bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-nutrients as Adjunctive Treatment for Bipolar Disorder: A randomized-controlled trial
Authors: Mehl-Madrona Lewis , McFarlane Patrick
Published: June 2023

Introduction

An open-label trial suggested that a comprehensive micronutrient supplement, Empower Plus Advanced, in combination with Fish Oil, could reduce symptoms in adults with bipolar disorder. A double-blind, randomized, controlled feasibility trial explored the parameters necessary for a large-scale trial.

Methods

Participants (N=69) from a family medicine training clinic with diagnoses of bipolar disorder in the electronic health record were randomized in a 3:2 ratio to Multi-nutrients or Placebo. Diagnoses were confirmed via psychiatric interview or chart review (for obvious cases). The primary outcome measure was change on a composite z-score combining changes on the clinical global impressions scale (CGI), changes on the UKU Side Effects Scale, and changes in medication doses. The GLM repeated measures procedure of SPSS compared continuous outcome measures. Chi-square testing compared responders to non-responders.

Results

Data were analyzed for 50 participants. The mean difference of the composite z-score for the primary outcome variables was statistically significant (p = 0.019) and for the composite z-score of all variables (primary and secondary) combined (p = 0.047). In non-parametric chisquare analysis, significantly more in the Nutrient group improved on the CGI (rated 1 or 2) (p = 0.04; OR = 4.0; 52% responders vs. 22% in the Placebo Group). All secondary outcome measures showed nonsignificant trends in the expected direction. Patients in both groups made significant improvement in all measures. The only adverse events occurring more among the Multi-nutrient group were nausea and loose stools, not statistically significant.

Conclusions

Multi-nutrients show promise for adjunctive treatment of bipolar disorder. We observed substantial benefits for all patients of closer surveillance, medication adjustment (mostly reduction), and increased human contact. Future studies would benefit from use of a longer lead-in period during which medications can be adjusted and participants can decide if they are willing to take Multi-nutrients for an extended time. Our data suggest that primary care patients with bipolar disorder would fare better on lower medications doses and more frequent visits. Further clinical trials are warranted.
Interim Safety and Immunogenicity of COVID-19 Omicron-BA.1 Variant-Containing Vaccine in Children
Authors: Dixit Avika , Bennett Richard , Ali Kashif , Griffin Carl , Clifford Robert A. , Turner Mark , Poston Rosanne , Hautzinger Kelly , Yeakey Anne , Girard Bethany , Zhou Wen , Deng Weiping , Zhou Honghong , Ghamloush Sabine Schnyder , Kuter Barbara J. , Slobod Karen , Miller Jacqueline M. , Priddy Frances , Das Rituparna ,   the ROVER Study Investigators
Published: June 2023

Objectives

We report interim safety and immunogenicity results from a phase 3 study of omicron-BA.1 variant-containing (mRNA-1273.214) primary vaccination series (Part 1) and booster dose (Part 2) in children aged 6 months to 5 years (NCT05436834).

Methods

In Part 1, SARS-CoV-2 unvaccinated participants, including participants who received placebo in the KidCOVE study (NCT04796896), received 2 doses of mRNA-1273.214 (25-μg omicron-BA.1 and ancestral Wuhan-Hu-1 mRNA 1:1 co-formulation) primary series. In Part 2, participants who previously completed the mRNA-1273 (25-µg) primary series in KidCOVE received a mRNA-1273.214 (10-μg) booster dose. Primary objectives were safety, reactogenicity, and immunogenicity, including prespecified immune response success criteria.

Results

At the data cutoff (December 5, 2022), 179 participants had received ≥1 dose of mRNA-1273.214 primary series (Part 1) and 539 participants had received a mRNA-1273.214 booster dose (Part 2). The safety profile of mRNA-1273.214 primary series and booster dose was consistent with that of the mRNA-1273 primary series in this same age group, with no new safety concerns identified and no vaccine-related serious adverse events observed. Compared with neutralizing antibody responses induced by the mRNA-1273 primary series, both the mRNA-1273.214 primary series and booster elicited responses that were superior against omicron-BA.1 and non-inferior against ancestral Wuhan-Hu-1(D614G).

Conclusions

mRNA-1273.214 was immunogenic against BA.1 and D614G in children aged 6 months to 5 years, with a comparable safety profile to mRNA-1273, when given as a 2-dose primary series or as a booster dose after the mRNA-1273 primary series.

Clinical Trial Registry

NCT05436834
Path to Medical AGI: Unify Domain-specific Medical LLMs with the Lowest Cost
Authors: Zhou Juexiao , Chen Xiuying , Gao Xin
Published: June 2023

Medical artificial general intelligence (AGI) is an emerging field that aims to develop systems specifically designed for medical applications that possess the ability to understand, learn, and apply knowledge across a wide range of tasks and domains. Large language models (LLMs) represent a significant step towards AGI. However, training cross-domain LLMs in the medical field poses significant challenges primarily attributed to the requirement of collecting data from diverse domains. This task becomes particularly difficult due to privacy restrictions and the scarcity of publicly available medical datasets. Here, we propose Medical AGI (MedAGI), a paradigm to unify domain-specific medical LLMs with the lowest cost, and suggest a possible path to achieve medical AGI. With an increasing number of domain-specific professional multimodal LLMs in the medical field being developed, MedAGI is designed to automatically select appropriate medical models by analyzing users’ questions with our novel adaptive expert selection algorithm. It offers a unified approach to existing LLMs in the medical field, eliminating the need for retraining regardless of the introduction of new models. This characteristic renders it a future-proof solution in the dynamically advancing medical domain. To showcase the resilience of MedAGI, we conducted an evaluation across three distinct medical domains: dermatology diagnosis, X-ray diagnosis, and analysis of pathology pictures. The results demonstrated that MedAGI exhibited remarkable versatility and scalability, delivering exceptional performance across diverse domains. Our code is publicly available to facilitate further research athttps://github.com/JoshuaChou2018/MedAGI.
HOW HEALTHCARE EXPENDITURES AFFECT COVID-19 FATALITY RATE ACROSS EUROPEAN COUNTRIES?
Authors: Coccia Mario , Benati Igor
Published: June 2023

The goal of this study is to examine the relationship between healthcare expenditures and health capacity, and variability in COVID-19 case fatality rate between European countries. In particular, the purpose of the present study is to see whether statistical evidence supports the hypothesis that the reduction of COVID-19 fatality, between European countries, can be explained by leveraging health expenditures and if so to form some quantitative analyses and estimates of the relation between health expenditures and COVID-19 fatality rate between countries. The research is based on a sample of European countries and data from various sources, including Eurostat, World Bank, and OECD databases. Results suggest that countries with higher COVID-19 fatality rate in 2020 (when pandemic starts) in comparison to countries with lower COVID-19 fatality had (higher) +50.5% of fatality in 2020, +52.9% in 2022, lower health expenditure as % of GDP −5.5%, health expenditure per capita −34.5%, R&D expenditures in health −30.3%, lower reduction of COVID-19 fatality from 2022-2022 by −57.2 % vs 59.3% of the other group. Results also show a negative association between COVID-19 Fatality in 2022 and Health expenditure as a share of GDP 2020 (r=−0.42,p-value 0.05); COVID-19 Fatality in 2022 and Vaccinations in December 2021 (r=−0.75,p-value 0.01). Difference of COVID-19 Fatality 22-20 has also negative correlation coefficients given byr=−0.48 (p-value 0.05) with Health expenditure as a share of GDP of 2020 and byr=−0.52 (p-value 0.01) with vaccinations in December 2021. Partial correlation, controlling population over 65yo in 2020, confirms previous results. The contribution here expands the knowledge in these research topics by endeavoring to clarifyhowhigher health expenditures improve the preparedness and resilience in crisis management of countries to face unforeseen epidemic or pandemic similar to COVID-19 in society.
Creation of a Shortened Version of the of the Sleep Disorders Questionnaire (SDQ)
Authors: Biard Kathleen , Koninck Joseph De , Douglass Alan B.
Published: June 2023

The 176-item Sleep Disorders Questionnaire (SDQ) was initially developed using canonical discriminant function analysis on 4 groups of sleep disorder patients, but it was never studied by factor analysis in its entirety. Several authors have criticized 2 of its subscales as being confounded with each other, and its narcolepsy scale as substantially over-diagnosing narcolepsy. This study describes its first exploratory factor analysis (EFA), the intent of which was to reassess item membership on the 4 existing subscales and to derive new scales to improve differential diagnosis between patient groups. It was also hoped that EFA could reduce the total number of questions, to increase speed of completion. The EFA was performed on the anonymized SDQ results from a retrospective review of the charts of 2131 persons from 7 sleep disorders clinics and research centers. Factors were assessed via scree plots and eigenvalues. The EFA identified four main factors: insomnia, daytime sleepiness, substance use, and sleep-disordered breathing. The insomnia factor had 3 subfactors: psychological symptoms of insomnia, subjective description of insomnia, and insomnia due to periodic limb movements. The sleepiness factor had two subfactors: daytime sleepiness and neurological symptoms of narcolepsy. The novel substance use factor was homogeneous, as was the sleep-disordered breathing factor. Importantly, the EFA reassigned items from the original SDQ’s NAR, PSY, and PLM subscales to five of the new subscales. The Sleep Apnea (SA) subscale emerged mostly unchanged. The 7 resulting factors comprised only 66 items of the original 176-item SDQ. These results have allowed the creation of a new shorter questionnaire, to be called the SDQ-2. External validation of the SDQ-2 is currently underway. It will likely prove to be a superior differential diagnostic instrument for sleep disorders clinics, compared to the original SDQ.
The Greek version of the Richards-Campbell Sleep Questionnaire: Reliability and validity assessment
Authors: Sampani Christina-Athanasia , Charalampopoulos Marios , Triantafyllaki Panagiota , Triantafyllou Christos , Papageorgiou Dimitrios
Published: June 2023

Aim

To translate the RCSQ into Greek and to determine the reliability and validity of the Greek version of the RCSQ as a measure of sleep among ICU patients in a Greek hospital.

Methods

This study investigated the night-time sleep of 50 patients admitted to the general ICU of General Hospital of Athens “G. Gennimatas” between January 2022– March 2023.

The RCSQ questionnaire was used for the present study with the written permission of its author. All guidelines for translating and adapting psychometric scales were followed for translating the RCSQ into Greek. Demographic-clinical characteristics (sex, age, days in hospital, days on mechanical ventilation, days on spontaneous breathing, whether they underwent tracheotomy and the type of tracheotomy, and whether they received a mild sedation formulation to promote sleep) were collected from the participants. Reliability was tested using Cronbach’s alpha coefficient.

Results

The Cronbach’s correlation coefficientαwas calculated 0.906 revealing excellent reliability of the RCSQ. No question removal significantly increased the coefficient value.

Conclusion

The Greek version of the Richards-Campbell Sleep Questionnaire could be used as an alternative to polysomnography when assessing sleep quality in intensive care unit patients.
Mapping out the higher education curricula to locate pre-service teachers training in health education: the case for critical pedagogy
Authors: Soultatou Pelagia , Athanasiou Kyriacos , Bagos Pantelis G
Published: June 2023

WITHDRAWAL STATEMENT

The authors have withdrawn their manuscript owing to several errors discovered in the manuscript regarding analyses and also language use. Also the Tables have been missing from the manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
‘Giving birth is like going to war’:Obstetric violence in public maternity centers in Niger
Authors: Alio Amina P. , Garba Rahmatou M. , Mittal Mona , McCormick Anna P. , Mahamane Moha
Published: June 2023

Obstetric violence has been recognized as a significant risk factor for maternal morbidity and mortality globally. However, there is lack of literature on the abuse of birthing women and their maternal rights in formal healthcare settings in Niger. This paper explores women’s experiences of violence in public maternity care in Niger to identify drivers, facilitators, manifestations, and consequences of the maltreatment of women during labor and delivery. We qualitatively explored the experiences of women who gave birth in a public maternity hospital or clinic within the 5 years preceding the study. We conducted five key informant interviews to help inform recruitment and interview protocols, a listening session with eight mothers, and individual interviews with 50 women from four areas of the urban region of Niamey. The 58 participating mothers shared experiences that included physical abuse (slapping), verbal abuse (insults), psychological abuse (mockery), discrimination (social status/ economic status), financial coercion (demanding money prior to care), and harmful birthing practices (forcing the baby out with elbows). Socio-cultural aspects driving maltreatment of women included beliefs about expression of pain during labor and delivery, while social connection and the presence of the physician during delivery were protective factors. Our study findings reflect global concerns about obstetric violence and its consequences. Given the high burden of maternal and infant morbidity and mortality in Niger, it is critical to train clinical staff in safe and respectful maternity care, to improve supervision of care, to institute legal recourse for women, and to consider the integration of traditional birth attendants in clinical settings.
Assessment of Ultra Processed Foods consumption in Senegal: Validation of the Nova-UPF screener
Authors: Kébé Saliou Diombo , Diouf Adama , Sylla Papa Mamadou Dit Doudou , Kane Kalidou , Costa Caroline dos Santos , Leite Fernanda Helena Marrocos , Andrade Giovanna Calixto , Badiane Abdou , Moubarac Jean-Claude , Idohou-Dossou Nicole , Monteiro Carlos Augusto
Published: June 2023

Abstract

Background

Ultra-processed foods (UPF), as proposed by the Nova food classification system, are linked to the development of obesity and several non-communicable chronic diseases and deaths from all causes. The Nova-UPF screener developed in Brazil is a simple and quick tool to assess and monitor the consumption of these food products. The aim of this study was to adapt and validate, against the 24-hour dietary recall, this short food-based screener to assess UPF consumption in the Senegalese context.

Methods

The tool adaptation was undertaken using DELPHI methodology with national experts and data from a food market survey. The validation study was conducted in the urban area of Dakar in a sample of 301 adults, using as a reference the dietary share of UPF on the day prior to the survey, expressed as a percentage of total energy intake obtained via 24-hour recall. Association between the Nova-UPF score and the dietary share of UPF was evaluated using linear regression models. The Pabak index was used to assess the agreement in participants’ classification according to quintiles of Nova-UPF score and quintiles of the dietary share of UPF.

Results

The results show a direct association (p-value<0.001) between intervals of the Nova- UPF score and the average dietary share of UPF. There was a near perfect agreement in the distribution of individuals according to score’s quintiles and UPF dietary share quintiles (Pabak index = 0.84).

Conclusion

The study concluded that the score provided by the Nova-UPF screener adapted to the Senegalese context is a valid estimate of UPF consumption.
Distinct Neurodevelopmental Patterns and Intermediate Integration-Based Predictive Modeling in Autism Spectral Disorder
Authors: Wang Yanlin , Ma Shiqiang , Ma Ruimin , Xiao Linxia , Tang Shi , Wei Yanjie , Pan Yi
Published: June 2023

Autism Spectrum Disorder (ASD) is known to exhibit a more rapid expansion in brain structure during the early years of life compared to typically developing children (TD). This is of utmost importance in understanding atypical brain development and forecasting the onset of ASD. However, the precise age-related cortical changes (trajectories) that could pinpoint atypical brain development in ASD remain largely unknown. In this study, we characterize the distinct developmental patterns of cortical morphology in individuals with ASD, investigate the important neural biomarkers for ASD diagnostics, and propose a deep-learning workflow that combined graph convolutional networks with low-rank multi-model tensor fusion (LMFGCN) for ASD prediction. Our findings reveal that the constituents of gray matter volume (GV), cortical thickness (CT), and surface area (SA) exhibit separable developmental trajectories in ASD. Furthermore, we identify regional differences in CT and SA that underscore the separable brain developmental trajectories, both of which contribute to changes in GV. Our study also demonstrates that LMFGCN, an end-to-end deep-learning model with intermediate integrative approach, outperforms early and late integration methods and other state-of-the-art models in ASD classification. Overall, our results highlight the importance of distinguishing between cortical SA and CT for understanding ASD pathobiology, particularly during the early brain overgrowth period, and demonstrate the potential utility of LMFGCN in ASD classification.
Elevated concentrations of polymyxin B elicit a biofilm-specific resistance mechanism inVibrio cholerae
Authors: Pauzé-Foixet Julien , Duperthuy Marylise
Published: June 2023

Vibrio choleraecan form biofilms both in the aquatic environment and in the human intestine, facilitating the release of hyper-infectious aggregates. Due to the increasing antibiotic resistance that impedes treatment of infections, alternatives need to be found. One of these alternatives is antimicrobial peptides, including polymyxin B (PmB), which is already used to treat infections caused by antibiotic-resistant bacteria. In this study, we first investigated the resistance ofV. choleraeO1 El Tor strain A1552 to various antimicrobials under aerobic and anaerobic conditions. An increased resistance to PmB is observed in anaerobiosis, with a 3-fold increase in the dose required for 50% growth inhibition. We then studied the impact of the PmB on the formation and the degradation ofV. choleraebiofilms to PmB. Our results show that PmB affects more efficiently biofilm formation under anaerobic conditions. On the other hand, preformed biofilms are susceptible to degradation by PmB at concentrations close to the minimum inhibitory concentration (MIC), resulting in approximately 50% reduction of the biomass. At higher concentrations, we observed less degradation and an opacification of the biofilm structures within 20 minutes post-treatment, suggesting a densification of the structure. This densification does not seem to result from the overexpression of matrix genes but rather from the release of DNA through cellular lysis, forming a protective shield that limits the penetration of the PmB into the biofilm.

Importance

Vibrio choleraeis an intestinal pathogen capable of forming biofilms and resisting antimicrobials both in the aquatic environment and during infection. Understanding and determining the resistance ofV. choleraeto antimicrobials during the infection is crucial to improve patient care. During the infection and in the aquatic environment,V. choleraeform biofilms, structures that are known for their significance in antimicrobial resistance. In this study, we investigated the antimicrobial resistance ofV. choleraein both aerobic and anaerobic conditions, in their planktonic and biofilm forms. The major finding of this study is the identification of a resistance mechanism specific to elevated concentrations of polymyxin B, a last-resort antimicrobial used in the treatment of infections caused by multidrug-resistant Gram-negative bacteria. This resistance mechanism likely involves the lysis of bacterial cells on the surface of the biofilm, resulting in the release of DNA that provides a protective shield against PmB for bacteria within the biofilm matrix.
Concerted transformation of a hyper-paused transcription complex and its reinforcing protein
Authors: Zuber Philipp K. , Said Nelly , Hilal Tarek , Wang Bing , Loll Bernhard , González-Higueras Jorge , Ramírez-Sarmiento César A. , Belogurov Georgiy A. , Artsimovitch Irina , Wahl Markus C. , Knauer Stefan
Published: June 2023

RfaH, a paralog of the universally conserved NusG, binds to RNA polymerases (RNAP) and ribosomes to activate expression of virulence genes. In free, autoinhibited RfaH, an α-helical KOW domain sequesters the RNAP-binding site. Upon recruitment to RNAP paused at anopssite, KOW is released and refolds into a β-barrel, which binds the ribosome. Our structures ofops-paused transcription elongation complexes alone and bound to the autoinhibited and activated RfaH reveal swiveled, pre-translocated pause states stabilized by anopshairpin in the non-template DNA. Autoinhibited RfaH binds and twists theopshairpin, expanding the RNA:DNA hybrid to 11 base pairs and triggering the KOW release. Once activated, RfaH hyper-stabilizes the pause, which thus requires anti-backtracking factors for escape. Our results suggest that the entire RfaH cycle is solely determined by theopsand RfaH sequences and provide insights into mechanisms of recruitment and metamorphosis of NusG homologs across all life.

HIGHLIGHTS

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The nontemplate DNA strand of anops-paused transcription complex forms a hairpin

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Autoinhibited RfaH binds and twists theopshairpin to expand the RNA:DNA hybrid

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RfaH-hairpin contacts are solely responsible for triggering RfaH activation

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Upon recruitment, RfaH hyper-stabilizes the pause and promotes RNAP backtracking
Dendrimeric DNA Coordinate Barcoding Design for Spatial RNA Sequencing
Authors: Cao Jiao , Zheng Zhong , Sun Di , Chen Xin , Cheng Rui , Lv Tianpeng , An Yu , Zheng Junhua , Song Jia , Wu Lingling , Yang Chaoyong
Published: June 2023

Spatially resolved transcriptomic technologies show promise in revealing complex pathophysiological processes, but developing sensitive, high-resolution, and cost-effective methodology is challenging. Here, we report adendrimeric DNAcoordinate barcodingdesign for spatialRNAsequencing (Decoder-seq). This technology combined dendrimeric nano-substrates with microfluidic coordinate barcoding to generate high-density spatial DNA arrays with deterministically combinatorial barcodes in a resolution-flexible and cost-effective manner (∼$0.5/mm2). Decoder-seq achieved high RNA capture efficiency, ∼68.9% that ofin situsequencing, and enhanced the detection of lowly expressed genes by ∼five-fold compared to 10× Visium. Decoder-seq visualized a spatial single-cell atlas of mouse hippocampus at near-cellular resolution (15 μm) and revealed dendrite-enriched mRNAs. Application to renal cancers dissected the heterogeneous tumor microenvironment of two subtypes, and identified spatial gradient expressed genes with the potential in predicting tumor prognosis and progression. Decoder-seq is compatible with sensitivity, resolution, and cost, making spatial transcriptomic analysis accessible to wider biomedical applications and researchers.
Inserting a Neuropixels probe into awake monkey cortex: two probes, two methods
Authors: Namima Tomoyuki , Kempkes Erin , Smith Bob , Pasupathy Anitha
Published: June 2023

Neuropixels probes have revolutionized neurophysiological studies in the rodent, but inserting these probes through the much thicker primate dura remains a challenge. Here we describe two methods we have developed for the insertion of two types of Neuropixels probes acutely into the awake monkey cortex. For the fine rodent probe, which is unable to pierce native primate dura, we developed a duraleyelet method to insert the probe repeatedly without breakage. For the thicker NHP probe, we developed an artificial dura system to insert the probe. We have now conducted successful experiments in 3 animals across 7 recording chambers with the procedures described here and have achieved stable recordings over several months in each case. Here we describe our hardware, surgical preparation, methods for insertion and methods for removal of broken probe parts. We hope that our methods are of value to primate physiologists everywhere.
Covering Hierarchical Dirichlet Mixture Models on binary data to enhance genomic stratifications in Onco-Hematology
Authors: Dall’Olio Daniele , Sträng Eric , Turki Amin T , Tettero Jesse M , Barbus Martje , Schulze-Rath Renate , Elicegui Javier Martinez , Matteuzzi Tommaso , Merlotti Alessandra , Carota Luciana , Sala Claudia , Della Porta Matteo G , Giampieri Enrico , Hernández-Rivas Jesús María , Bullinger Lars , Castellani Gastone ,   HARMONY Healthcare Alliance Consortium
Published: June 2023

Onco-hematological studies are increasingly adopting statistical mixture models to support the advancement of the genetically-driven classification systems for blood cancer. Targeting enhanced patients stratification based on the sole role of molecular biology attracted much interest and contributes to bring personalized medicine closer to reality. In particular, Dirichlet processes have become the preferred method to approach the fit of mixture models. Usually, the multinomial distribution is at the core of such models. However, despite their advanced statistical formalism, these processes are not to be considered black box techniques and a better understanding of their working mechanisms enables to improve their employment and explainability. Focused on genomic data in Acute Myeloid Leukemia, this work unfolds the driving factors and rationale of the Hierarchical Dirichlet Mixture Models of multinomials on binary data. In addition, we introduce a novel approach to perform accurate patients clustering via multinomials based on statistical considerations. The newly reported adoption of the Multivariate Fisher’s Non-Central Hypergeometric distributions reveals promising results and outperformed the multinomials in clustering both on simulated and real onco-hematological data.

Author summary

Explainable models are particularly attractive nowadays since they have the advantage to convince clinicians and patients. In this work we show that a deeper understanding of the Hierarchical Dirichlet Mixture Model, a non-black box method, can lead to better data modelling. In onco-hematology Hierarchical Dirichlet Mixture Models typically help to cluster molecular alterations rather than patients. Here, an intuitive statistical approach is presented to tackle patient classification based on the Hierarchical Dirichlet Mixture Models outcome. Additionally, molecular alterations are usually modelled by Hierarchical Dirichlet Mixture Models as a mixture of multinomial distributions. This work highlights that the alternative Fisher’s Non-Central Hypergeometric distribution can provide even better results and can give a higher priority to rare molecular alterations for patient classification.
Effect of using Diffusion-Weightage Imaging on Diagnostic Accuracy of MRI in catching Parotid carcinoma: A meta-analysis
Authors: Desai Dev , Todorovski Marko , Malafi Maria Eleni , Shah Abhijay B. , Andharia Dev
Published: June 2023

Background

A wide variety of benign and malignant tumors can develop in the salivary gland, which makes up roughly 3-5% of all head and neck tumors. Making a precise pre-operative distinction between benign and malignant salivary gland tumors, or identifying the precise histologic subtype, is crucial since this knowledge has a significant impact on the treatment strategy. The results of fine-needle aspiration cytology can occasionally be inaccurate since it is an intrusive procedure for diagnosing parotid tumors before surgery. Because of the tiny sample size or the deep placement of the tumor, it is sometimes impossible to gather adequate samples therefore Salivary gland tumors are increasingly being evaluated before surgery using MRI since it can pinpoint their precise location, size, and surrounding tissues.

Methods

Medical literature was comprehensively searched and reviewed without restrictions to particular study designs, or publication dates using PubMed, Cochrane Library, and Google Scholar databases for all relevant literature. The extraction of necessary data proceeded after specific inclusion and exclusion criteria were applied. The inclusion criteria were as follows:; (1) Literature that provided information about the accurate diagnosis with MRI(DWI) and only MRI ; (2) papers published in English; (3) papers with appropriate patient criteria. The exclusion criteria were: (1) articles that were not full text, (2) unpublished articles, and (3) non-English articles. In this Meta-Analysis, a total of 8 RCTs with a total of 944 patients were selected, out of which 3 RCTs with a total of 356 patients were selected for MRI and 5 RCTs with a total of 588 patients were selected for MRI+DWI study. wherein two writers independently assessed the caliber of each study as well as the use of the Cochrane tool for bias risk apprehension. The statistical software packages RevMan (Review Manager, version 5.3), SPSS (Statistical Package for the Social Sciences, version 20), and Excel in Stata 14 were used to perform the statistical analyses.

Results

We calculated the sensitivity and specificity of MRI in diagnosing parotid gland lesions in the different papers, For the MRI, The sensitivity is 0.81 with a CI of 95% in a range of 0.77 to 0.86, the mean being 0.049. The Sensitivity of the MRI is 0.790 with a CI of 95% in a range of (0.772 to 0.809) the mean being (0.0183). The Specificity of the MRI is 0.794 with a CI of 95% in a range of (0.613 to 0.975) the mean being (0.181). For the MRI+DWI study, The Sensitivity of the MRI+DWI is 0.618 with a CI of 95% in a range of (0.498 to 0.737); the mean being (0.119). The Specificity of the MRI+DWI is 0.892 with a CI of 95% in a range of (0.813 to 0.97) the mean being (0.079).

Conclusion

In addition to simple MRI or Single DWI MRI, A combination of both would detect higher lesions and it should be helpful for staging and early diagnosis purposes only.
Prediction of tumor-specific splicing from somatic mutations as a source of neoantigen candidates
Authors: Lang Franziska , Sorn Patrick , Suchan Martin , Henrich Alina , Albrecht Christian , Koehl Nina , Beicht Aline , Riesgo-Ferreiro Pablo , Holtsträter Christoph , Schrörs Barbara , Weber David , Löwer Martin , Sahin Ugur , Ibn-Salem Jonas
Published: June 2023

Splicing is dysregulated in many tumors and may result in tumor-specific transcripts that can encode neoantigens, which are promising targets for cancer immunotherapy. Detecting tumor-specific splicing is challenging because many non-canonical splice junctions identified in tumor transcriptomes also appear in healthy tissues.

Here, we developed splice2neo to integrate the predicted splice effects from somatic mutations with splice junctions detected in tumor RNA-seq for individual cancer patients. Splice2neo excludes splice junctions from healthy tissue samples, annotates resulting transcript and peptide sequences, and provides targeted re-quantification of supporting RNA-seq reads. We developed a stringent detection rule to predict splice junctions as mutation-derived targets and identified 1.7 target splice junctions per tumor with a false discovery rate below 5% in a melanoma cohort. We confirmed tumor-specificity using independent, healthy tissue samples. Furthermore, using tumor-derived RNA, we confirmed individual exon skipping events experimentally. Most target splice junctions encoded neoepitope candidates with predicted MHC-I or MHC-II binding. Compared to neoepitope candidates derived from non-synonymous point mutations, the splicing-derived MHC-I neoepitope candidates had a lower self-similarity to corresponding wild-type peptides.

In conclusion, we demonstrate that identifying mutation-derived and tumor-specific splice junctions can lead to additional neoantigen candidates to expand the target repertoire for cancer immunotherapies.

Key Points

splice2neo is a versatile tool for identifying and analyzing of splice junctions as a source of neoantigen candidates

We identified mutation-retrieved splice junctions supported by RNA-seq in melanoma samples

The predicted target splice junctions exhibited a strong tumor-specificity as they were absent in healthy tissues.

Target splice junctions often lead to frame-shift peptides and encode promising neoantigen candidates
Polygenic risk score prediction accuracy convergence
Authors: Henches Léo , Kim Jihye , Yang Zhiyu , Rubinacci Simone , Pires Gabriel , Albiñana Clara , Boetto Christophe , Julienne Hanna , Frouin Arthur , Auvergne Antoine , Suzuki Yuka , Djebali Sarah , Delaneau Olivier , Ganna Andrea , Vilhjálmsson Bjarni , Privé Florian , Aschard Hugues
Published: June 2023

Polygenic risk scores (PRS) trained from genome-wide association study (GWAS) results are set to play a pivotal role in biomedical research addressing multifactorial human diseases. The prospect of using these risk scores in clinical care and public health is generating both enthusiasm and controversy, with varying opinions about strengths and limitations across experts1. The performances of existing polygenic scores are still limited, and although it is expected to improve with increasing sample size of GWAS and the development of new powerful methods, it remains unclear how much prediction can be ultimately achieved. Here, we conducted a retrospective analysis to assess the progress in PRS prediction accuracy since the publication of the first large-scale GWASs using six common human diseases with sufficient GWAS data. We show that while PRS accuracy has grown rapidly for years, the improvement pace from recent GWAS has decreased substantially, suggesting that further increasing GWAS sample size may translate into very modest risk discrimination improvement. We next investigated the factors influencing the maximum achievable prediction using recently released whole genome-sequencing data from 125K UK Biobank participants, and state-of-the-art modeling of polygenic outcomes. Our analyses point toward increasing the variant coverage of PRS, using either more imputed variants or sequencing data, as a key component for future improvement in prediction accuracy.
Engineering Human Pluripotent Stem Cell Lines to Evade Xenogeneic Transplantation Barriers
Authors: Pizzato Hannah A. , Alonso-Guallart Paula , Woods James , Johannesson Bjarki , Connelly Jon P. , Fehniger Todd A. , Atkinson John P. , Pruett-Miller Shondra M. , Monsma Frederick J. , Bhattacharya Deepta
Published: June 2023

Allogeneic human pluripotent stem cell (hPSC)-derived cells and tissues for therapeutic transplantation must necessarily overcome immunological rejection by the recipient. To define these barriers and to create cells capable of evading rejection for preclinical testing in immunocompetent mouse models, we genetically ablatedβ2m,Tap1,Ciita,Cd74,Mica, andMicbto limit expression of HLA-I, HLA-II, and natural killer cell activating ligands in hPSCs. Though these and even unedited hPSCs readily formed teratomas in cord blood-humanized immunodeficient mice, grafts were rapidly rejected by immunocompetent wild-type mice. Transplantation of these cells that also expressed covalent single chain trimers of Qa1 and H2-Kbto inhibit natural killer cells and CD55, Crry, and CD59 to inhibit complement deposition led to persistent teratomas in wild-type mice. Expression of additional inhibitory factors such as CD24, CD47, and/or PD-L1 had no discernible impact on teratoma growth or persistence. Transplantation of HLA-deficient hPSCs into mice genetically deficient in complement and depleted of natural killer cells also led to persistent teratomas. Thus, T cell, NK cell, and complement evasion are necessary to prevent immunological rejection of hPSCs and their progeny. These cells and versions expressing human orthologs of immune evasion factors can be used to refine tissue- and cell type-specific immune barriers, and to conduct preclinical testing in immunocompetent mouse models.
Unveiling targeted cell-free DNA methylation regions through paired methylome analysis of tumor and normal tissues
Authors: Li Tingyi , Patel Krupal B , Yu Xiaoqing , Yao Sijie , Wang Liang , Chung Christine H , Wang Xuefeng
Published: June 2023

Liquid biopsy analysis of cell-free DNA (cfDNA) has revolutionized cancer research by enabling non-invasive assessment of tumor-derived genetic and epigenetic changes. In this study, we conducted a comprehensive paired-sample differential methylation analysis (psDMR) on reprocessed methylation data from two large datasets, CPTAC and TCGA, to identify and validate differentially methylated regions (DMRs) as potential cfDNA biomarkers for head and neck squamous cell carcinoma (HNSC). Our hypothesis is that the paired sample test provides a more suitable and powerful approach for the analysis of heterogeneous cancers like HNSC. The psDMR analysis revealed a significant number of overlapped hypermethylated DMRs between two datasets, indicating the reliability and relevance of these regions for cfDNA methylation biomarker discovery. We identified several candidate genes, includingCALCA, ALX4, andHOXD9, which have been previously established as liquid biopsy methylation biomarkers in various cancer types. Furthermore, we demonstrated the efficacy of targeted region analysis using cfDNA methylation data from oral cavity squamous cell carcinoma and nasopharyngeal carcinoma patients, further validating the utility of psDMR analysis in prioritizing cfDNA methylation biomarkers. Overall, our study contributes to the development of cfDNA-based approaches for early cancer detection and monitoring, expanding our understanding of the epigenetic landscape of HNSC, and providing valuable insights for liquid biopsy biomarker discovery not only in HNSC and other cancer types.
Genetic similarity between relatives provides evidence on the presence and history of assortative mating
Authors: Sunde Hans Fredrik , Eftedal Nikolai Haahjem , Cheesman Rosa , Corfield Elizabeth C. , Kleppesto Thomas H. , Seierstad Anne Caroline , Ystrom Eivind , Eilertsen Espen Moen , Torvik Fartein Ask
Published: June 2023

Assortative mating – the non-random mating of individuals with similar traits – is known to increase trait-specific genetic variance and genetic similarity between relatives. However, empirical evidence is limited for many traits, and the implications hinge on whether assortative mating has started recently or many generations ago. Here we show theoretically and empirically that genetic similarity between relatives can provide evidence on the presence and history of assortative mating. First, we employed path analysis to understand how assortative mating affects genetic similarity between family members across generations, finding that similarity between distant relatives is more affected than close relatives. Next, we correlated polygenic indices of 47,135 co-parents from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and found genetic evidence of assortative mating in nine out of sixteen examined traits. The same traits showed elevated similarity between relatives, especially distant relatives. Six of the nine traits, including educational attainment, showed greater genetic variance among offspring, which is inconsistent with stable assortative mating over many generations. These results suggest an ongoing increase in familial similarity for these traits. The implications of this research extend to genetic methodology and the understanding of social and economic disparities.
The ChickenGTEx pilot analysis: a reference of regulatory variants across 28 chicken tissues
Authors: Guan Dailu , Bai Zhonghao , Zhu Xiaoning , Zhong Conghao , Hou Yali ,   The ChickenGTEx Consortium, Lan Fangren , Diao Shuqi , Yao Yuelin , Zhao Bingru , Zhu Di , Li Xiaochang , Pan Zhangyuan , Gao Yahui , Wang Yuzhe , Zou Dong , Wang Ruizhen , Xu Tianyi , Sun Congjiao , Yin Hongwei , Teng Jinyan , Xu Zhiting , Lin Qing , Shi Shourong , Shao Dan , Degalez Fabien , Lagarrigue Sandrine , Wang Ying , Wang Mingshan , Peng Minsheng , Rocha Dominique , Charles Mathieu , Smith Jacqueline , Watson Kellie , Buitenhuis Albert Johannes , Sahana Goutam , Lund Mogens Sandø , Warren Wesley , Frantz Laurent , Larson Greger , Lamont Susan J. , Si Wei , Zhao Xin , Li Bingjie , Zhang Haihan , Luo Chenglong , Shu Dingming , Qu Hao , Luo Wei , Li Zhenhui , Nie Qinghua , Zhang Xiquan , Zhang Zhe , Zhang Zhang , Liu George E. , Cheng Hans , Yang Ning , Hu Xiaoxiang , Zhou Huaijun , Fang Lingzhao
Published: June 2023

Chicken is a valuable model for understanding fundamental biology, vertebrate evolution and diseases, as well as a major source of nutrient-dense and lean-protein-enriched food globally. Although it is the first non-mammalian amniote genome to be sequenced, the chicken genome still lacks a systematic characterization of functional impacts of genetic variants. Here, through integrating 7,015 RNA-Seq and 2,869 whole-genome sequence data, the Chicken Genotype- Tissue Expression (ChickenGTEx) project presents the pilot reference of regulatory variants in 28 chicken tissue transcriptomes, including millions of regulatory effects on primary expression (including protein-coding genes, lncRNA and exon) and post-transcriptional modifications (alternative splicing and 3’ untranslated region alternative polyadenylation). We explored the tissue-sharing and context-specificity of these regulatory variants, their underlying molecular mechanisms of action, and their utility in interpreting adaptation and genome-wide associations of 108 chicken complex traits. Finally, we illustrated shared and lineage-specific features of gene regulation between chickens and mammals, and demonstrated how the ChickenGTEx resource can further assist with translating genetic findings across species.

One-Sentence Summary

The ChickenGTEx provides a multi-tissue reference of regulatory variants for chicken genetics and genomics, functional genomics, precision breeding, veterinary medicine, vertebrate evolution and even human biomedicine.
Attenuation of colitis-induced visceral hypersensitivity and pain by silencing TRPV1-expressing fibers in rat colon
Authors: Mazor Yoav , Engelmayer Nurit , Nashashibi Halla , Rottenfußer Lisa , Lev Shaya , Binshtok Alexander M
Published: June 2023

Background and Aims

Abdominal pain in patients with inflammatory bowel disease (IBD) is common and debilitating. In our study, we aim to utilize transient receptor potential vanilloid 1 (TRPV1) channels, large-pore cation channels expressed on nociceptors, as a drug delivery system to selectively inhibit visceral nociceptors and thus visceral pain in a rodent model of IBD.

Methods

We induced colitis in rats using intrarectal dinitrobenzene sulfonic acid. Visceral hypersensitivity, spontaneous pain, and responsiveness of the hind paws to noxious heat stimuli were examined before and after the intrarectal application of sodium channel blocker QX-314 alone or together with TRPV1 channel activators or blockers.

Results

Intrarectal co-application of QX-314 with TRPV1 channel activator capsaicin significantly inhibited colitis-induced gut hypersensitivity. Furthermore, in the model of colitis, but not in naïve rats, QX-314 alone was sufficient to reverse gut hypersensitivity. The blockade of TRPV1 channels prevented this effect of QX-314. Finally, applying QX-314 alone to the inflamed gut inhibited colitis-induced ongoing pain.

Conclusions

Selective silencing of nociceptors by QX-314 entering via exogenously or endogenously activated TRPV1 channels diminish IBD-induced gut hypersensitivity. These results yet again confirm the central role of TRPV1-expressing nociceptive neurons in IBD pain. The lack of QX-314 effect on naïve rats suggests its selective analgesic effect in IBD pain. Moreover, our results demonstrating the effect of QX-314 alone imply the role of a tonically active TRPV1 channel in the pathophysiology of IBD pain. This approach provides proof-of-concept for using charged activity blockers for selective and effective blockade of visceral pain.
New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets
Authors: Giannelli Serena Gea , Luoni Mirko , Bellinazzi Benedetta , Iannielli Angelo , Middeldorp Jinte , Philippens Ingrid , Körbelin Jakob , Broccoli Vania
Published: June 2023

Adeno-Associated Virus 9 (AAV9) is a delivery platform highly exploited to develop gene-based treatments for neurological disorders given its low pathogenicity and brain tissue tropism. However, the efficacy of this vector is dampened by its relatively low efficiency to cross the adult blood-brain barrier (BBB) and inherent targeting to the liver upon intravenous delivery. We generated a new peptide display library starting from a galactose binding-deficient AAV9 capsid and selected two new AAV9 engineered capsids, named AAV-Se1 and AAV-Se2, with an enhanced targeting in mouse and marmoset brains after intravenous delivery. Interestingly, the loss of the galactose binding strongly reduced the undesired targeting to peripheral organs, and above all liver, while not compromising the transduction of the brain vasculature. However, we had to reconstitute the galactose binding in order to efficiently infect non-endothelial brain cells. Thus, the combinatorial actions of the galactose-binding domain and the installed exogenous displayed peptide are crucial to enhance BBB crossing together with brain cell transduction. We also identified Ly6C1 as primary receptor for AAV-Se2 which is a Ly6A homologue highly expressed in the brain endothelial cells. This study describes a new strategy to select neurotropic AAV9 variants and identifies two novel capsids with high brain endothelial infectivity and extremely low liver targeting based on manipulating the AAV9 galactose binding domain.