bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anxiety, Depression, and Common Chronic Diseases, and Their Association With Social Determinants in Saudi Primary Care
Authors: Baghdadi Leena R. , Alhassan Mohammed Khalid , Alotaibi Fawaz Hindi , AlSelaim Khalid Badr , Alzahrani Abdulrahman Abdulkhaliq , AlMusaeed Faisal Fahad 
Published: November 2021

Introduction: Patients with chronic diseases can experience psychological conditions, including anxiety and depression. However, the association between chronic diseases and these psychological conditions remains unclear. This study aimed to identify the relationship between anxiety, depression, and common chronic diseases (hypertension, type 2 diabetes, dyslipidemia, and rheumatoid arthritis), and their association with social determinants at an outpatient primary care setting. Methods: The validated hospital anxiety and depression scale was administered electronically to eligible participants. For each condition (anxiety and depression), participants were categorized as normal, borderline abnormal, and abnormal, according to their score out of 21 (≤7 = normal, 8-10 = borderline abnormal, ≥11 = abnormal). The scores and numbers of participants in each category were analyzed and compared with their demographic characteristics and chronic diseases for associations and relationships. Results: We recruited 271 participants (mean age of 51.65 + 11.71 years) attending primary care clinics. Of these patients, 17.7% and 8.9% had borderline abnormal and abnormal depression, respectively, and 10.3% and 8.9% of patients had borderline abnormal anxiety and abnormal anxiety. Common social determinants and lifestyle factors were examined. Age, gender, and sugary drinks’ consumption significantly increased the odds of hypertension and type 2 diabetes; vigorous physical activity 3 times a week, decreased the odds of developing these chronic diseases. Adjusted regression models showed a statistically significant association between the hospital anxiety and depression scale score for borderline and abnormal anxiety and the presence of type 2 diabetes (OR 3.04 [95% CI 1.13, 8.19], P-value = .03 and OR 4.65 [95% CI 1.63,13.22], P-value <.03, respectively) and dyslipidemia (OR 5.93 [95% CI 1.54, 22.86], P-value = .01, and OR 4.70 [95% CI 0.78, 28.35], P-value = .09, respectively). The odds of developing depression were 4 times higher ( P-value .04) in patients with rheumatoid arthritis. Conclusion: Among patients attending primary care outpatient clinics, anxiety, and depression were significantly associated with type 2 diabetes and rheumatoid arthritis, respectively. Social determinants and lifestyle factors play a major role in the development of common chronic diseases in Saudi Arabia. Primary care physicians should consider the patients’ psychological status, sociodemographic status, and lifestyle risks during the management of chronic diseases.
Age-Adjusted D-Dimer in the Prediction of Pulmonary Embolism: Systematic Review and Meta-analysis
Authors: Iwuji Kenneth , Almekdash Hasan , Nugent Kenneth M. , Islam Ebtesam , Hyde Briget , Kopel Jonathan , Opiegbe Adaugo , Appiah Duke 
Published: November 2021

Background: Pulmonary embolism (PE), depending on the severity, carries a high mortality and morbidity. Proper evaluation, especially in patients with low probability for PE, is important to avoid unnecessary diagnostic testing. Objective: To review the diagnostic utility of conventional versus age-adjusted D-dimer cutoff values in patients 50 years and older with suspected pulmonary embolism. Methods: Systematic review with univariant and bivariant meta-analysis. Data sources: We searched PubMed, MEDLINE, and EBSCO for studies published before September 20th, 2020. We cross checked the reference list of relevant studies that compares conventional versus age-adjusted D-dimer cutoff values in patients with suspected pulmonary embolism. Study selection: We included primary published studies that compared both conventional (500 µg/L) and age-adjusted (age × 10 µg/L) cutoff values in patients with non-high clinical probability for pulmonary embolism. Results: Nine cohorts that included 47 720 patients with non-high clinical probability were included in the meta-analysis. Both Age-adjusted D-dimer and conventional D-dimer have high sensitivity. However, conventional D-dimer has higher false positive rate than age-adjusted D-dimer. Conclusion: Age-adjusted D-dimer cutoffs combined with low risk clinical probability assessment ruled out PE diagnosis in suspected patients with a decreased rate of false positive tests.
The Interests of Family Medicine Residents in Future Faculty Positions Across the Senior Year
Authors: Weidner Amanda , McGuire Marcia , Stutzman Kim , Glass Justin , Stevens Nancy Gray 
Published: November 2021

Background and Objectives The shortage of residency faculty in the pipeline is a growing concern to meet future workforce needs, though there is little research on attracting residents to be future faculty or what factors would influence their interest in this role. The objectives of this study were: (1) To assess the interest of third year residents (R3s) in faculty positions, and the various factors that might positively or negatively affect this decision; (2) to compare whether this changes across the R3 year; and (3) to compare between chief residents and other R3s. Methods Longitudinal survey at two points in time for each of three consecutive cohorts of R3s (2016-2018) from a regional network of family medicine residency programs. Results Among the final sample of R3s (176/545, 32% response), nearly half were interested in a residency faculty role. Strong positive influences on interest include the teaching role, advising/mentoring role, range of practice scope, and ability to perform procedures; salary and administrative responsibilities detract from interest. Among the matched sample of 96 R3s who also responded at Time 2 (55% response), non-chief residents had an increase in knowledge of and interest in the faculty role across the R3 year. Conclusions Nearly half of senior family medicine residents report positive interest in residency faculty positions and in most components of the role. Mentorship may encourage more residents to consider these positions upon graduation or shortly thereafter. More research on other specialties and with career follow up is recommended.
Can Life Experiences Predict Readiness for Residency? A Family Medicine Residency’s Analysis
Authors: Busha Michael E. , McMillen Brock , Greene Jeffrey , Gibson Kristine , Channell Adam , Ziemkowski Peter 
Published: November 2021

BACKGROUND Program directors for Family Medicine residencies must navigate an increasingly complex recruitment landscape. With increasing United States allopathic and osteopathic graduates and continued high volumes of international graduates, the ability to identify application characteristics that predict quality residents both for filtering applications for interview offers and ranking is vital. Our study concentrates on the predictive value of reported life experiences including volunteerism, work experiences, prior career, research experience, and participation in medical student organizations including student leadership. METHODS Through a retrospective cohort study, we extracted the described life experiences from resident application materials. We then obtained initial clinical performance data on the Family Medicine inpatient service during the first six months of residency to determine readiness for residency. This analysis occurred in 2020 and included all matriculants in the graduating classes of 2013 through 2020 for a single residency. Of 110 matriculating residents, data were available for 97(88%). RESULTS Applicants with a history of a prior career demonstrated improved overall readiness for residency with competency domain-specific advantages in Interpersonal and Communication Skills and Systems-Based Practice. In contrast, applicants reporting participation in research performed below peers in all competency domains. Applicant reports on volunteerism, work experience, academic productivity and student involvement did not correlate with initial clinical performance. CONCLUSIONS Residency directors should recognize applicants with prior careers as likely having strong communications and systems-based practice skills. All other examined experiences should be evaluated within the context of broader applicant assessments including research experience which overall has a potential negative correlation to clinical readiness.
Safety and Effectiveness of Outpatient Total Ankle Arthroplasty
Authors: Kayum Shahin , Kooner Sahil , Khan Ryan M. , Halai Mansur , Awoke Adam , Kanani Asa , Montgomery Spencer , Meldrum Alexander , Daniels Timothy R. 
Published: November 2021

Background: Total ankle arthroplasty (TAA) is a surgical procedure commonly reserved for patients suffering from symptomatic end-stage ankle arthritis. As the number of TAAs increases, so does the associated economic burden. Given these economic constraints, there has been interest in the feasibility of outpatient TAA. The purpose of this study is to evaluate the safety, efficacy, and satisfaction of patients undergoing outpatient TAA. Methods: This is a retrospective case series of consecutive patients who underwent outpatient TAA from July 2018 to June 2019. Inclusion criteria included any patient undergoing a primary TAA in the outpatient setting. This was defined as discharge on the same day of surgery or within 12 hours of surgery. All surgeries were completed by a single experienced surgeon through an anterior approach using the Cadence Total Ankle System. Prior to surgery, all patients received a popliteal nerve block. Patients were then discharged home with oral analgesic and a popliteal nerve catheter, which they removed after 48 hours. The primary outcome of interest was postoperative pain control, which was measured using a numeric scale. Secondary outcomes included complication rate, readmission rate, and patient satisfaction. A review of the current literature was then completed to supplement our results. Results: In total, 41 patients were included in our analysis. In terms of the primary outcome, the average numeric scale score was 1.98, indicating excellent pain control. Additionally, nearly all 41 patients stated they were very satisfied with their postoperative pain control regimen. In terms of secondary outcomes, the majority of patients stated they were satisfied with discharge on the same day as surgery. There were no readmissions or major complications in our outpatient TAA cohort. When asked if they would recommend the care they experienced to a friend with the same condition, 95% of patients said that they would recommend this care pathway. Our literature review included 5 original studies, which were all retrospective level IV studies. These studies uniformly demonstrated the safety and efficacy of outpatient TAA. Conclusions: The results of our study demonstrate the outpatient TAA is associated with excellent pain control using a multidisciplinary pain approach. The use of standardized outpatient postoperative pathways was effective in preventing readmissions and complications, while still resulting in high patient satisfaction scores. A review of the literature complemented our results, as there are largely no significant differences between outpatient and inpatient TAA. Level of Evidence: Level IV, case series.
Single-Cell Multiomics Reveals Increased Plasticity, Resistant Populations and Stem-Cell-like Blasts in KMT2A-Rearranged Leukemia
Authors: Chen Changya , Yu Wenbao , Alikarami Fatemeh , Qiu Qi , Chen Chia-hui , Flournoy Jennifer , Gao Peng , Uzun Yasin , Fang Li , Hu Yuxuan , Zhu Qin , Wang Kai , Libbrecht Clara , Felmeister Alex , Rozich Isaiah , Ding Yang-yang , Hunger Stephen P , Wu Hao , Brown Patrick A. , Guest Erin , Barrett David M , Bernt Kathrin M. , Tan Kai 
Published: November 2021

Abstract
KMT2A-rearranged (KMT2A-r) infant ALL is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single cell multi-omics analyses. We uncovered the following critical new insights: leukemia cells from patients younger than 6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune mediated control. Our analysis also revealed pre-existing lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in two patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank AML. These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single cell multi-omics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.

Disclosures
Bernt: Merck: Other: Spouse is an employee of Merck.; Syndax: Research Funding.
ALKBH5 Functions As an Oncogene in Multiple Myeloma
Authors: Qu Jianwei , Hou Yifan , Chen Qingxiao , Chen Jing , LI YI , Zhang Enfan , Gu Huiyao , Xu Ruyi , Liu Yang , He Jingsong , Huang He , Cai Zhen 
Published: November 2021

Abstract
Background: RNA N 6-methyladenosine (m 6A) plays a critical role in regulating gene expression and determining cell fate. The dysregulation of m 6A modulators, including α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5), has been reported to promote tumor development through their enzymatic function. However, the functions of mRNA m 6A and its modulators in multiple myeloma (MM) are largely unknown.
Methods: We queried publicly available MM datasets to study the expression profile of m 6A modulators (METTL3, METTL14, WTAP, FTO, and ALKBH5) in MM and their relationships with clinical outcomes in patients with MM. Both gain- and loss-of-function studies were performed to investigate the role of ALKBH5 in MM. The cell proliferation assay, colony formation assay, Annexin V apoptosis analysis, and 5-ethynyl-2′-deoxyuridine (EdU) assay were performed to evaluate the functions of ALKBH5 in MM in vitro. Human MM cell line xenograft models were constructed to examine the effects of ALKBH5 knockdown or overexpression on MM growth in vivo. The rescue assay using catalytically inactive mutant ALKBH5-H204A was conducted to determine whether demethylation activity was required for the function of ALKBH5 in MM. Then, we performed RNA sequencing and m 6A sequencing to explore the key targets that mediated ALKBH5 function in MM. We investigated the gene regulatory mechanism of ALKBH5 in MM by m 6A immunoprecipitation assay, RNA immunoprecipitation assay, RNA decay assay, dual-luciferase reporter assay, and so forth. Gene set enrichment analysis and Western blotting were employed to determine the downstream signaling pathways regulated by ALKBH5 and the recognized target.
Results: ALKBH5 was overexpressed in MM and associated with a poor prognosis in patients with MM. The increased ALKBH5 expression was required for the survival and growth of MM cells in vitro and in vivo. Mechanistically, m 6A demethylation activity was required for ALKBH5 to exert tumorigenic effects in MM. Tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) was identified as a functionally important target of ALKBH5. ALKBH5 regulated TRAF1 expression via affecting mRNA stability of TRAF1 in an m 6A- and YTHDF2-dependent manner. ALKBH5 promoted MM cell growth and survival partly through TRAF1-mediated activation of NF-κB and MAPK signaling pathways.
Conclusion: Our findings showed that ALKBH5 played an oncogenic role in MM and highlighted that ALKBH5 could potentially be a novel therapeutic target in MM.

Disclosures
No relevant conflicts of interest to declare.
Expert-independent classification of mature B-cell neoplasms using standardized flow cytometry: a multicentric study
Authors: Böttcher Sebastian , Engelmann Robby , Grigore Georgiana , Fernandez Paula , Caetano Joana , Flores-Montero Juan , van der Velden Vincent H. J. , Novakova Michaela , Philippé Jan , Ritgen Matthias , Burgos Leire , Lecrevisse Quentin , Lange Sandra , Kalina Tomas , Verde Velasco Javier , Fluxa Rodriguez Rafael , van Dongen Jacques J. M. , Pedreira Carlos E. , Orfao, Alberto 
Published: November 2021

Abstract
Reproducible expert-independent flow-cytometric criteria for the differential diagnoses between mature B-cell neoplasms are lacking. We developed an algorithm-driven classification for these lymphomas by flow cytometry and compared it to the WHO gold standard diagnosis. Overall, 662 samples from 662 patients representing 9 disease categories were analyzed at 9 laboratories using the previously published EuroFlow 5-tube-8-color B-cell chronic lymphoproliferative disease antibody panel. Expression levels of all 26 markers from the panel were plotted by B-cell entity to construct a univariate, fully standardized diagnostic reference library. For multivariate data analysis, we subsequently used canonical correlation analysis of 176 training cases to project the multidimensional space of all 26 immunophenotypic parameters into 36 2-dimensional plots for each possible pairwise differential diagnosis. Diagnostic boundaries were fitted according to the distribution of the immunophenotypes of a given differential diagnosis. A diagnostic algorithm based on these projections was developed and subsequently validated using 486 independent cases. Negative predictive values exceeding 92.1% were observed for all disease categories except for follicular lymphoma. Particularly high positive predictive values were returned in chronic lymphocytic leukemia (99.1%), hairy cell leukemia (97.2%), follicular lymphoma (97.2%), and mantle cell lymphoma (95.4%). Burkitt and CD10+ diffuse large B-cell lymphomas were difficult to distinguish by the algorithm. A similar ambiguity was observed between marginal zone, lymphoplasmacytic, and CD10− diffuse large B-cell lymphomas. The specificity of the approach exceeded 98% for all entities. The univariate immunophenotypic library and the multivariate expert-independent diagnostic algorithm might contribute to increased reproducibility of future diagnostics in mature B-cell neoplasms.
Metabolic profile changes in serum of migraine patients detected using 1H-NMR spectroscopy
Authors: Harder Aster V. E. , Vijfhuizen Lisanne S. , Henneman Peter , Willems van Dijk Ko , van Duijn Cornelia M. , Terwindt Gisela M. , van den Maagdenberg Arn M. J. M. 
Published: November 2021

Abstract
Background
Migraine is a common brain disorder but reliable diagnostic biomarkers in blood are still lacking. Our aim was to identify, using proton nuclear magnetic resonance (1H-NMR) spectroscopy, metabolites in serum that are associated with lifetime and active migraine by comparing metabolic profiles of patients and controls.

Methods
Fasting serum samples from 313 migraine patients and 1512 controls from the Erasmus Rucphen Family (ERF) study were available for 1H-NMR spectroscopy. Data was analysed using elastic net regression analysis.

Results
A total of 100 signals representing 49 different metabolites were detected in 289 cases (of which 150 active migraine patients) and 1360 controls. We were able to identify profiles consisting of 6 metabolites predictive for lifetime migraine status and 22 metabolites predictive for active migraine status. We estimated with subsequent regression models that after correction for age, sex, BMI and smoking, the association with the metabolite profile in active migraine remained. Several of the metabolites in this profile are involved in lipid, glucose and amino acid metabolism.

Conclusion
This study indicates that metabolic profiles, based on serum concentrations of several metabolites, including lipids, amino acids and metabolites of glucose metabolism, can distinguish active migraine patients from controls.
Novel deep learning-based solution for identification of prognostic subgroups in liver cancer (Hepatocellular carcinoma)
Authors: Owens Alice R. , McInerney Caitríona E. , Prise Kevin M. , McArt Darragh G. , Jurek-Loughrey Anna 
Published: November 2021

Abstract
Background
Liver cancer (Hepatocellular carcinoma; HCC) prevalence is increasing and with poor clinical outcome expected it means greater understanding of HCC aetiology is urgently required. This study explored a deep learning solution to detect biologically important features that distinguish prognostic subgroups. A novel architecture of an Artificial Neural Network (ANN) trained with a customised objective function (LRSC) was developed. The ANN should discover new data representations, to detect patient subgroups that are biologically homogenous (clustering loss) and similar in survival (survival loss) while removing noise from the data (reconstruction loss). The model was applied to TCGA-HCC multi-omics data and benchmarked against baseline models that only use a reconstruction objective function (BCE, MSE) for learning. With the baseline models, the new features are then filtered based on survival information and used for clustering patients. Different variants of the customised objective function, incorporating only reconstruction and clustering losses (LRC); and reconstruction and survival losses (LRS) were also evaluated. Robust features consistently detected were compared between models and validated in TCGA and LIRI-JP HCC cohorts.

Results
The combined loss (LRSC) discovered highly significant prognostic subgroups (P-value = 1.55E−77) with more accurate sample assignment (Silhouette scores: 0.59–0.7) compared to baseline models (0.18–0.3). All LRSC bottleneck features (N = 100) were significant for survival, compared to only 11–21 for baseline models. Prognostic subgroups were not explained by disease grade or risk factors. Instead LRSC identified robust features including 377 mRNAs, many of which were novel (61.27%) compared to those identified by the other losses. Some 75 mRNAs were prognostic in TCGA, while 29 were prognostic in LIRI-JP also. LRSC also identified 15 robust miRNAs including two novel (hsa-let-7g; hsa-mir-550a-1) and 328 methylation features with 71% being prognostic. Gene-enrichment and Functional Annotation Analysis identified seven pathways differentiating prognostic clusters.

Conclusions
Combining cluster and survival metrics with the reconstruction objective function facilitated superior prognostic subgroup identification. The hybrid model identified more homogeneous clusters that consequently were more biologically meaningful. The novel and prognostic robust features extracted provide additional information to improve our understanding of a complex disease to help reveal its aetiology. Moreover, the gene features identified may have clinical applications as therapeutic targets.