bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, and Executive Function Impairment in Metopic Craniosynostosis
Authors: Almeida Mariana N. , Alper David P. , Long Aaron S. , Barrero Carlos , Williams Mica C. G. , Boroumand Sam , Glahn Joshua , Shah Jinesh , Swanson Jordan , Alperovich Michael
Published: December 2023

Background:

Favorable behavioral interactions are critical for academic and interpersonal success. An association between metopic synostosis and behavioral impairments has not been fully elucidated. Behavioral dysfunction in school-age children with surgically corrected metopic synostosis was evaluated using targeted testing to detect the most common behavioral abnormalities in this population.

Methods:

Parents of children 6 to 18 years of age with metopic synostosis completed the Conners Rating Scales, 3rd edition (Short Form) (Conners-3; attention-deficit/hyperactivity disorder), Social Responsiveness Scale, 2nd edition (SRS-2; autism spectrum disorder), Behavior Rating Inventory of Executive Function, 2nd edition (executive functioning), and Child’s Behavioral Checklist (behavioral/emotional functioning). Children also completed neurocognitive testing. Multivariable regression was used to determine predictors of clinically significant behavioral impairments.

Results:

Sixty children were enrolled. Average age at surgery was 9.2 ± 7.9 months, with an average age at assessment of 10.3 ± 3.5 years. Nearly half of patients demonstrated symptoms associated with attention-deficit/hyperactivity disorder, demonstrated by reaching or exceeding borderline clinical levels for inattention and hyperactivity subscales of the Conners-3. Greater age at surgery was associated with worse executive function, measured by reaching or exceeding clinically significant levels of the executive function subscale of the Conners-3 (P = 0.04) and subscales of the Behavior Rating Inventory of Executive Function, 2nd edition (Behavioral Regulator Index [P = 0.05], Cognitive Regulatory Index [P = 0.03], and Global Executive Composite [P = 0.04]).

Conclusions:

Nearly half of patients with surgically corrected metopic synostosis reached borderline clinical scores for inattention and hyperactivity. Older age at surgery was associated with worse executive function. Prompt surgical correction of metopic synostosis may portend improved long-term emotional and behavioral function.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Indications for Furlow Double-Opposing Z-Plasty in Patients with Velopharyngeal Insufficiency following 2-Flap Palatoplasty
Authors: Park Tae Hyun , Kang Hyun Su , Ryu Jeong Yeop , Lee Joon Seok , Yang Jung Dug , Chung Ho Yun , Choi Kang Young
Published: December 2023

Background:

Various surgical methods have been developed for treating velopharyngeal insufficiency (VPI); however, the choice of surgical treatment is controversial. The pharyngeal flap, which is commonly used, has a high success rate but frequently leads to airway complications. Furlow double-opposing Z-plasty (DOZ) does not deform the velopharyngeal port; therefore, it is expected to show good speech outcomes while reducing airway complications if an appropriate indication is noted. This study aimed to identify indications for DOZ in cases of VPI after palatoplasty.

Methods:

Nonsyndromic patients who underwent palatoplasty were prospectively followed from 2008 to 2016, and those diagnosed with VPI were treated with DOZ. Preoperative facial computed tomography (CT) and postoperative nasometric assessment results were examined. Surgical indication was set based on a 30% threshold value for postoperative nasalance.

Results:

Comparing the preoperative CT measurements of both groups, high need ratio (NR), wide width of the nasopharynx (WNP), and long velopharyngeal depth (VPD) were contributing factors to VPI occurrence (P < 0.05). Analyzing preoperative CT and postoperative speech evaluation results, a linear relationship was observed between preoperative NR, WNP, and VPD and postoperative nasalance. In cases where NR was less than 0.81, WNP was less than 27.64 mm, and VPD was less than 20.34 mm, DOZ showed favorable outcomes (P < 0.05).

Conclusions:

Preoperative CT evaluation should be performed in patients with VPI. When WNP, VPD, and NR values are small, DOZ can achieve sufficient correction of VPI and reduce the risk of airway complications. In cases where the indication range is exceeded, the pharyngeal flap is considered.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
The Clinical Value of Apparent Diffusion Coefficient of Readout Segmentation of Long Variable Echo Trains and Correlation With Ki-67 Expression in Distal Rectal Cancer
Authors: Pan Yu-Ning , Gu Meng-Yin , Mao Quan-Liang , Wang Hui-Ying , Liang Yi-Chuan , Zhang Lin , Tang Guang-Yu
Published: December 2023

Objective

The aim of the study is to explore the clinical value of the apparent diffusion coefficient (ADC) derived from the readout segmentation of long variable echo trains (RESOLVE) technique for identifying clinicopathologic features of distal rectal cancer and correlations between ADC and Ki-67 expression.

Methods

The data of 112 patients with a proven pathology of distal rectal cancer who underwent preoperative magnetic resonance imaging were retrospectively analyzed. The mean ADC value was measured using the “full-layer and center” method. Differences in ADC values and Ki-67 expression in different clinical stages, pathological types, and tumor differentiation were compared using analysis of variance. Correlations between ADC value and clinicopathologic features were assessed using Spearman correlation analysis.

Results

Interobserver agreement of confidence levels from 2 radiologists was excellent for ADC measurement (k =  0.85). Patients with a lower clinical stage, well-differentiated adenocarcinomas, and a higher possibility of mucinous adenocarcinoma exhibited a positive correlation with higher ADC values, but these factors were negatively correlated with Ki-67 expression (all P < 0.05). We found that ADC value was negatively correlated with Ki-67 expression (r = −0.62, P < 0.001).

Conclusions

The ADC value generated by RESOLVE sequences was significantly associated with clinicopathologic features and Ki-67 expression in patients with distal rectal cancer in this study. Thus, the ADC value could be considered a new noninvasive imaging biomarker that could be helpful in predicting the biological properties of distal rectal cancer.
EFFECTS OF HYPERBARIC OXYGEN THERAPY ON INTESTINAL ISCHEMIA-REPERFUSION AND ITS MECHANISM
Authors: Song Shurui , Li Ruojing , Wu Changliang , Dong Jing , Wang Peige
Published: December 2023

Ischemia can cause reversible or irreversible cell or tissue damage, and reperfusion after ischemia not only has no therapeutic effect but also aggravates cell damage. Notably, gut tissue is highly susceptible to ischemia-reperfusion (IR) injury under many adverse health conditions. Intestinal IR (IIR) is an important pathophysiological process in critical clinical diseases. Therefore, it is necessary to identify better therapeutic methods for relieving intestinal ischemia and hypoxia. Hyperbaric oxygenation refers to the intermittent inhalation of 100% oxygen in an environment greater than 1 atm pressure, which can better increase the oxygen level in the tissue and change the inflammatory pathway. Currently, it can have a positive effect on hypoxia and ischemic diseases. Related studies have suggested that hyperbaric oxygen can significantly reduce ischemia-hypoxic injury to the brain, spinal cord, kidney, and myocardium. This article reviews the pathogenesis of IR and the current treatment measures, and further points out that hyperbaric oxygen has a better effect in IR. We found that not only improved hypoxia but also regulated IR induced injury in a certain way. From the perspective of clinical application, these changes and the application of hyperbaric oxygen therapy have important implications for treatment, especially IIR.
Hemoglobin A1c and Reoperation After Surgery for Stress Incontinence or Prolapse
Authors: Bachar Austin , Wang Xi , Herzog Kiersten , Sahil Suman , Cheng An-Lin , Ohene-Agyei Jada A. , Shepherd Jonathan P. , Sutkin Gary
Published: December 2023

Importance

Few studies compare the link between hemogobin A1c (HbA1c) and urogynecologic surgical complications.

Objective

The objective of this study was to determine the association between HbA1c and reoperation in women undergoing surgery for stress urinary incontinence (SUI) or pelvic organ prolapse (POP).

Study Design

We performed 2 separate retrospective cohort analyses using Cerner's HealthFacts Database (750 hospitals; 519,000,000 patient encounters from January 1, 2010, to November 30, 2018). We included women undergoing surgery for (1) SUI or (2) apical POP by International Classification of Diseases coding who had HbA1c at the initial procedure. Each analysis compared those undergoing reoperation for complications or recurrence and those who did not. Multivariable logistic regression assessed the association between reoperation and HbA1c both as a continuous variable and comparing the commonly accepted cutoff ≥8.

Results

Of 30,180 SUI surgical procedures and 26,389 POP surgical procedures, 1,625 (5.4%) and 805 (3.1%) had HbA1c. Median (interquartile range) HbA1c in grams per deciliter was similar by reoperation status (SUI: 6.0 [5.6–6.8] vs 6.1 [5.6–6.9], P = 0.35; POP: 6.2 [5.6–6.6] vs 6.1 [5.7–6.8], P = 0.60). Reoperation was also similar using the HbA1c ≥8% cutoff (SUI: 6.9% vs 7.4%, P = 0.79; POP: 6.3% vs 5.4%, P = 0.77). On multivariate analysis, HbA1c value was not a significant predictor of reoperation either as a continuous (SUI: odds ratio [OR] = 0.966, 95% CI = 0.833–1.119; POP: OR = 1.040, 95% CI = 0.801–1.350) or dichotomous variable ≥8 (SUI: OR = 0.767, 95% CI = 0.407–1.446; POP: OR = 0.988, 95% CI = 0.331–2.951). Mean follow-up was 4.28–5.13 years.

Conclusion

Although other studies have shown a link between diabetes and complications, we were unable to show an association between HbA1c values and rates of reoperation.
Challenging fungal infections in cystic fibrosis: a case of mixed Aspergillus species infection and antifungal combination testing
Authors: Pontes Laís , Reichert-Lima Franqueline , Perini Leme Giordano Ana Luisa , Moretti Maria Luiza , Zaninelli Schreiber Angélica
Published: December 2023

Aspergillus stands as the predominant fungal genus in the airways of cystic fibrosis (CF) patients, significantly contributing to their morbidity and mortality. Aspergillus fumigatus represents the primary causative species for infections, though the emergence of rare species within the Aspergillus section Fumigati has become noteworthy. Among these, Aspergillus lentulus is particularly significant due to its frequent misidentification and intrinsic resistance to azole antifungal agents. In the invasive aspergillosis and resistant infections, combination antifungal therapy has proven to be an effective approach. This report documents a case involving the death of a CF patient due to a pulmonary exacerbation linked to the colonization of multiple Aspergillus species, including A. lentulus, A. fumigatus, and A. terreus, and treated with Itraconazole (ITC) monotherapy. We delineated the procedures used to characterize the Aspergillus isolates in clinical settings and simulated in vitro the impact of the combination antifungal therapy on the isolates obtained from the patient. We evaluated three different combinations: Amphotericin B (AMB) + Voriconazole (VRC), AMB + Anidulafungin (AND), and VRC + AND. Notably, all strains isolated from the patient exhibited a significant decrease in their minimum inhibitory concentration (MIC) or minimum effective concentration (MEC) values when treated with all combinations. The VRC + AMB combination demonstrated the most synergistic effects. This case report emphasizes the importance of susceptibility testing and precise identification of Aspergillus species to enhance patient prognosis. It also underscores the potential benefits of combined antifungal treatment, which, in this case, could have led to a more favorable patient outcome.
Early Detection of Diabetic Neuropathy Based on Health Belief Model: A Scoping Review
Authors: Purwanti Okti Sri , Nursalam  , Pandin Moses Glorino Rumambo
Published: December 2023

Introduction

Uncontrolled blood sugar levels may result in complications, namely diabetic neuropathy. Diabetic neuropathy is a nerve disorder that causes symptoms of numbness, foot deformity, dry skin, and thickening of the feet. The severity of diabetic neuropathy carries the risk of developing diabetic ulcers and amputation. Early detection of diabetic neuropathy can prevent the risk of diabetic ulcers.

Methods

This research studied articles in 6 databases via Scopus, Ebsco, Pubmed, Sage journal, Science Direct, and Springer link with the keywords “screening Neuropathy” AND “Detection Neuropathy” AND “Scoring Neuropathy” AND “Diabetic” published in 2019-2023. This study identified articles based on the English language, variables, and population. This research used PRISMA Flow-Chart 2020 to record the article filtering process.

Results

This research identified articles through PRISMA Flow-Chart 2020, obtaining 25 articles that discussed early detection of diabetic neuropathy.

Conclusion

Early detection of diabetic neuropathy prevents the occurrence of diabetic neuropathy. The method for early detection of neuropathy is using a neuropathy questionnaire and physical examination. Neuropathy questionnaires are Michigan Neuropathy Screening Instrument (MNSI), Toronto Clinical Neuropathy Score (TCNS), and Diabetic Neuropathy Classification (BDC). Physical examination tools include biotesimeters, vibrations, neurotesimeters, tuning forks, monofilament threads, ultrasonography (USG) results, artificial intelligence (AI), and nomograms.
Perception of primary care services among the Afroperuvian population
Authors: Juárez Chávez Elisa , Urday Fernández Dayana , Konda Kelika A. , Villalobos Ruiz José , Cuba Fuentes María Sofía
Published: December 2023

The Peruvian public healthcare system has various shortcomings that impact the experiences and perceptions of quality among the general population and, particularly, among minority populations, including the Afro-Peruvian community. In this context, understanding the population’s experiences in healthcare services and their perceptions regarding the treatment received from healthcare providers is crucial for developing improvement recommendations. Through in-depth interviews, our study explored the usage experiences and perceptions regarding the treatment received from public primary healthcare providers among 19 Afro-Peruvian individuals in Lima. Our analysis revealed that, in general, there is mistreatment of healthcare providers. This is not only recognized as a deficiency of the providers (human resources) but also as a consequence of a system that does not promote the quality of care, including issues such as inadequate infrastructure, low salaries, and limited time for patient care. Additionally, expressions of discrimination based on differences, primarily socioeconomic, were identified. Our findings provide insights for enhancing healthcare services in terms of treatment, effective communication, and infrastructure at the primary healthcare level.
The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/β-catenin to RTK/MAPK signaling
Authors: Madan Babita , Wadia Shawn , Patnaik Siddhi , Harmston Nathan , Tan Emile , Huat Tan Iain Bee , Nes W. David , Petretto Enrico , Virshup David M.
Published: December 2023

Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here we report for the first time that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulates the abundance of specific C4-methyl sterols lophenol and dihydro-TMAS. Highlighting its clinical relevance, FAXDC2 is repressed in Wnt/β-catenin high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulates in the cancerous tissues and not in adjacent normal tissues. FAXDC2 links Wnts to RTK/MAPK signaling. Wnt inhibition drives increased recycling of RTKs and activation of the MAPK pathway, and this requires FAXDC2. Blocking Wnt signaling in Wnt-high cancers causes both differentiation and senescence; and this is prevented by knockout of FAXDC2. Our data shows the integration of three ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.

Abstract Figure
A compendium of Amplification-Related Gain Of Sensitivity (ARGOS) genes in human cancer
Authors: Rendo Veronica , Schubert Michael , Khuu Nicholas , Suarez Peredo Rodriguez Maria F , Huang Kaimeng , Swift Michelle , He Yizhou , Zerbib Johanna , Smith Ross , Raaijmakers Jonne , Bandopadhayay Pratiti , Guenther Lillian M. , Hwang Justin H. , Iniguez Amanda , Moody Susan , Seo Ji-Heui , Stover Elizabeth , Garraway Levi , Hahn William C. , Stegmaier Kimberly , Medema René H. , Chowdhury Dipanjan , Colomé-Tatché Maria , Ben-David Uri , Beroukhim Rameen , Foijer Floris
Published: December 2023

Chromosomal gains are among the most frequent somatic genetic alterations occurring in cancer. While the effect of sustained oncogene expression has been characterized, the impact of copy-number gains affecting collaterally-amplified “bystander” genes on cellular fitness remains less understood. To investigate this, we built a comprehensive map of dosage compensations across human cancers by integrating expression and copy number profiles from over 8,000 TCGA tumors and CCLE cell lines. Further, we analyzed the effect of gene overexpression across 17 human cancer ORF screens to provide an overview of genes that prove toxic to cancer cells when overexpressed. Combining these two independent approaches we propose a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes. These genes are located in commonly amplified regions of the genome, have lower expression levels than expected by their copy-number status, and are toxic to cancer cells when overexpressed. We experimentally validatedCDKN1AandRBM14as high-confidence pan-cancer ARGOS genes in lung and breast cancer cell line models. We additionally suggest that RBM14’s mechanism of toxicity involves altered DNA damage response and innate immune signaling processes following gene overexpression. Finally, we provide a comprehensive catalog of compensated, toxic, and ARGOS genes as a community resource.
Developing and optimizing machine learning algorithms for predicting in-hospital patient charges for Congestive Heart Failure Exacerbations, Chronic Obstructive Pulmonary Disease Exacerbations and Diabetic Ketoacidosis
Authors: Arnold Monique , Liou Lathan , Boland Mary Regina
Published: December 2023

Background

Hospitalizations for exacerbations of congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and diabetic ketoacidosis (DKA) are costly in the United States.

Objective

The purpose of this study is to predict in-hospital charges for each condition using Machine Learning (ML) models.

Methods

We conducted a retrospective cohort study on national discharge records of hospitalized adult patients from January 1st, 2016, to December 31st, 2019. We used numerous ML techniques to predict in-hospital total cost.

Results

We found that linear regression (LM), gradient boosting (GBM) and extreme gradient boosting (XGB) models had good predictive performance and were statistically equivalent, with training R-Squared values ranging from 0.49–0.95 for CHF; 0.56–0.95 for COPD; and 0.32–0.99 for DKA. We identified important key features driving costs, including patient age, length-of-stay, number of procedures. and elective/non-elective admission.

Conclusions

ML methods may be used to accurately predict costs and identify drivers of high cost for COPD exacerbations, CHF exacerbations and DKA. Overall, our findings may inform future studies that seek to decrease the underlying high patient costs for these conditions.
A Novel Question-Answering Framework for Automated Abstract Screening Using Large Language Models
Authors: Akinseloyin Opeoluwa , Jiang Xiaorui , Palade Vasile
Published: December 2023

Objective

This paper aims to address the challenges in abstract screening within Systematic Reviews (SR) by leveraging the zero-shot capabilities of large language models (LLMs).

Methods

We employ LLM to prioritise candidate studies by aligning abstracts with the selection criteria outlined in an SR protocol. Abstract screening was transformed into a novel question-answering (QA) framework, treating each selection criterion as a question addressed by LLM. The framework involves breaking down the selection criteria into multiple questions, properly prompting LLM to answer each question, scoring and re-ranking each answer, and combining the responses to make nuanced inclusion or exclusion decisions.

Results

Large-scale validation was performed on the benchmark of CLEF eHealth 2019 Task 2: Technology- Assisted Reviews in Empirical Medicine. Focusing on GPT-3.5 as a case study, the proposed QA framework consistently exhibited a clear advantage over traditional information retrieval approaches and bespoke BERT- family models that were fine-tuned for prioritising candidate studies (i.e., from the BERT to PubMedBERT) across 31 datasets of four categories of SRs, underscoring their high potential in facilitating abstract screening.

Conclusion

Investigation justified the indispensable value of leveraging selection criteria to improve the performance of automated abstract screening. LLMs demonstrated proficiency in prioritising candidate studies for abstract screening using the proposed QA framework. Significant performance improvements were obtained by re-ranking answers using the semantic alignment between abstracts and selection criteria. This further highlighted the pertinence of utilizing selection criteria to enhance abstract screening.
Association Between Uric Acid and Hemorrhagic Transformation: A Systematic Review and Meta-Analysis
Authors: Qian Ying , Li Na , Li Yuanyuan , Tao Chenxi , Liu Zhenhong , Zhang Guoxia , Yang Fan , Zhang Hongrui , Gao Yonghong
Published: December 2023

Background

The relationship between uric acid (UA) and hemorrhagic transformation (HT) remained controversial. The purpose of this study was to investigate the relationship between UA degrees and the risk of HT after acute ischemic stroke (AIS).

Methods and methods

Electronic databases were sought for studies on UA and HT from inception to October 31, 2023. Two researchers independently reviewed the studies for inclusion. STATA Software 16.0 was used to compute the standardized mean difference (SMD) and 95% confidence interval (CI) of the pooled and post-outlier outcomes. The heterogeneity was evaluated using the I2statistic and the Galbraith plot, and sensitivity analysis was also performed. Begg’s funnel plot and Egger’s test were used to assess publication bias.

Results

12 trials were included in the meta-analysis, with a total of 4,708 individuals. Low UA degrees were linked to higher HT post-AIS patients following the pooled SMDs’ forest plot (SMD = -0.34, 95% CI = -0.60–0.08,P= 0.010). The high heterogeneity (I2= 89.0%,P<0.001) was found in the studies. Six papers were outside the Galbraith plot regression line and there was no heterogeneity when they were excluded (I2= 45.8%,P= 0.100). Meanwhile, the repeated SMDs (SMD = -0.487, 95% CI = -0.632–0.342,P= 0.000) still meant that the HT group had lower UA degrees. There was no publication bias in our meta-analysis following Begg’s funnel plot or Egger’s test.

Conclusions

The meta-analysis illustrated a substantial positive connection between UA degrees and HT, with lower UA separately linked with higher HT post-AIS. It provided a certain theoretical basis for the later related research.
Differential detection workflows for multi-sample single-cell RNA-seq data
Authors: Gilis Jeroen , Perin Laura , Malfait Milan , Van den Berge Koen , Assefa Alemu Takele , Verbist Bie , Risso Davide , Clement Lieven
Published: December 2023

In single-cell transcriptomics, differential gene expression (DE) analyses typically focus on testing differences in the average expression of genes between cell types or conditions of interest. Single-cell transcriptomics, however, also has the promise to prioritise genes for which the expression differ in other aspects of the distribution. Here we develop a workflow for assessing differential detection (DD), which tests for differences in the average fraction of samples or cells in which a gene is detected. After benchmarking eight different DD data analysis strategies, we provide a unified workflow for jointly assessing DE and DD. Using simulations and two case studies, we show that DE and DD analysis provide complementary information, both in terms of the individual genes they report and in the functional interpretation of those genes.
rtestim: Time-varying reproduction number estimation with trend filtering
Authors: Liu Jiaping , Cai Zhenglun , Gustafson Paul , McDonald Daniel J.
Published: December 2023

To understand the transmissibility and spread of infectious diseases, epidemiologists turn to estimates of the instantaneous reproduction number. While many estimation approaches exist, their utility may be limited. Challenges of surveillance data collection, model assumptions that are unverifiable with data alone, and computationally inefficient frameworks are critical limitations for many existing approaches. We propose a discrete spline-based approach that solves a convex optimization problem---Poisson trend filtering---using the proximal Newton method. It produces a locally adaptive estimator for instantaneous reproduction number estimation with heterogeneous smoothness. Our methodology remains accurate even under some process misspecifications and is computationally efficient, even for large-scale data. The implementation is easily accessible in a lightweight R package rtestim (dajmcdon.github.io/rtestim/).
Prevalence of orthostatic intolerance in Long Covid clinic patients: A multicentre observational study
Authors: Lee Cassie , Greenwood Darren C , Master Harsha , Balasundaram Kumaran , Williams Paul , Scott Janet T. , Wood Conor , Cooper Rowena , Darbyshire Julie L. , Gonzalez Ana Espinosa , Davies Helen E. , Osborne Thomas , Corrado Joanna , Iftekhar Nafi , Rogers Natalie , Delaney Brendan , Greenhalgh Trish , Sivan Manoj
Published: December 2023

Purpose

Orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with symptoms and comorbidities.

Methods

Participants were recruited from 8 UK long covid clinics, and healthy volunteers from general population. All undertook standardised National Aeronautics and Space Administration Lean Test (NLT). Participants’ history of typical OI symptoms (e.g. dizziness, palpitations) prior to and during the NLT were recorded.

Results

277 long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or PoTS, 10% had asymptomatic OH. 130 (47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. 41 (15%) had an abnormal NLT, 20 (7%) met criteria for PoTS and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive to one reading, resulted in 11% of long covid participants meeting criteria for PoTS, but not in healthy volunteers.

Conclusion

More than half of long covid patients experienced OI symptoms during NLT and more than one in ten patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced.

Trial registration numbersNCT05057260, ISRCTN15022307
The Montreal Cognitive Assessment: Normative Data from a Large, Population-Based Sample of Healthy Adults in China
Authors: Wei Qiang , Du Baogen , Liu Yuanyuan , Cao Shanshan , Yin Shanshan , Zhang Ying , Bai Tongjian , Wu Xingqi , Tian Yanghua , Hu Panpan , Wang Kai
Published: December 2023

Background

The Montreal Cognitive Assessment (MoCA) is a valuable tool for detecting cognitive impairment, but its accuracy is significantly influenced by demographic and socio-cultural factors. Consequently, the development of appropriate normative values becomes particularly crucial in ensuring its reliable use and interpretation.

Objective

Generate MoCA normative values based on demographics for healthy chinese adults.

Methods

The assessment conducted in this study utilizes the MoCA scale, specifically employing the Mandarin-8.1 version (Chinese Mandarin version). Based on the geographical distribution of administrative regions in mainland china, this study recruited a total of 3,097 healthy individuals aged over 20 years. Drawing on insights from prior normative studies, we performed multiple linear regression analysis, incorporating age, gender, and education level as predictor variables, to examine their associations with the total score and sub-cognitive domains of MoCA. Subsequently, we established normative values and cut-off values stratified by age and education level.

Results

The participants in this study (n=3,097) exhibit a balanced gender distribution, with an average age of 54.46 years (SD 14.38) and an average education period of 9.49 years (SD 4.61). The study population demonstrates an average MoCA score of 23.25 points (SD 4.82). The findings from the multiple linear regression analysis indicate that the total score of MoCA is influenced by age and education level, collectively accounting for 46.8% of the total variance. Higher age and lower education level are correlated with lower MoCA total scores.

Conclusion

This study offers normative MoCA values specific to the Chinese population. Furthermore, the research findings indicate that a score of 26 may not represent the most optimal cut-off value. When assessing MoCA scores, it is imperative to comprehensively account for the participants’ age and educational background.
Empowering GWAS Discovery through Enhanced Genotype Imputation
Authors: De Marino Adriano , Mahmoud Abdallah Amr , Bohn Sandra , Lerga-Jaso Jon , Novković Biljana , Manson Charlie , Loguercio Salvatore , Terpolovsky Andrew , Matushyn Mykyta , Torkamani Ali , Yazdi Puya G.
Published: December 2023

Genotype imputation, crucial in genomics research, often faces accuracy limitations, notably for rarer variants. Leveraging data from the 1000 Genomes Project, TOPMed and UK Biobank, we demonstrate that Selphi, our novel imputation method, significantly outperforms Beagle5.4, Minimac4 and IMPUTE5 across various metrics (12.5%-26.5% as measured by error count) and allele frequencies (13.0%-27.1% for low-frequency variants).This improvement in accuracy boosts variant discovery in GWAS and improves polygenic risk scores.
HIV risk score and prediction model in the United States: A Scoping Review Protocol
Authors: Patel Maitri , Vaddiparti Krishna , Christina Parisi , Woody Aislin , Cook Robert , Prosperi Mattia , Pyche Courtney , Cook Christa , Liu Yiyang
Published: December 2023

Human immunodeficiency virus (HIV) remains a significant public health concern in the United States, affecting approximately 1.2 million individuals, with a substantial portion unaware of their infection status. Identifying individuals at elevated risk of HIV infection through predictive models holds promise for enhancing public health efforts. A preliminary search from PubMed revealed a handful of studies focused on developing HIV risk prediction models or risk scores, each employing varying methodologies such as logistic regression and machine learning. These studies targeted a diverse population including men who have sex with men, emergency department visitors, and the general population, drawing data from surveys, surveillance, and electronic health records. Despite these individual efforts, there is a notable absence of comprehensive review papers summarizing the outcomes of these studies. Addressing this gap, this scoping review systematically identifies and synthesizes results from existing predictive models for HIV risk. The primary objective is to determine the variables used in HIV risk scoring and prediction models, contributing to a more comprehensive understanding of HIV risk assessment. This protocol describes the thorough procedure for conducting a scoping review. It outlines the inclusion and exclusion criteria for relevant studies and offers the search methods that will be used in PubMed, EMBASE, and CINAHL. Detailed paper screening, data extraction, and risk of bias assessment process were described.
White matter hyperintensity genetic risk factorTRIM47regulates autophagy in brain endothelial cells
Authors: Yeung Sunny Hoi-Sang , Lee Ralph Hon-Sun , Cheng Gerald Wai-Yeung , Ma Iris Wai-Ting , Kofler Julia , Kent Candice , Ma Fulin , Herrup Karl , Fornage Myriam , Arai Ken , Tse Kai-Hei
Published: December 2023

White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. GWAS identified TRIM47 at 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found selectively expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially-induced autophagy while downregulated in hypertension-like conditions. Usingin silicosimulation, immunocytochemistry and super-resolution microscopy, we identified the highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencingTrim47significantly increased autophagy with ULK1 phosphorylation induction, transcription and vacuole formation. Together, we confirm that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.

SUMMARY STATEMENT

TRIM47, top genetic risk factor for white matter hyperintensity formation, is a negative regulator of autophagy in brain endothelial cells and implicates a novel cellular mechanism for age-related cerebrovascular changes.
Neural codes for visual numerosity independent of other quantities are present both in the dorsal and in the ventral stream of the human brain
Authors: Karami Alireza , Castaldi Elisa , Eger Evelyn , Piazza Manuela
Published: December 2023

Representing the number of items in sets (numerosity) is a core and evolutionary ancient ability. In a recent fMRI study Castaldi et al. (eLife 2019) showed that visual numerosity is represented independently from other visual features starting from early visual areas and progressively amplified along the dorsal stream hierarchy up to parietal areas. However, because in this study we recorded the brain activity from a restricted brain volume, and performed the analyses only in a series of retinotopically organized regions of interest along the dorsal stream, we still miss an exhaustive picture of the full network of regions encoding pure numerosity across the whole brain. In this research advance, we extend the findings of Castaldi et al. in two significant ways. First, we recorded the whole brain which allowed us to characterize the neural responses to numerosity beyond the dorsal stream using a searchlight analysis in addition to an ROIs approach. Second, in addition to the classical model-based analytical approach, such as RSA, we compared the neural representational geometries across the different regions using multi-dimensional scaling, an hypothesis-free approach capable of unveiling latent neural dimensions that might otherwise go unnoticed. Our results confirm that numerosity is represented over and above other visual features in early visual areas and progressively enhanced in associative areas of the dorsal stream but also, notably, of the ventral stream. We also found that numerosity representations in association areas differ substantially from those of early visual areas, and that in associative regions of both streams numerosity is represented on a similar manifold akin to a curved number line, a structure suggestive of their similar involvement in numerosity-based decision making. Taken together, these results call for an important revision of the existing neurocognitive models of number cognition.

Impact statement

Visual numerosity is represented in associative areas of dorsal and ventral streams on a neural manifold that also reflects decision variables, suggesting a common role in numerosity decision-making.
Regulator of Chromosome Condensation (RCC1) a novel therapeutic target in pancreatic ductal adenocarcinoma drives tumor progression via the c-Myc-RCC1-Ran axis
Authors: Bannoura Sahar F. , Aboukameel Amro , Khan Husain Yar , Uddin Md. Hafiz , Jang Hyejeong , Beal Eliza , Thangasamy Amalraj , Kim Seongho , Wagner Kay Uwe , Mohammad Ramzi , Al-Hallak Mohammed Najeeb , Pasche Boris C. , Azmi Asfar S.
Published: December 2023

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. Here we for the first time evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC subsistence and drug resistance. RCC1 expression was found to be elevated in PDAC tissues in comparison with normal pancreatic tissues and was linked to poor prognosis. RCC1 silencing in a panel of PDAC cells by RNA interference and CRISPR-Cas9 resulted in reduced cellular proliferation in 2D and 3D cultures. RCC1 KD reduced migratory and clonogenic ability, enhanced apoptosis, and altered cell cycle distribution in human PDAC cells as well as cells isolated from the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx1-Cre (KPC) mouse tumors. Subcutaneous cell-derived xenografts show significantly attenuated growth of RCC1 KO tumors. Mechanistically, RCC1 knockdown resulted in disruption of subcellular Ran distribution indicating that stable nuclear Ran localization is critical for PDAC proliferation. Nuclear and cytosolic proteomic analysis revealed altered subcellular proteome in RCC1 KD KPC-tumor-derived cells. Altered cytoplasmic protein pathways include several metabolic pathways and PI3K-Akt signaling pathway. Pathways enriched in altered nuclear proteins include cell cycle, mitosis, and RNA regulation. RNA sequencing of RCC1 KO cells showed widespread transcriptional alterations. Upstream of RCC1, c-Myc activates the RCC1-Ran axis, and RCC1 KO enhances the sensitivity of PDAC cells to c-Myc inhibitors. Finally, RCC1 knockdown resulted in the sensitization of PDAC cells to Gemcitabine. Our results indicate that RCC1 is a potential therapeutic target in PDAC that warrants further clinical investigations.
Increasing marine trophic web knowledge through DNA analyses of fish stomach contents: a step towards an Ecosystem Based Approach to fisheries research
Authors: Canals Oriol , Lanzén Anders , Mendibil Iñaki , Bachiller Eneko , Corrales Xavier , Andonegi Eider , Cotano Unai , Rodríguez-Ezpeleta Naiara
Published: December 2023

Multispecies and ecosystem models, which are key for the implementation of ecosystem-based approaches to fisheries management, require extensive data on the trophic interactions between marine organisms, including changes over time. DNA metabarcoding (the simultaneous identification of all taxa in a sample by sequencing a short DNA region) could be used for speeding up large-scaled stomach content data collection. Yet, for DNA metabarcoding to be routinely implemented, technical challenges should be addressed, such as the potentially complicated sampling logistics, the detection of a high proportion of predator DNA, and the inability to provide reliable abundance estimations. Here, we present a DNA metabarcoding assay developed to examine the diet of five commercially important fish, which is feasible to be incorporated into routinary samplings. The method is devised to speed up the analysis process by avoiding the stomach dissection and content extraction steps, while preventing the amplification of predator DNA by using blocking primers. Tested in mock samples and in real stomachs, the method has proven effective and shows great effectiveness discerning diet variations due to predator ecology or prey availability. Additionally, by applying our protocol to mackerel stomachs previously analysed by visual inspection, we showcase how DNA metabarcoding could complement visually based data by detecting overlooked prey by the visual approach. We finally discuss how DNA metabarcoding-based data can contribute to trophic data collection. Our work reinforces the potential of DNA metabarcoding for the study and monitoring of fish trophic interactions and provides a basis for its incorporation into routine monitoring programs, which will be critical for the implementation of ecosystem-based approaches to fisheries management.
Quantifying stem cell derived islet graft volume and composition with [18F]F-DBCO-exendin and [18F]FDOPA positron emission tomography
Authors: Lithovius Väinö , Lahdenpohja Salla , Ibrahim Hazem , Saarimäki-Vire Jonna , Uusitalo Lotta , Montaser Hossam , Mikkola Kirsi , Yim Cheng-Bin , Keller Thomas , Rajander Johan , Balboa Diego , Barsby Tom , Solin Olof , Nuutila Pirjo , Grönroos Tove J. , Otonkoski Timo
Published: December 2023

Stem cell derived islets (SC-islets) are being developed as a novel source of beta cells that would enable large scale cell replacement therapy for insulin dependent diabetes. Therapeutic use of SC-islets carries an inherent risk of unwanted growth; and multiple strategies are being explored for optimizing long-term SC-islet graft effectiveness. However, a method for noninvasivein vivomonitoring for SC-islet graft safety and efficacy is lacking, as current insulin secretion measurements are inadequate. Here, we demonstrate the potential of positron emission tomography (PET) for monitoring SC-islet grafts using two tracers: GLP1-receptor binding [18F]F-DBCO-exendin and dopamine precursor [18F]FDOPA. We could detect and longitudinally monitor human SC-islet grafts in calf muscles of immunocompromised mice. Importantly, graft volume quantified with PET strongly correlated with actual graft volume (r2=0.91 for [18F]F-DBCO-exendin). PET using [18F]F-DBCO-exendin allowed delineation of cystic structures and its uptake correlated with graft beta cell proportion, enabling study of SC-islet graft purity noninvasively. [18F]FDOPA performed similarly to [18F]F-DBCO-exendin, but with slightly weaker sensitivity. Uptake of neither tracer was biased in SC-islet grafts genetically rendered hyper- or hypoactive. Insulin secretion measurements under fasted, glucose-stimulated or hypoglycemic conditions did not correlate with graft volume. In conclusion, [18F]F-DBCO-exendin and [18F]FDOPA PET constitute powerful approaches to noninvasively assess SC-islet graft volume and composition regardless of their functionality. PET imaging could therefore be leveraged for optimizing safety and effectiveness of SC-islet grafts in patients with insulin dependent diabetes.
Resource selection at fine-scale: What drives the decision of a generalist herbivore?
Authors: Boyers Melinda , Parrini Francesca
Published: December 2023

Spatial patterns in topography and forage distribution significantly influence the movements and choices of large herbivores. However, understanding the foraging strategies of free-grazing herbivores at different temporal and spatial scales remains limited, as different behavioural decisions can apply at different hierarchical levels, This study investigates the fine-scale foraging strategies of zebra (Equus quagga) in a South African savanna, with a specific focus on their selection of green vegetation at the plant and feeding patch levels. We used the Normalized Difference Vegetation Index (NDVI) as a proxy for vegetation productivity and quality. Our findings reveal that zebra adapted their foraging strategies according to the scale and season. During the late-dry season and early-wet season, selection for greenness was at both the grass tuft and feeding site levels. In contrast, during the mid-dry season, their selection was predominantly at the tuft level, focusing solely on greenness. These insights emphasize the importance of conducting multi-level studies when investigating factors influencing foraging decisions. Findings at one hierarchical level may not necessarily apply across other levels of investigation, highlighting the need for a nuanced and comprehensive approach to understanding the complex foraging behaviours of these animals.
Anp32e protects against accumulation of H2A.Z at Sox motif containing promoters during zebrafish gastrulation
Authors: Halblander Fabian N. , Meng Fanju W. , Murphy Patrick J.
Published: December 2023

Epigenetic regulation of chromatin states is crucial for proper gene expression programs and progression during development, but precise mechanisms by which epigenetic factors influence differentiation remain poorly understood. Here we find that the histone variant H2A.Z accumulates at Sox motif-containing promoters during zebrafish gastrulation while neighboring genes become transcriptionally active. These changes coincide with reduced expression ofanp32e, the H2A.Z histone removal chaperone, suggesting that loss of Anp32e may lead to increases in H2A.Z during differentiation. Remarkably, genetic removal of Anp32e in embryos leads to H2A.Z accumulation prior to gastrulation, and precocious developmental transcription of Sox motif associated genes. Altogether, our results provide compelling evidence for a mechanism in which Anp32e restricts H2A.Z accumulation at Sox motif-containing promoters, and subsequent down-regulation of Anp32e enables temporal up-regulation of Sox motif associated genes.

Highlights

An early-developmental time course of zebrafish chromatin accessibility is achieved using an integrated UMAP analysis of datasets from two separate published studies.

CUT&Tag sequencing is used to characterize the genomic localization for the histone chaperone ANP32E.

Changes in Anp32e enrichment coincide with opposing changes in H2A.Z enrichment during zebrafish gastrulation.

Precociously expressed genes in embryos lacking Anp32e are disproportionately Sox-marked and may represent H2A.Z-mediated developmental accelerations.