Measuring the gap: correlating synthetic-to-real drift with PHI de-identification performance

Abstract: Abstract Clinical text de-identification enables the use of electronic health records while protecting patient privacy, but public training data remain scarce and often have mismatched documentation styles. Recent works have proposed using large language models (LLMs) to generate synthetic clinical notes, but it remains unclear if they reflect distributions of real clinical notes. We examine how lexical and semantic drift across training and evaluation corpora affects protected health information (PHI) tagger performance. We generated synthetic notes from scratch for four categories using five generator LLMs and one judge LLM. Next, we fine-tuned small de-identification models on real, synthetic, and mixed corpora, and evaluated them on three external benchmarks under a harmonized label schema. Models trained on broad, clinically oriented sources transfer better than those on legal or narrowly synthetic data. These results suggest that although synthetic data lacks some real-world distributional properties, it remains useful in low-resource settings. We found that compact distributional and embedding-based drift measures moderately correlate with out-of-distribution F1 score, a practically important result because drift estimation can improve synthetic-data quality control and alignment.


Chromothripsis in Treatment Resistance in Multiple Myeloma

Abstract: Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells, of which the prognostic factors include chromosomal abnormality, β-2 microglobulin, and albumin. Recently, the term chromothripsis has emerged, which is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event. Many studies have shown an association of chromothripsis with the prognosis in several cancers; however, few studies have investigated it in MM. Here, we studied the association between chromothripsis-like patterns and treatment resistance or prognosis. First, we analyzed nine MM cell lines (U266, MM.1S, RPMI8226, KMS-11, KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-28-PE, and NCI-H929) and bone marrow samples of four patients who were diagnosed with MM by next-generation sequencing-based copy number variation analysis. The frequency of the chromothripsis-like pattern was observed in seven cell lines. We analyzed the treatment-induced chromothripsis-like patterns in KMS-12-BM and KMS-12-PE cells. As a result, breakpoints and chromothripsis-like patterns were increased after drug treatment in the relatively resistant KMS-12-BM. We further analyzed the patients’ results according to the therapeutic response, which was divided into sensitive and resistant, as suggested by the International Myeloma Working Group. The chromothripsis-like pattern was more frequently observed in the resistant group. In the sensitive group, the frequency of the chromothripsis-like pattern decreased after treatment, whereas the resistant group showed increased chromothripsis-like patterns after the treatment. These results suggest that the chromothripsis-like pattern is associated with treatment response in MM.

Kyoung Joo Lee
Ki Hong Lee
Kyong-Ah Yoon
Ji Yeon Sohn
Eunyoung Lee
Hyewon Lee
Hyeon-Seok Eom
Sun-Young Kong


Editor’s introduction to this issue (G&I 18:3, 2020)


Perspectives of Integrative Cancer Genomics in Next Generation Sequencing Era

Abstract: The explosive development of genomics technologies including microarrays and next generation sequencing (NGS) has provided comprehensive maps of cancer genomes, including the expression of mRNAs and microRNAs, DNA copy numbers, sequence variations, and epigenetic changes. These genome-wide profiles of the genetic aberrations could reveal the candidates for diagnostic and/or prognostic biomarkers as well as mechanistic insights into tumor development and progression. Recent efforts to establish the huge cancer genome compendium and integrative omics analyses, so-called "integromics", have extended our understanding on the cancer genome, showing its daunting complexity and heterogeneity. However, the challenges of the structured integration, sharing, and interpretation of the big omics data still remain to be resolved. Here, we review several issues raised in cancer omics data analysis, including NGS, focusing particularly on the study design and analysis strategies. This might be helpful to understand the current trends and strategies of the rapidly evolving cancer genomics research.

So Mee Kwon
Hyunwoo Cho
Ji Hye Choi
Byul A Jee
Yuna Jo
Hyun Goo Woo


Mutation Analysis of Synthetic DNA Barcodes in a Fission Yeast Gene Deletion Library by Sanger Sequencing

Abstract: Incorporation of unique barcodes into fission yeast gene deletion collections has enabled the identification of gene functions by growth fitness analysis. For fine tuning, it is important to examine barcode sequences, because mutations arise during strain construction. Out of 8,708 barcodes (4,354 strains) covering 88.5% of all 4,919 open reading frames, 7,734 barcodes (88.8%) were validated as high-fidelity to be inserted at the correct positions by Sanger sequencing. Sequence examination of the 7,734 high-fidelity barcodes revealed that 1,039 barcodes (13.4%) deviated from the original design. In total, 1,284 mutations (mutation rate of 16.6%) exist within the 1,039 mutated barcodes, which is comparable to budding yeast (18%). When the type of mutation was considered, substitutions accounted for 845 mutations (10.9%), deletions accounted for 319 mutations (4.1%), and insertions accounted for 121 mutations (1.6%). Peculiarly, the frequency of substitutions (67.6%) was unexpectedly higher than in budding yeast (~28%) and well above the predicted error of Sanger sequencing (~2%), which might have arisen during the solid-phase oligonucleotide synthesis and PCR amplification of the barcodes during strain construction. When the mutation rate was analyzed by position within 20-mer barcodes using the 1,284 mutations from the 7,734 sequenced barcodes, there was no significant difference between up-tags and down-tags at a given position. The mutation frequency at a given position was similar at most positions, ranging from 0.4% (32/7,734) to 1.1% (82/7,734), except at position 1, which was highest (3.1%), as in budding yeast. Together, well-defined barcode sequences, combined with the next-generation sequencing platform, promise to make the fission yeast gene deletion library a powerful tool for understanding gene function.

Minho Lee
Shin-Jung Choi
Sangjo Han
Miyoung Nam
Dongsup Kim
Dong-Uk Kim
Kwang-Lae Hoe


Semantic Modeling for SNPs Associated with Ethnic Disparities in HapMap Samples

Abstract: Single-nucleotide polymorphisms (SNPs) have been emerging out of the efforts to research human diseases and ethnic disparities. A semantic network is needed for in-depth understanding of the impacts of SNPs, because phenotypes are modulated by complex networks, including biochemical and physiological pathways. We identified ethnicity-specific SNPs by eliminating overlapped SNPs from HapMap samples, and the ethnicity-specific SNPs were mapped to the UCSC RefGene lists. Ethnicity-specific genes were identified as follows: 22 genes in the USA (CEU) individuals, 25 genes in the Japanese (JPT) individuals, and 332 genes in the African (YRI) individuals. To analyze the biologically functional implications for ethnicity-specific SNPs, we focused on constructing a semantic network model. Entities for the network represented by "Gene," "Pathway," "Disease," "Chemical," "Drug," "ClinicalTrials," "SNP," and relationships between entity-entity were obtained through curation. Our semantic modeling for ethnicity-specific SNPs showed interesting results in the three categories, including three diseases ("AIDS-associated nephropathy," "Hypertension," and "Pelvic infection"), one drug ("Methylphenidate"), and five pathways ("Hemostasis," "Systemic lupus erythematosus," "Prostate cancer," "Hepatitis C virus," and "Rheumatoid arthritis"). We found ethnicity-specific genes using the semantic modeling, and the majority of our findings was consistent with the previous studies - that an understanding of genetic variability explained ethnicity-specific disparities.

HyoYoung Kim
Won Gi Yoo
Junhyung Park
Heebal Kim
Byeong-Chul Kang


Rore: robust and efficient antioxidant protein classification via a novel dimensionality reduction strategy based on learning of fewer features

Abstract: Abstract In protein identification, researchers increasingly aim to achieve efficient classification using fewer features. While many feature selection methods effectively reduce the number of model features, they often cause information loss caused by merely selecting or discarding features, which limits classifier performance. To address this issue, we present Rore, an algorithm based on a feature-dimensionality reduction strategy. By mapping the original features to a latent space, Rore retains all relevant feature information while using fewer representations of the latent features. This approach significantly preserves the original information and overcomes the information loss problem associated with previous feature selection. Through extensive experimental validation and analysis, Rore demonstrated excellent performance on an antioxidant protein dataset, achieving an accuracy of 95.88% and MCC of 91.78%, using vectors including only 15 features. The Rore algorithm is available online at http://112.124.26.17:8021/Rore .

Chaolu Meng
Yongqi Hou
Quan Zou
Lei Shi
Xi Su
Ying Ju


Effect of tofogliflozin on cardiac sympathetic nerve activity in type 2 diabetes mellitus patients with heart failure (TARGET-HF): rationale and design of the single-arm intervention trial

Abstract: Abstract Background Cardiac sympathetic nervous dysfunction is linked to poor prognosis in heart failure with reduced ejection fraction (HFrEF), and patients with HFrEF complicated by type 2 diabetes mellitus (T2DM) represent a particularly high risk. Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce heart failure (HF) hospitalizations in patients with T2DM, but the mechanisms underlying these benefits are not fully understood; modulation of cardiac sympathetic activity has been proposed as one contributor. The TARGET-HF trial will investigate whether tofogliflozin improves cardiac sympathetic nerve activity, assessed by I-123 metaiodobenzylguanidine (MIBG) scintigraphy, along with other cardiovascular parameters in patients with HFrEF and T2DM. Methods This single-arm prospective interventional study will enroll 50 patients with HFrEF (left ventricular ejection fraction < 40%), T2DM (hemoglobin A1c level, 6.5–10.0%), and estimated glomerular filtration rate ≥ 30mL/min/1.73 m². Participants will receive oral tofogliflozin (20 mg/day) for 24 weeks. The primary endpoint is the change in the heart-to-mediastinum ratio on delayed I-123 MIBG scintigraphy from baseline to 24 weeks. Secondary endpoints include changes in the early heart-to-mediastinum ratio, washout rate, echocardiographic parameters, and various biomarkers related to HF, inflammation, and metabolism. Discussion The TARGET-HF trial is the first interventional study to comprehensively evaluate the effects of tofogliflozin on cardiac sympathetic nerve activity using I-123 MIBG scintigraphy in patients with HFrEF and T2DM. By integrating nuclear imaging, echocardiography, and metabolic and biochemical biomarkers, this study aims to clarify the mechanisms underlying the cardioprotective effects of SGLT2 inhibitors. Improved understanding of these mechanisms may refine patient selection and guide targeted therapeutic strategies in HF management. Trial registration Japan Registry of Clinical Trials; approval number: jRCTs041210022 (February 6, 2021).

Takahiro Okumura
Yasuko K Bando
Satoshi Isobe
Naotoshi Fujita
Fusako Sera
Yuki Ikeda
Ayumu Yajima
Toshiyuki Nagai
Hiroaki Hiraiwa
Ryota Morimoto
Toshihisa Anzai
Koichi Node
Junya Ako
Yasushi Sakata
Toyoaki Murohara

Cardiovascular Diabetology. Endocrinology Reports


Autonomic-inflammatory crosstalk in diabetic atherogenesis: a neuroimmune triad (HRV-LMR-hsCRP) predicts carotid plaque risk in type 2 diabetes

Abstract: Abstract Background and aim Type 2 diabetes mellitus (T2D) is associated with a high risk of cardiovascular complications, including carotid atherosclerosis (CAS). This study aimed to investigate the link between CAS and T2D by identifying novel risk factors and examining the relationship between autonomic dysfunction (via heart rate variability, HRV) and systemic inflammation. Methods We conducted a retrospective observational study of 232 T2D patients, categorized into three groups based on carotid ultrasound: normal arteries (n = 47), intima-media thickening (n = 49), and carotid plaques (n = 136). Differences in clinical and inflammatory markers across groups were analyzed. Independent risk factors for CAS were identified using multivariate logistic regression, and a predictive model was developed and evaluated by Receiver Operating Characteristic (ROC) curve analysis. To infer causality, a bidirectional two-sample Mendelian randomization (MR) analysis was performed using summary-level data from large-scale genome-wide association studies (GWAS). Results Significant differences were observed in age, insulin usage, and inflammatory markers (NLR, PLR, LMR) among the groups (all p < 0.05). Logistic regression identified age, SDNN (a measure of HRV), LMR, and hs-CRP as independent risk factors for CAS. The combined model integrating hs-CRP, SDNN, and LMR demonstrated exceptional predictive accuracy for CAS (AUC = 0.941; 95% CI: 0.912–0.969). MR analysis provided genetic evidence supporting a causal relationship between genetically predicted HRV reduction and increased carotid intima-media thickness. Conclusion Our findings underscore the critical interplay between autonomic dysfunction and inflammation in the development of CAS in T2D. The proposed integrative model shows high potential for risk stratification. Future large-scale multicenter studies are warranted to validate these findings and elucidate the underlying mechanisms.

Xinrui Zhou
Xiaowei Bai
Li Ding
Shuai Zhang
Ya Li


Streptococcus equi subsp. zooepidemicus triggered NETs formation in neutrophils depending on GSDMD activation

Abstract: Abstract Streptococcus equi subsp. zooepidemicus (SEZ) is an opportunistic pathogen that poses a significant threat to a diverse array of species. Neutrophils can release neutrophil extracellular traps (NETs) to eliminate bacteria. However, the role of NETs in SEZ infection remains poorly understood. This study aims to investigate the impact of gasdermin D (GSDMD) on NETs formation during SEZ infection. Our results reveal that SEZ infection induces murine lethality, accompanied by extensive neutrophil infiltration in the spleen, as corroborated by peritoneal lavage and hematological analyses. Mechanistically, ex vivo infection of bone marrow-derived neutrophils triggered robust NETosis, indicating that this process constitutes a critical anti-SEZ defense. Intriguingly, although SEZ infection upregulated GSDMD expression, genetic ablation of GSDMD paradoxically enhanced neutrophil recruitment to infection sites. Surprisingly, this amplified recruitment failed to augment NETs production, suggesting that GSDMD is essential for NETs release, which was evidenced by disulfiram treatment, a specific inhibitor of GSDMD pore formation. Consequently, GSDMD-deficient mice exhibited heightened lethality upon SEZ challenge, confirming the non-redundant function of GSDMD in orchestrating protective responses to infection. These results underscore the importance of neutrophils in the immune response against SEZ infection and reinforce the crucial role of GSDMD in NETs formation.

Ziteng Deng
Haoxian Xie
Yunfei Huang
Jiedan Liao
Jianfeng Guo
Yajuan Li
Qinqin Sun
Qiang Fu

Physical anthropology. Somatology
Veterinary medicine


Prediction of Genes Related to Positive Selection Using Whole-Genome Resequencing in Three Commercial Pig Breeds

Abstract: Selective sweep can cause genetic differentiation across populations, which allows for the identification of possible causative regions/genes underlying important traits. The pig has experienced a long history of allele frequency changes through artificial selection in the domestication process. We obtained an average of 329,482,871 sequence reads for 24 pigs from three pig breeds: Yorkshire (n = 5), Landrace (n = 13), and Duroc (n = 6). An average read depth of 11.7 was obtained using whole-genome resequencing on an Illumina HiSeq2000 platform. In this study, cross-population extended haplotype homozygosity and cross-population composite likelihood ratio tests were implemented to detect genes experiencing positive selection for the genome-wide resequencing data generated from three commercial pig breeds. In our results, 26, 7, and 14 genes from Yorkshire, Landrace, and Duroc, respectively were detected by two kinds of statistical tests. Significant evidence for positive selection was identified on genes ST6GALNAC2 and EPHX1 in Yorkshire, PARK2 in Landrace, and BMP6, SLA-DQA1, and PRKG1 in Duroc.These genes are reportedly relevant to lactation, reproduction, meat quality, and growth traits. To understand how these single nucleotide polymorphisms (SNPs) related positive selection affect protein function, we analyzed the effect of non-synonymous SNPs. Three SNPs (rs324509622, rs80931851, and rs80937718) in the SLA-DQA1 gene were significant in the enrichment tests, indicating strong evidence for positive selection in Duroc. Our analyses identified genes under positive selection for lactation, reproduction, and meat-quality and growth traits in Yorkshire, Landrace, and Duroc, respectively.

HyoYoung Kim
Kelsey Caetano-Anolles
Minseok Seo
Young-jun Kwon
Seoae Cho
Kangseok Seo
Heebal Kim


ERRATUM: Acknowledgments Correction. Cell-Free miR-27a, a Potential Diagnostic and Prognostic Biomarker for Gastric Cancer

Jong-Lyul Park
Mirang Kim
Kyu-Sang Song
Seon-Young Kim
Yong Sung Kim


Compression rates of microbial genomes are associated with genome size and base composition

Abstract: Abstract Background To what degree a string of symbols can be compressed reveals important details about its complexity. For instance, strings that are not compressible are random and carry a low information potential while the opposite is true for highly compressible strings. We explore to what extent microbial genomes are amenable to compression as they vary considerably both with respect to size and base composition. For instance, microbial genome sizes vary from less than 100,000 base pairs in symbionts to more than 10 million in soil-dwellers. Genomic base composition, often summarized as genomic AT or GC content due to the similar frequencies of adenine and thymine on one hand and cytosine and guanine on the other, also vary substantially; the most extreme microbes can have genomes with AT content below 25% or above 85% AT. Base composition determines the frequency of DNA words, consisting of multiple nucleotides or oligonucleotides, and may therefore also influence compressibility. Using 4,713 RefSeq genomes, we examined the association between compressibility, using both a DNA based- (MBGC) and a general purpose (ZPAQ) compression algorithm, and genome size, AT content as well as genomic oligonucleotide usage variance (OUV) using generalized additive models. Results We find that genome size (p < 0.001) and OUV (p < 0.001) are both strongly associated with genome redundancy for both type of file compressors. The DNA-based MBGC compressor managed to improve compression with approximately 3% on average with respect to ZPAQ. Moreover, MBGC detected a significant (p < 0.001) compression ratio difference between AT poor and AT rich genomes which was not detected with ZPAQ. Conclusion As lack of compressibility is equivalent to randomness, our findings suggest that smaller and AT rich genomes may have accumulated more random mutations on average than larger and AT poor genomes which, in turn, were significantly more redundant. Moreover, we find that OUV is a strong proxy for genome compressibility in microbial genomes. The ZPAQ compressor was found to agree with the MBGC compressor, albeit with a poorer performance, except for the compressibility of AT-rich and AT-poor/GC-rich genomes.


Editor's Introduction to This Issue


Characterization of Chromatin Structure-associated Histone Modifications in Breast Cancer Cells

Abstract: Chromatin structure and dynamics that are influenced by epigenetic marks, such as histone modification and DNA methylation, play a crucial role in modulating gene transcription. To understand the relationship between histone modifications and regulatory elements in breast cancer cells, we compared our chromatin immunoprecipitation sequencing (ChIP-Seq) histone modification patterns for histone H3K4me1, H3K4me3, H3K9/16ac, and H3K27me3 in MCF-7 cells with publicly available formaldehyde-assisted isolation of regulatory elements (FAIRE)-chip signals in human chromosomes 8, 11, and 12, identified by a method called FAIRE. Active regulatory elements defined by FAIRE were highly associated with active histone modifications, like H3K4me3 and H3K9/16ac, especially near transcription start sites. The H3K9/16ac-enriched genes that overlapped with FAIRE signals (FAIRE-H3K9/14ac) were moderately correlated with gene expression levels. We also identified functional sequence motifs at H3K4me1-enriched FAIRE sites upstream of putative promoters, suggesting that regulatory elements could be associated with H3K4me1 to be regarded as distal regulatory elements. Our results might provide an insight into epigenetic regulatory mechanisms explaining the association of histone modifications with open chromatin structure in breast cancer cells.

Chang Pyo Hong
Moon Kyung Choe
Tae-Young Roh


Prediction of Metal Ion Binding Sites in Proteins from Amino Acid Sequences by Using Simplified Amino Acid Alphabets and Random Forest Model

Abstract: Metal binding proteins or metallo-proteins are important for the stability of the protein and also serve as co-factors in various functions like controlling metabolism, regulating signal transport, and metal homeostasis. In structural genomics, prediction of metal binding proteins help in the selection of suitable growth medium for overexpression’s studies and also help in obtaining the functional protein. Computational prediction using machine learning approach has been widely used in various fields of bioinformatics based on the fact all the information contains in amino acid sequence. In this study, random forest machine learning prediction systems were deployed with simplified amino acid for prediction of individual major metal ion binding sites like copper, calcium, cobalt, iron, magnesium, manganese, nickel, and zinc.


Identification and Functional Characterization of P159L Mutation in  in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5)

Abstract: Mutation in HNF1B, the hepatocyte nuclear factor-1β (HNF-1β) gene, results in maturity-onset diabetes of the young (MODY) 5, which is characterized by gradual impairment of insulin secretion. However, the functional role of HNF-1β in insulin secretion and glucose metabolism is not fully understood. We identified a family with early-onset diabetes that fulfilled the criteria of MODY. Sanger sequencing revealed that a heterozygous P159L (CCT to CTT in codon 159 in the DNA-binding domain) mutation in HNF1B was segregated according to the affected status. To investigate the functional consequences of this HNF1B mutation, we generated a P159L HNF1B construct. The wild-type and mutant HNF1B constructs were transfected into COS-7 cells in the presence of the promoter sequence of human glucose transporter type 2 (GLUT2). The luciferase reporter assay revealed that P159L HNF1B had decreased transcriptional activity compared to wild-type (p < 0.05). Electrophoretic mobility shift assay showed reduced DNA binding activity of P159L HNF1B. In the MIN6 pancreatic β-cell line, overexpression of the P159L mutant was significantly associated with decreased mRNA levels of GLUT2 compared to wild-type (p < 0.05). However, INS expression was not different between the wild-type and mutant HNF1B constructs. These findings suggests that the impaired insulin secretion in this family with the P159L HNF1B mutation may be related to altered GLUT2 expression in β-cells rather than decreased insulin gene expression. In conclusion, we have identified a Korean family with an HNF1B mutation and characterized its effect on the pathogenesis of diabetes.

Eun Ky Kim
Ji Seon Lee
Hae Il Cheong
Sung Soo Chung
Soo Heon Kwak
Kyong Soo Park


Association of cumulative exposure and dynamic change patterns of metabolic syndrome score with cardiometabolic multimorbidity progression among middle-aged and older Chinese adults: a longitudinal analysis based on CHARLS

Abstract: Abstract Background Cardiometabolic multimorbidity (CMM) leads to adverse health outcomes. Based on data from the China Health and Retirement Longitudinal Study (CHARLS), we aimed to explore the cumulative exposure and dynamic change patterns of metabolic syndrome score (MetSS) with CMM progression among middle-aged and older Chinese adults. Methods Age and sex specific MetSS was assessed according to equations which were developed for Chinese. K-means clustering analysis was used to classify MetSS changes, and cumulative MetSS (cuMetSS) was calculated as follows: (MetSS2012 + MetSS2015)/2 × time (2015 − 2012). The progression of CMM was defined starting with CMD-free, developing into first CMD (FCMD), further progressing into CMM. Logistic regression analyses and restricted cubic splines (RCS) were performed to evaluate the association of MetSS with CMM progression in 3 models. Subgroup and interaction analyses were subsequently undertaken to investigate the effect of physical activity on the associations of baseline MetSS, cuMetSS and MetSS change patterns with FCMD and CMM risk, respectively. Results A total of 3,322 participants were eligible for analysis, of whom 679 experienced FCMD and 101 progressed to CMM. The K-means method classified 4 clusters. Logistic analyses revealed that the risk of CMM both increased with baseline MetSS and cuMetSS increment in all 3 models. Baseline MetSS on continuous scale was not significantly associated with FCMD (all P > 0.05). Yet cuMetSS on continuous scale was significantly associated with increased risk of FCMD when adjusted age and gender (model 1: OR, 95% CI, P: 1.02, 1.01 to 1.03, 0.006), additionally adjusted education, marital status, residence, drinking status, smoking status, BMI and comorbidity (model 2: 1.02, 1.00 to 1.03, 0.008). Further additional adjustment for physical activity (model 3) yielded no statistical significance (P > 0.05). Further subgroup analyses suggested that significance was only noted in subgroups with inactive or vigorous physical activity. Conclusions Our findings indicate that cumulative exposure and dynamic change patterns of MetSS were associated with FCMD and CMM, yet there is a modifiable effect of physical activity on the associations of cuMetSS and MetSS change patterns with FCMD risk. Graphical Abstract

Jingjing Zhang
Xiaoyu Ding
Qiuyi Xia
Jialin Cong
Hairong Zhang
Zhicheng Song
Li Wang
Anye Du
Yuan Yuan


Wearable cardioverter‐defibrillator: friend or foe in suspected myocarditis?

Abstract: Abstract Aim Wearable cardioverter defibrillator (WCD, LifeVest, and Zoll) therapy has become a useful tool to bridge a temporarily increased risk for sudden cardiac death. However, despite extensive use, there is a lack of evidence whether patients with myocarditis and impaired LVEF may benefit from treatment with a WCD. Methods and results We conducted a single‐centre retrospective observational study analysing patients with a WCD prescribed between September 2015 and April 2020 at our institution. In total, 135 patients were provided with a WCD, amongst these 76 patients (mean age 48.9 ± 13.7 years; 84.2% male) for clinically suspected myocarditis. Based on the results of the endomyocardial biopsy and, where available cardiac magnetic resonance imaging, 39 patients (51.3%) were diagnosed with myocarditis and impaired LVEF and 37 patients (48.7%) with dilated cardiomyopathy (DCM) without evidence of cardiac inflammation. The main immunohistopathological myocarditis subtype was lymphocytic myocarditis in 36 (92.3%) patients, and four patients (10.3%) of this group had an acute myocarditis. Three patients had cardiac sarcoidosis (7.7%). Ventricular tachycardia occurred in seven myocarditis (in total 41 VTs; 85.4% non‐sustained) and one DCM patients (in total one non‐sustained ventricular tachycardia). Calculated necessary WCD wearing time until ventricular tachycardia occurrence is 86.41 days in myocarditis compared with 6.46 years in DCM patients. Conclusions Our data suggest that myocarditis patients may benefit from WCD therapy. However, as our study is not powered for outcome, further randomized studies powered for the outcome morbidity and mortality are necessary.

Florian Blaschke
Philipp Lacour
Phi Long Dang
Abdul Shokor Parwani
Felix Hohendanner
Thula Walter
Karin Klingel
Uwe Kühl
Frank R. Heinzel
Mohammad Sherif
Leif‐Hendrik Boldt
Burkert Pieske
Carsten Tschöpe

Diseases of the circulatory (Cardiovascular) system


A CONSORT‐guided, randomized controlled clinical trial of nebulized administration of dexamethasone and saline on lower airway cytokine mRNA expression in horses with moderate asthma

Abstract: Abstract Background Nebulized administration of dexamethasone on cytokine regulation in horses with moderate asthma has not been investigated. Objective To investigate the changes in expression of inflammatory cytokine mRNA after nebulized administration of dexamethasone treatment of horses with moderate asthma. Animals Horses with naturally occurring moderate asthma (n = 16) and healthy control horses (n = 4). All horses were kept in a dusty environment during the study. Methods Prospective, parallel, randomized, controlled, blinded clinical trial. Blood endogenous cortisol, tracheal mucus, and bronchoalveolar lavage (BAL) were sampled before and after 13 days treatment with either nebulized administration of dexamethasone (15 mg once daily) or 0.9% saline (3 mL). Treatment groups were randomly allocated via randomization function (Microsoft Excel). Amplification of target mRNA in BAL fluid (IL‐1β, IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, IL‐12, IL‐17, IL‐23, IFN‐γ, Eotaxin‐2, and TNF‐α) was achieved by qPCR, and the relative expression software tool was used to analyze BAL inflammatory cytokine mRNA. Results Horses treated with nebulized administration of dexamethasone had increased relative expression of IL‐5 (1.70‐fold), IL‐6 (1.71‐fold), IL‐17 (3.25‐fold), IL‐12 (1.66‐fold), and TNF‐α (1.94‐fold), and decreased relative expression of IL‐23 (1.76‐fold; P = .04) in samples collected on Day 14, in comparison to samples collected on Day 0 (all P < .05). Horses treated with nebulized administration of saline had no significant difference in the relative expression of any gene (all P > .05). Conclusions and Clinical Importance Nebulized administration of dexamethasone was associated with increased expression of inflammatory cytokine mRNA. There was no improvement in inflammatory airway cytology associated with either dexamethasone or saline treatment.


Genetic analysis of suicide: a sample study in Tuscany (Central Italy)

Abstract: Many studies have examined the genetic contribution to suicide. However, data on suicide in the Italian population are scarce. We therefore aimed to address this gap by investigating a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence, Italy between 2007 and 2017. This cohort included 86 men and 25 women. DNA samples were obtained from tissues or blood, and 22 genes from multiple neurobiological pathways previously shown to be associated with the pathogenesis of suicide were analysed. Next-generation sequencing was used to compare these gene sequences with those from a large, normal population. In this study, we identified 19 gene variants that were present at significantly lower frequencies in our Italian cohort than in the general population. In addition, four missense mutations were identified in four different genes: Monoamine Oxidase A (MAOA), 5-Hydroxytryptamine Receptor 2 A (HTR2A), Sodium Voltage-Gated Channel Alpha Subunit 8 (SCN8A), and Nitric Oxide Synthase 3 (NOS3). Our study identified several potential genetic links with suicide in a cohort of Italians and supports a relationship between specific genetic variants and suicidal behaviour in this population. Key pointsThis study shows a genetic analysis of suicide.This study examines a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence, Italy between 2007 and 2017. DNA samples were obtained from tissues or blood, and 22 genes from multiple neurobiological pathways were investigated.The study supports a relationship between specific genetic variants and suicidal behaviour.

Martina Focardi
Barbara Gualco
Vilma Pinchi
Norelli Gian-Aristide
Regina Rensi
Elisabetta Pelo
Ilaria Carboni
Ugo Ricci

Criminal law and procedure
Public aspects of medicine


Echocardiographic Evaluation of Indices of Severity of Pulmonary Stenosis in Dogs: Reproducibility and Effects of General Anesthesia

Abstract: ABSTRACT Background The effects of general anesthesia (GA) on less flow‐dependent (velocity ratio, velocity time integral [VTI] ratio and indexed pulmonary valve area [iPVA]) and flow‐dependent (mean [PVmeanPG] and maximum pressure gradient [PVmaxPG]) indices of severity of pulmonary stenosis (PS) are unclear. Objectives Determine the effects of GA on indices of severity of PS in dogs undergoing an interventional procedure (IP). Determine the reproducibility of indices of severity of PS. Animals Thirty‐nine dogs with PS. Methods Prospective cross‐sectional study. Five repeated echocardiograms were performed over 3 days. Day 1: two echocardiograms were performed by 2 different operators. Day 2: echocardiograms were performed before and after GA but before IP. Day 3: an echocardiogram was performed after the IP. Results After GA, median (IQR) cardiac index (2.1 [1.6–2.6] L/min/m2), PVmeanPG (45.0 [26.0–55.2] mmHg), PVmaxPG (76.6 [46.6–100.3] mmHg) were decreased (p ≤0.001) compared to before GA (2.8 [2.2–3.0] L/min/m2, 55.9 [47.6–73.1] mmHg, 96.1 [81.6–127.0] mmHg, respectively). There were no differences (p ≥0.35) in velocity ratio, VTI ratio, or iPVA after GA. Intra‐operator and inter‐operator coefficients of variation (95% CI) were highest for iPVA (13.8% [10.4–18.4] and 13.5% [11.0–18.4], respectively) and lowest for velocity ratio (9.2% [7.7–12.3] and 9.3% [7.7–12.4], respectively). Conclusions and Clinical Importance PVmeanPG and PVmaxPG might be misleading in states of reduced flow. An integrative assessment of severity of PS that includes less flow‐dependent indices is recommended. Reproducibility of indices of severity of PS should be considered when re‐evaluating dogs with PS.

Evan S. Ross
Lance C. Visser
Lalida Tantisuwat
Khursheed Mama
Brianna M. Potter
Brian A. Scansen


Re‐do MitraClip in patients with functional mitral valve regurgitation and advanced heart failure

Abstract: Abstract Aim Percutaneous mitral valve repair (PMVR) via MitraClip implantation is a therapeutic option for severe mitral regurgitation (MR) in advanced stages of heart failure (HF). However, progressive left ventricular dilation in these patients may lead to recurrent MR after PMVR and consequent re‐do MitraClip implantation. Here, we describe the characteristics and outcomes of this clinical scenario. Methods and results Patients with systolic HF and functional MR undergoing a re‐do MitraClip procedure were retrospectively analysed. Inclusion criteria were age ≥18 years, technical, device and procedural success at first MitraClip procedure, functional MR and systolic HF with an ejection fraction (EF) of <45%. Seventeen out of 684 patients undergoing PMVR with the MitraClip device at our institution between September 2009 and July 2019 were included. All patients displayed advanced HF with an EF of 20% (±9.9) and highly elevated N‐terminal pro‐brain natriuretic peptide. Technical success of the re‐do MitraClip procedure was 100%, whereas procedural and device success were only achieved in 11 patients (65%). Unsuccessful re‐do procedures were related to lower EF and implantation of more than one clip at initial procedure. However, despite reduction in MR grade and no occurrence of significant mitral stenosis after the procedure, the mortality during 12 months follow‐up remained high (8 of 17; 47%). Conclusions In a cohort of patients with advanced HF undergoing PMVR, re‐do MitraClip procedure was feasible, but procedural success was unsatisfactory and morbidity and mortality remained high, possibly reflecting the advanced stage of HF in these patients.

Michael M. Kreusser
Andreas Weber
Nicolas A. Geis
Leonie Grossekettler
Martin J. Volz
Sonja Hamed
Hugo A. Katus
Sven T. Pleger
Norbert Frey
Philip W. Raake


HEART Camp Connect—Promoting adherence to exercise in adults with heart failure with preserved ejection fraction

Abstract: Abstract Aims Most adults with stable heart failure are safe to exercise at a moderate intensity for 150 min/week. Regular participation in exercise may improve outcomes in adults with heart failure with preserved ejection fraction (HFpEF). Few adults with HFpEF initiate and sustain long‐term exercise. To promote exercise adherence in adults with HFpEF, we developed the Heart Failure Exercise and Resistance Training (HEART) Camp Connect intervention that is tested in this clinical trial. This trial tests our central hypothesis that theory‐informed coaching strategies delivered virtually will promote long‐term adherence to exercise in adults with HFpEF and drive clinically meaningful, and cost‐effective improvements in physiological and patient‐reported outcomes. Our aims are to (a) evaluate the effects of virtual and in‐person exercise and coaching on long‐term adherence, (b) determine a benchmark of minutes of moderate intensity exercise associated with health status as related to key biobehavioural outcomes, (c) examine behaviour change theory‐defined constructs as mediators of exercise adherence and (d) evaluate intervention costs. Methods This 18 month, three‐group, repeated measures randomized controlled trial is enrolling 300 adults with HFpEF. Participants are randomized to enhanced usual care (EUC), virtual coaching, or in‐person coaching. Our intervention applies coaching strategies, informed by behaviour change theories, in one‐on‐one and group settings weekly for 12 months. Our objective is to compare the effects of each delivery method to the other and EUC on exercise adherence (defined as ≥ 120 min of moderate intensity exercise/week) at 12 months (primary endpoint) and 18 months (sustainability endpoint). Secondary outcomes include minutes of moderate intensity exercise needed to drive minimal clinically important differences in health status, biomarkers, patient‐reported symptoms and cost. Behaviour change theory‐defined constructs (e.g., self‐efficacy and outcome expectations) will be tested as mediators of exercise adherence. Results We expect that virtual coaching is equally as efficacious and more cost effective at promoting exercise adherence as in‐person coaching. Effects on exercise adherence may be mediated by theory‐defined constructs. We also expect to identify a threshold for minutes of moderate intensity exercise to potentially serve as an adherence benchmark in adults with HFpEF, one that may differ from the 120 min of exercise in our current definition. Conclusions These findings could shift the paradigm of exercise coaching in HF towards virtual delivery and increase the generalizability and reach of exercise training. This is especially important for adults with HFpEF as they are excluded from Medicare reimbursement for traditional cardiopulmonary rehabilitation.

Windy W. Alonso
Sara E. Bills
Scott W. Lundgren
Steven J. Keteyian
Joseph Norman
Alfred L. Fisher
Cheng Zheng
Kevin A. Kupzyk
Fernando A. Wilson
Tiffany J. Dudley
Bunny J. Pozehl


Early detection of anthracycline‐ and trastuzumab‐induced cardiotoxicity: value and optimal timing of serum biomarkers and echocardiographic parameters

Abstract: Abstract Aims To evaluate echocardiographic and biomarker changes during chemotherapy, assess their ability to early detect and predict cardiotoxicity and to define the best time for their evaluation. Methods and results Seventy‐two women with breast cancer (52 ± 9.8 years) treated with anthracyclines (26 also with trastuzumab), were evaluated for 14 months (6 echocardiograms/12 laboratory tests). We analysed: high‐sensitivity cardiac troponin T, NT‐proBNP, global longitudinal strain (GLS), left ventricle end‐systolic volume (LVESV), left ventricle end‐diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF). Cardiotoxicity was defined as a reduction in LVEF>10% compared with baseline with LVEF<53%. High‐sensitivity troponin T levels rose gradually reaching a maximum peak at 96 ± 13 days after starting chemotherapy (P < 0.001) and 62.5% of patients presented increased values during treatment. NT‐proBNP augmented after each anthracycline cycle (mean pre‐cycle levels of 72 ± 68 pg/mL and post‐cycle levels of 260 ± 187 pg/mL; P < 0.0001). Cardiotoxicity was detected in 9.7% of patients (mean onset at 5.2 months). In the group with cardiotoxicity, the LVESV was higher compared with those without cardiotoxicity (40 mL vs. 29.5 mL; P = 0.045) at 1 month post‐anthracycline treatment and the decline in GLS was more pronounced (−17.6% vs. −21.4%; P = 0.03). Trastuzumab did not alter serum biomarkers, but it was associated with an increase in LVESV and LVEDV (P < 0.05). While baseline LVEF was an independent predictor of later cardiotoxicity (P = 0.039), LVESV and GLS resulted to be early detectors of cardiotoxicity [odds ratio = 1.12 (1.02–1.24), odds ratio = 0.66 (0.44–0.92), P < 0.05] at 1 month post‐anthracycline treatment. Neither high‐sensitivity troponin T nor NT‐proBNP was capable of predicting subsequent cardiotoxicity. Conclusions One month after completion of anthracycline treatment is the optimal time to detect cardiotoxicity by means of imaging parameters (LVESV and GSL) and to determine maximal troponin rise. Baseline LVEF was a predictor of later cardiotoxicity. Trastuzumab therapy does not affect troponin values hence imaging techniques are recommended to detect trastuzumab‐induced cardiotoxicity.

Belén Díaz‐Antón
Rodrigo Madurga
Blanca Zorita
Samantha Wasniewski
Andrea Moreno‐Arciniegas
Beatriz López‐Melgar
Natalia Ramírez Merino
Roberto Martín‐Asenjo
Patricia Barrio
Maximiliano German Amado Escañuela
Jorge Solís
Francisco Javier Parra Jiménez
Eva Ciruelos
José María Castellano
Leticia Fernández‐Friera


Abstract: Introduction: The pelvic floor muscle (PFM) could affect female sexual functions. The hip muscles are morphologically and functionally linked to PFM and are important elements of female sexual attraction. Aim: To determine the relationship between female sexual function and hip muscle strength and PFM functions in women with stress urinary incontinence (SUI). Methods: A total of 42 women with SUI were recruited in this study. Female sexual function was measured using the pelvic organ prolapse urinary incontinence sexual function questionnaire (PISQ). PFM functions were measured using a perineometer. Hip muscle strength was measured using a Smart KEMA tension sensor. The relationship between female sexual function and PFM function and hip muscle strength was assessed using Pearson correlation coefficients and multiple regression analyses with forward selection. Main Outcome Measures: PISQ score, PFM functions (strength and endurance), and strength of hip extensor, abductor, and adductor were the main outcome measures. Results: For the behavioral/emotive domain in the PISQ, hip extensor strength (r = 0.452), PFM strength (r = 0.441), PFM endurance (r = 0.362), and hip adductor strength (r = 0.324) were significantly correlated and hip extensor strength emerged in multiple regression. For the physical domain in the PISQ, hip abductor strength (r = 0.417), PFM endurance (r = 0.356), hip adductor strength (r = 0.332), and PFM strength (r = 0.322) were significantly correlated and hip abductor strength entered in multiple regression. For partner-related domain in the PISQ, hip adductor (r = 0.386) and abductor strength (r = 0.314) were significantly correlated and hip adductor strength appeared in multiple regression. For the PISQ total score, hip extensor strength (r = 0.484), PFM endurance (r = 0.470), hip adductor strength (r = 0.424), hip abductor strength (r = 0.393), and PFM strength (r = 0.387) were significantly correlated and hip extensor strength and PFM endurance emerged in multiple regression. Conclusion: The female sexual function could be related to not only PFM functions but also hip muscle strength in women with SUI. Hwang UJ, Lee MS, Jung SH, Ahn SH, Kwon OY. Relationship Between Sexual Function and Pelvic Floor and Hip Muscle Strength in Women With Stress Urinary Incontinence. Sex Med 2021;9:100325.

U.J. Hwang, PhD, PT
M.S. Lee, PhD, MD
S.H. Jung, PhD, PT
S.H. Ahn, MS, PT
O.Y. Kwon, PhD, PT


From BIG Data Center to China National Center for Bioinformation

Computer applications to medicine. Medical informatics


Pollutants and fish predator/prey behavior: A review of laboratory and field approaches

Abstract: Fish behavior can be altered by contaminants. There is an extensive literature on laboratory behavioral assays, with many chemicals impairing feeding or predator avoidance. However, there is not extensive work on fishes that live in contaminated environments. Therefore, we then review our recent research on feeding and trophic relations of populations from contaminated estuaries compared with relatively unpolluted sites. The mummichog Fundulus heteroclitus, is a non-migratory fish; those from more contaminated areas are poor predators and slower to capture active prey (grass shrimp, Palaemonetes pugio). In the field, they consume much detritus and sediment, which is not nutritious. They are less active than fish from cleaner sites and more vulnerable to predation. They have altered thyroid glands and neurotransmitter levels, which may underlie altered behaviors. Fish from the reference site kept in tanks with sediment and food from the polluted site showed bioaccumulation and reduced prey capture after two months, although fish from the polluted site did not show significant improvement when maintained in a clean environment. Poor nutrition and predator avoidance may be responsible for their being smaller and having a shorter life span than reference fish. Bluefish Pomatomus saltatrix, are a marine species in which the young-of-the-year spend their first summer in estuaries. We found bioaccumulation of contaminants and reduced activity, schooling, and feeding in young-of-the-year bluefish from a relatively unpolluted site that were fed prey fish from a contaminated site. They also had altered thyroid glands and neurotransmitter levels. Many field-caught specimens had empty stomachs, which is rare in this species. In the fall, when they migrate back out to the ocean, they are smaller, slower, and more likely to starve or to be eaten than those that spent their summer in cleaner estuaries [Current Zoology 58 (1): 9-20, 2012].


Unravelling the interplay of ecological processes structuring the bacterial rare biosphere

Abstract: Abstract Most ecological communities harbor many rare species (i.e., the rare biosphere), however, relatively little is known about how distinct ecological processes structure their existence. Here, we used spatiotemporal data on soil bacterial communities along a natural ecosystem gradient to model the relative influences of assembly processes structuring the rare and common biospheres. We found a greater influence of homogeneous selection (i.e., imposed by spatiotemporally constant variables) mediating the assembly of the rare biosphere, whereas the common biosphere was mostly governed by variable selection (i.e., imposed by spatial and/or temporal fluctuating variables). By partitioning the different types of rarity, we found homogeneous selection to explain the prevalence of permanently rare taxa, thus suggesting their persistence at low abundances to be restrained by physiological traits. Conversely, the dynamics of conditionally rare taxa were mostly structured by variable selection, which aligns with the ability of these taxa to switch between rarity and commonness as responses to environmental spatiotemporal variations. Taken together, our study contributes to the establishment of a link between conceptual and empirical developments in the ecology of the soil microbial rare biosphere. Besides, this study provides a framework to better understand, model, and predict the existence and dynamics of microbial rare biospheres across divergent systems and scales.

Xiu Jia
Francisco Dini-Andreote
Joana Falcão Salles


HFA of the ESC Position paper on the management of LVAD supported patients for the non LVAD specialist healthcare provider Part 1: Introduction and at the non‐hospital settings in the community

Abstract: Abstract The accepted use of left ventricular assist device (LVAD) technology as a good alternative for the treatment of patients with advanced heart failure together with the improved survival of the LVAD‐supported patients on the device and the scarcity of donor hearts has significantly increased the population of LVAD‐supported patients. The expected and non‐expected device‐related and patient–device interaction complications impose a significant burden on the medical system exceeding the capacity of the LVAD implanting centres. The ageing of the LVAD‐supported patients, mainly those supported with the ‘destination therapy’ indication, increases the risk for those patients to experience comorbidities common in the older population. The probability of an LVAD‐supported patient presenting with medical emergency to a local emergency department, internal, or surgical ward of a non‐LVAD implanting centre is increasing. The purpose of this trilogy is to supply the immediate tools needed by the non‐LVAD specialized physician: ambulance clinicians, emergency ward physicians, general cardiologists, internists, anaesthesiologists, and surgeons, to comply with the medical needs of this fast‐growing population of LVAD‐supported patients. The different issues discussed will follow the patient's pathway from the ambulance to the emergency department and from the emergency department to the internal or surgical wards and eventually to the discharge home from the hospital back to the general practitioner. In this first part of the trilogy on the management of LVAD‐supported patients for the non‐LVAD specialist healthcare provider, after the introduction on the assist devices technology in general, definitions and structured approach to the assessment of the LVAD‐supported patient in the ambulance and emergency department is presented including cardiopulmonary resuscitation for LVAD‐supported patients.

Binyamin Ben Avraham
Marisa Generosa Crespo‐Leiro
Gerasimos Filippatos
Israel Gotsman
Petar Seferovic
Tal Hasin
Luciano Potena
Davor Milicic
Andrew J.S. Coats
Giuseppe Rosano
Frank Ruschitzka
Marco Metra
Stefan Anker
Johann Altenberger
Stamatis Adamopoulos
Yaron D. Barac
Ovidiu Chioncel
Nicolaas De Jonge
Jeremy Elliston
Maria Frigeiro
Eva Goncalvesova
Avishay Grupper
Righab Hamdan
Yoav Hammer
Loreena Hill
Osnat Itzhaki Ben Zadok
Miriam Abuhazira
Jacob Lavee
Wilfried Mullens
Sanemn Nalbantgil
Massimo F. Piepoli
Piotr Ponikowski
Arsen Ristic
Arjang Ruhparwar
Aviv Shaul
Laurens F. Tops
Steven Tsui
Stephan Winnik
Tiny Jaarsma
Finn Gustafsson
Tuvia Ben Gal


Biomechanical Stimulation of Muscle Constructs Influences Phenotype of Bone Constructs by Modulating Myokine Secretion

Abstract: ABSTRACT Diabetes is a chronic metabolic disorder that can lead to diabetic myopathy and bone diseases. The etiology of musculoskeletal complications in such metabolic disorders and the interplay between the muscular and osseous systems are not well understood. Exercise training promises to prevent diabetic myopathy and bone disease and offer protection. Although the muscle‐bone interaction is largely biomechanical, the muscle secretome has significant implications for bone biology. Uncoupling effects of biophysical and biochemical stimuli on the adaptive response of bone during exercise training may offer therapeutic targets for diabetic bone disease. Here, we have developed an in vitro model to elucidate the effects of mechanical strain on myokine secretion and its impact on bone metabolism decoupled from physical stimuli. We developed bone constructs using cross‐linked gelatin, which facilitated osteogenic differentiation of osteoprogenitor cells. Then muscle constructs were made from fibrin, which enabled myoblast differentiation and myotube formation. We investigated the myokine expression by muscle constructs under strain regimens replicating endurance (END) and high‐intensity interval training (HIIT) in hyperglycemic conditions. In monocultures, both regimens induced higher expression of Il15 and Igf1, whereas END supported more myoblast differentiation and myotube maturation than HIIT. When co‐cultured with bone constructs, HIIT regimen increased Glut4 expression in muscle constructs more than END, supporting higher glucose uptake. Likewise, the muscle constructs under the HIIT regimen promoted a healthier and more matured bone phenotype than END. Under static conditions, myostatin (Mstn) expression was significantly downregulated in muscle constructs co‐cultured with bone constructs compared with monocultures. Together, our in vitro co‐culture system allowed orthogonal manipulation of mechanical strain on muscle constructs while facilitating bone‐muscle biochemical cross‐talk. Such systems can provide an individualized microenvironment that allows decoupled biomechanical manipulation, help identify molecular targets, and develop engineered therapies for metabolic bone disease. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Harshini Suresh Kumar
Edwina N. Barnett
John L. Fowlkes
Evangelia Kalaitzoglou
Ramkumar T. Annamalai

Orthopedic surgery
Diseases of the musculoskeletal system


Abstract: Introduction: Dehydroepiandrosterone sulfate (DHEAS) has been reported to be associated with sexual function and general psychological health respectively, however, no one has ever examined their mutual relationships in a single study. Aim: The aim of the present study was to find out whether DHEAS, general psychological health, and erectile function were all associated with each other. Methods: A cross-sectional study was conducted on 34 patients with erectile dysfunction (ED) and 32 healthy controls (HC). The levels of serum DHEAS were assessed by chemiluminescence method. Erectile function and general psychological health were measured by International Index for Erectile Function-5 (IIEF-5) and General Health Questionnaire 20(GHQ-20) respectively. Main Outcome measure: The primary outcome measure of this study was the mutual correlations of serum DHEAS levels, general psychological health and erectile function. Results: Compared to HC, patients with ED had a significant lower serum levels of DHEAS (6.43 ± 2.70 μmol/L vs 9.48 ± 2.82 μmol/L, P < .001) and higher scores on GHQ-20 (35.06 ± 8.56 vs 24.97 ± 2.55, P < .001). Multivariate binary logistic regression showed that both serum levels of DHEAS (OR = 0.667, 95% CI = 0.512–0.869, P = .003) and psychological distress (scores of GHQ-20 > 28) (OR = 6.921, 95% CI = 1.821–26.305, P = .005) were significantly associated with ED. However, no significant association between psychological distress and serum levels of DHEAS was found (OR = 0.798, 95% CI = 0.623–1.021, P = .072) after controlling for ED. Partial correlation analysis revealed that both scores of GHQ-20 (r = −0.595, P < .001) and DHEAS (r = 0.450, P < .001) were significantly correlated with scores of IIEF-5, while no significant relationship was found between scores of GHQ-20 and DHEAS (r = 0.116, P = .363) after controlling for scores of IIEF-5 and age. Conclusion: Both serum levels of DHEAS and general psychological health are significantly associated with erectile dysfunction in sexually active adult men but the relationship between general psychological health and erectile function seems to be independent of DHEAS.Li K, Liang S, Shi Y, et al. The Relationships of Dehydroepiandrosterone Sulfate, Erectile Function and General Psychological Health. Sex Med 2021;9:100386.

Kanglai Li, BD
Shangyan Liang, MD
Yuyan Shi, BD
Ying Zhou, MD
Liping Xie, BD
Jiali Feng, BD
Zhongcheng Chen, MD
Qingling Li, MD
Zhaoyu Gan, PhD


Recent advances in cardio‐oncology: a report from the ‘Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019’

Abstract: Abstract While anti‐cancer therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted therapy, are constantly advancing, cardiovascular toxicity has become a major challenge for cardiologists and oncologists. This has led to an increasing demand of cardio‐oncology units in Europe and a growing interest of clinicians and researchers. The Heart Failure 2019 meeting of the Heart Failure Association of the European Society of Cardiology in Athens has therefore created a scientific programme that included four dedicated sessions on the topic along with several additional lectures. The major points that were discussed at the congress included the implementation and delivery of a cardio‐oncology service, the collaboration among cardio‐oncology experts, and the risk stratification, prevention, and early recognition of cardiotoxicity. Furthermore, sessions addressed the numerous different anti‐cancer therapies associated with cardiotoxic effects and provided guidance on how to treat cancer patients who develop cardiovascular disease before, during, and after treatment.

for the Heart Failure Association Cardio‐Oncology Study Group of the European Society of Cardiology


Neural stem cell treatment for perinatal brain injury: A systematic review and meta‐analysis of preclinical studies

Abstract: Abstract Perinatal brain injury can lead to significant neurological and cognitive deficits and currently no therapies can regenerate the damaged brain. Neural stem cells (NSCs) have the potential to engraft and regenerate damaged brain tissue. The aim of this systematic review was to evaluate the preclinical literature to determine whether NSC administration is more effective than controls in decreasing perinatal brain injury. Controlled interventional studies of NSC therapy using animal models of perinatal brain injury were identified using MEDLINE and Embase. Primary outcomes were brain infarct size, motor, and cognitive function. Data for meta‐analysis were synthesized and expressed as standardized mean difference (SMD) with 95% confidence intervals (CI), using a random effects model. We also reported secondary outcomes including NSC survival, migration, differentiation, and effect on neuroinflammation. Eighteen studies met inclusion criteria. NSC administration decreased infarct size (SMD 1.09; CI: 0.44, 1.74, P = .001; I2 = 74%) improved motor function measured via the impaired forelimb preference test (SMD 2.27; CI: 0.85, 3.69, P = .002; I2 = 86%) and the rotarod test (SMD 1.88; CI: 0.09, 3.67, P = .04; I2 = 95%). Additionally, NSCs improved cognitive function measured via the Morris water maze test (SMD of 2.41; CI: 1.16, 3.66, P = .0002; I2 = 81%). Preclinical evidence suggests that NSC therapy is promising for the treatment of perinatal brain injury. We have identified key knowledge gaps, including the lack of large animal studies and uncertainty regarding the necessity of immunosuppression for NSC transplantation in neonates. These knowledge gaps should be addressed before NSC treatment can effectively progress to clinical trial.

Madeleine J. Smith
Madison Claire Badawy Paton
Michael C. Fahey
Graham Jenkin
Suzanne L. Miller
Megan Finch‐Edmondson
Courtney A. McDonald


Impact of a cardio‐oncology unit on prevention of cardiovascular events in cancer patients

Abstract: Abstract Aims As the world population grows older, the co‐existence of cancer and cardiovascular comorbidities becomes more common, complicating management of these patients. Here, we describe the impact of a large Cardio‐Oncology unit in Southern Italy, characterizing different types of patients and discussing challenges in therapeutic management of cardiovascular complications. Methods and results We enrolled 231 consecutive patients referred to our Cardio‐Oncology unit from January 2015 to February 2020. Three different types were identified, according to their chemotherapeutic statuses at first visit. Type 1 included patients naïve for oncological treatments, Type 2 patients already being treated with oncological treatments, and Type 3 patients who had already completed cancer treatments. Type 2 patients presented the highest incidence of cardiovascular events (46.2% vs. 12.3% in Type 1 and 17.9% in Type 3) and withdrawals from oncological treatments (5.1% vs. none in Type 1) during the observation period. Type 2 patients presented significantly worse 48 month‐survival (32.1% vs. 16.7% in Type 1 and 17.9% in Type 3), and this was more evident when in the three groups we focused on patients with uncontrolled cardiovascular risk factors or overt cardiovascular disease at the first cardiologic assessment. Nevertheless, these patients showed the greatest benefit from our cardiovascular assessments, as witnessed by a small, but significant improvement in ejection fraction during follow‐up (Type 2b: from 50 [20; 67] to 55 [35; 65]; P = 0.04). Conclusions Patients who start oncological protocols without an accurate baseline cardiovascular evaluation are at major risk of developing cardiac complications due to antineoplastic treatments.

Alessandra Cuomo
Valentina Mercurio
Gilda Varricchi
Maria Rosaria Galdiero
Francesca Wanda Rossi
Antonio Carannante
Grazia Arpino
Luigi Formisano
Roberto Bianco
Chiara Carlomagno
Carmine De Angelis
Mario Giuliano
Elide Matano
Marco Picardi
Domenico Salvatore
Ferdinando De Vita
Erika Martinelli
Carminia Maria Della Corte
Floriana Morgillo
Michele Orditura
Stefania Napolitano
Teresa Troiani
Carlo G. Tocchetti


Investigation of the presence of specific neural antibodies in dogs with epilepsy or dyskinesia using murine and human assays

Abstract: Abstract Background Autoimmune mechanisms represent a novel category for causes of seizures and epilepsies in humans, and LGI1‐antibody associated limbic encephalitis occurs in cats. Hypothesis/Objectives To investigate the presence of neural antibodies in dogs with epilepsy or dyskinesia of unknown cause using human and murine assays modified for use in dogs. Animals Fifty‐eight dogs with epilepsy of unknown cause or suspected dyskinesia and 57 control dogs. Methods Serum and CSF samples were collected prospectively as part of the diagnostic work‐up. Clinical data including onset and seizure/episode type were retrieved from the medical records. Screening for neural antibodies was done with cell‐based assays transfected with human genes for typical autoimmune encephalitis antigens and tissue‐based immunofluorescence assays on mouse hippocampus slices in serum and CSF samples from affected dogs and controls. The commercial human und murine assays were modified with canine‐specific secondary antibody. Positive controls were from human samples. Results The commercial assays used in this study did not provide unequivocal evidence for presence of neural antibodies in dogs including one dog with histopathologically proven limbic encephalitis. Low titer IgLON5 antibodies were present in serum from one dog from the epilepsy/dyskinesia group and in one dog from the control group. Conclusion and Clinical Importance Specific neural antibodies were not detected using mouse and human target antigens in dogs with epilepsy and dyskinesia of unknown origin. These findings emphasize the need for canine‐specific assays and the importance of control groups.

Lea Hemmeter
Christian G. Bien
Corinna I. Bien
Andrea Tipold
Jasmin Neßler
Andrea Bathen‐Nöthen
Kaspar Matiasek
Maik Dahlhoff
Clare Rusbridge
Carina Rotter Black
Kai Rentmeister
Holger A. Volk
Andrea Fischer


Internal Carotid Artery Ectasia: The Value of Imaging Studies Prior to Biopsy of a Retropharyngeal Mass

Abstract: The presence of retropharyngeal tissue mass often raises the suspicion of malignancy, especially in elderly patients. This prompts urgent biopsy to investigate tissue histology. We discuss a case where this is contraindicated as the retropharyngeal mass was illustrated by CT scanning and confirmed with MRI to be a tortuous coursing internal carotid artery. An awareness of this unusual anatomical variation and a careful interpretation of imaging studies both at the stage of differential diagnosis and pre-operative screening are essential to avoid damage to important structures, causing unnecessary complications.

Kenneth Chan
Polly S Richards
Mike G Dilkes


Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell‐free products and human pluripotent stem cell‐derived mesenchymal stem cells

Abstract: Abstract Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.

Li‐Tzu Wang
Ko‐Jiunn Liu
Huey‐Kang Sytwu
Men‐Luh Yen
B. Linju Yen


Papillary thyroid carcinoma presenting as an asymptomatic pelvic bone metastases

Abstract: Thyroid carcinoma is rare comprising 1% of all malignancies and commonly presents as a neck lump. Papillary thyroid carcinoma unlike follicular thyroid carcinoma tends not to metastasise to distant sites.We present a case of papillary thyroid carcinoma presenting as a solitary asymptomatic pelvic bone metastases and highlight current management of bone metastases. A 59-year old female was found on abdominal computerised tomography to have an incidental finding of a 4.5 cm soft tissue mass in the right iliac bone. Biopsy of the lesion confirmed metastatic thyroid carcinoma. There was no history of a neck lump, head and neck examination was normal. Further imaging confirmed focal activity in the right lobe of the thyroid. A total thyroidectomy and level VI neck dissection was performed and histology confirmed follicular variant of papillary carcinoma.Early detection of bone metastases have been shown to improve prognosis and thyroid carcinoma should be considered as a potential primary malignancy.


Abstract: ABSTRACT:  Introduction: Treatment for vulvodynia is challenging and a multidisciplinary approach is recommended. Aim: To examine the effectiveness, safety and treatment satisfaction of vulvovaginal microablative laser treatment for vulvodynia. Methods: Case study of women who received laser treatment as part of a multidisciplinary treatment program for vulvodynia. Subjective improvement was compared to a retrospective cohort of women treated for vulvodynia without LASER therapy. LASER treatment was offered to women with vulvodynia presenting to a gynecologic pain clinic of a tertiary university hospital. LASER treatments were performed with a microablative 2,940 nm Er:YAG LASER and potentially repeated after 1 month. Main outcome measures: Change in local vulvar pain was assessed with cotton-swab tests and rated on a numeric rating scale (NRS). Treatment discomfort and short-term adverse events were recorded. The Freiburg Index of Patient Satisfaction was used to assess treatment satisfaction. Subjective symptom improvement was assessed with the Patient Global Impression of Improvement questionnaire. Results: 35 women received at least 1 laser treatment, with overall mild treatment adverse effects (mean pain NRS 2.4 ± 1.9) and good treatment satisfaction (mean total score of 27.6 ±5.1; potential range 8–32). One month after last LASER treatment the pain NRS on vulvar cotton swab test improved from 6.1 ± 2.6 at baseline to 3.1 ± 2.6 (P < .001), and 74% of women (n = 26) reported symptom improvement. At 9–12 months follow-up 66% reported ongoing symptom improvement, with no significant difference to the control group of 32 women. Conclusion: Microablative Er:YAG vulvovaginal LASER therapy appears safe and well accepted among vulvodynia patients, but there was no significant difference in symptom improvement compared to a control group.Trutnovsky G, Bliem B, Greimel E, et al. Microablative Erbium: YAG Laser Therapy for Vulvodynia – A Report on Efficacy, Safety, and Treatment Satisfaction. Sex Med 2021;9:100432.

Gerda Trutnovsky, MD
Brigitte Bliem, MD
Elfriede Greimel, PhD
Karl Tamussino, MD
Daniela Gold, PhD


Epinephrine infusion during venoarterial extracorporeal membrane oxygenation support for cardiogenic shock: simply inefficient or deleterious?


Clinical utility of fungal culture and antifungal susceptibility in cats and dogs with histoplasmosis

Abstract: Abstract Background Culture can be used for diagnosis and antifungal susceptibility testing in animals with fungal infections. Limited information is available regarding the diagnostic performance of culture and the susceptibility patterns of Histoplasma spp. isolates. Hypothesis/Objectives Describe the clinical utility of culture and the susceptibility patterns of Histoplasma spp. isolates causing histoplasmosis in cats and dogs. Animals Seventy‐one client‐owned animals, including 33 cats and 19 dogs with proven or probable histoplasmosis. Methods Culture was attempted from tissue or fluid samples. Diagnostic performance of culture, cytopathology, and antigen detection were compared with final diagnosis. Susceptibility to antifungal agents was determined for a subset (11 from dogs, 9 from cats) of culture isolates. Results Culture had a diagnostic sensitivity of 17/33 (52%; 95% confidence interval [CI], 34%‐69%) and 15/19 (79%; 95% CI, 61%‐97%) and specificity of 6/6 (100%; 95% CI, 54%‐100%) and 10/10 (100%; 95% CI, 69%‐100%) in cats and dogs, respectively. Culture was not positive in any animal in which cytopathology and antigen testing were negative. Target drug exposure (area under the concentration curve [AUC]/minimum inhibitory concentration [MIC] >25) should be easily achieved for all isolates for itraconazole, voriconazole, or posaconazole. Five of 20 (25%) isolates had fluconazole MIC ≥32 μg/mL and achieving target drug exposure is unlikely. Conclusions and Clinical Importance Fungal culture did not improve diagnostic sensitivity when used with cytopathology and antigen detection. Susceptibility testing might help identify isolates for which fluconazole is less likely to be effective.

Andrew S. Hanzlicek
Kate S. KuKanich
Audrey K. Cook
Steven Hodges
John M. Thomason
Rupika DeSilva
Akhilesh Ramachandran
Michelle M. Durkin


Vitamin D Receptor Expression in Dogs

Abstract: Background There is growing evidence linking low blood vitamin D concentration to numerous diseases in people and in dogs. Vitamin D influences cellular function by signaling through the vitamin D receptor (VDR). Little is known about which non‐skeletal tissues express the VDR or how inflammation influences its expression in the dog. Objectives To define which non‐skeletal canine tissues express the VDR and to investigate expression in inflamed small intestine. Animals Thirteen non‐skeletal tissues were collected prospectively from 6 control dogs. Thirty‐five dogs diagnosed with a chronic enteropathy (CE) and 24 control dogs were prospectively enrolled and duodenal biopsies were evaluated for VDR expression. Methods Prospective; blinded assessment of canine intestinal VDR. Dogs with CE were included once other identifiable causes of intestinal disease were excluded. Age matched controls were included with no intestinal clinical signs. VDR expression was assessed immunohistochemically in all samples, using a Rat IgG VDR monoclonal antibody. Quantitative real‐time polymerase chain reaction (qPCR) was also used for duodenal biopsies. Results VDR expression as assessed by immunohistochemistry (IHC) was highest in the kidney, duodenum, skin, ileum and spleen, and weak in the colon, heart, lymph node, liver, lung, and ovary. Gastric and testicular tissue did not express the VDR. There was no statistical difference in duodenal VDR expression between the 24 healthy dogs and 34 dogs with CE when quantified by either qPCR (P = 0.87) or IHC (P = 0.099). Conclusions and Clinical Importance The lack of down regulation of VDR expression in inflamed intestine contrasts with previous studies in humans. Our findings support future studies to investigate whether vitamin D and its analogues can be used to modulate intestinal inflammation in the dog.

J.A. Cartwright
A.G. Gow
E. Milne
D. Drummond
S. Smith
I. Handel
R.J. Mellanby


A novel Huntington's disease mouse model to assess the role of neuroinflammation on disease progression and to develop human cell therapies

Abstract: Abstract Huntington's disease (HD) is a fatal autosomal‐dominant neurodegenerative disease caused by a trinucleotide CAG repeat expansion of the huntingtin gene (HTT) that affects 1 in every 10 000 individuals in the United States. Our lab developed a novel immune deficient HD mouse strain, the YACNSG, from a commonly used line, the YAC128 mouse, to enable transplantation studies using engineered human cells in addition to studying the impact of the immune system on disease progression. The primary goal of this project was to characterize this novel immune deQficient HD mouse model, using behavioral assays and histology to compare this new model to the immune competent YAC128 and immune deficient mice that had engraftment of a human immune system. Flow cytometry was used to confirm that the YACNSG strain lacked immune cells, and in vivo imaging was used to assess human mesenchymal stem/stromal cell (MSC) retention compared with a commonly used immune deficient line, the NSG mouse. We found that YACNSG were able to retain human MSCs longer than the immune competent YAC128 mice. We performed behavioral assessments starting at 4 months of age and continued testing monthly until 12 months on the accelerod and in the open field. At 12 months, brains were isolated and evaluated using immunohistochemistry for striatal volume. Results from these studies suggest that the novel immune deficient YACNSG strain of mice could provide a good model for human stem‐cell based therapies and that the immune system appears to play an important role in the pathology of HD.

Heather Dahlenburg
David Cameron
Sheng Yang
Angelica Bachman
Kari Pollock
Whitney Cary
Missy Pham
Kyle Hendrix
Jeannine White
Haley Nelson
Peter Deng
Joseph S. Anderson
Kyle Fink
Jan Nolta


A synthetic genetic array screen for interactions with the RNA helicase <i>DED1</i> during cell stress in budding yeast

Abstract: AbstractDuring cellular stress it is essential for cells to alter their gene expression to adapt and survive. Gene expression is regulated at multiple levels, but translation regulation is both a method for rapid changes to the proteome and, as one of the most energy-intensive cellular processes, a way to efficiently redirect cellular resources during stress conditions. Despite this ideal positioning, many of the specifics of how translation is regulated, positively or negatively, during various types of cellular stress remain poorly understood. To further assess this regulation, we examined the essential translation factor Ded1, an RNA helicase that has been previously shown to play important roles in the translational response to cellular stress. In particular, ded1ded1Saccharomyces cerevisiae

Sara B Carey
Hannah M List
Ashwin Siby
Paolo Guerra
Timothy A Bolger


Genome-wide identification of quantitative trait loci for important plant and flower traits in petunia using a high-density linkage map and an interspecific recombinant inbred population derived from Petunia integrifolia and P. axillaris

Abstract: Petunia: Enhancing commercial cultivars Uncovering the genetics behind desirable traits in petunia plants could help improve commercial cultivars. While petunia plants are a key feature of the global horticultural industry, the limited genetic variability in commercial plants makes it difficult to improve desired plant traits. Zhanao Deng at the University of Florida, US, and co-workers conducted a genome-wide QTL identification study using a crossbred population combining two petunia  species, P. integrifolia and P. axillaris. The team phenotyped the petunias in an open-air sub-tropical field rather than in an artificial environment like previous studies. They identified and characterized 17 genetic loci for seven important aesthetic traits, ranging from flower count to plant size. The petunia species had very different genetic backgrounds, likely stemming from their different geographic origins. The two species each can contribute novel genes for enhancing cultivated petunia cultivars.

Zhe Cao
Yufang Guo
Qian Yang
Yanhong He
Mohammed I. Fetouh
Ryan M. Warner
Zhanao Deng


Impact of diastolic dysfunction on outcome in heart failure patients with mid‐range or reduced ejection fraction

Abstract: Abstract Aims The role of diastolic dysfunction (DD) in prognostic evaluation in heart failure (HF) patients with impaired systolic function remains unclear. We investigated the impact of echocardiography‐defined DD on survival in HF patients with mid‐range (HFmrEF, EF 41–49%) and reduced ejection fraction (HFrEF, EF < 40%). Methods and results A total of 2018 consecutive hospitalized HF patients were retrospectively included and divided in two groups based on baseline EF: HFmrEF group (n = 951, aged 69 ± 13 years, 74.2% male) and HFrEF group (n = 1067, aged 68 ± 13 years, 76.3% male). Clinical data were collected and analysed. All patients completed ≥1 year clinical follow‐up. The primary endpoint was defined as all‐cause death (including heart transplantation) and cardiovascular (CV)‐related death. All‐cause mortality (30.8% vs. 24.9%, P = 0.003) and CV mortality (19.1% vs. 13.5%, P = 0.001) were significantly higher in the HFrEF group than the HFmrEF group during follow‐up [median 24 (13–36) months]. All‐cause mortality increased in proportion to DD severity (mild, moderate, and severe) in either HFmrEF (17.1%, 25.4%, and 37.0%, P < 0.001) or HFrEF (18.9%, 30.3%, and 39.2%, P < 0.001) patients. The risk of all‐cause mortality [hazard ratio (HR) = 1.347, P = 0.015] and CV mortality (HR = 1.508, P = 0.007) was significantly higher in HFrEF patients with severe DD compared with non‐severe DD after adjustment for identified clinical and echocardiographic covariates. For HFmrEF patients, severe DD was independently associated with increased all‐cause mortality (HR = 1.358, P = 0.046) but not with CV mortality (HR = 1.155, P = 0.469). Conclusions Echocardiography‐defined severe DD is independently associated with increased all‐cause mortality in patients with HFmrEF and HFrEF.

Dan Liu
Kai Hu
Kolja Lau
Tobias Kiwitz
Katharina Robitzkat
Clara Hammel
Björn Daniel Lengenfelder
Georg Ertl
Stefan Frantz
Peter Nordbeck


Influence of dietary restriction and low‐intensity exercise on weight loss and insulin sensitivity in obese equids

Abstract: Background The importance of including exercise with dietary modification for the management of obese equids is not clearly understood. Objectives To evaluate the effect of a practical low‐intensity exercise regimen, in addition to dietary restriction, on indices of insulin sensitivity (SI) and plasma adipokine concentrations in obese equids. Animals Twenty‐four obese (body condition score [BCS] ≥ 7/9) horses and ponies. Methods Over a 12‐week period, animals received either dietary restriction only (DIET) or dietary restriction plus low‐intensity exercise (DIET+EX). All animals were provided with a restricted ration of grass hay at 1.25% body weight (BW) on a dry matter basis, providing 82.5% estimated digestible energy requirements. The DIET+EX group undertook low‐intensity exercise 5 days per week on an automated horse walker. Before and after weight loss, total body fat mass (TBFM) was determined, indices of SI were calculated using minimal model analysis of a frequently sampled IV glucose tolerance test, and adipokines plus inflammatory biomarkers were measured using validated assays. Results Decreases in BCS, BW, and TBFM were similar between groups (all P > .05). After weight loss, animals in both groups had decreased basal insulin and leptin concentrations, and increased adiponectin concentrations (all P < .001). Furthermore, animals in the DIET+EX group had significantly improved SI and decreased serum amyloid A concentrations relative to animals in the DIET group (both P = .01). Conclusions and Clinical Importance Regular low‐intensity exercise provided additional health benefits compared with dietary restriction alone in this population of obese equids.

Nicholas J. Bamford
Samantha J. Potter
Courtnay L. Baskerville
Patricia A. Harris
Simon R. Bailey


Extensions of BLUP Models for Genomic Prediction in Heterogeneous Populations: Application in a Diverse Switchgrass Sample

Abstract: Genomic prediction is a useful tool to accelerate genetic gain in selection using DNA marker information. However, this technology typically relies on standard prediction procedures, such as genomic BLUP, that are not designed to accommodate population heterogeneity resulting from differences in marker effects across populations. In this study, we assayed different prediction procedures to capture marker-by-population interactions in genomic prediction models. Prediction procedures included genomic BLUP and two kernel-based extensions of genomic BLUP which explicitly accounted for population heterogeneity. To model population heterogeneity, dissemblance between populations was either depicted by a unique coefficient (as previously reported), or a more flexible function of genetic distance between populations (proposed herein). Models under investigation were applied in a diverse switchgrass sample under two validation schemes: whole-sample calibration, where all individuals except selection candidates are included in the calibration set, and cross-population calibration, where the target population is entirely excluded from the calibration set. First, we showed that using fixed effects, from principal components or putative population groups, appeared detrimental to prediction accuracy, especially in cross-population calibration. Then we showed that modeling population heterogeneity by our proposed procedure resulted in highly significant improvements in model fit. In such cases, gains in accuracy were often positive. These results suggest that population heterogeneity may be parsimoniously captured by kernel methods. However, in cases where improvement in model fit by our proposed procedure is null-to-moderate, ignoring heterogeneity should probably be preferred due to the robustness and simplicity of the standard genomic BLUP model.


Aspirin in primary prevention and the risk of heart failure: a systematic review and meta‐analysis of controlled trials

Ana Beatrice Magalhães deOliveira
Beatriz Luchiari
Isabella Bonilha
Joaquim Barreto
Ana Claudia Cavalcante Nogueira
Guilherme Duprat Ceniccola
Carisi Anne Polanczyk
Andrei Carvalho Sposito
Luiz Sérgio Fernandes deCarvalho


Utility of serum amyloid A in monitoring clinical response to antimicrobial treatment in horses with bacterial pneumonia

Abstract: Abstract Background Serum amyloid A (SAA) is a major acute phase protein in horses which could be a useful tool for assessing clinical response to treatment of bacterial pneumonia in adult horses. Objectives To monitor SAA concentration in response to treatment and identify associations among SAA concentration, WBC and neutrophil counts, and fibrinogen in bacterial pneumonia in adult horses. Animals Eighteen adult horses with bacterial pneumonia. Methods Prospective clinical study. Horses hospitalized with bacterial pneumonia were enrolled and SAA concentration and vital signs were assessed daily. SAA concentration was measured by a handheld meter. CBC and plasma fibrinogen were assessed on days 0, 1, and 2, then every 3 days until discharge. Data were not normally distributed and therefore were log transformed. Log‐transformed data were analyzed and comparisons were performed on LSMeans by the 2‐sided Student's t‐test at the 5% level of significance. Results Geometric mean SAA concentration on day 0 was 537 μg/mL (SE 383 μg/mL). Geometric mean SAA concentration decreased significantly over time (P = .0001), peaking at day 2 (geomean 1038 μg/mL, SE 261.7 μg/mL) and decreasing until discharge. Plasma concentration of fibrinogen (P = .06), neutrophil count (P = .48), and WBC count (P = .07) did not change significantly over time. Conclusions and Clinical Importance SAA concentration decreased significantly over the course of treatment and correlated with clinical improvement of pneumonia whereas fibrinogen, neutrophil, and WBC counts did not.

Kate L. Hepworth‐Warren
Krista Estell
Bobby Cowles
Deborah Amodie
Mark Crisman


Proteomic profiling for detection of early‐stage heart failure in the community

Abstract: Abstract Aims Biomarkers may provide insights into molecular mechanisms underlying heart remodelling and dysfunction. Using a targeted proteomic approach, we aimed to identify circulating biomarkers associated with early stages of heart failure. Methods and results A total of 575 community‐based participants (mean age, 57 years; 51.7% women) underwent echocardiography and proteomic profiling (CVD II panel, Olink Proteomics). We applied partial least squares‐discriminant analysis (PLS‐DA) and a machine learning algorithm [eXtreme Gradient Boosting (XGBoost)] to identify key proteins associated with echocardiographic abnormalities. We used Gaussian mixture modelling for unbiased clustering to construct phenogroups based on influential proteins in PLS‐DA and XGBoost. Of 87 proteins, 13 were important in PLS‐DA and XGBoost modelling for detection of left ventricular remodelling, left ventricular diastolic dysfunction, and/or left atrial reservoir dysfunction: placental growth factor, kidney injury molecule‐1, prostasin, angiotensin‐converting enzyme‐2, galectin‐9, cathepsin L1, matrix metalloproteinase‐7, tumour necrosis factor receptor superfamily members 10A, 10B, and 11A, interleukins 6 and 16, and α1‐microglobulin/bikunin precursor. Based on these proteins, the clustering algorithm divided the cohort into two distinct phenogroups, with each cluster grouping individuals with a similar protein profile. Participants belonging to the second cluster (n = 118) were characterized by an unfavourable cardiovascular risk profile and adverse cardiac structure and function. The adjusted risk of presenting echocardiographic abnormalities was higher in this phenogroup than in the other (P < 0.0001). Conclusions We identified proteins related to renal function, extracellular matrix remodelling, angiogenesis, and inflammation to be associated with echocardiographic signs of early‐stage heart failure. Proteomic phenomapping discriminated individuals at high risk for cardiac remodelling and dysfunction.

Nicholas Cauwenberghs
František Sabovčik
Alessio Magnus
Francois Haddad
Tatiana Kuznetsova


Oral milrinone for management of refractory right ventricular failure in patients with left ventricular assist devices

Abstract: Abstract Aims We present a single‐centre retrospective experience using oral milrinone in patients with a left ventricular assist device (LVAD) and concurrent refractory right ventricular failure. Methods and results All patients implanted with LVAD between January 2013 and July 2021 from a high‐volume advanced heart failure service were reviewed. Eight patients were initiated on oral milrinone during this period. Oral milrinone was started 1.5 [inter‐quartile range (IQR) 1–2.3] years after LVAD implantation and continued for 1.2 (IQR 0.5–2.8) years. Therapeutic milrinone levels were achieved (232.2 ± 153.4 ng/mL) with 62.4 ± 18% of time within the therapeutic range. Two patients had adverse events (non‐sustained ventricular tachycardia and ventricular fibrillation effectively treated by internal cardioverter defibrillator) but did not require milrinone discontinuation. Four deaths occurred, one after transplant and three from disease progression determined to be unrelated to oral milrinone use. Three patients continue oral milrinone therapy in the community. There was no significant difference found after the initiation of oral milrinone on any of the physiological measures; however, there were trends in reduction of New York Heart Association class from 3.4 ± 0.5 to 3.0 ± 0.8 (P = 0.08), reduction of right atrial/wedge pressure from 0.9 ± 0.3 to 0.5 ± 0.2 (P = 0.08), and improvement of right ventricular stroke work index from 3.8 ± 2 to 5.8 ± 2.7 (P = 0.16). Conclusions Oral milrinone appears safe for long‐term use in the outpatient setting when combined with therapeutic monitoring in this complex medical cohort with limited management options. Further study is needed to ascertain whether this treatment is effective in reducing heart failure symptoms and admissions.

Waqas Akhtar
Charles Butcher
Andrew Morley‐Smith
Fernando Riesgo Gil
Owais Dar
Veronica Baston
John Dunning
Haifa Lyster


Allogenic blood patch pleurodesis for management of pneumothorax in a Cavalier King Charles Spaniel puppy with multiple pulmonary blebs and bullae

Abstract: Abstract A 9‐week‐old male intact Cavalier King Charles Spaniel was presented for evaluation of acute onset dyspnea caused by left‐sided pneumothorax. Thoracic computed tomography (CT) identified multiple pulmonary bullae and blebs in multiple lung lobes. Rupture of ≥1 pulmonary blebs or bullae, precipitated by low impact trauma, was the suspected cause of pneumothorax. A volume of 7.5 mL/kg of fresh whole blood was collected from a type‐matched donor dog and administered into the left pleural space using a thoracostomy tube. The pneumothorax was successfully resolved and no adverse effects of blood patch pleurodesis were noted. The dog was clinically normal 12 months later.

Conor Moloney
Antonella Puggioni
Myles McKenna


Correlates of malnutrition in patients with heart failure: the role of social support

Abstract: Abstract Aims Heart failure (HF) is a major public health challenge. Malnutrition has a significant effect on HF prognosis. Understanding the impact of social and clinical factors on the risk of malnutrition is necessary because it may aid in improving the health status of HF patients. Methods and results Three hundred twenty patients with HF who were hospitalized in a heart centre in Shiraz, Iran, from March to November 2022 were studied. Two validated questionnaires were used to evaluate malnutrition and social support: (1) Mini‐Nutritional Assessment Short Form and (2) Medical Outcomes Study Social Support Survey. The participants were then divided into three groups: those with normal nutritional status (scores 12–14), those at risk of malnutrition (scores 7–11), and those who were malnourished (scores 0–6). The potential correlates of malnutrition (including socio‐demographic, clinical, comorbidities, and laboratory factors) were included in the study. Then, ordinal logistic regression was used to investigate the correlates of malnutrition. The mean age of the participants was 64.2 ± 11.2 years, and more than half were male and married. Normal nutritional status was seen in 110 (34.4%) participants, 151 (47.2%) were at risk of malnutrition, and 58 (18.1%) were malnourished. The mean social support score of the participants was 61.65 ± 12.91. According to the adjusted odds ratios (95% confidence intervals) obtained from multivariate analysis, increased risk of malnutrition was associated with having a lower social support score [0.95 (0.93–0.97), P‐value ≤ 0.001], lower body mass index [0.91 (0.86–0.97), P‐value = 0.004], higher New York Heart Association classification [1.26 (1.02–1.56), P‐value = 0.03], longer duration of disease [1.006 (1.001–1.01), P‐value = 0.006], and lower serum albumin level [0.25 (0.08–0.75), P‐value = 0.01]. Conclusions Besides the clinical conditions affecting the risk of malnutrition in patients with HF, social support may play an important role. Including this factor in HF guidelines and developing educational programmes may help improve HF patients' health.

Mohammad Hossein Sharifi
Maryam Afshari
Hossein Molavi Vardanjani
Amirreza Nikmanesh
Mohammad Hossein Nikoo


Pro‐tumorigenic Effects of Transforming Growth Factor Beta 1 in Canine Osteosarcoma

Abstract: Background Transforming growth factor beta 1 (TGFβ1) is a pleiotropic cytokine that contributes to reparative skeletal remodeling by inducing osteoblast proliferation, migration, and angiogenesis. Organic bone matrix is the largest bodily reservoir for latent TGFβ1, and active osteoblasts express cognate receptors for TGFβ1 (TGFβRI and TGFβRII). During malignant osteolysis, TGFβ1 is liberated from eroded bone matrix and promotes local progression of osteotropic solid tumors by its mitogenic and prosurvival activities. Hypothesis Canine osteosarcoma (OS) cells will possess TGFβ1 signaling machinery. Blockade of TGFβ1 signaling will attenuate pro‐tumorigenic activities in OS cells. Naturally occurring primary OS samples will express cognate TGFβ1 receptors; and in dogs with OS, focal malignant osteolysis will contribute to circulating TGFβ1 concentrations. Animals Thirty‐three dogs with appendicular OS. Methods Expression of TGFβ1 and its cognate receptors, as well as the biologic effects of TGFβ1 blockade, was characterized in OS cells. Ten spontaneous OS samples were characterized for TGFβRI/II expressions by immunohistochemistry. In 33 dogs with OS, plasma TGFβ1 concentrations were quantified and correlated with bone resorption. Results Canine OS cells secrete TGFβ1, express cognate receptors, and TGFβ1 signaling blockade decreases proliferation, migration, and vascular endothelial growth factor secretion. Naturally occurring OS samples abundantly and uniformly express TGFβRI/II, and in OS‐bearing dogs, circulating TGFβ1 concentrations correlate with urine N‐telopeptide excretion. Conclusions and Clinical Importance Canine OS cells possess TGFβ1 signaling machinery, potentially allowing for the establishment of an autocrine and paracrine pro‐tumorigenic signaling loop. As such, TGFβ1 inhibitors might impede localized OS progression in dogs.

R.F. Portela
B.A. Fadl‐Alla
H.C. Pondenis
M.L. Byrum
L.D. Garrett
K.L. Wycislo
L.B. Borst
T.M. Fan


The Ability of Different Imputation Methods to Preserve the Significant Genes and Pathways in Cancer

Abstract: Deciphering important genes and pathways from incomplete gene expression data could facilitate a better understanding of cancer. Different imputation methods can be applied to estimate the missing values. In our study, we evaluated various imputation methods for their performance in preserving significant genes and pathways. In the first step, 5% genes are considered in random for two types of ignorable and non-ignorable missingness mechanisms with various missing rates. Next, 10 well-known imputation methods were applied to the complete datasets. The significance analysis of microarrays (SAM) method was applied to detect the significant genes in rectal and lung cancers to showcase the utility of imputation approaches in preserving significant genes. To determine the impact of different imputation methods on the identification of important genes, the chi-squared test was used to compare the proportions of overlaps between significant genes detected from original data and those detected from the imputed datasets. Additionally, the significant genes are tested for their enrichment in important pathways, using the ConsensusPathDB. Our results showed that almost all the significant genes and pathways of the original dataset can be detected in all imputed datasets, indicating that there is no significant difference in the performance of various imputation methods tested. The source code and selected datasets are available on http://profiles.bs.ipm.ir/softwares/imputation_methods/.

Rosa Aghdam
Taban Baghfalaki
Pegah Khosravi
Elnaz Saberi Ansari