bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiology Reports Do Not Accurately Portray the Severity of Cervical Neural Foraminal Stenosis
Authors: Lee Yunsoo , Ziad Issa Tariq , Mazmudar Aditya S. , Tarawneh Omar H. , Toci Gregory R. , Lambrechts Mark J. , DiDomenico Eric J. , Kwak Daniel , Becsey Alexander N. , Henry Tyler W. , Haider Ameer A. , Larkin Collin J. , Kaye Ian David , Kurd Mark F. , Canseco Jose A. , Hilibrand Alan S. , Vaccaro Alexander R. , Kepler Christopher K. , Schroeder Gregory D.
Published: March 2024

Study Design:

Retrospective study.

Objective:

(1) To compare cervical magnetic resonance imaging (MRI) radiology reports to a validated grading system for cervical foraminal stenosis (FS) and (2) to evaluate whether the severity of cervical neural FS on MRI correlates to motor weakness or patient-reported outcomes.

Background:

Radiology reports of cervical spine MRI are often reviewed to assess the degree of neural FS. However, research looking at the association between these reports and objective MRI findings, as well as clinical symptoms, is lacking.

Patients and Methods:

We retrospectively identified all adult patients undergoing primary 1 or 2-level anterior cervical discectomy and fusion at a single academic center for an indication of cervical radiculopathy. Preoperative MRI was assessed for neural FS severity using the grading system described by Kim and colleagues for each level of fusion, as well as adjacent levels. Neural FS severity was recorded from diagnostic radiologist MRI reports. Motor weakness was defined as an examination grade <4/5 on the final preoperative encounter. Regression analysis was conducted to evaluate whether the degree of FS by either classification was related to patient-reported outcome measure severity.

Results:

A total of 283 patients were included in the study, and 998 total levels were assessed. There were significant differences between the MRI grading system and the assessment by radio-logists (P < 0.001). In levels with moderate stenosis, 28.9% were classified as having no stenosis by radiology. In levels with severe stenosis, 29.7% were classified as having mild-moderate stenosis or less. Motor weakness was found similarly often in levels of moderate or severe stenosis (6.9% and 9.2%, respectively). On regression analysis, no associations were found between baseline patient-reported outcome measures and stenosis severity assessed by radiologists or MRI grading systems.

Conclusion:

Radiology reports on the severity of cervical neural FS are not consistent with a validated MRI grading system. These radiology reports underestimated the severity of neural foraminal compression and may be inappropriate when used for clinical decision-making.

Level of Evidence:

Level III.
Impact of Weekday on Short-term Surgical Outcomes After Lumbar Fusion Surgery
Authors: Heard Jeremy C. , Ezeonu Teeto , Lee Yunsoo , Narayanan Rajkishen , Issa Tariq , McCall Cordero , Dulitzki Yoni , Resnick Dylan , Zucker Jeffrey , Shaer Alexander , Kurd Mark , Hilibrand Alan S. , Vaccaro Alexander R. , Kepler Christopher K. , Schroeder Gregory D. , Canseco Jose A.
Published: March 2024

Study Design:

Retrospective cohort study.

Objective:

The purpose of this study is to investigate whether weekday lumbar spine fusion surgery has an impact on surgical and inpatient physical therapy (PT) outcomes.

Summary of Background Data:

Timing of surgery has been implicated as a factor that may impact outcomes after spine surgery. Previous literature suggests that there may be an adverse effect to having surgery on the weekend.

Methods:

All patients ≥18 years who underwent primary lumbar spinal fusion from 2014 to 2020 were retrospectively identified. Patients were subdivided into an early subgroup (surgery between Monday and Wednesday) and a late subgroup (surgery between Thursday and Friday). Surgical outcome variables included inpatient complications, 90-day readmissions, and 1-year revisions. PT data from the first inpatient PT session included hours to PT session, AM-PAC Daily Activity or Basic Mobility scores, and total gait trial distance achieved.

Results:

Of the 1239 patients identified, 839 had surgery between Monday and Wednesday and 400 had surgery between Thursday and Friday. Patients in the later surgery subgroup were more likely to experience a nonsurgical neurologic complication (3.08% vs. 0.86%, P=0.008); however, there was no difference in total complications. Patients in the early surgery subgroup had their first inpatient PT session earlier than patients in the late subgroup (15.7 vs. 18.9 h, P<0.001). However, patients in the late subgroup achieved a farther total gait distance (98.2 vs. 75.4, P=0.011). Late surgery was a significant predictor of more hours of PT (est.=0.256, P=0.016) and longer length of stay (est.=2.277, P=0.001). There were no significant differences in readmission and revision rates.

Conclusions:

Patients who undergo surgery later in the week may experience more nonsurgical neurologic complications, longer wait times for inpatient PT appointments, and longer lengths of stay. This analysis showed no adverse effect of later weekday surgery as it relates to total complications, readmissions, and reoperations.

Level of Evidence:

Level III.
Management of massive hemothorax resulting from traumatic diaphragm rupture with kidney avulsion injury by combined anterior thoracoabdominal approaches
Authors: Lin Keng-Li , Lin Heng-Fu , Tseng Yi-Shiou , Wu Chien , Wang Hu-Lin Christina
Published: March 2024

Blunt trauma resulting in diaphragm rupture, kidney avulsion injury, and subsequent hemothorax is rare and requires immediate surgical intervention. After diagnosis, urgent laparotomy with thoracotomy is needed to control renal bleeding. However, because of limitations in imaging studies, confirming this diagnosis is not straightforward, thus underscoring the importance of proper patient’s posturing. It is recommended that in cases of massive hemothorax combined with intra-abdominal bleeding, no matter performing thoracotomy or laparotomy first, the attending surgeons have to put patients in a position appropriate for simultaneous thoracoabdominal approach. It avoids surgical delays that could lead to fatal outcomes.
Impact of Body-contouring Surgery Post Bariatric Surgery on Patient Well-being, Quality of Life, and Body Image: Saudi Arabia-based Cross-sectional Study
Authors: Neel Omar Fouda , Algaidi Yaser , Alsubhi Mohammed Naif , Al-Terkawi Reem Abdulmonem , Salem Abdelrahman , Mortada Hatan
Published: March 2024

Background:

Body-contouring surgery is commonly performed to address functional and aesthetic issues that can arise following bariatric surgery. However, there is limited understanding of the psychological impact of this procedure on Saudi Arabian patients who have undergone bariatric surgery. This study aimed to explore the effects of body-contouring surgery on the psychological well-being, quality of life, and body image of individuals who have undergone bariatric surgery.

Methods:

This cross-sectional study assessed the psychological impact of body-contouring surgery by measuring levels of depression and generalized anxiety disorder using the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) scale, respectively.

Results:

The study included a total of 227 participants, with 112 (49.3%) undergoing body-contouring surgery. Among the entire sample, 77.5% experienced excess skin folds following bariatric surgery. The prevalence of depression was 6% in the body-contouring group, lower than the 8% observed in the non–body-contouring group (P = 0.073). Notably, anxiety was significantly lower in the body-contouring group, with a prevalence of 4% compared with 6% in the non–body-contouring group (P = 0.006). Additionally, patients who had undergone body-contouring surgery reported higher scores for emotional well-being when compared with those who had not undergone body-contouring (P = 0.011).

Conclusions:

The study suggests that body-contouring surgery improves the physical appearance of bariatric-surgery patients and reduces anxiety and depression, leading to improved psychological well-being. Further research, including larger and more diverse populations, such as multicenter studies at a regional or international level, is needed to validate these findings.
Experiences of Workplace Violence in Graduate Nursing Clinical Education
Authors: Gigli Kristin H. , Gonzalez John D.
Published: March 2024

Background:

Exposure to workplace violence (WPV) is common in health care, and little is known about nurse practitioner (NP) students’ experiences during graduate nursing clinical education.

Purpose:

This study described experiences of WPV among NP students during their clinical education.

Methods:

We conducted a cross-sectional, quantitative survey of a random sample of NPs licensed in Texas examining graduate nursing education experiences.

Results:

A total of 334 NPs responded, a 12% response rate. More than a quarter (27%) experienced WPV during their graduate nursing clinical experience. Preceptors were the most reported perpetrators (44%). Most NPs remained in their clinical site after their WPV experience (55%); a majority felt they had no alternative clinical placement option.

Conclusions:

Nurse practitioner students experience WPV, and there may be implications for educational persistence and their careers. Future work should attempt to reduce the frequency of student WPV experiences and examine implications for NP careers.
A Novel EPC1::KDM2B Fusion in High-grade Endometrial Stromal Sarcoma
Authors: Vroobel Katherine M. , Khalid Sana , Cavalchini Silvia , Attygalle Ayoma D.
Published: March 2024

The spectrum of endometrial stromal sarcoma (ESS) has expanded substantially since the publication of the most recent World Health Organisation (WHO) Classification of Female Genital Tumours and the advent of widely available genomic testing. We describe a uterine mesenchymal tumor harboring a novel EPC1::KDM2B fusion, best classified within the umbrella of high-grade endometrial stromal sarcoma (HGESS). This tumor was composed of a uniform population of spindled cells with some myxoid stroma, a mitotic rate of up to 21/10 high-power fields, and a largely pushing margin with focal vascular invasion. Immunohistochemistry showed strong and diffuse cyclin D1 positivity while CD10, WT1, DOG1, CD117, CD34, CD99, S100, MelanA, SMA, desmin, and h-caldesmon were negative. The tumor was confined to the uterus and no recurrence has been detected thus far, albeit with a short follow-up interval of 9 mo.
Macrophage polarization disorder in the endometrial immune microenvironment may contribute to recurrent implantation failure
Authors: Liu Yun , Tan Xian-Ming , He Tian-Tian
Published: March 2024

Objective:

To investigate the role and mechanisms by which macrophages (MΦ) contribute to the immune environment of the endometrium in cases of recurrent implantation failure (RIF).

Methods:

Endometrial transcriptome data from women with and without RIF (control group) were collected. The CIBERSORT software was used to determine the abundance of immune cells within the endometrial tissue based on expression profiles. Weighted gene co-expression network analysis was used to identify crucial regulatory genes and pathways.

Results:

Application of CIBERSORT confirmed significant infiltration of macrophages in the RIF group. SOX6, TTC21A, KLHL31, NFIA, TNNT1, TPM1, CPVL, FUS, PEX5, and SLC43A3 were all closely correlated with M2 and M0 macrophages. Metascape and DisNor analyses revealed that these genes contribute to the regulation of macrophage polarization via the Wnt signaling pathway.

Conclusion:

This study identified dysregulation of macrophage polarization within the immune microenvironment of the endometrium in patients with RIF. A comprehensive analysis was conducted to investigate the potential mechanisms underlying this disorder. Dysregulation of macrophage polarization in the endometrium of patients with RIF is strongly associated with the Wnt signaling pathway.
Pretransplant Screening for Prevention of Hyperacute Graft Loss in Pig-to-primate Kidney Xenotransplantation
Authors: Hisadome Yu , Eisenson Daniel L. , Santillan Michelle R. , Iwase Hayato , Yamada Kazuhiko
Published: March 2024

Background.

Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation.

Methods.

We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays.

Results.

High complement-dependent cytotoxicity was associated with HAR/AHXR as expected. However, we also found that high levels of IgG were independently associated with HAR/AHXR, and we developed 2 indices to interpret and predict the risk of IgG-mediated HAR/AHXR.

Conclusions.

Based on the data in this study, we have established a new 2-step screening, which will be used for future clinical kidney xenotransplantation trials.
Long-term Kidney Transplant Survival Across the Globe
Authors: Hariharan Sundaram , Rogers Natasha , Naesens Maarten , Pestana J. Medina , Ferreira Gustavo F. , Requião-Moura Lucio R. , Foresto Renato D. , Kim S. Joseph , Sullivan Katrina , Helanterä Ilkka , Goutaudier Valentin , Loupy Alexandre , Kute Vivek B. , Cardillo Massimo , Tanabe Kazunari , Åsberg Anders , Jensen Trond , Mahillo Beatriz , Jeong Jong Cheol , Anantharaman Vathsala , Callaghan Chris , Ravanan Rommel , Manas Derek , Israni Ajay K. , Mehta Rajil B.
Published: March 2024

Background.

The outcomes after kidney transplantation (KT), including access, wait time, and other issues around the globe, have been studied. However, issues do vary from one country to another.

Methods.

We obtained data from several countries from North America, South America, Europe, Asia, and Australia, including the number of patients awaiting KT from 2015, transplant rate per million population (pmp), proportion of living donor and deceased donor (LD/DD) KT, and posttransplant survival. We also sought opinions on key difficulties faced by each of these countries with respect to KT and long-term survival.

Results.

Variation in access to KT across the globe was noted. Countries with the highest rates of KT pmp included the United States (79%) and Spain (71%). A higher proportion of LD transplants was noted in Japan (93%), India (85%), Singapore (63%), and South Korea (63%). A higher proportion of DD KTs was noted in Spain (90%), Brazil (90%), France (85%), Italy (85%), Finland (85%), Australia–New Zealand (80%), and the United States (77%). The 5-y graft survival for LD was highest in South Korea (95%), Singapore (94%), Italy (93%), Finland (93%), and Japan (93%), whereas for DD, it was South Korea (93%), Italy (88%), Japan (86%), and Singapore (86%). The common issues surrounding KTs are access and a limited number of LDs and DDs. Key issues identified for long-term survival were increasing age of donors and recipients, higher recipient comorbidity, and posttransplant events, such as alloimmune injury to the kidney, infection, cancer, and suboptimal adherence to therapy.

Conclusions.

A unified approach is necessary to improve issues surrounding KT as the demand continues to increase.
Prognostic Value of Mitral Annular Calcification in Liver Transplant Patients: Implication in Posttransplant Outcomes
Authors: Jang Hwa-Young , Han Sang-Bin , Jeong Jun-Hyeop , Kwon Hye-Mee , Kim Kyoung-Sun , Kim Jae-Hwan , Kim Sung-Hoon , Jun In-Gu , Song Jun-Gol , Hwang Gyu-Sam
Published: March 2024

Background.

With the rise of metabolic diseases and aging in liver transplant (LT) candidates, mitral annular calcification (MAC) is more recognizable. Despite cardiovascular risk becoming a leading cause of mortality in LT recipients, the influence of MAC remains unexamined. This study investigates the prevalence, related factors, and impact of MAC on LT outcomes.

Methods.

We explored 4148 consecutive LT patients who underwent routine pretransplant echocardiography from 2008 to 2019. Multivariate logistic analysis and the tree-based Shapley additive explanation scores in machine learning were used to evaluate the significant and important related factors. The primary outcome was 30-d major adverse cardiac events (MACE), and the secondary outcome was a median of 5-y cumulative all-cause mortality.

Results.

MAC was found in 123 (3.0%) patients. Significant and important related factors included age, alcoholic liver disease, chronic kidney disease, hyperuricemia, hypertension, and coronary artery disease. The MACE rate was higher in patients with MAC compared with those without MAC at 30 d (P < 0.001, adjusted hazard ratio 1.67; 95% confidence interval, 1.08-2.57). Patients with MAC had poorer cumulative overall survival probability compared with those without MAC (P = 0.0016; adjusted hazard ratio 1.47; 95% confidence interval, 1.01-2.15). Specifically, women with MAC had a poorer survival probability compared with men without MAC (65.0% versus 80.7%, P < 0.001) >10 y post-LT.

Conclusions.

The presence of MAC before LT was linked to increased 30-d MACE and lower long-term survival rates, especially in women. Identification and management of MAC and potential risk factors are crucial for improving post-LT survival.
Taurine Deficiency Is a Hallmark of Injured Kidney Allografts
Authors: Rinaldi Anna , Cippà Pietro E. , Nemazanyy Ivan , Anglicheau Dany , Pallet Nicolas
Published: March 2024

Background.

Taurine is one of the most abundant amino acids in humans. Low taurine levels are associated with cellular senescence, mitochondrial dysfunction, DNA damage, and inflammation in mouse, all of which can be reversed by supplementation. It is unknown whether taurine metabolism is associated with kidney allograft function and survival.

Methods.

We performed urine metabolomic profiling of kidney transplant recipients in the early and late phases after transplantation combined with transcriptomic analysis of human kidney allografts. Single-nucleus RNA sequencing data sets of mouse kidneys after ischemia–reperfusion injury were analyzed. We analyzed the association of urinary taurine levels and taurine metabolism genes with kidney function, histology, and graft survival.

Results.

Urine taurine concentrations were significantly lower in kidney transplant recipients who experienced delayed graft function. In a mouse model of ischemia–reperfusion injury, the taurine biosynthesis gene, CSAD, but not the taurine transporter SLC6A6, was repressed. In the late stage of transplantation, low level of taurine in urine was associated with impaired kidney function and chronic structural changes. Urine taurine level in the lowest tertile was predictive of graft loss. Expression of the taurine transporter SLC6A6 in the upper median, but not CSAD, was associated with chronic kidney injury and was predictive of graft loss.

Conclusions.

Low urine taurine level is a marker of injury in the kidney allograft, is associated with poor kidney function, is associated with chronic histological changes, and is predictive of graft survival. The differential expression of CSAD and SLC6A6, depending on the time after transplantation and marks of injury, highlights different mechanisms affecting taurine metabolism.
Concurrent JCPyV-DNAemia Is Correlated With Poor Graft Outcome in Kidney Transplant Recipients With Polyomavirus-associated Nephropathy
Authors: Zhang Hui , Luo Jin-Quan , Zhao Guo-Dong , Huang Yang , Yang Shi-Cong , Chen Pei-Song , Li Jun , Wu Cheng-Lin , Qiu Jiang , Chen Xu-Tao , Huang Gang
Published: March 2024

Background.

Co-infection of JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) is uncommon in kidney transplant recipients, and the prognosis is unclear. This study aimed to investigate the effect of concurrent JCPyV-DNAemia on graft outcomes in BKPyV-infected kidney transplant recipients with polyomavirus-associated nephropathy (PyVAN).

Methods.

A total of 140 kidney transplant recipients with BKPyV replication and PyVAN, 122 without concurrent JCPyV-DNAemia and 18 with JCPyV-DNAemia were included in the analysis. Least absolute shrinkage and selection operator regression analysis and multivariate Cox regression analysis were used to identify prognostic factors for graft survival. A nomogram for predicting graft survival was created and evaluated.

Results.

The median tubulitis score in the JCPyV-DNAemia-positive group was higher than in JCPyV-DNAemia-negative group (P = 0.048). At last follow-up, the graft loss rate in the JCPyV-DNAemia-positive group was higher than in the JCPyV-DNAemia-negative group (50% versus 25.4%; P = 0.031). Kaplan–Meier analysis showed that the graft survival rate in the JCPyV-DNAemia-positive group was lower than in the JCPyV-DNAemia-negative group (P = 0.003). Least absolute shrinkage and selection operator regression and multivariate Cox regression analysis demonstrated that concurrent JCPyV-DNAemia was an independent risk factor for graft survival (hazard ratio = 4.808; 95% confidence interval: 2.096-11.03; P < 0.001). The nomogram displayed favorable discrimination (C-index = 0.839), concordance, and clinical applicability in predicting graft survival.

Conclusions.

Concurrent JCPyV-DNAemia is associated with a worse graft outcome in BKPyV-infected kidney transplant recipients with PyVAN.
Investigating the impact of temperature on growth rate of the root rot fungus, Gymnopus fusipes
Authors: Pettifor Bethany J , Kajamuhan Anparasy , Denman Sandra , McDonald James E.
Published: March 2024

Gymnopus fusipes is an understudied root rot pathogen associated with multiple tree species and is linked to episodes of oak decline across the United Kingdom and Europe. Although the reported distribution of G. fusipes is broad, many observations rely solely on visual identification of fruiting bodies, which can be unreliable, and lack confirmation by molecular and/or isolation data to verify this broad ecological range. Given the paucity of information regarding the true ecological distribution of G. fusipes, it is difficult to predict and model the potential distribution of the species under both current and future climate scenarios. In this study, to determine the growth capabilities of G. fusipes across a range of ecologically relevant temperatures, five geographically diverse isolates of G. fusipes were grown at five different temperatures ranging from 4˚C to 37˚C, to determine the optimal temperature for G. fusipes growth, and to establish whether geographically diverse isolates exhibit local adaptation to temperature tolerance. Incubation temperature had a significant effect on G. fusipes growth rate, with 25˚C representing the optimum (p < 0.001). Isolates had differing growth rates at each of the temperatures, with an isolate from the UK having the highest overall growth rate across all five temperatures tested (p < 0.001), and at the optimum, increased by a mean value of over 4915 mm2. Local adaptation to temperature tolerance was not found in the isolates tested. These data demonstrate the optimal incubation temperature for future laboratory studies on G. fusipes and provide the first data on the growth rate of this pathogen across ecologically relevant climate ranges that may inform land managers, modellers, and policy makers in predicting the current and potentially future geographical limits of this widespread root rot pathogen.
Conserved patterns of sequence diversification provide insight into the evolution of two-component systems in Enterobacteriaceae
Authors: Barretto Luke A. F. , Van Patryc-Khang T. , Fowler Casey C.
Published: March 2024

Two-component regulatory systems (TCSs) are a major mechanism used by bacteria to sense and respond to their environments. Many of the same TCSs are used by biologically diverse organisms with different regulatory needs, suggesting that the functions of TCS must evolve. To explore this topic, we analysed the amino acid sequence divergence patterns of a large set of broadly conserved TCS across different branches of Enterobacteriaceae, a family of Gram-negative bacteria that includes biomedically important genera such as Salmonella, Escherichia, Klebsiella and others. Our analysis revealed trends in how TCS sequences change across different proteins or functional domains of the TCS, and across different lineages. Based on these trends, we identified individual TCS that exhibit atypical evolutionary patterns. We observed that the relative extent to which the sequence of a given TCS varies across different lineages is generally well conserved, unveiling a hierarchy of TCS sequence conservation with EnvZ/OmpR as the most conserved TCS. We provide evidence that, for the most divergent of the TCS analysed, PmrA/PmrB, different alleles were horizontally acquired by different branches of this family, and that different PmrA/PmrB sequence variants have highly divergent signal-sensing domains. Collectively, this study sheds light on how TCS evolve, and serves as a compendium for how the sequences of the TCS in this family have diverged over the course of evolution.
Development of a Tremor Detection Algorithm for use in an Academic Movement Disorders Center
Authors: Saad Mark , Hefner Sofia , Donovan Suzann , Bernhard Doug , Tripathi Richa , Factor Stewart A. , Powell Jeanne , Kwon Hyeokhyen , Sameni Reza , Esper Christine D. , McKay J. Lucas
Published: March 2024

Tremor, defined as an “involuntary, rhythmic, oscillatory movement of a body part,” is a key feature of many neurological conditions, but is still clinically assessed by visual observation. Methodologies for objectively quantifying tremor are promising but remain non-standardized across centers. Our center performs full-body behavioral testing with 3D motion capture for clinical and research purposes for patients with Parkinson’s disease, essential tremor, and other conditions. The objective of this study was to assess the ability of several candidate processing pipelines to identify the presence or absence of tremor in kinematic data from movement disorders patients compared to expert ratings from movement disorders specialists. We curated a database of 2,272 separate kinematic data recordings from our center, each of which was contemporaneously annotated as tremor present or absent by a clinical provider. We compared the ability of six separate processing pipelines to recreate clinician ratings based on F1 score, in addition to accuracy, precision, and recall. We found generally comparable performance across algorithms. The averageF1 score was 0.84±0.02 (Mean±SD; range 0.81−0.87), with allF1 confidence intervals overlapping. The highest performing algorithm (cross-validatedF1 = 0.87) was a hybrid that used engineered features adapted from an algorithm in longstanding clinical use with a modern Support Vector Machine classifier. Taken together, our results suggest the potential to update legacy clinical decision support systems to incorporate modern machine learning classifiers in order to create better performing tools.
Large-scale plasma proteomics in the UK Biobank modestly improves prediction of major cardiovascular events in a population without previous cardiovascular disease
Authors: Royer Patrick , Björnson Elias , Adiels Martin , Josefson Rebecca , Hagberg Eva , Gummesson Anders , Bergström Göran
Published: March 2024

Background and Aims

Improved identification of individuals at high risk of developing cardiovascular disease would enable targeted interventions and potentially lead to reductions in mortality and morbidity. Our aim was to determine whether use of large-scale proteomics improves prediction of cardiovascular events beyond traditional risk factors (TRFs).

Methods

Using proximity extension assays, 2919 plasma proteins were measured in 38 380 participants of the UK Biobank. Both data- and hypothesis-driven feature selection and trained models using extreme gradient boosting machine learning were used to predict risk of major cardiovascular events (MACE: fatal and non-fatal myocardial infarction, stroke and coronary artery revascularisation) during a 10-year follow-up. Area under the curve (AUC) and net reclassification index (NRI) were used to evaluate the additive value of selected protein panels to MACE prediction by Systematic COronary Risk Evaluation 2 (SCORE2) or the 10 TRFs used in SCORE2.

Results

SCORE2 and SCORE2 refitted to UK Biobank data predicted MACE with AUCs of 0.740 and 0.749, respectively. Data-driven selection identified 114 proteins of greatest relevance for prediction. Prediction of MACE was not improved by using these proteins alone (AUC of 0.758) but was significantly improved by combining these proteins with SCORE2 or the 10 TRFs (AUC=0.771, p<001, NRI=0.140, and AUC=0.767, p=0.03, NRI 0.053, respectively). Hypothesis-driven protein selection (113 proteins from five previous studies) also improved risk prediction beyond TRFs while a random selection of 114 proteins did not.

Conclusions

Large-scale plasma proteomics with data- and hypothesis-driven protein selection modestly improves prediction of future MACE beyond TRFs.

Structured Graphical Abstract legend.
CD1c Dendritic Cells are depleted and accompanied by new HLA-DRhiPhenotypes in Rheumatoid Arthritis Blood
Authors: Geier Christian , Qudsi Haani , Gabr Jihad Ben , Winchester Robert , Perl Andras
Published: March 2024

Rheumatoid arthritis (RA) in an autoimmune disease that leads to inflammation of synovial joints and other organs. Many RA patients ‘share’ a common peptide sequence within the HLA-DR (DR) molecule expressed on antigen-presenting cells (APC), suggesting that DRhicells are important in RA. Here, we use DRhito broadly define and immunophenotype RA APC, including potential APC not meeting standard definitions for lymphocytes, monocytes, dendritic cells (DC) from RA patients and healthy controls (HC). We measured mean fluorescence intensities (MFI) of molecules associated with DC (CD141, CD1c, CD11c, CD123, CD303), monocytes (CD14, CD16); granulocytic markers (CD15, CCR3), co-stimulatory molecules and chemokine receptors. DC2 (CD1c+) showed higher CD56, CD86, CD275, and CCR7 in RA. DC2 frequencies were much lower in RA: 3.2% of DRhi[IQR 2.41 to 4.46] in RA vs. 6.9% [IQR 3.96 to 9.08] in HC; p=0.005. CD15 was increased in all RA APC subsets (p<0.01). A distinct CD15+CD16+population appeared in RA, representing 1.5% of leukocytes [IQR 0.68 to 3.32] (vs 0.1% in HC [IQR 0.08 to 0.46]; p<0.001) and contributed a mean of 2.34% to overall DRhi. The CD15+CD16+subset was CD303+, CD83+and CD275+with much less CD123 relative to reference plasmacytoid DC (p<0.01). In conclusion, APC alterations in RA include depletion of DC2 and increased CD15. Moreover, the APC (DRhi) compartment in RA contains cells with shared dendritic cell and granulocytic features; this phenotype suggests these apparent APC may participate in the pathophysiology of rheumatoid arthritis via the presentation of self-antigen(s) to CD4+T lymphocytes.
Look-alike modelling in violence-related research: a missing data approach
Authors: Barbosa Estela Capelas , Blom Niels , Bunce Annie
Published: March 2024

Violence as a phenomena has been analysed in silo due to difficulties in accessing data and concerns for the safety of those exposed. While there is some literature on violence and its associations using individual datasets, analyses using combined sources of data are very limited. Ideally data from the same individuals would enable linkage and a longitudinal understanding of experiences of violence and their (health) impacts and consequences. However, in the absence of directly linked data, look-alike modelling may provide an innovative and cost-effective approach to exploring patterns and associations in violence-related research in a multi-sectorial setting.

We approached the problem of data integration as a missing data problem to create a synthetic combined dataset. We combined data from the Crime Survey of England and Wales with administrative data from Rape Crisis, focussing on victim-survivors of sexual violence in adulthood. Multiple imputation with chained equations were employed to collate/impute data from different sources. To test whether this procedure was effective, we compared regressions analyses for the individual and combined synthetic datasets on a binary, continuous and categorical variables. Our results show that the effect sizes for the combined dataset reflect those from the dataset used for imputation. The variance is higher, resulting in fewer statistically significant estimates. We extended our testing to an outcome measures and finally applied the technique to a variable fully missing in one data source. Our approach reinforces the possibility to combine administrative with survey datasets using look-alike methods to overcome existing barriers to data linkage.
A framework for conducting time-varying genome-wide association studies: An application to body mass index across childhood in six multiethnic cohorts
Authors: Burrows Kimberley , Heiskala Anni , Bradfield Jonathan P. , Balkhiyarova Zhanna , Ning Lijiao , Boissel Mathilde , Chan Yee-Ming , Froguel Philippe , Bonnefond Amelie , Hakonarson Hakon , Alves Alessander Couto , Lawlor Deborah A , Kaakinen Marika , Järvelin Marjo-Riitta , Grant Struan F.A. , Tilling Kate , Prokopenko Inga , Sebert Sylvain , Canouil Mickaël , Warrington Nicole M ,   Early Growth Genetics (EGG) Consortium
Published: March 2024

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS on each of the estimated phenotypes identified 28 genome-wide significant variants at 13 loci across the 12 estimated phenotypes, one of which was novel (inDAOA)and had not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover novel biological mechanisms influencing quantitative traits.
Divergent effects of C4a, C4adesArg, and thrombin on platelet aggregation and phosphorylation of ERK and Akt in human endothelial cells
Authors: Liu Mengyao , Tran Luu Vy K. , Wang Hongbin
Published: March 2024

Prior studies have established C4a as an untethered ligand for protease-activated receptors (PAR)1 and PAR4, which can increase ERK phosphorylation and [Ca2+]iinflux in human endothelial cells (ECs). C4adesArgis a stable metabolite produced from C4a through cleavage of an arginine at the carboxyl terminus by plasma carboxypeptidases B/N. PAR1 and PAR4 are typical receptors for thrombin and transduce cellular responses to the serine protease generated by the activation of coagulation pathways. Here, we aim to address whether C4adesArgcan induce the same effects as C4a through PAR1 and PAR4, and whether C4a and C4adesArgcan activate the same downstream signaling effectors as thrombin through PAR1 and PAR4.

We demonstrated that C4adesArginduces ERK phosphorylation and [Ca2+]iinflux with the reduced efficacy as compared to C4a in human ECs. Distinct from C4a, C4adesArg-induced ERK phosphorylation was only inhibited by the PAR4 antagonist tcY-NH2, indicating that C4adesArg-mediated ERK phosphorylation is PAR4-dependent. Both C4a and C4adesArgat a concentration of 3 μM failed to induce platelet aggregation. Moreover, both C4a and C4adesArginduce significant Akt phosphorylation, whereas thrombin causes Akt dephosphorylation in human ECs.

Our study revealed that the absence of the C-terminal arginine in C4a decreases its efficacy and changes its preference for receptor of ERK and Akt activations in human ECs, suggesting that the C-terminal arginine of C4a might govern its binding specificity and/or affinity to PAR1 and/or PAR4. Unlike thrombin, both C4a and C4adesArgfail to induce platelet aggregation at supraphysiological concentrations. Contrary to thrombin, both C4a and C4adesArginduce significant Akt phosphorylation, indicating a unique role of C4a and C4adesArgin inflammation and coagulation through their association with PAR1 and/or PAR4.
A rapid and efficientin vivoinoculation method for introducing tree stem canker pathogens onto leaves: Suitable for large-scale assessment of resistance in poplar breeding progeny
Authors: Li Zheng , Zhang Bingyu , Fu Yuchen , Suo Yutian , Zhang Yinan , Feng Jinxia , Pan Long , Shen Wanna , Liu Huixiang , Su Xiaohua , Zhao Jiaping
Published: March 2024

Hybrid breeding, a direct and efficient strategy for disease control and management in tree species, is currently limited by the selection method of resist clones: the “in vitrostem segment inoculation method.” This method, constrained by the availability of inoculating materials, cannot rapidly, efficiently, and cost-effectively screen the resistance of all hybrid clones. To overcome these limitations, we introduce a novel pathogen inoculation method for the resistance assessment of hybrid clones in the poplar-Valsa sordidapathosystem. This method involves inoculating the stem canker pathogen on the host leaf, a unique and promising approach we have successfully validated.

Results showed that stem canker pathogenV. sordidainduced the extended necrotic lesion and even induced the formation of pycnidium structure and conidia on the leaf surface five days after mycelium inoculation; 1) the upper 5-7thleaves exhibited higher resistance than the middle 18-20thleaves; 2) the shading conditions induced more severe symptoms on the leaves than lighting conditions; 3) the juvenile mycelium inoculums (4-day-cultured) were more susceptible to poplar leaves than the old ones (7-day-cultured). Our results demonstrate the robustness of the “in vivoleaf inoculation method” in revealing the resistance differentiation in poplar hybrid clones. According to the leaf necrotic area disease index, we divided these poplar clones into seven different resistance groups. The resistance assessed by leaf assessment was validated in 15 selected poplar clones using the “in vitrostem segment inoculation method.” Results showed that the effectiveness of these two methods was consistent. Moreover, the leaf inoculation method can be used to detect the pathogenicity diversity of the pathogen population of tree species. Compared to the conventional “in vitrostem segment inoculation method,” the leaf method has the advantages of abundant inoculation materials, easy operation, rapid disease onset, and almost no adverse effect on the host. It is particularly suitable for the resistance screening of all progeny and the early (seedling) phenotypic selection of resistant poplar clones in poplar stem disease resistance breeding. The “in vivoleaf inoculation method” holds significant promise in poplar breeding, tree pathology, and molecular biology research on tree stem diseases.
Role of the complement system in Long COVID
Authors: Farztdinov Vadim , Zühlke Boris , Sotzny Franziska , Steinbeis Fridolin , Seifert Martina , Kedor Claudia , Wittke Kirsten , Tober-Lau Pinkus , Zoller Thomas , Textoris-Taube Kathrin , Ludwig Daniela , Dierks Clemens , Bierbaum Dominik , Sander Leif Erik , Hanitsch Leif G , Witzenrath Martin , Kurth Florian , Mülleder Michael , Scheibenbogen Carmen , Ralser Markus
Published: March 2024

Long COVID, or Post-Acute COVID Syndrome (PACS), may develop following SARS-CoV-2 infection, posing a substantial burden to society. Recently, PACS has been linked to a persistent activation of the complement system (CS), offering hope for both a diagnostic tool and targeted therapy. However, our findings indicate that, after adjusting proteomics data for age, body mass index and sex imbalances, the evidence of complement system activation disappears. Furthermore, proteomic analysis of two orthogonal cohorts—one addressing PACS following severe acute phase and another after a mild acute phase—fails to support the notion of persistent CS activation. Instead, we identify a proteomic signature indicative of either ongoing infections or sustained immune activation similar to that observed in acute COVID-19, particularly within the mild-PACS cohort.
(Re-)modelling of the disease and mortality burden of the 1918-1920 influenza pandemic in Zurich, Switzerland
Authors: Ziegler Ella , Matthes Katarina L. , Middelkamp Peter W. , Schünemann Verena , Althaus Christian L. , Rühli Frank , Staub Kaspar
Published: March 2024

Background

Our study aims to enhance future pandemic preparedness by integrating lessons from historical pandemics, focusing on the multidimensional analysis of past outbreaks. It addresses the gap in existing modelling studies by combining various pandemic parameters in a comprehensive setting. Using Zurich as a case study, we seek a deeper understanding of pandemic dynamics to inform future scenarios.

Data and methods

We use newly digitized weekly aggregated epidemic/pandemic time series (incidence, hospitalisations, mortality and sickness absences from work) to re-model the 1918-1920 pandemic in Zurich and investigate how different parameters correspond, how transmissibility changed during the different waves, and how public health interventions were associated with changes in these pandemic parameters.

Results

In general, the various time series show a good temporal correspondence, but differences in their expression can also be observed. The first wave in the summer of 1918 did lead to illness, absence from work and hospitalisations, but to a lesser extent to increased mortality. In contrast, the second, longest and strongest wave in the autumn/winter of 1918 also led to greatly increased (excess) mortality in addition to the burden of illness. The later wave in the first months of 1920 was again associated with an increase in all pandemic parameters. Furthermore, we can see that public health measures such as bans on gatherings and school closures were associated with a decrease in the course of the pandemic, while the lifting or non-compliance with these measures was associated with an increase of reported cases.

Discussion

Our study emphasizes the need to analyse a pandemic’s disease burden comprehensively, beyond mortality. It highlights the importance of considering incidence, hospitalizations, and work absences as distinct but related aspects of disease impact. This approach reveals the nuanced dynamics of a pandemic, especially crucial during multi-wave outbreaks.
Reconciling founder variant multiplicity of HIV-1 infection with the rate of CD4+decline
Authors: Baxter James , Arenas Ch. Julián Villabona , Thompson Robin N. , Hué Stéphane , Regoes Roland R. , Kouyos Roger D. , Günthard Huldrych F. , Albert Jan , Brown Andrew Leigh , Atkins Katherine E.
Published: March 2024

Three quarters of new HIV-1 infections are reported to be initiated by a single genetic variant. Infections initiated by multiple variants have been linked with higher recipient set point viral loads (SpVL) and a faster rate of CD4+T cell decline, indicative of a worse clinical prognosis if left untreated. These findings have not been universally replicated, however, and a mechanism through which multiple variants might lead to a worse prognosis is yet to be elucidated. In this study, we first summarised the existing evidence for this ‘dose response’ phenomenon for HIV-1, and quantified how likely we are to observe a true difference in set point viral load between multiple and single variant infections. Next, we considered whether the association between higher SpVL and multiple variant infection could exist in the absence of a causal mechanism. For a fixed diversity, high transmitter SpVL could simultaneously lead to high recipient SpVL through the inheritance of a ‘high virulence’ genotype and a greater probability that recipient infection is initiated by multiple genetic variants. Nonetheless, a high transmitter SpVL also shortens the duration of infection, consequently reducing the likelihood of the higher SpVL individual transmitting and restricting the overall accumulation of viral diversity. We combined data-driven models of transmission, heritability and HIV-1 disease progression to test whether an association between multiple variant infection and clinical progression is expected. First, we found that we are unlikely to record a significant difference in SpVL between multiple and single variant infections, at frequencies of multiple variant infections consistent with empirical observations. Second, we found that we would not expect multiple variant infections to lead to higher SpVL or faster CD4+T cell decline without a causal mechanism. Specifically, the probability that infection is initiated by multiple variants is greatest at the highest transmitter SpVLs, yet the relationship between transmitter and recipient SpVL is relatively weak. This finding supports the hypothesis that a within-patient causal mechanism is required to explain the association of multiple variant infection with higher viral loads and faster CD4+T cell decline. Further investigation into events happening during and just after transmission are required to enhance our understanding of this association.
Common variants at 22q12.2 are associated with susceptibility to Tuberculosis
Authors: Chang Xuling , Li Zheng , Thai Phan Vuong Khac , Ha Dang Thi Minh , Thuong Nguyen Thuy Thuong , Silcocks Matthew , Chee Cynthia Bin Eng , Nhu Nguyen Thi Quynh , Heng Chew-Kiat , Teo Yik Ying , Yuan Jian-Min , Koh Woon-Puay , Caws Maxine , Khor Chiea Chuen , Dorajoo Rajkumar , Dunstan Sarah J
Published: March 2024

Tuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Past genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, yet a significant portion of TB heritability remains unexplained. In this study, we conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating independent East Asian data, and identified a novel pulmonary TB (PTB) susceptibility locus at 22q12.2 [rs6006426, OR(95%Cl)=1.097(1.066, 1.130),Pmeta=3.31×10-10]. Our lead SNP was found to affect the expression ofSF3A1in various immune-related cells (Pranging from 1.48×10-9to 6.17×10-18). Furthermore, a significant association was observed between rs6006426 and cigarette smoking (P<0.044). When exploring the interplay between genetic marker, smoking and TB, our findings indicated that smoking status significantly mediated the effect of rs6006426 on PTB (βindirect-effect=-0.004,Pindirect-effect=0.020). Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.