bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of virulence-related determinants between the ST59-t437 and ST239-t030 genotypes of methicillin-resistant Staphylococcus aureus
Authors: Liao Feng , Gu Wenpeng , Fu Xiaoqing , Yuan Bin , Zhang Yunhui
Published: October 2021

Background

Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen for human infection. Hospital-acquired (HA) and community-acquired (CA) MRSA infections are serious clinical problems worldwide. In this study, we selected typical HA-MRSA strain and CA-MRSA isolates from our previous research and compared their phenotypic and pathogenic abilities both in vitro and in vivo.

Results

ST59-t437-SCCmecIVa (YNSA7) and ST59-t437-SCCmecVb (YNSA53) belonged to two prevalent subclones of CA-MRSA, while ST239-t030-SCCmecIII (YNSA163) was an HA-MRSA epidemic clone in Southwest China. ST59-t437 strains demonstrated faster growth ability, higher survival rate resistance to human blood, and more toxin secretion levels and cytotoxicity than ST239-t030. The virulence and regulatory genes of hld, psm-α, RNAIII, agrA, and crtN were highly expressed on CA-MRSA isolates, especially the ST59-t437-SCCmecIVa subclone. However, the ST239-t030 strain had the strongest adhesion and biofilm ability among these MRSA bacteria. Animal experiments revealed the most serious lethal effect on BALB/c mice caused by the YNSA7 strain infection. The survival rates of BALB/c mice infected with the three MRSA strains were 16.7, 50.0 and 100.0% for YNSA7, YNSA53 and YNSA163, respectively. Histopathological analyses of infected animals indicated that the lungs were the most seriously damaged organs, especially for ST59-t437 MRSA. Severe inflammatory reactions, tissue destruction, and massive exudation of inflammatory mediators and cells could be identified in ST59-t437 strain-infected animals.

Conclusions

In general, ST59-t437 strains showed higher pathogenic ability than the ST239-t030 isolate, while ST239-t030 MRSA revealed the features prevalent in hospital settings, specifically for adhesion and biofilm ability.
Prognostic value of CAD-RADS classification by coronary CTA in patients with suspected CAD
Authors: Huang Zengfa , Zhang Shutong , Jin Nan , Hu Yun , Xiao Jianwei , Li Zuoqin , Yang Yang , Sun Ruihong , Wang Zheng , Li Xiang , Xie Yuanliang , Wang Xiang
Published: October 2021

Background

The study sought to compare Coronary Artery Disease Reporting and Data System (CAD-RADS) classification with traditional coronary artery disease (CAD) classifications and Duke Prognostic CAD Index for predicting the risk of all-cause mortality in patients with suspected CAD.

Methods

9625 consecutive suspected CAD patients were assessed by coronary CTA for CAD-RADS classification, traditional CAD classifications and Duke Prognostic CAD Index. Kaplan–Meier and multivariable Cox models were used to estimate all-cause mortality. Discriminatory ability of classifications was assessed using time dependent receiver-operating characteristic (ROC) curves and The Hosmer–Lemeshow goodness-of-fit test was employed to evaluate calibration.

Results

A total of 540 patients died from all causes with a median follow-up of 4.3 ± 2.1 years. Kaplan–Meier survival curves showed the cumulative events increased significantly associated with CAD-RADS, three traditional CAD classifications and Duke Prognostic CAD Index. In multivariate Cox regressions, the risk for the all-cause death increased from HR 0.861 (95% CI 0.420–1.764) for CAD-RADS 1 to HR 2.761 (95% CI 1.961–3.887) for CAD-RADS 4B&5, using CAD-RADS 0 as the reference group. The relative HRs for all-cause death increased proportionally with the grades of the three traditional CAD classifications and Duke Prognostic CAD Index. The area under the time dependent ROC curve for prediction of all-cause death was 0.7917, 0.7805, 0.7991for CAD-RADS in 1 year, 3 year, 5 year, respectively, which was non-inferior to the traditional CAD classifications and Duke Prognostic CAD Index.

Conclusions

The CAD-RADS classification provided important prognostic information for patients with suspected CAD with noninvasive evaluation, which was non-inferior than Duke Prognostic CAD Index and traditional stenosis-based grading schemes in prognostic value of all-cause mortality. Traditional and simplest CAD classification should be preferable, given the more number of groups and complexity of CAD-RADS and Duke prognostic index, without using more time consuming classification.
Hierarchical structure in the activities of daily living and trajectories of disability prior to death in elderly Chinese individuals
Authors: Han Yaofeng , Xue Jihui , Pei Wei , Fang Ya
Published: October 2021

Background

The global burden of disability continues to increase. Understanding the hierarchical structure of activities of daily living (ADL) and the trajectories of disability of elderly individuals is pivotal to developing early interventions.

Purpose

To determine the hierarchical structure of the ability of Chinese elderly individuals to perform ADL and further describe the trajectories of disability prior to death.

Methods

Longitudinal item response theory model (LIRT) was constructed for 28,345 elderly participants in the Chinese Longitudinal Healthy Longevity Survey, in which ADL were measured using the Katz scale from 1998 to 2018, until the participants’ death. Two difficulty parameters (κ−partial and κ−total) were used in the LIRT defining the thresholds for hierarchical structure in ADL (κ−partial: no limitation to partial limitation, κ−total: partial limitation to totally limited). Disability values estimated from the LIRT were fitted to a mixed-effects model to examine the manner in which the trajectories of disability varied with different subject characteristics.

Results

The findings confirmed the earliest loss in the capability to perform ADL (bathing(κ-partial = − 1.396), toileting(κ-partial = − 0.904)) at the level of partial limitation, with an overlap of partial and totally limited (total bathing, partial dressing, partial transferring, total dressing, partial feeding, partial continence), and finally a total loss of capability for toileting, feeding, transferring, and continence (κ-total = 3.647). Disability trajectories varied with sex (β = 0.041, SE = 0.001), place of residence (β = 0.010, SE = 0.001), and marital status (β = 0.144, SE = 0.001). Females, individuals living in urban areas, and those who lived without a spouse had a poorer disability status.

Conclusion

The loss in the ability to perform ADL has a hierarchical structure. Subject characteristics affect trajectories of disability in the elderly Chinese population.
Conversion from mycophenolate mofetil to mizoribine in the early stages of BK polyomavirus infection could improve kidney allograft prognosis: a single-center study from China
Authors: Li Ping , Cheng Dongrui , Wen Jiqiu , Ni Xuefeng , Xie Kenan , Li Xue , Chen Jinsong
Published: October 2021

Background

Some studies have suggested mizoribine (MZR) could inhibit the replication of BK polyomavirus (BKPyV). The purpose of this study was to explore whether conversion from mycophenolate mofetil (MMF) to MZR in the early stages of BKPyV infection can improve kidney allograft prognosis.

Methods

Twenty-one kidney transplant recipients with BKPyV viruria/viremia and ten with BK polyomavirus-associated allograft nephropathy (BKPyVAN) received MZR conversion therapy were retrospectively identified. The clearance rate of urine and blood BKPyV DNA, change of serum creatinine (SCr), uric acid (UA), hemoglobin (HB), white blood cell (WBC), lymphocyte ratio, platelet (PLT), routine urinalysis, panel reactive antibody (PRA), and gastrointestinal disorders during follow-up of the 2 groups were evaluated and compared.

Results

After MZR conversion therapy, the clearance rate of urine and blood viral load in BKPyV viruria/viremia group were 85.7 and 100 %, while that in BKPyVAN were 40 and 87.5 %, respectively. Stable SCr were observed in all cases of BKPyV viruria/viremia group, while that of BKPyVAN was only 40 % (P < 0.001) and one even progressed to end-stage renal disease. The results of routine urinalysis in the two groups showed no significant changes before and after MZR conversion therapy. However, in BKPyV viruria/viremia group, four cases developed acute rejection and one had positive PRA-II but no donor specific antibody, requiring conversion back to MMF. Hyperuricemia was the common adverse effect of MZR.

Conclusions

Conversion from MMF to MZR could help clear BKPyV infection. As compared to BKPyVAN, patients who underwent initiation of MZR conversion therapy in the early stages of BKPyV infection maintained stable allograft function. Prospective studies with larger sample size are needed to ascertain this preliminary finding.
Perceptions and knowledge of telemedicine in Ecuadorian practicing physicians: an instrument adaptation, validation and translation from English to Spanish
Authors: Alvarado-Villa Geovanny , KuonYeng-Escalante Christian , Sagñay-Pinilla Nicolás , Vera Paz Carlos , Cherrez-Ojeda Ivan
Published: October 2021

Background

During the COVID-19 pandemic, multiple countries have taken measures, such as isolation and quarantine, to prevent person-to-person spread of disease. These actions forced many physicians to adopt new techniques, such as telemedicine, to continue patient care, which has proven to be useful in continued care for those with non-COVID-19 pathologies. Various factors, such as security, confidentiality, cost-effectiveness, comfort, and the risk of malpractice, influence the perception of telemedicine among medical practitioners. The aim of this study was to adapt an existing instrument and validate it into a new Spanish version. The instrument is about the perceptions and knowledge of telemedicine in healthcare professionals.

Methods

The original questionnaire surveyed 6 domains with 40 questions, and each question was measured with a five-point Likert scale ranging from very high [5] to very low [1]. The survey was translated to Spanish using machine translation. The translation was reviewed independently, and then, a consensus was achieved regarding minor changes in the syntax of the survey to facilitate understanding. After expert feedback and questionnaire review, the research team members proposed reducing the instrument to 13 items in 4 domains due to the similarity of some questions. The sample was divided into 2randomly selected groups. Eligibility criteria included physicians providing private or public services with active medical/clinical practice.

Results

In total, 382 surveys were collected and separated into two random samples, S1 and S2 (198 and 184, respectively). In exploratory factor analysis (EFA), the 13 items were grouped into four theoretical domains, and item 7 presented cross loading between factors and was removed. Confirmatory factor analysis was performed to assess the scale reliability and interscale associations; three models were tested. Global Cronbach’s alpha for internal consistency was 0.76 for the EFA. The goodness of fit measures root mean square error of approximation and comparative fit index were 0.009 and 0.999, respectively, for the best model.

Conclusions

The translated instrument was clear, with adequate internal consistency, readability, and appropriate for application in the physician setting. This validated questionnaire made it possible to evaluate physicians’ knowledge of telemedicine to increase its use, especially during the COVID-19 pandemic.
Comparison of machine learning algorithms applied to symptoms to determine infectious causes of death in children: national survey of 18,000 verbal autopsies in the Million Death Study in India
Authors: Idicula-Thomas Susan , Gawde Ulka , Jha Prabhat
Published: October 2021

Background

Machine learning (ML) algorithms have been successfully employed for prediction of outcomes in clinical research. In this study, we have explored the application of ML-based algorithms to predict cause of death (CoD) from verbal autopsy records available through the Million Death Study (MDS).

Methods

From MDS, 18826 unique childhood deaths at ages 1–59 months during the time period 2004–13 were selected for generating the prediction models of which over 70% of deaths were caused by six infectious diseases (pneumonia, diarrhoeal diseases, malaria, fever of unknown origin, meningitis/encephalitis, and measles). Six popular ML-based algorithms such as support vector machine, gradient boosting modeling, C5.0, artificial neural network, k-nearest neighbor, classification and regression tree were used for building the CoD prediction models.

Results

SVM algorithm was the best performer with a prediction accuracy of over 0.8. The highest accuracy was found for diarrhoeal diseases (accuracy = 0.97) and the lowest was for meningitis/encephalitis (accuracy = 0.80). The top signs/symptoms for classification of these CoDs were also extracted for each of the diseases. A combination of signs/symptoms presented by the deceased individual can effectively lead to the CoD diagnosis.

Conclusions

Overall, this study affirms that verbal autopsy tools are efficient in CoD diagnosis and that automated classification parameters captured through ML could be added to verbal autopsies to improve classification of causes of death.
The role of Sociodemographic factors on goal achievement in a community-based diabetes prevention program behavioral lifestyle intervention
Authors: Devaraj Susan M. , Napoleone Jenna M. , Miller Rachel G. , Rockette-Wagner Bonny , Arena Vincent C. , Mitchell-Miland Chantele , Saad Mohammed Bu , Kriska Andrea M.
Published: October 2021

Background

The Diabetes Prevention Program (DPP) behavioral lifestyle intervention was effective among a diverse sample of adults with prediabetes. Demonstrated effectiveness in translated versions of the DPP lifestyle intervention (such as Group Lifestyle Balance, DPP-GLB) led to widescale usage with national program oversight and reimbursement. However, little is known about the success of these DPP-translation programs across subgroups of sociodemographic factors. This current effort investigated potential disparities in DPP-translation program primary goal achievement (physical activity and weight) by key sociodemographic factors.

Methods

Data were combined from two 12-month community-based DPP-GLB trials among overweight/obese individuals with prediabetes and/or metabolic syndrome. We evaluated change in weight (kilograms and percent) and activity (MET-hrs/week) and goal achievement (yes/no; ≥5% weight loss and 150 min per week activity) after 6 and 12 months of intervention within and across subgroups of race/ethnicity (non-Hispanic white, non-Hispanic black), employment status, education, income, and gender.

Results

Among 240 participants (85%) with complete data, most sociodemographic subgroups demonstrated significant weight loss. However, non-Hispanic white lost more weight at both 6 and 12 months compared to non-Hispanic black participants [median weight loss (IQR), 6 months: 5.7% (2.7–9.0) vs. 1.5% (1.2–7.5) p = .01 and 12 months: 4.8% (1.1–9.6) vs. 1.1% (− 2.0–3.7) p = .01, respectively]. In addition, a larger percentage of non-Hispanic white demonstrated a 5% weight loss at 6 and 12 months. Employment was significantly related to 12-month weight loss, with retired participants being the most successful. Men, participants with graduate degrees, and those with higher income were most likely to meet the activity goal at baseline and 12 months. Differences in physical activity goal achievement across gender, education, and income groups were significant at baseline, attenuated after 6 months, then re-emerged at 12 months.

Conclusions

The DPP-GLB was effective in promoting weight loss and helped to alleviate disparities in physical activity levels after 6 months. Despite overall program success, differences in weight loss achievement by race/ethnicity were found and disparities in activity re-emerged after 12 months of intervention. These results support the need for intervention modification providing more tailored approaches to marginalized groups to maximize the achievement and maintenance of DPP-GLB behavioral goals.

Trial registration

NCT01050205, NCT02467881.
Weekly team-based learning scores and participation are better predictors of successful course performance than case-based learning performance: role of assessment incentive structure
Authors: Carrasco Gonzalo A. , Behling Kathryn C. , Lopez Osvaldo
Published: October 2021

Background

Incentives for preparation and participation in case-based (CBL) and team-based learning (TBL) differ by virtue of differences in assessment, allowing us to evaluate the role these incentives play in preparation and participation in these activities as well as overall course performance.

Methods

Weekly TBL and CBL participation and performance as well as performance on the course final examination were recorded. Student participation was quantified and correlated with: (1) CBL preparation, participation, teamwork and completion of learning objectives scores, and (2) TBL individual readiness assurance test (iRAT) scores.

Results

Student final examination scores (n = 95) were more strongly correlated with TBL than CBL performance. No significant correlation was found between iRAT and CBL scores. Student participation was measured in 3 CBL groups (8 students/group) and 4 TBL teams (6 students/team). TBL participation was more strongly correlated with final examination scores than CBL participation. TBL participation was also correlated with iRAT scores. CBL scores for preparation, participation, teamwork and completion of learning objectives did not significantly correlate with iRAT scores or TBL participation.

Conclusion

These results suggest that the assessment incentives and methods used in TBL result in student performance that better predicts performance on summative examinations.
Faculty perceptions of factors that indicate successful educational outcomes of medical students’ research projects: a focus group study
Authors: Möller Riitta , Wallberg Annika , Shoshan Maria
Published: October 2021

Background

A growing number of medical schools have individual scholarly projects as a component of their curricula. The fact that all students, and not only those with research interests, have to carry out a project puts high demands on the projects and their supervision. Evidence is lacking for how to produce scholarly projects with satisfactory outcomes. This study aimed to explore the observations of faculty teachers regarding factors that predict the educational outcomes of medical students’ scholarly projects.

Methods

Two focus group interviews were held with seven of the 16 faculty coordinators who were external reviewers of students’ research projects. The audio-recorded interview transcripts were analyzed using qualitative content analysis. We employed a constant comparative approach to create categories firmly grounded in the participants’ experiences. A successful project was defined as coordinators’ perception that the stated learning outcomes were achieved, in terms of students’ ability to demonstrate a scientific attitude.

Results

Five categories emerged from the data: Supervision, Project setup, Student characteristics, Curriculum structure, and Institutional guidance. The supervisors’ experience and availability to students were mentioned as key factors for successful outcomes. Further, a clear aim and adaptation to the time frame were stated to be project-related factors that were also supervisors’ responsibilities. Important student-related factors were skills related to scientific writing, taking ownership of and managing the projects, and making use of feedback. Finally, the course requirements, support, and control accomplished by faculty coordinators played important roles.

Conclusions

Contributing factors to achievement of the learning outcomes were supervisors’ commitment and experience, and the projects being suitable for the time frame and having a clearly stated research question. Furthermore, the students’ prowess at scientific writing, adequate handling of feedback, and ability to assume ownership of the project contributed to the final outcome, as did adherence to curricular instructions.
Process evaluation for the Care Homes Independent Pharmacist Prescriber Study (CHIPPS)
Authors: Birt Linda , Dalgarno Lindsay , Wright David J , Alharthi Mohammed , Inch Jackie , Spargo Maureen , Blacklock Jeanette , Poland Fiona , Holland Richard C , Alldred David P. , Hughes Carmel M. , Bond Christine M. ,   on behalf of the CHIPPS study team, Blyth Annie , Watts Laura , Daffu-O’Reilly Amrit
Published: October 2021

Background

Medicines management in care homes requires significant improvement. CHIPPS was a cluster randomised controlled trial to determine the effectiveness of integrating pharmacist independent prescribers into care homes to assume central responsibility for medicines management. This paper reports the parallel mixed-methods process evaluation.

Method

Intervention arm consisted of 25 triads: Care homes (staff and up to 24 residents), General Practitioner (GP) and Pharmacist Independent Prescriber (PIP). Data sources were pharmaceutical care plans (PCPs), pharmacist activity logs, online questionnaires and semi-structured interviews. Quantitative data were analysed descriptively. Qualitative data were analysed thematically. Results were mapped to the process evaluation objectives following the Medical Research Council framework.

Results

PCPs and activity logs were available from 22 PIPs. Questionnaires were returned by 16 PIPs, eight GPs, and two care home managers. Interviews were completed with 14 PIPs, eight GPs, nine care home managers, six care home staff, and one resident. All stakeholders reported some benefits from PIPs having responsibility for medicine management and identified no safety concerns. PIPs reported an increase in their knowledge and identified the value of having time to engage with care home staff and residents during reviews. The research paperwork was identified as least useful by many PIPs. PIPs conducted medication reviews on residents, recording 566 clinical interventions, many involving deprescribing; 93.8% of changes were sustained at 6 months. For 284 (50.2%) residents a medicine was stopped, and for a quarter of residents, changes involved a medicine linked to increased falls risk. Qualitative data indicated participants noted increased medication safety and improved resident quality of life. Contextual barriers to implementation were apparent in the few triads where PIP was not known previously to the GP and care home before the trial. In three triads, PIPs did not deliver the intervention.

Conclusions

The intervention was generally implemented as intended, and well-received by most stakeholders. Whilst there was widespread deprescribing, contextual factors effected opportunity for PIP engagement in care homes. Implementation was most effective when communication pathways between PIP and GP had been previously well-established.

Trial registration

The definitive RCT was registered with the ISRCTN registry (registration number ISRCTN 17847169).
Characterization of receptor tyrosine kinase activation and biological activity of toceranib phosphate in canine urothelial carcinoma cell lines
Authors: Korec Daniela I. , Louke Darian S. , Breitbach Justin T. , Geisler Jennifer A. , Husbands Brian D. , Fenger Joelle M.
Published: October 2021

Background

Urothelial carcinoma (UC) accounts for > 90% of canine tumors occurring in the urinary bladder. Toceranib phosphate (TOC) is a multi-target receptor tyrosine kinase (RTK) inhibitor that exhibits activity against members of the split kinase family of RTKs. The purpose of this study was to evaluate primary UC tumors and UC cell lines for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, and KIT to assess whether dysregulation of these RTKs may contribute to the observed biological activity of TOC.

Results

Transcript for VEGFR2, PDGFRα, PDGFRβ, and KIT was detected in all UC tissue samples and UC cell lines. The Proteome Profiler™ Human Phospho-RTK Array Kit (R & D Systems) provided a platform to assess phosphorylation of 42 different RTKs in primary UC tumors and UC cell lines. Evidence of PDGFRα and PDGFRβ phosphorylation was present in only 11% or 33% of UC tumors, respectively, and 25% of UC cell lines. Treatment of UC cell lines with TOC had no significant impact on cell proliferation, including UC cell lines with evidence of PDGFRβ phosphorylation.

Conclusions

Phosphorylation of several key RTKs targeted by TOC is present in a small subset of primary UC tumors and UC cell lines, suggesting that these RTKs do not exist in a state of continuous activation. These data suggest that activation of RTKs targeted by TOC is present in a small subset of UC tumors and UC cell lines and that treatment with TOC at physiologically relevant concentrations has no direct anti-proliferative effect on UC cells.
Correction to: Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers
Authors: Draganov Dobrin D. , Santidrian Antonio F. , Minev Ivelina , Nguyen Duong , Kilinc Mehmet Okyay , Petrov Ivan , Vyalkova Anna , Lander Elliot , Berman Mark , Minev Boris , Szalay Aladar A.
Published: October 2021

An amendment to this paper has been published and can be accessed via the original article.
Factors affecting improvement of neurologic status evaluated by Quantitative Myasthenia Gravis Score for patients with thymomatous myasthenia gravis after extended thymectomy
Authors: Haoshuai Zhu , Jianyong Zou , Lei Yang , Bo Zeng , Xiao Jiefei , Zhang Xin , Chen Zhenguang , Chunhua Su
Published: October 2021

Background

The length of time for clinical improvement of patients with thymomatous myasthenia gravis (MG) after extended thymectomy is not clear. The purpose of this study was to determine the length of time after thymectomy in patients with thymomatous MG to achieve a 3-point reduction of Quantitative Myasthenia Gravis Score (QMGS), and identify variables associated with a failure to achieve the reduction.

Methods

The records of patients with thymomatous MG who underwent extended thymectomy from January 2005 to December 2018 were retrospectively reviewed. The primary end point was a reduction of 3 points of QMGs and the secondary end point was another reduction of 3 points of QMGs.

Results

A total of 481 patients were included in the analysis, the mean age of the patients was 41.63 ± 8.55 years, and approximately 60% were male. The median time to achieve a 3 point decrease in QMGS was 6 months, and the median time to achieve another 3 point decrease was 30 months. Multivariable analysis indicated that age ≥ 42 years and Masaoka-Koga stage > I were associated with a lower probability of achieving a 3 point decrease in QMGS (HR = 0.55 and 0.65, respectively). Likewise, multivariable analysis indicated that age ≥ 42 years and Masaoka-Koga stage > I were associated with a lower probability of achieving a second 3 point decrease in QMGS (HR = 0.53 and 0.53, respectively).

Conclusions

In patients with thymomatous MG who receive thymectomy, age ≥ 42 years and Masaoka-Koga stage > I are associated with a worse prognosis and failure to achieve a 3 point decrease in QMGS.
Corneal in vivo confocal microscopy to detect belantamab mafodotin-induced ocular toxicity early and adjust the dose accordingly: a case report
Authors: Marquant Kevin , Quinquenel Anne , Arndt Carl , Denoyer Alexandre
Published: October 2021

Background

New targeted antibody–drug conjugates (ADCs) against multiple myeloma are known to induce adverse effects that may lead to treatment discontinuation. Preclinical studies reported early severe ocular damage related to the use of belantamab mafodotin (belamaf), including ocular surface inflammation, severe dry eye, and a specific toxicity to the cornea, namely microcystic keratopathy. While belamaf-induced ocular changes have not been prospectively studied, a better understanding of mechanisms involved as well as kinetics may aid in anticipating dose adjustment rather than stopping the treatment once clinical ocular damage is too severe.

Case presentation

A 61-year-old woman scheduled for belamaf as a fifth-line treatment against multiple myeloma was prospectively included. Clinical examinations were performed before and every 3 weeks afterward, together with in vivo confocal microscopy (IVCM) of the cornea. Visual acuity, symptoms, slit-lamp examination, and ultrastructural changes of the cornea were recorded according to the received dose of belamaf. More precisely, kinetics, shape, density, and location of the toxic corneal lesions have been followed and analyzed using IVCM. Also, specific lesions at the sub-basal nerve plexus layer were detected and characterized for the first time. This advanced approach allowed a better understanding of the belamaf-induced toxicity, further balancing the dose to maintain good vision and eye health while continuing the treatment.

Conclusions

Systematic ultrastructural analysis and follow-up of the corneal state during ADCs treatment for multiple myeloma may open new avenues in the therapeutic approach. Early preclinical detection of ocular damage may accurately contribute to finding the correct dose for each patient and not stopping the treatment due to severe ocular adverse effects.
Deep-learning model for screening sepsis using electrocardiography
Authors: Kwon Joon-myoung , Lee Ye Rang , Jung Min-Seung , Lee Yoon-Ji , Jo Yong-Yeon , Kang Da-Young , Lee Soo Youn , Cho Yong-Hyeon , Shin Jae-Hyun , Ban Jang-Hyeon , Kim Kyung-Hee
Published: October 2021

Background

Sepsis is a life-threatening organ dysfunction and a major healthcare burden worldwide. Although sepsis is a medical emergency that requires immediate management, screening for the occurrence of sepsis is difficult. Herein, we propose a deep learning-based model (DLM) for screening sepsis using electrocardiography (ECG).

Methods

This retrospective cohort study included 46,017 patients who were admitted to two hospitals. A total of 1,548 and 639 patients had sepsis and septic shock, respectively. The DLM was developed using 73,727 ECGs from 18,142 patients, and internal validation was conducted using 7774 ECGs from 7,774 patients. Furthermore, we conducted an external validation with 20,101 ECGs from 20,101 patients from another hospital to verify the applicability of the DLM across centers.

Results

During the internal and external validations, the area under the receiver operating characteristic curve (AUC) of the DLM using 12-lead ECG was 0.901 (95% confidence interval, 0.882–0.920) and 0.863 (0.846–0.879), respectively, for screening sepsis and 0.906 (95% confidence interval (CI), 0.877–0.936) and 0.899 (95% CI, 0.872–0.925), respectively, for detecting septic shock. The AUC of the DLM for detecting sepsis using 6-lead and single-lead ECGs was 0.845–0.882. A sensitivity map revealed that the QRS complex and T waves were associated with sepsis. Subgroup analysis was conducted using ECGs from 4,609 patients who were admitted with an infectious disease, and the AUC of the DLM for predicting in-hospital mortality was 0.817 (0.793–0.840). There was a significant difference in the prediction score of DLM using ECG according to the presence of infection in the validation dataset (0.277 vs. 0.574, p < 0.001), including severe acute respiratory syndrome coronavirus 2 (0.260 vs. 0.725, p = 0.018).

Conclusions

The DLM delivered reasonable performance for sepsis screening using 12-, 6-, and single-lead ECGs. The results suggest that sepsis can be screened using not only conventional ECG devices but also diverse life-type ECG machines employing the DLM, thereby preventing irreversible disease progression and mortality.
Application of ensemble clustering and survival tree analysis for identifying prognostic clinicogenomic features in patients with colorectal cancer from the 100,000 Genomes Project
Authors: Wei Yuguo , Papachristou Nikolaos , Mueller Stefanie ,   Genomics England Research Consortium, Ambrose J. C. , Arumugam P. , Bleda M. , Boardman-Pretty F. , Boustred C. R. , Brittain H. , Caulfield M. J. , Chan G. C. , Fowler T. , Giess A. , Hamblin A. , Henderson S. , Hubbard T. J. P. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Kousathanas A. , Lahnstein L. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , O’Donovan P. , Odhams C. A. , Patch C. , Perez-Gil D. , Pereira M. B. , Pullinger J. , Rahim T. , Rendon A. , Rogers T. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smith S. C. , Sosinsky A. , Stuckey A. , Tanguy M. , Thomas E. R. A. , Thompson S. R. , Tucci A. , Walsh E. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Chang Wai Hoong , Lai Alvina G.
Published: October 2021

Objective

The objective of this study was to employ ensemble clustering and tree-based risk model approaches to identify interactions between clinicogenomic features for colorectal cancer using the 100,000 Genomes Project.

Results

Among the 2211 patients with colorectal cancer (mean age of diagnosis: 67.7; 59.7% male), 16.3%, 36.3%, 39.0% and 8.4% had stage 1, 2, 3 and 4 cancers, respectively. Almost every patient had surgery (99.7%), 47.4% had chemotherapy, 7.6% had radiotherapy and 1.4% had immunotherapy. On average, tumour mutational burden (TMB) was 18 mutations/Mb and 34.4%, 31.3% and 25.7% of patients had structural or copy number mutations in KRAS, BRAF and NRAS, respectively. In the fully adjusted Cox model, patients with advanced cancer [stage 3 hazard ratio (HR)  =  3.2; p  <  0.001; stage 4 HR  =  10.2; p  <  0.001] and those who had immunotherapy (HR  =  1.8; p  <  0.04) or radiotherapy (HR  =  1.5; p  <  0.02) treatment had a higher risk of dying. The ensemble clustering approach generated four distinct clusters where patients in cluster 2 had the best survival outcomes (1-year: 98.7%; 2-year: 96.7%; 3-year: 93.0%) while patients in cluster 3 (1-year: 87.9; 2-year: 70.0%; 3-year: 53.1%) had the worst outcomes. Kaplan–Meier analysis and log rank test revealed that the clusters were separated into distinct prognostic groups (p  <  0.0001). Survival tree or recursive partitioning analyses were performed to further explore risk groups within each cluster. Among patients in cluster 2, for example, interactions between cancer stage, grade, radiotherapy, TMB, BRAF mutation status were identified. Patients with stage 4 cancer and TMB  ≥  1.6 mutations/Mb had 4 times higher risk of dying relative to the baseline hazard in that cluster.
An exploration of the sociodemographic and health conditions associated with self-rated wellbeing for Aboriginal and Torres Strait Islander adults
Authors: Gall A. , Diaz A. , Garvey G. , Anderson K. , Lindsay D. , Howard K.
Published: October 2021

Objective

To identify sociodemographic factors and health conditions associated with self-rated wellbeing for Aboriginal and Torres Strait Islander adults. Participants were recruited via investigator networks and an online panel provider with an established nationwide panel of Aboriginal and Torres Strait Islander adults. Those interested were invited to complete a survey that included an assessment of wellbeing using a visual analogue scale. Data was collected from October–November 2019 and August–September 2020. Exploratory analyses were conducted to ascertain factors associated with self-rated wellbeing for Aboriginal and Torres Strait Islander adults.

Results

Having more than enough money to last until next pay day, full-time employment, completion of grade 12, having a partner, and living with others were significantly associated with higher wellbeing among Aboriginal and Torres Strait Islander adults. A self-reported history of depression, anxiety, other mental health conditions, heart disease, or disability were associated with lower self-rated wellbeing scores. Our findings indicate a need for further investigation among these socioeconomic and patient groups to identify how to improve and support the wellbeing of Aboriginal and Torres Strait Islander adults.
DNA methylation profiling identifies two distinct subgroups in breast cancers with low hormone receptor expression, mainly associated with HER2 amplification status
Authors: Jurmeister Philipp , Weber Karsten , Villegas Sonia , Karn Thomas , Untch Michael , Thieme Anne , Müller Volkmar , Taube Eliane , Fasching Peter , Schmitt Wolfgang D. , Marmé Frederik , Stickeler Elmar , Sinn Bruno V. , Jank Paul , Schem Christian , Klauschen Frederick , van Mackelenbergh Marion , Denkert Carsten , Loibl Sibylle , Capper David
Published: October 2021

Background

Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1–10% of tumor cells should be regarded as hormone receptor positive. However, clinical data show that these patients have worse outcome compared to patients with hormone receptor expression above 10%. We performed DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas to clarify the status for this infrequent but important patient subgroup.

Results

In unsupervised clustering and dimensionality reduction, breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with triple negative breast cancer (TNBC) reference samples (8/10; “LowHR TNBC-like”). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; “LowHR HRpos-like”). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples and clinical outcome parameters were more similar to TNBCs and differed from LowHR HRpos-like cases.

Conclusions

We here demonstrate that LowHR breast cancer comprises two epigenetically distinct groups. Our data strongly suggest that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.
Automated fragment formula annotation for electron ionisation, high resolution mass spectrometry: application to atmospheric measurements of halocarbons
Authors: Guillevic Myriam , Guillevic Aurore , Vollmer Martin K. , Schlauri Paul , Hill Matthias , Emmenegger Lukas , Reimann Stefan
Published: October 2021

Background

Non-target screening consists in searching a sample for all present substances, suspected or unknown, with very little prior knowledge about the sample. This approach has been introduced more than a decade ago in the field of water analysis, together with dedicated compound identification tools, but is still very scarce for indoor and atmospheric trace gas measurements, despite the clear need for a better understanding of the atmospheric trace gas composition. For a systematic detection of emerging trace gases in the atmosphere, a new and powerful analytical method is gas chromatography (GC) of preconcentrated samples, followed by electron ionisation, high resolution mass spectrometry (EI-HRMS). In this work, we present data analysis tools to enable automated fragment formula annotation for unknown compounds measured by GC-EI-HRMS.

Results

Based on co-eluting mass/charge fragments, we developed an innovative data analysis method to reliably reconstruct the chemical formulae of the fragments, using efficient combinatorics and graph theory. The method does not require the presence of the molecular ion, which is absent in$$\sim$$∼40% of EI spectra. Our method has been trained and validated on >50 halocarbons and hydrocarbons, with 3–20 atoms and molar masses of 30–330 g mol$$^{-1}$$-1, measured with a mass resolution of approx. 3500. For >90% of the compounds, more than 90% of the annotated fragment formulae are correct. Cases of wrong identification can be attributed to the scarcity of detected fragments per compound or the lack of isotopic constraint (no minor isotopocule detected).

Conclusions

Our method enables to reconstruct most probable chemical formulae independently from spectral databases. Therefore, it demonstrates the suitability of EI-HRMS data for non-target analysis and paves the way for the identification of substances for which no EI mass spectrum is registered in databases. We illustrate the performances of our method for atmospheric trace gases and suggest that it may be well suited for many other types of samples. The L-GPL licenced Python code is released under the name ALPINAC for ALgorithmic Process for Identification of Non-targeted Atmospheric Compounds.
Automated liver lesion detection in 68Ga DOTATATE PET/CT using a deep fully convolutional neural network
Authors: Wehrend Jonathan , Silosky Michael , Xing Fuyong , Chin Bennett B.
Published: October 2021

Background

Gastroenteropancreatic neuroendocrine tumors most commonly metastasize to the liver; however, high normal background 68Ga-DOTATATE activity and high image noise make metastatic lesions difficult to detect. The purpose of this study is to develop a rapid, automated and highly specific method to identify 68Ga-DOTATATE PET/CT hepatic lesions using a 2D U-Net convolutional neural network.

Methods

A retrospective study of 68Ga-DOTATATE PET/CT patient studies (n = 125; 57 with 68Ga-DOTATATE hepatic lesions and 68 without) was evaluated. The dataset was randomly divided into 75 studies for the training set (36 abnormal, 39 normal), 25 for the validation set (11 abnormal, 14 normal) and 25 for the testing set (11 abnormal, 14 normal). Hepatic lesions were physician annotated using a modified PERCIST threshold, and boundary definition by gradient edge detection. The 2D U-Net was trained independently five times for 100,000 iterations using a linear combination of binary cross-entropy and dice losses with a stochastic gradient descent algorithm. Performance metrics included: positive predictive value (PPV), sensitivity, F1 score and area under the precision–recall curve (PR-AUC). Five different pixel area thresholds were used to filter noisy predictions.

Results

A total of 233 lesions were annotated with each abnormal study containing a mean of 4 ± 2.75 lesions. A pixel filter of 20 produced the highest mean PPV 0.94 ± 0.01. A pixel filter of 5 produced the highest mean sensitivity 0.74 ± 0.02. The highest mean F1 score 0.79 ± 0.01 was produced with a 20 pixel filter. The highest mean PR-AUC 0.73 ± 0.03 was produced with a 15 pixel filter.

Conclusion

Deep neural networks can automatically detect hepatic lesions in 68Ga-DOTATATE PET. Ongoing improvements in data annotation methods, increasing sample sizes and training methods are anticipated to further improve detection performance.
A blockchain index structure based on subchain query
Authors: Xing Xiaogang , Chen Yuling , Li Tao , Xin Yang , Sun Hongwei
Published: October 2021

Blockchain technology has the characteristics of decentralization and tamper resistance, which can store data safely and reduce the cost of trust effectively. However, the existing blockchain system has weak performance in data management, and only supports traversal queries with transaction hashes as keywords. The query method based on the account transaction trace chain (ATTC) improves the query efficiency of historical transactions of the account. However, the efficiency of querying accounts with longer transaction chains has not been effectively improved. Given the inefficiency and single method of the ATTC index in the query, we propose a subchain-based account transaction chain (SCATC) index structure. First, the account transaction chain is divided into subchains, and the last block of each subchain is connected by a hash pointer. The block-by-block query mode in ATTC is converted to the subchain-by-subchain query mode, which shortens the query path. Multiple transactions of the same account in the same block are merged and stored, which simplifies the construction cost of the index and saves storage resources. then, the construction algorithm and query algorithm is given for the SCATC index structure. Simulation analysis shows that the SCATC index structure significantly improves query efficiency.
Biosynthesis of ethyl caffeate via caffeoyl-CoA acyltransferase expression in Escherichia coli
Authors: Lee Shin-Won , Kim Han , Ahn Joong-Hoon
Published: October 2021

Hydroxycinnamic acids (HCs) are natural compounds that form conjugates with diverse compounds in nature. Ethyl caffeate (EC) is a conjugate of caffeic acid (an HC) and ethanol. It has been found in several plants, including Prunus yedoensis, Polygonum amplexicaule, and Ligularia fischeri. Although it exhibits anticancer, anti-inflammatory, and antifibrotic activities, its biosynthetic pathway in plants still remains unknown. This study aimed to design an EC synthesis pathway and clone genes relevant to the same. Genes involved in the caffeic acid synthesis pathway (tyrosine ammonia-lyase (TAL) and p-coumaric acid hydroxylase (HpaBC)) were introduced into Escherichia coli along with 4-coumaroyl CoA ligase (4CL) and acyltransferases (AtCAT) cloned from Arabidopsis thaliana. In presence of ethanol, E. coli harboring the above genes successfully synthesized EC. Providing more tyrosine through the overexpression of shikimate-pathway gene-module construct and using E. coli mutant enhanced EC yield; approximately 116.7 mg/L EC could be synthesized in the process. Synthesis of four more alkyl caffeates was confirmed in this study; these might potentially possess novel biological properties, which would require further investigation.
Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis
Authors: Vidic Clara , Zaniew Marcin , Jurga Szymon , Thiele Holger , Reutter Heiko , Hilger Alina C.
Published: October 2021

Introduction

DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures.

Materials and methods

Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome.

Results

Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family.

Conclusion

To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.