bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thoughts and perspectives of metagenome sequencing as a diagnostic tool for infectious disease: an interpretive phenomenological study
Authors: Trivett Hannah , Darby Alistair C. , Oyebode Oyinlola 
Published: January 2024

AbstractBackgroundEffective infectious disease diagnostics (IDD) are vital for informing clinical decision-making regarding the treatment and patient management of disease and infections. Conventional clinical methods rely upon culture-dependent techniques, and there has been little shift in the acceptance and integration of culture-independent sequencing methods into routine clinical IDD. This study explored stakeholders’ experiences within IDD, including those working in clinical settings and those conducting research at the forefront of microbial genomics. We aimed to identify factors driving the development and implementation of metagenome sequencing as a routine diagnostic.MethodsVirtual semi-structured interviews were conducted with purposively selected individuals involved in IDD. The interviews explored the experiences of implementing metagenome sequencing as a diagnostic tool and decisions about which diagnostics are used for identifying bacteria-causing infections. Thematic analysis was used to analyse the data, and an Interpretive Phenomenological approach was used throughout.ResultsTen individuals were interviewed between July 2021 and October 2021, including Clinical scientists, consultants, and professors in academia. Their experience ranged from no knowledge of metagenome sequencing to an expert understanding of the phenomenon. Five themes emerged: Diagnostic Choice, Infrastructure, Open Data Sharing, COVID-19, and Communication. Participants recognised the need for new diagnostics to be implemented to overcome the limitations of current diagnostic approaches but highlighted the barriers to integrating new diagnostics into clinical settings, such as the impact on clinical decision-making, accreditation, and cost. However, participants felt that lessons could be learnt from using metagenomics in COVID-19 and how other diagnostic platforms have been integrated into clinical settings over the last 20 years.ConclusionsThe study provided clear evidence to address the knowledge gap in current literature and practice for developing and implementing metagenome sequencing as a potential IDD. The knowledge of new and upcoming genomic diagnostic testing is not equally distributed throughout the UK, impacting the understanding and drive to integrate metagenome sequencing into routine clinical diagnostics. Improvements in access to new diagnostics could improve patient treatment and management and positively impact public health.
Indole 3-acetate and response to therapy in borderline resectable or locally advanced pancreatic cancer
Authors: Braadland Peder R. , Farnes Ingvild , Kure Elin H. , Yaqub Sheraz , McCann Adrian , Ueland Per M , Labori Knut Jørgen , Hov Johannes R. 
Published: January 2024

AbstractBackgroundRecently, Tintelnotet alreported that a higher concentration of the bacterially produced metabolite indole 3-acetate (3-IAA) in blood was linked to a better response to chemotherapy in people with metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to extend these observations to people diagnosed with non-metastatic PDAC.Patients and methodsWe measured circulating 3-IAA in samples from a prospective population-based cohort of 124 individuals with borderline resectable or locally advanced PDAC who later underwent primary chemotherapy. The majority (61%) of the individuals were treated with FOLFIRINOX. We used univariable and multivariable Cox proportional hazards regression to estimate the association between pre-treatment 3-IAA and overall survival.ResultsThe median serum 3-IAA concentration before chemotherapy was 290 (interquartile range 203–417) ng/mL. The unadjusted hazard ratio (HR) for pre-treatment log2(3-IAA) was 0.93, 95% confidence interval (CI) [0.74–1.16], p=0.52. When adjusting for age, ECOG, CA19-9 and tumor classification, the HR for log2(3-IAA) was 0.87, 95% CI [0.68–1.12], p=0.28.ConclusionsOur findings suggest that the potentiating effect of 3-IAA observed in metastatic PDAC may not translate to borderline resectable or locally advanced PDAC. We recommend additional clinical validation of 3-IAA’s predictive value before implementation attempts in human studies are initiated.
Seroprevalence and Risk Factors of Chikungunya in Ethiopia: A Systematic Review and Meta-Analysis
Authors: Dagnaw Gashaw Getaneh , Gessese Abebe Tesfaye , Kinde Mebrie Zemene , Bitew Abebe Belete , Dejene Haileyesus , Desalegn Bereket , Abey Solomon Lulie 
Published: January 2024

AbstractThe recurrence of Chikungunya virus poses a significant public health concern, given its association with numerous epidemic episodes in Africa, Asia, and India. Since the virus was first detected in Ethiopia in 2016, the disease has been identified in different parts of the country, emphasizing the need for up-to-date epidemiological data on the status of Chikungunya in Ethiopia. We conducted a systematic review and meta-analysis using online published articles between 2016 and 2023 from PubMed, Scopus, and Google Scholar databases. The PRISMA guideline was thoroughly followed and registered in the Prospective Register of Systematic Reviews (PROSPERO). A set of keywords like ‘Chikungunya,’ ‘Chikungunya Virus,’ ‘Chikungunya Fever,’ ‘Prevalence,’ ‘Seroprevalence,’ “Risk Factor”, “Potential Factors”, and ‘Ethiopia’ were used in the search engines. A total of five articles met the eligibility criteria and were included for data extraction. Meta-analysis was performed using STATA 17 software. The pooled seroprevalence of Chikungunya in Ethiopia was 12.35%. The highest prevalence was reported in Southern Nations, Nationalities, and Peoples’ Region (SNNPR) at 43.6%, while the lowest seroprevalence was in Dire Dawa, at approximately 12%. Factors such as occupation, education, age, and sex contributed to prevalence variation. Subgroup meta-analysis showed heterogeneity across the types of studies employed. No indications of publication bias or small-study effects were found in the Begg’s test and Egger’s test. The findings will help us to understand the trend of Chikungunya in Ethiopia. The findings recommend proactive monitoring or active surveillance of viral diseases and the rigorous enforcement of health systems, as well as One Health measures in Ethiopia, to improve human public health.
Blood-based screening for HPV-associated cancers
Authors: Das Dipon , Hirayama Shun , Aye Ling , Bryan Michael E. , Naegele Saskia , Zhao Brian , Efthymiou Vasileios , Mendel Julia , Fisch Adam S. , Kröller Lea , Michels Birgitta E. , Waterboer Tim , Richmon Jeremy D. , Adalsteinsson Viktor , Lawrence Michael S. , Crowson Matthew G. , Iafrate A. John , Faden Daniel L. 
Published: January 2024

AbstractBackgroundHPV-associated oropharyngeal cancer (HPV+OPSCC) is the most common HPV-associated cancer in the United States yet unlike cervical cancer lacks a screening test. HPV+OPSCCs are presumed to start developing 10-15 years prior to clinical diagnosis. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive and specific biomarker for HPV+OPSCC. Taken together, blood-based screening for HPV+OPSCC may be feasible years prior to diagnosis.MethodsWe developed an HPV whole genome sequencing assay, HPV-DeepSeek, with 99% sensitivity and specificity at clinical diagnosis. 28 plasma samples from HPV+OPSCC patients collected 1.3-10.8 years prior to diagnosis along with 1:1 age and gender-matched controls were run on HPV-DeepSeek and an HPV serology assay.Results22/28 (79%) of cases and 0/28 controls screened positive for HPV+OPSCC with 100% detection within four years of diagnosis and a maximum lead time of 7.8 years. We next applied a machine learning model classifying 27/28 cases (96%) with 100% detection within 10 years. Plasma-based PIK3CA gene mutations, viral genome integration events and HPV serology were used to orthogonally validate cancer detection with 68% (19/28) of the cohort having multiple cancer signals detected. Molecular fingerprinting of HPV genomes was performed across patients demonstrating that each viral genome was unique, ruling out contamination. In patients with tumor blocks from diagnosis (15/28), molecular fingerprinting was performed within patients confirming the same viral genome across time.ConclusionsWe demonstrate accurate blood-based detection of HPV-associated cancers with lead times up to 10 years before clinical cancer diagnosis and in doing so, highlight the enormous potential of ctDNA-based cancer screening.
Quantitative MODS-Wayne Assay for Rapid Detection of Pyrazinamide Resistance inMycobacterium tuberculosisfrom Sputum Samples
Authors: Toscano-Guerra Emily , Alcántara Roberto , Gilman Robert , Grandjean Louis , Zimic Mirko , Sheen Patria 
Published: January 2024

ABSTRACTBackgroundTuberculosis (TB) remains a significant global health challenge, particularly with the rise of drug-resistant strains, such as Pyrazinamide (PZA)-resistant TB. This resistance hampers treatment effectiveness. Currently, there’s a lack of affordable and precise quantitative tests for detecting PZA resistance, highlighting the need for accessible diagnostic tools. Our study introduces a direct, accurate, and accessible susceptibility test for PZA resistance by quantifying pirazinoic acid (POA).MethodsWe analyzed 264 TB-positive samples (MP and TBN) to assess PZA susceptibility by measuring POA production. This was done using the MODS-Wayne qualitative assay and our developed quantitative approach (MODS-WQ). For MODS-WQ, TBN samples were processed in 7H9 media (MODS-WQ 7H9) and MP samples in citrate buffer (MODS-WQ CB). We measured POA levels using spectrophotometry against a calibration curve, with PZA susceptibility determined by a composite standard. We also investigated the correlation between POA levels and pyrazinamidase mutations. Multidrug-resistant samples were assessed using the MODS test, and statistical analyses were conducted.ResultsApproximately 23.48% of the samples showed PZA resistance, which included 62.8% of the multidrug-resistant (MDR) samples. The MODS-Wayne assay demonstrated an 87.8% sensitivity and 95.9% specificity for MP samples, and 62.5% sensitivity with 93.7% specificity for TBN samples. The MODS-WQ identified specific cut-off points—123.25 μM for MODS-WQ 7H9 and 664.7 μM for MODS-WQ CB—with corresponding sensitivities of 81.25% and 92.31%, and specificities of 77.22% and 95.93%. Significantly lower POA levels were observed in samples with mutations in the metal binding site compared to mutations on the enzyme’s periphery.ConclusionsThe citrate-buffered MODS-WQ demonstrates high sensitivity and specificity in quantifying POA. It offers a significant improvement over qualitative methods, effectively overcoming their subjectivity limitations in PZA resistance detection.
MORPHOMETRIC IMAGE ANALYSIS COMPARISON OF BASAL CELL CARCINOMAS & MELANOMAS OF THE HEAD & NECK VERSUS OTHER SITES
Authors: Hue Jonas , Ekanayake Jinendra , Dehmeshki Jamshid , Dhanda Jagtar 
Published: January 2024

AbstractBackgroundManagement of skin cancers are heavily dependent on clinical diagnosis via dermoscopy. Dermoscopic morphology of basal cell carcinomas (BCC) and melanomas influence diagnosis and may be influenced by anatomic location.ObjectiveIn this study, we aimed to investigate the morphologic differences between anatomic sites of the head and neck (H&N) versus other body sites in basal cell carcinomas and melanomas.Patients and methodsThe publicly available HAM10000 dataset was used in this study. Morphometric image analysis of the BCCs (n=422) and melanomas (n=868) in this dataset was performed using an open-source image analysis software. Univariate and multivariate statistical analysis was done to identify differences between H&N and other anatomic sites. The multifactorial data was further interrogated with dimensionality reduction techniques, linear discriminant analysis, principal component analysis and t-distributed stochastic neighbour embedding.ResultsUnivariate and multivariate statistical analyses revealed significant differences between H&N and other sites for both BCCs and melanomas (P<0.05). Fifty-three univariate and 11 multivariate features were found to be statistically significant in the BCC group. Thirteen univariate and 8 multivariate features were statistically significant in the melanoma group. Dimensionality reduction via linear discriminant analysis of the BCC groups revealed modest separation of the data by anatomical site. However, melanomas appeared to be more homogenous across H&N and other body sites.ConclusionBCCs of the H&N may be morphologically different to BCCs of other body sites. This may influence the accuracy of computer-assisted diagnostic tools and specialist clinicians working predominantly in the H&N region should exercise caution when employing these tools in clinical practice.
Retrospective Analysis of Blood Biomarkers of Neurological Injury in Human Cases of Viral Infection and Bacterial Sepsis
Authors: Bartlett Maggie L. , Goux Heather , Johnson Linwood , Schully Kevin L. , Gregory Melissa , Brandsma Joost , Chenoweth Josh G. , Clark Danielle V. , Rivera Luis Felipe , Lezcano-Coba Carlos , Vittor Amy Y. , Hayes Ronald , Galué Josefrancisco , Carrera Jean-Paul , Smith Darci R. 
Published: January 2024

AbstractBackgroundBlood biomarkers of neurological injury could provide a rapid diagnosis of central nervous system (CNS) injury caused by infections. An FDA-approved assay for mild traumatic brain injury (TBI) measures glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which signal astrocyte and neuronal injury, respectively. Here, we assessed the applicability of this biomarker assay for determining infection-induced brain injury.MethodsWe measured serum levels of GFAP and UCH-L1 retrospectively in serum samples from three study populations: 1) human cases infected with Venezuelan equine encephalitis virus (VEEV) and Madariaga virus (MADV) (n = 73), 2) human sepsis patients who were severely ill or diagnosed with encephalitis (n = 66), and 3) sepsis cases that were subsequently evaluated for cognitive impairment (n = 64).ResultsIn the virus infection group, we found elevated GFAP for VEEV (p = 0.014) and MADV (p = 0.011) infections, which correlated with seizures (p = 0.006). In the bacterial sepsis group, GFAP was elevated in cases diagnosed with encephalitis (p = 0.0007) and correlated with headaches (p = 0.0002). In the bacterial sepsis cases with a later cognitive assessment, elevated GFAP (p = 0.0057) at study enrollment was associated with cognitive impairment six months later with a positive prognostic capacity of 79% (CI: 66–95%; p = 0.0068).ConclusionsGFAP and UCH-L1 levels measured using an FDA-approved assay for TBI may indicate brain injury resulting from viral or bacterial infections and could predict the development of neurological sequelae.
Optimizing the number of models included in outbreak forecasting ensembles
Authors: Fox Spencer J. , Kim Minsu , Meyers Lauren Ancel , Reich Nicholas G. , Ray Evan L. 
Published: January 2024

AbstractBased on historical influenza and COVID-19 forecasts, we quantify the relationship between the number of models in an ensemble and its accuracy and introduce an ensemble approach that can outperform the current standard. Our results can assist collaborative forecasting efforts by identifying target participation rates and improving ensemble forecast performance.
Relationships of visual impairment and eye conditions with imaging markers, cognition, and diagnoses of dementia: a bi-directional Mendelian randomization study
Authors: Ferguson Erin L , Thoma Mary , Buto Peter , Wang Jingxuan , Glymour M. Maria , Hoffmann Thomas J , Choquet Hélène , Andrews Shea J , Yaffe Kristine , Casaletto Kaitlin , Brenowitz Willa D 
Published: January 2024

ABSTRACTObjectiveTo evaluate the causal relationships between visual acuity, eye conditions (focusing on cataracts and myopia), and Alzheimer disease (AD) and related dementias.DesignCohort and two sample bi-directional mendelian randomization (MR) study.SettingUK Biobank participants and summary statistics from previously published genome-wide association studies on cataract, myopia, and AD.ParticipantsUK Biobank participants (n=304,953) aged 55-70 without dementia at baseline, underwent genotyping, reported on eye conditions, and a subset completed visual acuity exams (n=113,756) or brain imaging (n=36,855)Main outcome measuresAll-cause dementia, AD, and vascular dementia (VaD) identified from electronic medical records.ResultsThe sample averaged 62.1 years (SD=4.1) of age at baseline, 4.7% had cataracts, and 3.9% had worse than 20/40 vision. History of cataracts (HR=1.18, 95% CI: 1.07 to 1.29) and 20/40 vision (HR=1.35, 95% CI: 1.06 to 1.70) were associated with higher hazard of all-cause dementia. In MR analyses to estimate causal effects, cataracts increased risk of VaD inverse-variance weighted (OR=1.92, 95% CI: 1.26-2.92) borderline increased all-cause dementia (OR =1.21, 95% CI: 0.98 to 1.50) but not AD (OR=1.01, 95% CI: 0.97-1.06). There was no significant association between observed or genetic risk for myopia and dementia. In MR for reverse causality using genetic risk for AD, AD was not significantly associated with cataracts (inverse-variance weighted OR=0.99, 95% CI: 0.96 to 1.01). Genetic risk for cataracts were associated with smaller total brain (β= −597.4 mm3, 95% CI: −1077.9 to −117.0) and grey matter volumes (β= −375.2 mm3, 95% CI: −680.1 to −70.2), but not other brain regions or cognition.ConclusionsOur findings suggest cataracts increase risk of dementia and may reduce brain volume. This lends further support to the hypothesis that cataract extraction may reduce risk for dementia.
Clinical significance of PD-1-binding soluble PD-L1 and MMPs in the microenvironment of gastric cancer and non-small cell lung cancer treated with PD-1/PD-L1 blockade
Authors: Ando Fumihiko , Kashiwada Takeru , Kuroda Shoko , Fujii Takenori , Takano Ryotaro , Miyabe Yoshishige , Sakatani Takashi , Asatsuma-Okumura Tomoko , Hashiguchi Masaaki , Kanazawa Yoshikazu , Ohashi Ryuji , Yoshida Hiroshi , Seike Masahiro , Gemma Akihiko , Iwai Yoshiko 
Published: January 2024

AbstractPurposeThe tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.Experimental DesignWe examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n =117) prior to surgery and NSCLC patients (n =72) prior to and two months after ICI treatment and extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients.ResultsbsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 was strongly and moderately correlated with MMP13 and MMP3, respectively. In GC, bsPD-L1 expression was associated with IFN-γ levels and intra-tumoral T cell infiltration; MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. MMP3 and MMP13 levels were altered during ICI treatment. Combination of bsPD-L1 and MMP levels identified two patient groups; bsPD-L1+MMP13highin GC and bsPD-L1+(MMP3 and MMP13)increasedin NSCLC were associated with poor prognosis, and bsPD-L1+MMP13lowin GC and bsPD-L1+(MMP3 or MMP13)decreasedin NSCLC were associated with favorable prognosis.ConclusionsPlasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.
Large language models for generating medical examinations: systematic review
Authors: Artsi Yaara , Sorin Vera , Konen Eli , Glicksberg Benjamin S. , Nadkarni Girish , Klang Eyal 
Published: January 2024

AbstractPurposeWriting multiple choice questions (MCQs) for the purpose of medical exams is challenging. It requires extensive medical knowledge, time and effort from medical educators. This systematic review focuses on the application of large language models (LLMs) in generating medical MCQs.MethodsThe authors searched for studies published up to November 2023. Search terms focused on LLMs generated MCQs for medical examinations. MEDLINE was used as a search database.ResultsOverall, eight studies published between April 2023 and October 2023 were included. Six studies used Chat-GPT 3.5, while two employed GPT 4. Five studies showed that LLMs can produce competent questions valid for medical exams. Three studies used LLMs to write medical questions but did not evaluate the validity of the questions. One study conducted a comparative analysis of different models. One other study compared LLM-generated questions with those written by humans.All studies presented faulty questions that were deemed inappropriate for medical exams. Some questions required additional modifications in order to qualify.ConclusionsLLMs can be used to write MCQs for medical examinations. However, their limitations cannot be ignored. Further study in this field is essential and more conclusive evidence is needed. Until then, LLMs may serve as a supplementary tool for writing medical examinations.
Rare splice and missense variants with evidence of pathogenicity in consanguineous families with autosomal recessive intellectual disability from Pakistan
Authors: Waheed Abdul , Eveleigh Robert , Perley Danielle , St-Cyr Janick , Lefebvre François , Khan Abdul Hameed , Majeed Zarqash , Majeed Abrish , Trajanoska Katerina , Cuella-Martin Raquel , Bhérer Claude , Ali Ghazanfar , Mooser Vincent , Taliun Daniel 
Published: January 2024

AbstractIntellectual disability (ID) is a neurodevelopmental disorder affecting up to 1-3% of people worldwide. Genetic factors, including rarede novoor rare homozygous mutations, explain many cases of autosomal dominant or recessive forms of ID. ID is clinically and genetically heterogeneous, with hundreds of genes associated with it. In this study, we performed high-depth whole-genome sequencing of twenty individuals from five consanguineous families from Pakistan, with nine individuals affected by mild or severe ID. We identified one splice and five missense rare variants (at allele frequencies below 0.001%) in a homozygous state in the affected individuals with supporting and moderate evidence of pathogenicity based on guidance from the American College of Medical Genetics and Genomics. These six variants mapped to different genes (SRD5A3,RDH11,RTF2,PCDHA2,ADAMTS17, andTRPC3), and onlySRD5A3had previously been known to cause ID. The p.Tyr169Cys mutation insideSRD5A3was predicted to be deleterious and affect protein structure by multiplein silicotools. In addition, we found one missense mutation, p.Pro1505Ser, insideUNC13Bwith conflicting evidence of pathogenic and benign effects. Further functional studies are required to confirm the pathogenicity of these variants and understand their role in ID. Our findings provide additional needed information for interpreting rare variants in the genetic testing of ID.