bluuebunny/crossref_metadata_2025 huggingface dataset:
Value assessment of artificial intelligence in medical imaging: a scoping review
Authors: Fasterholdt Iben , Naghavi-Behzad Mohammad , Rasmussen Benjamin S. B. , Kjølhede Tue , Skjøth Mette Maria , Hildebrandt Malene Grubbe , Kidholm Kristian
Published: October 2022

Background

Artificial intelligence (AI) is seen as one of the major disrupting forces in the future healthcare system. However, the assessment of the value of these new technologies is still unclear, and no agreed international health technology assessment-based guideline exists. This study provides an overview of the available literature in the value assessment of AI in the field of medical imaging.

Methods

We performed a systematic scoping review of published studies between January 2016 and September 2020 using 10 databases (Medline, Scopus, ProQuest, Google Scholar, and six related databases of grey literature). Information about the context (country, clinical area, and type of study) and mentioned domains with specific outcomes and items were extracted. An existing domain classification, from a European assessment framework, was used as a point of departure, and extracted data were grouped into domains and content analysis of data was performed covering predetermined themes.

Results

Seventy-nine studies were included out of 5890 identified articles. An additional seven studies were identified by searching reference lists, and the analysis was performed on 86 included studies. Eleven domains were identified: (1) health problem and current use of technology, (2) technology aspects, (3) safety assessment, (4) clinical effectiveness, (5) economics, (6) ethical analysis, (7) organisational aspects, (8) patients and social aspects, (9) legal aspects, (10) development of AI algorithm, performance metrics and validation, and (11) other aspects. The frequency of mentioning a domain varied from 20 to 78% within the included papers. Only 15/86 studies were actual assessments of AI technologies. The majority of data were statements from reviews or papers voicing future needs or challenges of AI research, i.e. not actual outcomes of evaluations.

Conclusions

This review regarding value assessment of AI in medical imaging yielded 86 studies including 11 identified domains. The domain classification based on European assessment framework proved useful and current analysis added one new domain. Included studies had a broad range of essential domains about addressing AI technologies highlighting the importance of domains related to legal and ethical aspects.
Effectiveness of a practical multi-setting lifestyle intervention on the main BMI trajectories from childhood to young adulthood: A community-based trial
Authors: Parvin Parnian , Masihay-Akbar Hasti , Cheraghi Leila , Razmjouei Soha , Shab-khaneh Amirali Zareie , Azizi Fereidoun , Amiri Parisa
Published: October 2022

Background

Preventing overweight in childhood and subsequent stages of life is still a global challenge. Despite numerous relevant lifestyle interventions, data on their impact on different BMI change pathways over time is rare. The present study aimed to investigate the effect of a multi-setting lifestyle intervention on BMI trajectories from childhood to young adulthood.

Methods

A multi-setting lifestyle intervention at the school, family, and community levels have been conducted in the Tehran Lipid and Glucose Study framework. A total of 2145 children (4–18 years, 49% boys, and 18% intervention) were recruited for the baseline assessment and were followed through five follow-up examinations during a median of 16.1 years. Using a group-based trajectory model, BMI trajectories from childhood to young adulthood were identified, and their association with the implemented intervention was assessed.

Results

Four trajectory groups of BMI from childhood to young adulthood were identified, including Normal weight (41%), Young adulthood overweight (36%), Early childhood increasing overweight and adulthood obesity (19%), and Early childhood increasing obesity (4%). Only Young adulthood overweight and Early childhood increasing obesity were affected by the intervention and were concomitant with lower BMI levels than the control group, with the highest estimated effect in the latter (β=-0.52 and p = 0.018; β=-1.48 and p < 0.001, respectively).

Conclusion

The current findings indicate the highest effectiveness of a practical, healthy lifestyle intervention on those whose obesity started in the early years of life or youth. Our results could help policymakers and planners design more targeted lifestyle modification and weight control interventions.

Trial registration

This study is registered at Iran Registry for Clinical Trials, a WHO primary registry (http://irct.ir). The Iran Registry for Clinical Trials ID and date are IRCTID:IRCT138705301058N1, 29/10/2008.
A mixed method investigation of teacher-identified barriers, facilitators and recommendations to implementing daily physical activity in Ontario elementary schools
Authors: Martyn Lauren , Bigelow Hannah , Graham Jeffrey D. , Ogrodnik Michelle , Chiodo Deborah , Fenesi Barbara
Published: October 2022

Background

Fewer than 17% of children worldwide are meeting the international recommendations for daily physical activity. Since most children are in school for the bulk of their day, the classroom has been identified as an ideal space to incorporate physical activity opportunities. In Ontario (Canada), the Daily Physical Activity (DPA) policy aims to ensure all elementary school children receive a minimum of 20 min of moderate to vigorous physical activity each school day during instructional time. However, a 2015 evaluation found that only half of Ontario teachers were meeting this expectation; this work advocated for additional research to monitor implementation and its predictors and to further identify fidelity recommendations. Thus, the current study investigated contemporary factors influencing DPA fidelity in Ontario elementary schools and provides teacher-identified recommendations to support DPA implementation.

Methods

The first part of the study was a quantitative approach surveying 186 elementary school teachers across Ontario. Descriptive statistics including frequencies and means were used to characterize barriers, facilitators, and recommendations to DPA implementation. Spearman’s correlations were used to assess the relation between the likelihood of DPA implementation and intrapersonal factors of gender, teaching experience, prior DPA training and personal physical activity participation. The second part of the study consisted of a qualitative approach using teacher interviews to explore in-depth teachers’ recommendations to support DPA implementation. A thematic analysis was used to analyze the transcripts and identify recommendations for DPA.

Results

Survey results showed that only 23% of teachers met the mandated 20 min of DPA per day. Barriers to implementation included space and time constraints, inadequate training, student behavioural issues and low self-efficacy. Gender, teaching experience and prior DPA training were not related to the likelihood of DPA implementation. Teachers who rated themselves as more physically fit were more likely to implement DPA. Teacher interviews elucidated key areas for improving DPA implementation including greater DPA training opportunities, resources, community partnerships, accountability and strategies that support school-wide implementation.

Conclusion

The current study demonstrated that fidelity to the DPA policy in Ontario elementary schools is on the decline. This work highlights unique factors implicated in DPA fidelity and brings to the forefront teacher recommendations to improve DPA implementation.
Desk based prompts to replace workplace sitting with stair climbing; a pilot study of acceptability, effects on behaviour and disease risk factors
Authors: Mat Azmi Intan Suhana Munira , Wallis Gareth A. , White Mike J. , Puig-Ribera Anna , Eves Frank F.
Published: October 2022

Background

Prolonged sitting is associated with increased risk of obesity, type 2 diabetes and cardiovascular disease. Occupational sitting accounts for up to 50 h/week for employees. This pilot study assessed the acceptability of stair climbing as an interruption to sitting throughout working hours, and provided preliminary data of the effects on glucose and lipid profiles.

Methods

A quasi-experimental design was conducted involving 16 sedentary office workers (five females and 11 males) for intervention (n = 8) and control groups (n = 8) with mean age of 36.38 (5.58). For the eight-week intervention, a continuous four-floor stair climb and descent was performed eight times/day spread evenly over the working day. A prompt to climb was presented on the participant’s computer eight times/day. Participants in the experimental group recorded daily floors climbed and steps (measured using pedometers) in a weekly log sheet. Blood samples were collected pre and post intervention to test effects on fasting glucose and 2 h plasma glucose, triglycerides, and total (TC), LDL and HDL cholesterol. Experimental participants were interviewed at the end of the study. The Wilcoxon signed rank test was used to compare the median changes (pre-post) of the dependent variables.

Results

On average, the experimental group climbed 121 floors/week when prompted. There were significant reductions in fasting blood glucose, TC and LDL, as well as the derived measures of ‘bad’ cholesterol and the TC/HDL ratio in the experimental group. Post-experimental interviews indicated that the interruption to sitting was well tolerated.

Conclusion

Prompted stair climbing activity had impacts on health outcomes and was found acceptable to employees at work.

Trial registration

Ethics for this study was approved by Science, Technology, Engineering and Mathematics Ethical Review Committee, University of Birmingham with ethics reference number ERN_15_0491.
Suggestive evidence of the genetic association of TMOD1 and PTCSC2 polymorphisms with thyroid carcinoma in the Chinese Han population
Authors: Tong Kaijun , Zhang Chang , Yang Tingting , Guo Rongbiao , Wang Xinyuan , Guan Renyang , Jin Tianbo
Published: October 2022

Background

The purpose of this study was to survey the associations of six single nucleotide polymorphisms (SNPs) in the TMOD1 and PTCSC2 genes with thyroid carcinoma (TC).

Method

Peripheral blood samples were obtained from 510 patients with TC and 509 normal controls. Six SNPs were genotyped by the Agena MassARRAY platform. Logistic regression was used to evaluate the association between SNPs and TC susceptibility by calculating odds ratios (ORs) and 95% confidence intervals (CIs). SNP-SNP interactions were analyzed by multifactor dimensionality reduction (MDR).

Results

Our study showed that rs925489 (OR = 1.45, p = 0.011) and rs965513 (OR = 1.40, p = 0.021) were significantly associated with an increased risk of TC. Rs10982622 decreased TC risk (OR = 0.74, p = 0.025). Further stratification analysis showed that rs10982622 reduced the susceptibility to TC in patients aged ≤ 45 years (OR = 0.69, p = 0.019) and in females (OR = 0.61, p = 0.014). Rs925489 increased TC risk in people aged > 45 years (OR = 1.54, p = 0.044) and in males (OR = 2.34, p = 0.003). In addition, rs965513 was related to an increased risk of TC in males (OR = 2.14, p = 0.007). Additionally, haplotypes in the block (rs925489|rs965513) significantly increased TC risk (p < 0.05). The best predictive model for TC was the combination of rs1052270, rs10982622, rs1475545, rs16924016, and rs925489.

Conclusion

TMOD1 and PTCSC2 polymorphisms were separately correlated with a remarkable decrease and increase in TC risk based on the analysis.
Interpretable machine learning predicts cardiac resynchronization therapy responses from personalized biochemical and biomechanical features
Authors: Haque Anamul , Stubbs Doug , Hubig Nina C. , Spinale Francis G. , Richardson William J.
Published: October 2022

Background

Cardiac Resynchronization Therapy (CRT) is a widely used, device-based therapy for patients with left ventricle (LV) failure. Unfortunately, many patients do not benefit from CRT, so there is potential value in identifying this group of non-responders before CRT implementation. Past studies suggest that predicting CRT response will require diverse variables, including demographic, biomarker, and LV function data. Accordingly, the objective of this study was to integrate diverse variable types into a machine learning algorithm for predicting individual patient responses to CRT.

Methods

We built an ensemble classification algorithm using previously acquired data from the SMART-AV CRT clinical trial (n = 794 patients). We used five-fold stratified cross-validation on 80% of the patients (n = 635) to train the model with variables collected at 0 months (before initiating CRT), and the remaining 20% of the patients (n = 159) were used as a hold-out test set for model validation. To improve model interpretability, we quantified feature importance values using SHapley Additive exPlanations (SHAP) analysis and used Local Interpretable Model-agnostic Explanations (LIME) to explain patient-specific predictions.

Results

Our classification algorithm incorporated 26 patient demographic and medical history variables, 12 biomarker variables, and 18 LV functional variables, which yielded correct prediction of CRT response in 71% of patients. Additional patient stratification to identify the subgroups with the highest or lowest likelihood of response showed 96% accuracy with 22 correct predictions out of 23 patients in the highest and lowest responder groups.

Conclusion

Computationally integrating general patient characteristics, comorbidities, therapy history, circulating biomarkers, and LV function data available before CRT intervention can improve the prediction of individual patient responses.
SIRPα antibody combined with oncolytic virus OH2 protects against tumours by activating innate immunity and reprogramming the tumour immune microenvironment
Authors: Kong Defeng , Yang Zhenrong , Li Guoliang , Wu Quanyou , Gu Zhaoru , Wan Duo , Zhang Qi , Zhang Xiaoli , Cheng Shujun , Liu Binlei , Zhang Kaitai , Zhang Wen
Published: October 2022

Background

The combination of oncolytic viruses (OVs) with immune checkpoint blockades is a research hotspot and has shown good efficacy. Here, we present the first attempt to combine oncolytic herpes simplex virus 2 (OH2) with an anti-SIRPα antibody as an antitumour treatment. Our results provide unique insight into the combination of innate immunity with OV.

Methods

We verified the polarization and activation of OH2 in RAW264.7 cells in vitro. Subsequently, we evaluated the antitumour ability of OH2 and anti-SIRPα combined therapy in a tumour-bearing mouse model. RNA-seq and Single-cell RNA-seq were used to characterize the changes in the tumour microenvironment.

Results

The OH2 lysates effectively stimulated RAW264.7 cells to polarize towards the M1 but not the M2 phenotype and activated the function of the M1 phenotype in vitro. In the macrophage clearance experiment, OH2 therapy induced polarization of M1 macrophages and participated in the antitumour immune response in a tumour-bearing mouse model. Treatment with a combination of OH2 and anti-SIRPα effectively inhibited tumour growth and significantly prolonged the survival time of the mice, and this result was more obvious in the mouse model with a larger tumour volume at the beginning of the treatment. These results suggest that combination therapy can more profoundly reshape the TME and activate stronger innate and adaptive immune responses.

Conclusions

Our data support the feasibility of oncolytic virus therapy in combination with anti-SIRPα antibodies and suggest a new strategy for oncolytic virus therapy.
Pigmentary mosaicism as a recurrent clinical manifestation in three new patients with mosaic trisomy 12 diagnosed postnatally: cases report and literature review
Authors: Martínez-Hernández A. , Martínez-Anaya D. , Durán-McKinster C. , Del Castillo-Ruiz V. , Navarrete-Meneses P. , Córdova E. J. , Villegas-Torres B. E. , Ruiz-Herrera A. , Juárez-Velázquez R. , Yokoyama-Rebollar E. , Cervantes-Barragán D. , Pedraza-Meléndez A. , Orozco L. , Pérez-Vera P. , Salas-Labadía C.
Published: October 2022

Background

To date, only twenty-one cases diagnosed postnatally with mosaic trisomy 12 have been reported. The most frequent phenotypic manifestations are developmental delay, dysmorphic facial features, congenital heart defects, digital alterations, and pigmentary disorders. In the present report, detailed clinical and genetic profiles of three unrelated new patients with mosaic trisomy 12 are described and compared with previously reported cases.

Case presentation

In the present report, we include the clinical, cytogenetic, and molecular description of three Mexican patients diagnosed postnatally with mosaic trisomy 12. At phenotypic level, the three patients present with developmental delay, dysmorphic facial features, congenital heart defects and skin pigmentary anomalies. Particularly, patient 1 showed unique eye alterations as bilateral distichiasis, triple rows of upper lashes, and digital abnormalities. In patient 2 redundant skin, severe hearing loss, and hypotonia were observed, and patient 3 presented with hypertelorism and telecanthus. Hyperpigmentation with disseminated pigmentary anomalies is a common trait in all of them. The cytogenetic study was carried out under the strict criteria of analysis, screening 50–100 metaphases from three different tissues, showing trisomy 12 mosaicism in at least one of the three different tissues analyzed. With SNParray, the presence of low-level mosaic copy number variants not previously detected by cytogenetics, and uniparental disomy of chromosome 12, was excluded. STR markers allowed to confirm the absence of uniparental disomy as well as to know the parental origin of supernumerary chromosome 12.

Conclusions

The detailed clinical, cytogenetic, and molecular description of these three new patients, contributes with relevant information to delineate more accurately a group of patients that show a heterogeneous phenotype, although sharing the same chromosomal alteration. The possibility of detecting mosaic trisomy 12 is directly associated with the sensitivity of the methodology applied to reveal the low-level chromosomal mosaicism, as well as with the possibility to perform the analysis in a suitable tissue.
Outcome of autologous stem cell transplantation in patients with favorable-risk acute myeloid leukemia in first remission
Authors: Chen Juan , Liu Li , Ma Runzhi , Pang Aiming , Yang Donglin , Chen Xin , Wei Jialin , He Yi , Zhang Rongli , Zhai Weihua , Ma Qiaoling , Jiang Erlie , Han Mingzhe , Zhou Jiaxi , Feng Sizhou
Published: October 2022

Objective

To evaluate the efficacy of autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with favorable-risk acute myeloid leukemia in first remission.

Method

Twenty patients who received auto-HSCT at our center between January 2014 and January 2021 were retrospectively reviewed.

Results

Until last follow-up, three patients in the cohort were dead due to relapse. The estimated 1-year and 5-year overall survival were 95.00% ± 4.87% and 83.82% ± 8.58%, respectively. The estimated 5-year RFS and CIR (cumulative incidence of relapse) were 85.00% ± 7.98% and 15.00% ±7.98%, respectively.

Conclusion

The outcome of auto-HSCT in patients with favorable-risk acute myeloid leukemia in first remission was excellent and auto-HSCT could be an effective treatment for these patients.
Bone-targeting delivery of platelet lysate exosomes ameliorates glucocorticoid-induced osteoporosis by enhancing bone-vessel coupling
Authors: Zheng Gang , Ma Hai-Wei , Xiang Guang-Heng , He Gao-Lu , Cai Han-Chen , Dai Zi-Han , Chen Yan-Lin , Lin Yan , Xu Hua-Zi , Ni Wen-Fei , Xu Cong , Liu Hai-Xiao , Wang Xiang-Yang
Published: October 2022

Background

Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs.

Results

In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs’ stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo.

Conclusions

PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP.

Graphical Abstract
Efficacy and safety of oral anticoagulants in elderly patients with stable coronary artery disease and atrial fibrillation
Authors: Zhang Xu , Wu Yangxun , Lv Chao , Zhang Shizhao , Liu Haiping , Wang Yuyan , Zou Yuting , Qin Liu’an , Zhang Junmeng , Yin Tong
Published: October 2022

Background

This study aimed to evaluate the efficacy and safety of oral anticoagulants (OACs) in real-world elderly patients with comorbidities of stable coronary artery disease (SCAD) and atrial fibrillation (AF).

Methods

Elderly patients (aged ≥ 65 years old) diagnosed with SCAD and AF were consecutively recruited and grouped into patients with or without oral anticoagulant (OAC) treatment. Follow-up was performed for 5 years. Major adverse cardiac events (MACEs) were defined as a composite of all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and systemic embolism. Major bleeding outcomes were defined as events that were type ≥ 3 based on the Bleeding Academic Research Consortium (BARC) criteria. The net clinical outcomes were defined as the combination of MACEs and bleeding of BARC type ≥ 3.

Results

A cohort of 832 eligible patients (78 ± 6.70 years) was included. Compared to the patients without OAC treatment (n = 531, 63.82%), the patients treated with OAC (n = 301, 36.18%) were much younger, had higher body mass index (BMI), and had lower prevalence of heart failure, chronic obstructive pulmonary disease (COPD), renal insufficiency, and previous myocardial infarction. During the follow-up of 5 years, compared to the patients without OAC treatment, patients with OAC had a significantly lower risk of MACEs (20.60% vs. 58.95%, adjusted HR: 0.21, 95% CI: 0.15–0.30,p < 0.001) but a higher risk of BARC ≥ 3 bleeding events (4.65% vs. 1.32%, adjusted HR: 4.71, 95% CI: 1.75–12.64,p = 0.002). In combination, a lower risk of net clinical outcomes could be observed in the patients with OACs (23.26% vs. 58.96%, adjusted HR: 0.27, 95% CI: 0.19–0.38,p < 0.001). Among the patients with OAC treatment, no significant difference was found for MACEs or BARC ≥ 3 bleeding events between the patients with or without comedications of oral antiplatelet agents.

Conclusions

A net clinical benefit of efficacy and safety could be observed in OAC-treated elderly patients with SCAD and AF. This benefit is independent of the comedications of oral antiplatelet treatment.
A research intelligence approach to assess the research impact of the Dutch university medical centres
Authors: Iping Rik , Kroon Marielle , Steegers Chantal , van Leeuwen Thed
Published: October 2022

Background

The way in which research impact is evaluated and assessed has long been under debate. In recent years the focus is moving away from the use of numerical indicators, towards an emphasis on narratives. The Dutch university medical centres (UMCs) have a long-standing tradition of using bibliometric indicators. Because of the declining interest in indicators alone, this study was designed to repurpose bibliometrics to answer specific strategic questions. In this article we discuss the strategic and policy-based questions, the methodology we used in uncovering relevant information and conclusions we draw from the analyses we performed. The aim of this article is to inform a broader audience about the potential applications of bibliometric information to support a new form of research intelligence.

Methods

In this study we used a curated set of publications from the UMCs. We performed different bibliometric analyses and used bibliometric visualization tools to shed light on research focus, open science practices, collaboration, societal impact and scientific impact.

Results

The analyses allowed us to visualize and contextualize the research focus of the UMCs as a whole, but also to show specific focus areas of each UMC. The UMCs are active in the full spectrum of biomedical research, and at the same time are very complementary to each other. Furthermore, we were able to show the development of open access of UMC publications over time, to support the national mission. Visualizing collaboration is a powerful way of showing both the international orientation and the regional and national engine function of UMCs in research. We were able to assess societal impact by looking at the different channels in which publications find their way to societally relevant sources such as news media, policy documents and guidelines. Finally, we assessed scientific impact and put this into an international perspective.

Conclusions

Research intelligence is able to transform bibliometric information by interpretation and annotation into highly relevant insights that can be used for several different strategic purposes and for research impact assessment in general.
Potential role of autophagy induced by FLT3-ITD and acid ceramidase in acute myeloid leukemia chemo-resistance: new insights
Authors: Zalpoor Hamidreza , Bakhtiyari Maryam , Akbari Abdullatif , Aziziyan Fatemeh , Shapourian Hooriyeh , Liaghat Mahsa , Zare-Badie Zahra , Yahyazadeh Sheida , Tarhriz Vahideh , Ganjalikhani-Hakemi Mazdak
Published: October 2022

Acute myeloid leukemia (AML) is a type of leukemia with a poor prognosis and survival characterized by abnormal cell proliferation and differentiation. Despite advances in treatment, AML still has a low complete remission rate, particularly in elderly patients, and recurrences are frequently seen even after complete remissions. The major challenge in treating AML is the resistance of leukemia cells to chemotherapy drugs. Thus, to overcome this issue, it can be crucial to conduct new investigations to explore the mechanisms of chemo-resistance in AML and target them. In this review, the potential role of autophagy induced by FLT3-ITD and acid ceramidase in chemo-resistance in AML patients are analyzed. With regard to the high prevalence of FLT3-ITD mutation (about 25% of AML cases) and high level of acid ceramidase in these patients, we hypothesized that both of these factors could lead to chemo-resistance by inducing autophagy. Therefore, pharmacological targeting of autophagy, FLT3-ITD, and acid ceramidase production could be a promising therapeutic approach for such AML patients to overcome chemo-resistance.
Human adenoviral (HAdV) chronic arthritis expands the infectious spectrum of primary agammaglobulinemia
Authors: de Frémont Grégoire Martin , Salmona Maud , Maillet François , Garzaro Margaux , Bertinchamp Rémi , Simonnet Arthur , Feghoul Linda , Maki Guitta , Roelens Marie , Chotard Emilie , Picard Capucine , Oksenhendler Eric , LeGoff Jérôme , Boutboul David
Published: October 2022

Inborn errors of immunity (IEI) are a heterogeneous entity with an increasing number of late diagnoses. Besides infections, inflammatory manifestations are a growing part of the clinical landscape of IEI. These complications are of unknown causes and often lead to the prescription of immunosuppressive agents that worsen the underlying immune defect. We here report the case of an adult patient diagnosed with chronic Human Adenovirus C-1 arthritis in the setting of primary agammaglobulinemia. Metagenomic next-generation sequencing led to the correct diagnosis and high-dose intravenous immunoglobulins resulted in complete recovery. This observation gives new insights into adenoviral immunity and underlines the importance of metagenomics in the diagnosis of inflammatory manifestations in immunocompromised patients.
Analysis of different adipose depot gene expression in cachectic patients with gastric cancer
Authors: Han Jun , Ding Zuoyou , Zhuang Qiulin , Shen Lei , Yang Fan , Sah Szechun , Wu Guohao
Published: October 2022

Purpose

This study aimed to identify the differentially expressed genes (DEGs) that contributed to the different amount of fat loss between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) among cachectic patients.

Methods

RNA sequencing was performed and bioinformatic tools were utilized to analyze the biological functions and construct regulation networks of DEGs. We presumed that iroquois homeobox 1 (IRX1) to be a hub gene and analyzed its clinical significance. Mouse model of cancer cachexia was established and differences between SAT and VAT were compared. The function of IRX1 on lipid metabolism was clarified by Oil Red O staining, qRT-PCR, and Western blotting in adipocytes.

Results

A total of 455 DEGs were screened between SAT and VAT in cachectic patients. Several hub genes were selected and IRX1 was presumed to contribute to the pathological difference between SAT and VAT in cancer cachexia. Patients with higher expression of IRX1 in SAT than VAT revealed significantly higher weight loss, IL-6 and TNF-α, as well as lower BMI, SAT, and VAT area. IRX1 expression in SAT was negatively correlated with SAT area. In cachectic mice, the expression of IRX1 in SAT was significantly higher than that in VAT. The inhibition effect on adipogenesis exerted by IRX1 was also proved in vitro.

Conclusion

These data supported that DEGs contribute to the different degrees of fat loss among adipose depots in cachectic patients. IRX1 in SAT promoted fat loss by inhibiting adipocyte differentiation and adipogenesis.
Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region
Authors: Fernández Lara P. , Deleyto-Seldas Nerea , Colmenarejo Gonzalo , Sanz Alba , Wagner Sonia , Plata-Gómez Ana Belén , Gómez-Patiño Mónica , Molina Susana , Espinosa-Salinas Isabel , Aguilar-Aguilar Elena , Ortega Sagrario , Graña-Castro Osvaldo , Loria-Kohen Viviana , Fernández-Marcos Pablo J. , Efeyan Alejo , Ramírez de Molina Ana
Published: October 2022

Background

Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway.

Results

We identify and validate rs2291007 within a conserved region in the 3′UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increasedFNIP2mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenousFnip2allele in mice. Primary cells derived fromFnip2C/C mice show increased mRNA stability, and more importantly,Fnip2C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels ofFNIP2in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction.

Conclusions

We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation ofFNIP2mRNA levels.

Graphical Abstract
Novel equi merozoite antigen (ema-1) gene heterogeneity in a geographically isolated Theileria equi population in Croatia
Authors: Coultous Robert , Gotić Jelena , McCann Martine , Sutton David , Beck Relja , Shiels Brian
Published: October 2022

Background

The apicomplexan haemoparasite Theileria equi, a causative agent of equine piroplasmosis, is an established pathogen of significant welfare and economic concern within the Croatian equine population. A previous large surveillance study of T. equi has identified two distinct parasite populations, one in the north and one in the south, geographically separated by the Dinaric Alps, which traverse the country. This study aimed to further investigate the genetic diversity within these two populations, focussing on allelic variability of the equi merozoite antigen gene, ema-1.

Methods

Following nested PCR of DNA isolates, the generated ema-1 amplicons were subsequently sequenced and compared by phylogenetic analysis to available sequences representing previously described ema-1 genotypes (groups A–C).

Results

Isolates from the southern T. equi population clustered with the existing ema-1 groups A and B. Strikingly, isolates from the northern population clustered into two novel ema-1 genotypes, named groups D and E.

Conclusions

This detection of hitherto unreported genotypes suggests that historic geographical isolation has led to a degree of divergent evolution in this northern T. equi population. Additionally, current global regulatory testing of equine piroplasmosis relies heavily on EMA-1 based immunodiagnostics, and the discovery of unique ema-1 genotypes may question the efficacy of current diagnostics in international equine movement, with ramifications for the global equine community.

Graphical Abstract
Artificial blood-feeding of phlebotomines (Diptera: Psychodidae: Phlebotominae): is it time to repurpose biological membranes in light of ethical concerns?
Authors: Sánchez Uzcátegui Yetsenia del Valle , dos Santos Eduardo José Melo , Matos Edilson Rodrigues , Silveira Fernando Tobias , Vasconcelos dos Santos Thiago , Póvoa Marinete Marins
Published: October 2022

Background

The aims of the present study were to evaluate and compare the efficacy of blood-feeding in phlebotomines through industrially processed membranes from the small intestine of pigs (used for the production of commercial sausages) and the skin of euthanized chicks.

Methods

Laboratory-bred Lutzomyia longipalpis and different field-caught phlebotomine species were subjected to the artificial feeding systems under similar conditions. Paired tests were performed using the control (skin from euthanized chicks) and test membranes (pig small intestine). The feeding rates were compared by paired t-test, and Pearson correlation was used to examine the relationship between the thickness of the membranes and feeding rate.

Results

The feeding rate was greater with the test membrane than with the control membrane for L. longipalpis (t-test, t = −3.3860, P = 0.0054) but not for the most frequent field-caught species, Nyssomyia antunesi (t-test, t = 0.7746, P = 0.4535). The average thicknesses of the control and test membranes were 184 ± 83 µm and 34 ± 12 µm, respectively (Mann–Whitney U-test, U = 0.00, Z = 2.8823, P = 0.0039); however, there was no correlation between feeding rate and membrane thickness. A moderate positive correlation was observed between the number of phlebotomines that fed and the total number of phlebotomines in the cage for each type of membrane and for each species.

Conclusions

The test membrane is a viable alternative for the artificial blood-feeding of phlebotomines, and is thus a potential substitute for the skin of animals that are euthanized for this purpose. Feeding rate was independent of membrane thickness.

Graphical Abstract
Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies
Authors: Fang Hu , Yan Helen H. N. , Bilardi Rebecca A. , Flensburg Christoffer , Yang Haocheng , Barbour Jayne A. , Siu Hoi Cheong , Turski Michelle , Chew Edward , Xu Zhen , Lam Siu T. , Sharma Rakesh , Xu Mengya , Li Junshi , Ip Ho W. , Cheung Carol Y. M. , Huen Michael S. Y. , Sweet-Cordero E. Alejandro , Majewski Ian J. , Leung Suet Y. , Wong Jason W. H.
Published: October 2022

Background

Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown.

Methods

This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs.

Results

Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCVsig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids.

Conclusions

In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.
Genome-wide screening for differentially methylated long noncoding RNAs identifies LIFR-AS1 as an epigenetically regulated lncRNA that inhibits the progression of colorectal cancer
Authors: Song Peng , Li Ying , Wang Feng , Pu Lingxiao , Bao Linsen , Gao Hengfei , Zhu Chuandong , Wang Meng , Tao Liang
Published: October 2022

Background

Aberrant DNA methylation is an epigenetic marker that has been linked to the pathogenesis of colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) have been increasingly identified to be associated with tumorigenic processes of CRC. Identifying epigenetically dysregulated lncRNAs and characterizing their effects during carcinogenesis are focuses of cancer research.

Methods

Differentially methylated loci and expressed lncRNAs were identified by integrating DNA methylome and transcriptome analyses using The Cancer Genome Atlas database. Bisulfite sequencing PCR (BSP) was performed to analyze LIFR-AS1 promoter methylation status. The functional roles of LIFR-AS1 in CRC were determined by in vitro and in vivo experiments.

Results

We identified a novel hypermethylated lncRNA, LIFR-AS1, that was downregulated and associated with tumorigenesis, metastasis, and poor prognosis in CRC. High methylation burden of LIFR-AS1 indicated a poor survival of CRC patients. Promoter hypermethylation of LIFR-AS1 in tumor tissues was confirmed by BSP. Functional assays revealed that LIFR-AS1 could competitively bind to hsa-miR-29b-3p, and repressed colon cancer cell proliferation, colony formation and invasion. LIFR-AS1 also inhibited tumor growth in a mouse xenograft model of CRC.

Conclusions

Our results showed that the identified DNA methylation-dysregulated lncRNAs may be potential biomarkers and highlighted a role for LIFR-AS1 as a tumor suppressor in CRC.
A large pericardial cystic lymphangioma presenting as acute-onset respiratory distress in a child: a case report
Authors: Pathiraja Hashan , Rasnayake Dhammike , Muthukumarana Thilini , de Silva Channa , Sathkorala Wasantha , Gunaratne Sandini , Rajindrajith Shaman , Mettananda Sachith
Published: October 2022

Background

Lymphangiomas are rare benign malformations of the lymphatics that occur due to blockage of the lymphatic system during fetal development. They commonly occur in the neck and axilla, while involvement of the pericardium is rare. We report herein the case of a 16-month-old Sri Lankan child with a large pericardial cystic lymphangioma presenting with sudden-onset shortness of breath.

Case presentation

A 16-month-old Sri Lankan boy presented with sudden-onset dyspnea for 1-day duration following a febrile illness that lasted 2 days. On examination, he was afebrile and had subcostal, intercostal, and suprasternal recessions, with a respiratory rate of 50 breaths per minute. He had a loud expiratory grunt. The chest expansion was reduced on the right side, which was dull to percussion. Auscultation revealed a marked reduction of air entry over the right lower and mid zones. Chest X-ray showed a well-demarcated opacity involving the lower and mid zones of the right hemithorax associated with a tracheal shift to the opposite side. Ultrasound scan of the chest revealed fluid-filled right hemithorax suggesting a septate pleural effusion. A contrast-enhanced computed tomography scan of the thorax showed a large multiloculated extrapulmonary cystic lesion involving the right hemithorax with a mediastinal shift towards the left side associated with displacement of the right-side mediastinal structures. He underwent mini-thoracotomy and surgical excision of the cyst. A large cyst originating from the pericardium was observed and excised during surgery. Histological examination revealed a lesion composed of cysts devoid of a lining epithelium but separated by connective tissue, mature adipose tissue, and lymphoid aggregates. The child showed complete recovery postoperatively with full expansion of the ipsilateral lung.

Conclusion

We report the case of a patient with cystic lymphangioma who was perfectly well and asymptomatic until 16 months of age. This case report presents the very rare occurrence of a large cystic lymphangioma originating from the pericardium. It highlights the importance of considering rare possibilities and performing prompt imaging in situations of diagnostic uncertainty to arrive at an accurate diagnosis that can be lifesaving.
Hemiballismus–hemichorea syndrome in an acute rehabilitation setting: two case reports
Authors: Tsai Luke , Shekhtman Benjamin , Stenquist Ryan , Schneider Ashley , Mapa Meilani , Amirianfar Edwin , Gater David R.
Published: October 2022

Background

We report two similar cases of patients diagnosed with hemiballismus–hemichorea syndrome secondary to uncontrolled hyperglycemia. Both patients were treated at an inpatient rehabilitation center and made a significant recovery in both function and activities of daily living. Although hemiballismus–hemichorea syndrome has known pharmacological treatments, little has been reported on the effectiveness of acute rehabilitation on managing and treating this syndrome.

Case presentation

The first case involves a 44-year-old Hispanic male with past medical history of type 2 diabetes mellitus, hypertension, anxiety, and depression who presented with continuous, uncontrollable, unilateral movements 1 month following a hospital admission for hyperglycemia. Magnetic resonance imaging findings showed lesions in the basal ganglia, confirming the diagnosis of hemiballismus–hemichorea syndrome. The patient was started on antipsychotic medications and antihyperglycemic medications controlling glucose levels, but continued to have hemiballismus symptoms. The second case involves a 78-year-old Haitian female with past medical history of type 2 diabetes mellitus and hypertension who presented with weakness and continuous, involuntary movements in her upper and lower extremities 1 month following a hospital admission for hyperglycemia and encephalopathy. Magnetic resonance imaging findings were positive for bilateral lesions in the basal ganglia, establishing a diagnosis of hemiballismus–hemichorea syndrome. After a 2-week stay at an acute rehabilitation center, both patients made a significant recovery in function and activities of daily living.

Conclusion

The aim in presenting these cases is to elucidate the etiology and progression of a rare disease process known as hemiballismus–hemichorea syndrome and to provide evidence for the potential positive impact of acute rehabilitation on patients with unresolved hemiballismus–hemichorea following an episode of hyperglycemia.
The interplay of daily affect and impulsivity measured by mobile surveys in bipolar disorder
Authors: Titone Madison K. , Depp Colin , Klaus Federica , Carrasco Jessica , Young Jared W. , Eyler Lisa T.
Published: October 2022

Background

Impulsivity is a prominent feature of bipolar disorder associated with various negative sequelae; moreover, it may be a precursor to shifts in affect or mood, but little is known about its association with affect on a day-to-day timescale. Ecological momentary assessments (a method that captures moment-to-moment ratings of psychological states by repeatedly sampling the same individual) of impulsivity and affect using mobile surveys allow for more nuanced examination of mechanisms of mood and behavior dysregulation. However, few existing studies have validated an ecological momentary assessment of impulsivity in bipolar disorder and examined its time-lagged associations with positive and negative affect. 70 participants with bipolar disorder and 102 healthy comparisons participated in an intensive longitudinal study: they underwent 14 days of ecological momentary assessment data collection annually for 1–4 years. Multiple measures of impulsivity and affect were collected using self-report, behavioral, and ecological momentary assessment modalities; these measures were compared, and levels of impulsivity were compared between bipolar disorder and healthy comparison groups. Time-lagged analyses using daily means explored the next-day predictive relationship of impulsivity on positive/negative affect, and vice versa.

Results

The ecological momentary measure of impulsivity was moderately correlated with the self-report but not behavioral impulsivity measure. Bipolar disorder participants evinced higher self-report, behavioral, and daily impulsivity than healthy comparison participants. Time-lagged analyses revealed a bi-directional association between high impulsivity and high next-day negative (but not positive) affect. Post hoc analyses showed that impulsivity specifically predicted next-day anger and anxiety.

Conclusions

Our multimodal assessment of impulsivity allowed for an examination of the day-to-day course of impulsivity and affect, crucial steps toward understanding the mechanisms of mood symptom and episode onset in bipolar disorder.