80%, respectively, while in the control group it was 4, 83%, and 80%, respectively.

Conclusion

Inspection/examination, foot care, and blood glucose control can decrease ulcer recurrence in DM patients.
Ocular complications of diabetes mellitus in a pediatric population and proposals for screening and follow-up programs
Authors: Diplotti Laura , Pignatto Silvia , Franco Francesca , Zanatta Manuela , Veritti Daniele , Cogo Paola , Lanzetta Paolo
Published: June 2023

Background:

Diabetes mellitus (DM) is one of the world’s greatest health emergencies of the 21st century. Ocular complications of DM are commonly chronic and progressive, but vision loss can be effectively prevented or delayed with early detection and timely treatment. Therefore, regular comprehensive ophthalmologic examinations are mandatory. Ophthalmic screening and dedicated follow-up for adults with DM are well established, whereas, there is no consensus on optimal recommendations for the pediatric population, reflecting the lack of clarity about the current burden of disease in this age group.

Objectives:

To determine the epidemiology of ocular complications of diabetes and to assess optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) macular features in a pediatric population with DM. To review ophthalmological screening and follow-up plans for the diabetic pediatric population.

Design:

Observational study.

Methods:

Retrospective consecutive cohort study of all 165 diabetic patients (330 eyes) aged 0–18 years, examined between January 2006 and September 2018 at the Pediatric Department of ‘S. Maria della Misericordia’ Udine Hospital who underwent at least one complete ophthalmologic examination at the Ophthalmology University Clinic at the Udine Hospital. OCT and OCTA data were available for 37 patients (72 eyes, 2 excluded). The associations between ocular complications and selected potential risk factors were evaluated by univariate analyses.

Results:

No patient had signs of ocular diabetic complications or any macular morphological or micro-vascular impairment, regardless of any potential risk factor. The prevalence of strabismus and refractive errors in the study group, was found to be similar to non-diabetic pediatric populations.

Conclusion:

Screening and follow-up of ocular diabetic complications in children and adolescents could be performed less frequently than in adults with diabetes. There is no need to screen potentially treatable visual disorders in diabetic children earlier or more frequently than in the healthy children thus reducing time spent in hospital and permitting a better tolerance to medical examinations in diabetic pediatric patients. We described the OCT and OCTA patterns in a pediatric population with DM.
kboolnet: a toolkit for the verification, validation, and visualization of reaction-contingency (rxncon) models
Authors: Carretero Chavez Willow , Krantz Marcus , Klipp Edda , Kufareva Irina
Published: June 2023

Background

Computational models of cell signaling networks are extremely useful tools for the exploration of underlying system behavior and prediction of response to various perturbations. By representing signaling cascades as executable Boolean networks, the previously developed rxncon (“reaction-contingency”) formalism and associated Python package enable accurate and scalable modeling of signal transduction even in large (thousands of components) biological systems. The models are split into reactions, which generate states, and contingencies, that impinge on reactions; this avoids the so-called “combinatorial explosion” of system size. Boolean description of the biological system compensates for the poor availability of kinetic parameters which are necessary for quantitative models. Unfortunately, few tools are available to support rxncon model development, especially for large, intricate systems.

Results

We present the kboolnet toolkit (https://github.com/Kufalab-UCSD/kboolnet, complete documentation at https://github.com/Kufalab-UCSD/kboolnet/wiki), an R package and a set of scripts that seamlessly integrate with the python-based rxncon software and collectively provide a complete workflow for the verification, validation, and visualization of rxncon models. The verification script VerifyModel.R checks for responsiveness to repeated stimulations as well as consistency of steady state behavior. The validation scripts TruthTable.R, SensitivityAnalysis.R, and ScoreNet.R provide various readouts for the comparison of model predictions to experimental data. In particular, ScoreNet.R compares model predictions to a cloud-stored MIDAS-format experimental database to provide a numerical score for tracking model accuracy. Finally, the visualization scripts allow for graphical representations of model topology and behavior. The entire kboolnet toolkit is cloud-enabled, allowing for easy collaborative development; most scripts also allow for the extraction and analysis of individual user-defined “modules”.

Conclusion

The kboolnet toolkit provides a modular, cloud-enabled workflow for the development of rxncon models, as well as their verification, validation, and visualization. This will enable the creation of larger, more comprehensive, and more rigorous models of cell signaling using the rxncon formalism in the future.
CastNet: a systems-level sequence evolution simulator
Authors: Rivera-Rivera Carlos J. , Grbic Djordje
Published: June 2023

Background

Simulating DNA evolution has been done through coevolution-agnostic probabilistic frameworks for the past 3 decades. The most common implementation is by using the converse of the probabilistic approach used to infer phylogenies which, in the simplest form, simulates a single sequence at a time. However, biological systems are multi-genic, and gene products can affect each other’s evolutionary paths through coevolution. These crucial evolutionary dynamics still remain to be simulated, and we believe that modelling them can lead to profound insights for comparative genomics.

Results

Here we present CastNet, a genome evolution simulator that assumes each genome is a collection of genes with constantly evolving regulatory interactions in between them. The regulatory interactions produce a phenotype in the form of gene expression profiles, upon which fitness is calculated. A genetic algorithm is then used to evolve a population of such entities through a user-defined phylogeny. Importantly, the regulatory mutations are a response to sequence mutations, thus making a 1–1 relationship between the rate of evolution of sequences and of regulatory parameters. This is, to our knowledge, the first time the evolution of sequences and regulation have been explicitly linked in a simulation, despite there being a multitude of sequence evolution simulators, and a handful of models to simulate Gene Regulatory Network (GRN) evolution. In our test runs, we see a coevolutionary signal among genes that are active in the GRN, and neutral evolution in genes that are not included in the network, showing that selective pressures imposed on the regulatory output of the genes are reflected in their sequences.

Conclusion

We believe that CastNet represents a substantial step for developing new tools to study genome evolution, and more broadly, coevolutionary webs and complex evolving systems. This simulator also provides a new framework to study molecular evolution where sequence coevolution has a leading role.
Generation of sheep with defined FecBB and TBXT mutations and porcine blastocysts with KCNJ5G151R/+ mutation using prime editing
Authors: Zhou Shiwei , Lenk Laura Johanna , Gao Yawei , Wang Yuhui , Zhao Xiaoe , Pan Menghao , Huang Shuhong , Sun Kexin , Kalds Peter , Luo Qi , Lillico Simon , Sonstegard Tad , Scholl Ute I. , Ma Baohua , Petersen Bjoern , Chen Yulin , Wang Xiaolong
Published: June 2023

Background

Rewriting the genomes of living organisms has been a long-standing aim in the biological sciences. The revelation of the CRISPR/Cas9 technology has revolutionized the entire biological field. Since its emergence, this technology has been widely applied to induce gene knockouts, insertions, deletions, and base substitutions. However, the classical version of this system was imperfect for inducing or correcting desired mutations. A subsequent development generated more advanced classes, including cytosine and adenine base editors, which can be used to achieve single nucleotide substitutions. Nevertheless, these advanced systems still suffer from several limitations, such as the inability to edit loci without a suitable PAM sequence and to induce base transversions. On the other hand, the recently emerged prime editors (PEs) can achieve all possible single nucleotide substitutions as well as targeted insertions and deletions, which show promising potential to alter and correct the genomes of various organisms. Of note, the application of PE to edit livestock genomes has not been reported yet.

Results

In this study, using PE, we successfully generated sheep with two agriculturally significant mutations, including the fecundity-related FecBB p.Q249R and the tail length-related TBXT p.G112W. Additionally, we applied PE to generate porcine blastocysts with a biomedically relevant point mutation (KCNJ5 p.G151R) as a porcine model of human primary aldosteronism.

Conclusions

Our study demonstrates the potential of the PE system to edit the genomes of large animals for the induction of economically desired mutations and for modeling human diseases. Although prime-edited sheep and porcine blastocysts could be generated, the editing frequencies are still unsatisfactory, highlighting the need for optimizations in the PE system for efficient generation of large animals with customized traits.
Factors associated with pediatric febrile illnesses in 27 countries of Sub-Saharan Africa
Authors: Ssentongo Paddy , Chinchilli Vernon M. , Shah Khush , Harbaugh Thaddeus , Ba Djibril M.
Published: June 2023

Background

Evidence on the relative importance of various factors associated with febrile illness in children and their heterogeneity across countries can inform the prevention, identification, and management of communicable diseases in resource-limited countries. The objective of the study is to assess the relative significance of factors associated with childhood febrile illness in 27 sub-Saharan African countries.

Methods

This cross-sectional study of 298,327 children aged 0 to 59 months assessed the strengths of associations of 18 factors with childhood fevers, using Demographic and Health Surveys (2010-2018) from 27 sub-Saharan African countries. A total of 7 child level factors (i.e., respiratory illness, diarrhea, breastfeeding initiation; vitamin A supplements; child's age; full vaccination; sex), 5 maternal factors (maternal education; maternal unemployment; antenatal care; maternal age, and maternal marriage status) and 6 household factors (household wealth; water source; indoor pollution, stool disposal; family planning needs and rural residence) were assessed. Febrile illness was defined as the presence of fever in 2 weeks preceding the survey.

Results

Among the 298,327 children aged 0 to 59 months included in the analysis, the weighted prevalence of fever was 22.65% (95% CI, 22.31%-22.91%). In the pooled sample, respiratory illness was the strongest factor associated with fever in children (adjusted odds ratio [aOR], 5.46; 95% CI, 5.26-5.67; P < .0001), followed by diarrhea (aOR, 2.96; 95% CI, 2.85-3.08; P < .0001), poorest households (aOR, 1.33; 95% CI,1.23-1.44; P < .0001), lack of maternal education (aOR, 1.25; 95% CI, 1.10-1.41; P < .0001), and delayed breastfeeding (aOR, 1.18; 95% CI, 1.14-1.22; P < .0001. Febrile illnesses were more prevalent in children older than >6 months compared to those 6 months and younger. Unsafe water, unsafe stool disposal, and indoor pollution were not associated with child fever in the pooled analysis but had a large country-level heterogeneity.

Conclusions

Major causes of fevers in sub-Saharan Africa could be attributed to respiratory infections and possibly viral infections, which should not be treated by antimalarial drugs or antibiotics. Point-of-care diagnostics are needed to identify the pathogenic causes of respiratory infections to guide the clinical management of fevers in limited-resource countries.
Predicting hyperkalemia in patients with advanced chronic kidney disease using the XGBoost model
Authors: Chang Hsin-Hsiung , Chiang Jung-Hsien , Tsai Chun-Chieh , Chiu Ping-Fang
Published: June 2023

Background

Hyperkalemia is a common complication of chronic kidney disease (CKD). Hyperkalemia is associated with mortality, CKD progression, hospitalization, and high healthcare costs in patients with CKD. We developed a machine learning model to predict hyperkalemia in patients with advanced CKD at an outpatient clinic.

Methods

This retrospective study included 1,965 advanced CKD patients between January 1, 2010, and December 31, 2020 in Taiwan. We randomly divided all patients into the training (75%) and testing (25%) datasets. The primary outcome was to predict hyperkalemia (K+ > 5.5 mEq/L) in the next clinic vist. Two nephrologists were enrolled in a human-machine competition. The area under the receiver operating characteristic curves (AUCs), sensitivity, specificity, and accuracy were used to evaluate the performance of XGBoost and conventional logistic regression models with that of these physicians.

Results

In a human-machine competition of hyperkalemia prediction, the AUC, PPV, and accuracy of the XGBoost model were 0.867 (95% confidence interval: 0.840–0.894), 0.700, and 0.933, which was significantly better than that of our clinicians. There were four variables that were chosen as high-ranking variables in XGBoost and logistic regression models, including hemoglobin, the serum potassium level in the previous visit, angiotensin receptor blocker use, and calcium polystyrene sulfonate use.

Conclusions

The XGBoost model provided better predictive performance for hyperkalemia than physicians at the outpatient clinic.
Neuroinflammation and Brain Disease
Authors: Bersano A. , Engele J. , Schäfer M.K.E.
Published: June 2023

Starting from the perspective of an immune-privileged site, our knowledge of the inflammatory processes within the central nervous system has increased rapidly over the last 30 years, leading to a rather puzzling picture today. Of particular interest is the emergence of disease- and injury-specific inflammatory responses within the brain, which may form the basis for future therapeutic approaches. To advance this important topic, we invite authors to contribute research and clinical papers to the Collection “Neuroinflammation and Brain Disease”.
Exploration of the role of emotional expression of treatment-resistant schizophrenia patients having followed virtual reality therapy: a content analysis
Authors: Hudon Alexandre , Lammatteo Veronica , Rodrigues-Coutlée Sophie , Dellazizzo Laura , Giguère Sabrina , Phraxayavong Kingsada , Potvin Stéphane , Dumais Alexandre
Published: June 2023

Background

Emotional responses are an important component of psychotherapeutic processes. Avatar therapy (AT) is a virtual reality-based therapy currently being developed and studied for patients suffering from treatment resistant schizophrenia. Considering the importance of identifying emotions in therapeutical processes and their impact on the therapeutic outcome, an exploration of such emotions is needed.

Methods

The aim of this study is to identify the underlying emotions at the core of the patient-Avatar interaction during AT by content analysis of immersive sessions transcripts and audio recordings. A content analysis of AT transcripts and audio recordings using iterative categorization was conducted for 16 patients suffering from TRS who underwent AT between 2017 and 2022 (128 transcripts and 128 audio recordings). An iterative categorization technique was conducted to identify the different emotions expressed by the patient and the Avatar during the immersive sessions.

Results

The following emotions were identified in this study: Anger, Contempt/ Disgust, Fear, Sadness, Shame/ Embarrassment, Interest, Surprise, Joy and Neutral. Patients expressed mostly neutral, joy and anger emotions whereas the Avatar expressed predominantly interest, disgust/contempt, and neutral emotions.

Conclusions

This study portrays a first qualitative insight on the emotions that are expressed in AT and serves as a steppingstone for further investigation in the role of emotions in the therapeutic outcomes of AT.
Knowledge support for environmental information on pharmaceuticals: experiences among Swedish Drug and Therapeutics Committees
Authors: Linder Elkanah , Wettermark Björn , Ovesjö Marie-Louise , Sporrong Sofia Kälvemark , Ramström Helena
Published: June 2023

Background

Two publicly available Swedish knowledge support systems, “Pharmaceuticals and Environment” on Janusinfo.se and Fass.se, provide environmental information on pharmaceuticals. Janusinfo is provided by the public healthcare system in Stockholm and Fass is provided by the pharmaceutical industry. The objectives of this study were to investigate the experiences among Swedish Drug and Therapeutics Committees (DTCs) with using the databases, retrieve development proposals for these, and investigate the DTCs’ challenges with working with pharmaceuticals in the environment.

Methods

A cross-sectional survey with 21 questions, both closed and open-ended, was distributed electronically in March 2022 to Sweden’s 21 DTCs. Descriptive statistics and inductive categorization were used for the analysis.

Results

A total of 132 respondents from 18 regions filled out the survey. The average regional response rate was 42%. The DTCs used the knowledge supports to consider environmental aspects of pharmaceuticals in their formularies and in education. Respondents were more familiar with Janusinfo compared to Fass but appreciated the availability of both. The DTCs especially valued the concrete proposals for certain active pharmaceutical ingredients on Janusinfo. Respondents requested that all medicinal products have environmental information on Fass. Challenges included lack of data, lack of transparency from the pharmaceutical industry and difficulties considering the environmental aspect of pharmaceuticals in their healthcare practice. Respondents wanted more knowledge, clear messages, and legislation to support their work to reduce the negative environmental impact of pharmaceuticals.

Conclusions

This study demonstrates that knowledge supports for environmental information on pharmaceuticals are valuable for the DTCs in Sweden, but the respondents experienced challenges in their work in this field. The study can provide insights to those in other countries interested in considering environmental aspects in their formulary decision-making.
Gene S-phase kinase associated protein 2 is a novel prognostic marker in human neoplasms
Authors: Li Guo-Sheng , Huang Tao , Zhou Hua-Fu
Published: June 2023

Background

Neoplasms are a series of diseases affecting human health. Prognostic and tumor status–related markers for various tumors should be identified.

Methods

Based on 19,515 samples from multiple sources, for the first time, this study provided an overview of gene S-phase kinase associated protein 2 (SKP2) in pan-cancer. Differential SKP2 expression in multiple comparison groups was identified by the Kruskal–Wallis test and Wilcoxon rank-sum test. The prognosis significance of SKP2 in individuals with neoplasm was evaluated through univariate Cox regression analysis and Kaplan-Meier curves. The area under the curve was utilized to detect the accuracy of SKP2 in predicting cancer status. Spearman’s rank correlation coefficients were calculated in all correlation analyses. Gene set enrichment analysis was used to identify essential signaling pathways of SKP2 in human neoplasms.

Results

The study disclosed the upregulated SKP2 expression in 15 neoplasms and decreased SKP2 expression in three cancers (p < 0.05). The transcription factor Forkhead Box M1 may contribute to the increased expression levels of SKP2 in certain tumors. Over-expressed SKP2 represented a risk factor for the prognosis of most cancer patients (hazard ratio > 1, p < 0.05). SKP2 expression made it feasible to distinguish neoplasm and control tissues of 21 neoplasms (sensitivity = 0.79, specificity = 0.87, area under the curve = 0.90), implying its potential in screening a series of neoplasms. Further, the research revealed the close association of SKP2 expression with DNA methyltransferases, mismatch repair genes, microsatellite instability, tumor mutational burden, neoantigen count, and immunity.

Conclusions

SKP2 plays an essential role in multiple neoplasms and may serve as a marker for treating and identifying these neoplasms.
Duration-dependent impact of cardiometabolic diseases and multimorbidity on all-cause and cause-specific mortality: a prospective cohort study of 0.5 million participants
Authors: Han Yuting , Hu Yizhen , Yu Canqing , Sun Dianjianyi , Pang Yuanjie , Pei Pei , Yang Ling , Chen Yiping , Du Huaidong , Liu Jingchao , Schmidt Dan , Avery Daniel , Chen Junshi , Chen Zhengming , Li Liming , Lv Jun
Published: June 2023

Background

The association of incident cardiometabolic multimorbidity (CMM) with mortality risk is rarely studied, and neither are the durations of cardiometabolic diseases (CMDs). Whether the association patterns of CMD durations with mortality change as individuals progress from one CMD to CMM is unclear.

Methods

Data from China Kadoorie Biobank of 512,720 participants aged 30–79 was used. CMM was defined as the simultaneous presence of two or more CMDs of interest, including diabetes, ischemic heart disease, and stroke. Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the duration-dependent associations of CMDs and CMM with all-cause and cause-specific mortality. All information on exposures of interest was updated during follow-up.

Results

During a median follow-up of 12.1 years, 99,770 participants experienced at least one incident CMD, and 56,549 deaths were documented. Among 463,178 participants free of three CMDs at baseline, compared with no CMD during follow-up, the adjusted HRs (95% CIs) between CMM and all-cause mortality, mortality from circulatory system diseases, respiratory system diseases, cancer, and other causes were 2.93 (2.80–3.07), 5.05 (4.74–5.37), 2.72 (2.35–3.14), 1.30 (1.16–1.45), and 2.30 (2.02–2.61), respectively. All CMDs exhibited a high mortality risk in the first year of diagnosis. Subsequently, with prolonged disease duration, mortality risk increased for diabetes, decreased for IHD, and sustained at a high level for stroke. With the presence of CMM, the above association estimates inflated, but the pattern of which remained.

Conclusion

Among Chinese adults, mortality risk increased with the number of the CMDs and changed with prolonged disease duration, the patterns of which varied among the three CMDs.
Real-world hepatitis C treatment outcomes and reinfections among people who inject drugs at a needle and syringe program in Stockholm, Sweden
Authors: Lindqvist K. , Thorin Z. , Kåberg M.
Published: June 2023

Background

People who inject drugs (PWID) represent a population with an increased prevalence of hepatitis C (HCV) infections. HCV treatment among PWID is essential to reach the WHO goal of eliminating HCV as a major public health threat by 2030. Despite better understanding of PWID subgroups and changes in risk behaviors over time, more knowledge about HCV treatment outcomes in different HCV prevalence populations and settings is warranted to enhance the continuum of care.

Methods

All Stockholm Needle and Syringe Program (NSP) participants who initiated HCV treatment between October 2017 and June 2020 were HCV RNA tested at end of treatment and twelve weeks thereafter to confirm cure with a sustained virological response (SVR). All cured participants were prospectively followed from SVR to the last negative HCV RNA test or a subsequent reinfection, until October 31, 2021.

Results

Overall, 409 NSP participants initiated HCV treatment, 162 at the NSP and 247 in another treatment setting. There were a total of 6.4% treatment dropouts (n = 26), 11.7% among participants treated at the NSP and 2.8% among those treated elsewhere (p < 0.001). Stimulant use (p < 0.05) and not being in an opioid agonist treatment program (p < 0.05) was associated with dropout. More participants treated outside the NSP were lost to follow-up between end of treatment and SVR (p < 0.05). During follow-up post-SVR, 43 reinfections occurred, corresponding to a reinfection rate of 9.3/100 PY (95% CI 7.0, 12.3). Factors associated with reinfection were younger age (p < 0.001), treatment while in prison (p < 0.01) and homelessness (p < 0.05).

Discussion

In this high HCV prevalence NSP setting, with a majority of stimulant users, treatment success was high and the level of reinfections manageable. To reach HCV elimination, there is a need to target specific PWID subgroups for HCV treatment, in both harm reduction and adjacent healthcare settings frequented by PWID.
Metabolomic phenotyping of obesity for profiling cardiovascular and ocular diseases
Authors: Zhong Pingting , Tan Shaoying , Zhu Zhuoting , Bulloch Gabriella , Long Erping , Huang Wenyong , He Mingguang , Wang Wei
Published: June 2023

Background

We aimed to evaluate the impacts of metabolomic body mass index (metBMI) phenotypes on the risks of cardiovascular and ocular diseases outcomes.

Methods

This study included cohorts in UK and Guangzhou, China. By leveraging the serum metabolome and BMI data from UK Biobank, this study developed and validated a metBMI prediction model using a ridge regression model among 89,830 participants based on 249 metabolites. Five obesity phenotypes were obtained by metBMI and actual BMI (actBMI): normal weight (NW, metBMI of 18.5–24.9 kg/m2), overweight (OW, metBMI of 25–29.9 kg/m2), obesity (OB, metBMI ≥ 30 kg/m2), overestimated (OE, metBMI-actBMI > 5 kg/m2), and underestimated (UE, metBMI-actBMI < − 5 kg/m2). Additional participants from the Guangzhou Diabetes Eye Study (GDES) were included for validating the hypothesis. Outcomes included all-cause and cardiovascular (CVD)-cause mortality, as well as incident CVD (coronary heart disease, heart failure, myocardial infarction [MI], and stroke) and age-related eye diseases (age-related macular degeneration [AMD], cataracts, glaucoma, and diabetic retinopathy [DR]).

Results

In the UKB, although OE group had lower actBMI than NW group, the OE group had a significantly higher risk of all-cause mortality than those in NW prediction group (HR, 1.68; 95% CI 1.16–2.43). Similarly, the OE group had a 1.7–3.6-fold higher risk than their NW counterparts for cardiovascular mortality, heart failure, myocardial infarction, and coronary heart disease (all P < 0.05). In addition, risk of age-related macular denegation (HR, 1.96; 95% CI 1.02–3.77) was significantly higher in OE group. In the contrast, UE and OB groups showed similar risks of mortality and of cardiovascular and age-related eye diseases (all P > 0.05), though the UE group had significantly higher actBMI than OB group. In the GDES cohort, we further confirmed the potential of metabolic BMI (metBMI) fingerprints for risk stratification of cardiovascular diseases using a different metabolomic approach.

Conclusions

Gaps of metBMI and actBMI identified novel metabolic subtypes, which exhibit distinctive cardiovascular and ocular risk profiles. The groups carrying obesity-related metabolites were at higher risk of mortality and morbidity than those with normal health metabolites. Metabolomics allowed for leveraging the future of diagnosis and management of ‘healthily obese’ and ‘unhealthily lean’ individuals.
Clinical characteristics of comorbid tic disorders in autism spectrum disorder: exploratory analysis
Authors: Kim Ye Rim , Song Da-Yea , Bong Guiyoung , Han Jae Hyun , Kim Joo-Hyun , Yoo Hee Jeong
Published: June 2023

Background

The frequency, clinical characteristics, and associated symptoms of comorbid tic disorders in individuals with autism spectrum disorder (ASD) remain unclear.

Methods

We included subsets of individuals from a larger genetic study who were diagnosed with ASD (n = 679; age: 4–18 years) and completed the Yale Global Tic Severity Scale (YGTSS) questionnaire. Based on the YGTSS score, the individuals were divided into two groups: ASD only (n = 554) and ASD with tics (n = 125). Individuals were assessed using the verbal and non-verbal intelligence quotient (IQ), Vineland Adaptive Behavior Scale (VABS-2), Social Responsiveness Scale-2 (SRS-2), Child Behavior Checklists (CBCL), and Yale-Brown Obsessive–Compulsive Scale (YBOCS), followed by between-group comparisons. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 26.

Results

Tic symptoms were observed in 125 (18.4%) participants; among them, most participants presented both motor and vocal tics (n = 40, 40.0%). The ASD with tics group had a significantly higher average age and full-scale IQ score than the ASD only group. After adjusting for age, the ASD with tics group had significantly higher scores in the SRS-2, CBCL, and YBOCS subdomains than the ASD only group. Furthermore, all variables except the non-verbal IQ and VABS-2 scores were positively correlated with the YGTSS total score. Finally, the proportion of tic symptoms was significantly higher among individuals with a higher IQ score (≥ 70).

Conclusions

The IQ score was positively correlated with the proportion of tic symptoms among individuals with ASD. Moreover, the severity of the core and comorbid symptoms of ASD was associated with the occurrence and severity of tic disorders. Our findings suggest the need for appropriate clinical interventions for individuals with ASD.

Trial registration This study retrospectively registered participants
Nine golden codes: improving the accuracy of Helicopter Emergency Medical Services (HEMS) dispatch—a retrospective, multi-organisational study in the East of England
Authors: Edmunds Christopher T. , Lachowycz Kate , McLachlan Sarah , Downes Andrew , Smith Andrew , Major Rob , Barnard Edward B. G.
Published: June 2023

Background

Helicopter Emergency Medical Services (HEMS) are a limited and expensive resource, and should be intelligently tasked. HEMS dispatch was identified as a key research priority in 2011, with a call to identify a ‘general set of criteria with the highest discriminating potential’. However, there have been no published data analyses in the past decade that specifically address this priority, and this priority has been reaffirmed in 2023. The objective of this study was to define the dispatch criteria available at the time of the initial emergency call with the greatest HEMS utility using a large, regional, multi-organizational dataset in the UK.

Methods

This retrospective observational study utilized dispatch data from a regional emergency medical service (EMS) and three HEMS organisations in the East of England, 2016–2019. In a logistic regression model, Advanced Medical Priority Dispatch System (AMPDS) codes with ≥ 50 HEMS dispatches in the study period were compared with the remainder to identify codes with high-levels of HEMS patient contact and HEMS-level intervention/drug/diagnostic (HLIDD). The primary outcome was to identify AMPDS codes with a > 10% HEMS dispatch rate of all EMS taskings that would result in 10–20 high-utility HEMS dispatches per 24-h period in the East of England. Data were analysed in R, and are reported as number (percentage); significance was p < 0.05.

Results

There were n = 25,491 HEMS dispatches (6400 per year), of which n = 23,030 (90.3%) had an associated AMPDS code. n = 13,778 (59.8%) of HEMS dispatches resulted in patient contact, and n = 8437 (36.6%) had an HLIDD. 43 AMPDS codes had significantly greater rates of patient contact and/or HLIDD compared to the reference group. In an exploratory analysis, a cut-off of ≥ 70% patient contact rate and/or ≥ 70% HLIDD (with a > 10% HEMS dispatch of all EMS taskings) resulted in 17 taskings per 24-h period. This definition derived nine AMPDS codes with high HEMS utility.

Conclusion

We have identified nine ‘golden’ AMPDS codes, available at the time of initial emergency call, that are associated with high-levels of whole-system and HEMS utility in the East of England. We propose that UK EMS should consider immediate HEMS dispatch to these codes.
16S rRNA gene sequencing of stool samples collected from patients with latent tuberculosis infection before, during, and two months after treatment with 3HP or 4R
Authors: Séraphin Marie Nancy , Bellot Julia , Peloquin Charles A. , Mai Volker
Published: June 2023

Objective

We present 16s rRNA gene sequencing (V1-V2 region) and sample data from a pilot observational cohort study to describe the gut microbiota dynamics of subjects with latent tuberculosis infection (LTBI) treated with daily 600 mg rifampicin for four months (4R) or a weekly dose of 900 mg combination of rifapentine and isoniazid for three months (3HP). Our objectives were to (1) document changes to the gut microbiota immediately following exposure to the rifamycins and (2) document recovery to baseline two months after treatment completion.

Data description

We enrolled six subjects with subjects with LTBI and prospectively followed them for 5–6 months. Each subject provided stool samples before, during, and two months after treatment. Six healthy controls were sampled in parallel with the patients with LTBIs. We report amplicon sequence variants (ASVs) and taxonomic assignments for 60 stool samples. Additionally, we provide access to the raw amplicon sequences, and subject responses to questionnaires about their diet, medication, and lifestyle changes over the study follow-up period. Furthermore, we provide the concentration of the parent and partially active rifamycin metabolite concentrations measured validated LC-MS-MS assays of phosphate buffer washes of the stool samples collected from the LTBI participants. This comprehensive dataset is a valuable resource for future systematic reviews and meta-analyses of the impact of LTBI therapy on the gut microbiota.
SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair
Authors: Wang Xin , Cao Chen , Tan Xiangyu , Liao Xueyao , Du Xiaofang , Wang Xueqian , Liu Ting , Gong Danni , Hu Zheng , Tian Xun
Published: June 2023

Background

Cisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy.

Results

We performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locus SETD8 (7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization after SETD8 downregulation. Knockdown of SETD8 increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition, SETD8 expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor of SETD8 was found to enhance cisplatin sensitivity both in vitro and in vivo.

Conclusions

SETD8 was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy.
Ahnak is required to balance calcium ion homeostasis and smooth muscle development in the urinary system
Authors: Lee Jong-Min , Lim Tae-Yang , Oh Sang-Bin , Lee Seung-Jun , Bae Yun Soo , Jung Han-Sung
Published: June 2023

Background

Various renal abnormalities, including hydronephrosis, polycystic kidney disease, and hydroureter, have been reported, and these abnormalities are present in DiGeorge syndrome, renal dysplasia, and acute kidney failure. Previous studies have shown that various genes are associated with renal abnormalities. However, the major target genes of nonobstructive hydronephrosis have not yet been elucidated.

Results

We examined neuroblast differentiation-associated protein Ahnak localization and analyzed morphogenesis in developing kidney and ureter. To investigated function of Ahnak, RNA-sequencing and calcium imaging were performed in wild type and Ahnak knockout (KO) mice. Ahnak localization was confirmed in the developing mouse kidneys and ureter. An imbalance of calcium homeostasis and hydronephrosis, which involves an expanded renal pelvis and hydroureter, was observed in Ahnak KO mice. Gene Ontology enrichment analysis on RNA-seq results indicated that ‘Channel Activity’, ‘Passive Transmembrane Transporter Activity’ and ‘Cellular Calcium Ion Homeostasis’ were downregulated in Ahnak KO kidney. ‘Muscle Tissue Development’, ‘Muscle Contraction’, and ‘Cellular Calcium Ion Homeostasis’ were downregulated in Ahnak KO ureter. Moreover, peristaltic movement of smooth muscle in the ureter was reduced in Ahnak KO mice.

Conclusions

Abnormal calcium homeostasis causes renal disease and is regulated by calcium channels. In this study, we focused on Ahnak, which regulates calcium homeostasis in several organs. Our results indicate that Ahnak plays a pivotal role in kidney and ureter development, and in maintaining the function of the urinary system.
Biological quality and phytochemical profiling of olive fruits using gas chromatography–mass spectrometry (GCMS) analysis
Authors: Ahmad Rizwan , Alqathama Aljawharah , Alam Mohammad Mahtab , Riaz Muhammad , Abdalla Ashraf N. , Aldholmi Mohammed , Al− Said Hamdi M. , Aljishi Fatema S. , Althomali Ebtihal H. , Alabdullah Murtada M. , Altaweel Nezar H. , Almubarak Ali F. , Asghar Sami. S.
Published: June 2023

The quality of olive fruit (OF) is widely affected due to geographical variation, affecting OF's chemical composition and biological properties. It is a novel and first-time study to evaluate the quality variation of 42 olive samples from different geographical origins based on phytochemical profile and their biological activities. The study reports the presence of unique chemical markers responsible for the difference in quality and biological activity of the olive samples. Biological activity (cytotoxic and antimicrobial) with GCMS phytochemical profile was evaluated. GCMS analysis confirmed the presence of 111 volatile compounds from various chemical classes with range (%) and average (%): esters (21.61–60.49) and 44.62, alcohols (20.73–49.2) and 38.06, hydrocarbons (3–38.88) and 15.39, ketones (0.16–3.87) and 0.75, acids (0.07–2.62) and 0.27, and aldehydes (0.12–1.47) and 0.45. The predominant ester was 13-methyl-pentadecanoic acid methyl ester, a differentiation marker between these samples. Cytotoxicity assay showed a significant inhibitory effect against MCF7 (8–64%) and HCT116 (0.11–44%) cell lines, whereas the extracts with the highest cytotoxicity observed were O17 (52.00 ± 2.00) and O25 (64.00 ± 4.88). The antimicrobial activity exhibited a range of zones of inhibition (mm) againstP. aeruginosa(0.00–17.00),E. coli(0.00–15.00),S. aureus(0.00–13), and resistantS. aureus,i.e., MRSA (0.00–12.00). The extracts with the highest antimicrobial activity, i.e., O8 and O39 had identical MIC and MBC of 12.5 and 25 µg/ml againstP. aeruginosa. In contrast, an MIC (50 and 25) and MBC (100 and 50) againstE. coliwere determined for O39 and O8. The statistical PCA and K-mean cluster analysis (P < 0.05) confirmed the presence of a high number of esters, alcohols, and hydrocarbons in GCMS data. Moreover, O8, O23, O25, and O39 were suggested as comparatively better varieties than those OF samples (P = 0.001). The presence of distinct volatile markers in these 42 OF samples may be further studied as a potential source of antimicrobials, food preservatives and therapeutic purposes.

Graphical abstract
Literature and Totality
Authors: Ansari Alya
Published: June 2023

This essay foregrounds the hermeneutic purchase of totality in contemporary literary criticism. Responding to the recent proliferation of the “gig work” novel, the essay takes up two interrelated lines of inquiry: How might we rethink the conceptual affordances of “totality” for the ongoing project of the critique of political economy? What would a rethinking of totality’s position in the conceptual architecture of literary criticism offer in the way of new heuristics for the analysis of the novel? Through recourse to G. W. F. Hegel’s Science of Logic and Michael Theunissen, Hans-Friedrich Fulda, and Rolf-Peter Horstmann’s Critical Presentation of Metaphysics: A Discussion of Hegel’s “Logic” (Kritische Darstellung der Metaphysik: Eine Diskussion über Hegels “Logik”), this essay proposes a method of literary analysis that approaches the formal aspects of the novel as defined through the historical-material conditions for the writing of the text. The essay then puts a close reading of Hilary Leichter’s Temporary in conversation with Sarah Brouillette’s account of the decline of the English-language literary novel to suggest how the formal properties of the contemporary gig work novel respond to the general crisis of novel production in the twenty-first century.
A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes
Authors: Swier Vicki J. , White Katherine A. , Johnson Tyler B. , Wang Xiaojun , Han Jimin , Pearce David A. , Singh Ruchira , Drack Arlene V. , Pfeifer Wanda , Rogers Christopher S. , Brudvig Jon J. , Weimer Jill M.
Published: June 2023

Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span and inconsistent subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, thereby limiting their use in preclinical studies. Here, we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with retinal degeneration and motor abnormalities, similar to deficits seen in humans diagnosed with the disease. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology, and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease-modifying therapeutics.
Different tether proteins of the same membrane contact site affect the localization and mobility of each other
Authors: Amado Lucia , Cogan Alexandra P. , González Montoro Ayelén
Published: June 2023

Membrane contact sites enable the exchange of metabolites between subcellular compartments and regulate organelle dynamics and positioning. These structures often contain multiple proteins that tether the membranes, establishing the apposition and functionalizing the structure. In this work, we used drug-inducible tethers in vivo in Saccharomyces cerevisiae to address how different tethers influence each other. We found that the establishment of a region of membrane proximity can recruit tethers, influencing their distribution between different locations or protein complexes. In addition, restricting the localization of one tether to a subdomain of an organelle caused other tethers to be restricted there. Finally, we show that the mobility of contact site tethers can also be influenced by other tethers of the same interface. Overall, our results show that the presence of other tethers at contact sites is an important determinant of the behavior of tethering proteins. This suggests that contact sites with multiple tethers are controlled by the interplay between specific molecular interactions and the cross-influence of tethers of the same interface.
A Dynamic Ankle Orthosis Reduces Tibial Compressive Force and Increases Ankle Motion Compared With a Walking Boot
Authors: JOHNSON PERRI A. , PAQUETTE MAX R. , DIANGELO DENIS J.
Published: June 2023

Purpose

Tibial bone stress injuries are a common overuse injury among runners and military cadets. Current treatment involves wearing an orthopedic walking boot for 3 to 12 wk, which limits ankle motion and leads to lower limb muscle atrophy. A dynamic ankle orthosis (DAO) was designed to provide a distractive force that offloads in-shoe vertical force and retains sagittal ankle motion during walking. It remains unclear how tibial compressive force is altered by the DAO. This study compared tibial compressive force and ankle motion during walking between the DAO and an orthopedic walking boot.

Methods

Twenty young adults walked on an instrumented treadmill at 1.0 m·s−1 in two brace conditions: DAO and walking boot. Three-dimensional kinematic, ground reaction forces, and in-shoe vertical force data were collected to calculate peak tibial compressive force. Paired t-tests and Cohen’s d effect sizes were used to assess mean differences between conditions.

Results

Peak tibial compressive force (P = 0.023; d = 0.5) and Achilles tendon force (P = 0.017; d = 0.5) were moderately lower in the DAO compared with the walking boot. Sagittal ankle excursion was 54.9% greater in the DAO compared with the walking boot (P = 0.05; d = 3.1).

Conclusions

The findings from this study indicated that the DAO moderately reduced tibial compressive force and Achilles tendon force and allowed more sagittal ankle excursion during treadmill walking compared with an orthopedic walking boot.