bluuebunny/crossref_metadata_2025 huggingface dataset:
Early non-compliance to ERAS in gynecological open surgery for malignancies, and post-operative complications: a multicenter, prospective, observational, cohort study
Authors: Ferrari Federico , Bizzarri Nicolò , Fagotti Anna , Scambia Giovanni , Gozzini Elisa , Soleymani Majd Hooman , Rota Matteo , Odicino Franco
Published: October 2024

Background

Open surgical procedures for gynecological malignancies have a potential risk of post-operative complications and hence prolonged hospitalization, despite adherence to an Enhanced Recovery After Surgery (ERAS) protocol.

Primary Objective

To investigate the relationship between non-compliance to an ERAS protocol in the post-operative setting and the rate of post-operative complications, in women who underwent open surgery for gynecological malignancies.

Study Hypothesis

Early non-compliance with the ERAS protocol increases the risk of post-operative complications.

Trial Design

Multicenter, prospective, observational, cohort study.

Major Inclusion Criteria

Patients with histologically proven gynecological cancer (endometrial, uterine, tubo-ovarian, and cervical) undergoing elective open surgery and managed according to ERAS guidelines.

Exclusion Criteria

Patients with post-operative recovery in an intensive care unit, undergoing anterior or total pelvic exenteration or intraperitoneal chemotherapy. Previous radiotherapy or previous non-gynecological major abdominal surgery.

Primary Endpoint

Association of non-compliance with the ERAS protocol using five selected indicators on post-operative day 2 with the rate of 30-day post-operative complications.

Sample Size

600 patients will be enrolled in the study.

Estimated Dates for Completing Accrual and Presenting Results

At present, 106 patients have been recruited. Based on this, the accrual should be completed in 2025. Results should be presented at the end of 2025.

Trial Registration

NCT05738902
“This Verdict was Created with the Help of Generative AI...?” On the Use of Large Language Models by Judges
Authors: Dhungel Anna-Katharina
Published: October 2024

In selected jurisdictions such as the USA, China, and Singapore, the integration of AI into judicial proceedings has become a tangible reality. Algorithms play a pivotal role in supporting decision-making processes during the formulation of judicial verdicts. Large Language Models (LLMs), such as ChatGPT, are also being increasingly used by judges, often in circumstances where the legal parameters surrounding their usage remain unclear. This comment delves into the realm of interdisciplinary research inquiries surrounding the application of AI in the judiciary. It begins by exploring how judges currently use ChatGPT in rendering verdicts within cases that have been publicly disclosed so far. Subsequently, it navigates through the array of questions different disciplines might pose concerning this development and discusses strategies for harmonizing these diverse perspectives in collaborative projects, potentially employing frameworks like the “orders of change” taxonomy. The article concludes with a call for increased research endeavors, particularly emphasizing the need for interdisciplinary cooperation to comprehensively address the application of AI in the judiciary.
Sexual and Reproductive Health Service Access among Aboriginal and Torres Strait Islander Young People in Regional NSW, Australia
Authors: Whitford Kate , Whybrow Bobby , Haire Bridget , Nikitas Alison , Williams Samantha , Monaghan Robert , Lafferty Lise
Published: October 2024

Owing to the historical and ongoing impacts of colonisation, there is a large health equity gap in sexual and reproductive health (SRH) outcomes between Aboriginal and Torres Strait Islander peoples and non‐Indigenous populations. Whilst qualitative research has identified the barriers and enablers to sexual healthcare engagement among young Aboriginal and Torres Strait Islander people in remote settings, little is known about the ways in which young people navigate sexual healthcare in a regional setting. This study aims to address this gap. Sixty‐five young (aged 15–29) Aboriginal and Torres Strait Islander people participated in semistructured interviews across three regional communities in New South Wales, Australia. The candidacy framework informed this analysis. A large proportion of participants expressed having agency and resources to attend health services for SRH needs (primarily STI testing and contraception). Women in particular described being supported by social networks to access SRH services. Male participants were less likely to identify their own candidacy for healthcare. Services that were culturally safe and had trustworthy, nonjudgemental staff and a feeling of community were easier to access (more permeable). Factors that decreased accessibility were confidentiality concerns, difficulty making appointments, and lack of visibility of services, or what they offer. Using the candidacy framework, this study identified the importance of culturally safe service provision, reducing barriers to accessing appointments and the provision of nonjudgemental care in engaging young Aboriginal and Torres Strait Islander people in SRH care. This study also highlighted the various strategies and actions that young Aboriginal and Torres Strait Islander people are already taking to protect their sexual health and that of their partners.
Plasmid‐Mediated Co‐Occurrence of mcr-1.1 in Extended‐Spectrum β‐Lactamase (ESBL)‐Producing Escherichia coli Isolated From the Indigenous Seminomadic Community in Malaysia
Authors: Yap Polly Soo Xi , Yeo Li-Fang , Teh Cindy Shuan Ju , Dhanoa Amreeta , Phipps Maude Elvira
Published: October 2024

The growing prevalence of commensal antibiotic resistant Escherichia coli poses a significant concern for the global spread of antibiotic resistance. Stool samples (n = 35) from a seminomadic indigenous community in Malaysia, the Jehai, were screened for multidrug‐resistant bacteria, specifically the extended‐spectrum β‐lactamase (ESBL) producers. Subsequently, whole‐genome sequencing was used to provide genomic insights into eight ESBL‐producing E. coli that colonised eight individuals. The ESBL E. coli isolates carry resistance genes from various antibiotic classes such as the β‐lactams (blaTEM, blaCTX-M−15 and blaCTX-M−55), quinolones (gyrA, qnrS and qnrS1) and aminoglycosides (aph(3′)-Ia, aph(6)-Id and aac(3)-IId). Three concerning convergence of ESBL, colistin and metal resistance determinants, with three plasmids from H‐type lineage harbouring blaCTX-M and mcr-1.1 genes were identified. Using the Oxford Nanopore Technology (ONT) Native Barcoding Kit (SQK‐NBD114.24) in conjunction with the R10.4.1 flow cell, which achieved an average read accuracy (Q > 10) of 99.84%, we further characterised the mcr-1.1‐bearing plasmids, ranging in size from 25 to 28 kb, from three strains of E. coli. This report represents the first whole genome analysis of multidrug‐resistant bacteria, specifically those resistant to colistin, found within the indigenous population in Malaysia. It strongly indicates that the pertinent issue of colistin resistance in the country is far more significant than previously estimated.
Phosphorus Restriction Prevents Rapamycin-Induced Kidney Damage in Rats
Authors: Raya Ana I. , Vidal Angela , López Ignacio , Rodríguez Mariano , Aguilera-Tejero Escolástico , Pineda Carmen
Published: October 2024

Introduction: There are conflicting reports about the effect or rapamycin on the kidneys. Rapamycin is known to promote phosphaturia that may be associated to renal injury. Methods: Detailed histopathological studies were performed on the kidneys of rats with normal (control) and reduced (Nx) renal mass that were treated with rapamycin (1.3 mg/kg for 22 days) or placebo. The effect of rapamycin was also evaluated in control and Nx rats fed different amounts of phosphorus: 0.6% P (NP), 1.2% P (HP), and 0.2% P (LP). Quantitative scores of kidney lesions were obtained for interstitial nephritis (IN), tubular damage (TD), and nephrocalcinosis (NC). Results: When compared with placebo, rapamycin administration to Nx rats resulted in significant increases in IN (4.17 ± 0.74 vs. 1.51 ± 0.53%) and TD (14.45 ± 1.51 vs. 8.61 ± 1.83%). Rapamycin also increased NC both in control (0.86 ± 0.23 vs. 0.14 ± 0.06%) and Nx (0.86 ± 0.32 vs. 0.15 ± 0.14%) rats. In control rats receiving rapamycin, feeding HP aggravated IN (3.25 ± 0.48%), TD (22.47 ± 4.56%), and NC (3.66 ± 0.75%), while feeding LP prevented development of any renal lesions. In Nx rats treated with rapamycin, HP intake also increased IN (8.95 ± 1.94%), TD (26.86 ± 3.95%), and NC (2.77 ± 0.60%), whereas feeding LP reduced all lesions to lower levels than in rats fed NP. Rapamycin treatment increased fractional excretion of P (FEP), and an excellent correlation between scores for renal lesions and FEP was found. Conclusion: Rapamycin has deleterious effects on kidney pathology causing lesions that are located mainly at tubular and tubulointerstitial level. Rapamycin-induced kidney damage is more evident in rats that already have decreased renal function and seems to be related to the phosphaturic effect of the drug. Dietary P restriction prevents kidney damage in rats treated with rapamycin.
Advantage of Postoperative Inflammatory Status after Laparoscopic Distal Pancreatectomy
Authors: Funakoshi Saori , Suzuki Yutaka , Yoshida Masao , Momose Hirokazu , Matsuki Ryota , Kogure Masaharu , Abe Nobutsugu , Sunami Eiji , Sakamoto Yoshihiro
Published: October 2024

Introduction: Laparoscopic distal pancreatectomy (LDP) is a safe and effective procedure; however, its impact on perioperative inflammatory reactions compared with open distal pancreatectomy (ODP) remains unclear. This study aimed to assess short-term outcomes following LDP and ODP regarding inflammatory reactions. Methods: This retrospective study of 77 consecutive patients who underwent distal pancreatectomy for low-grade malignancies between 2005 and 2022 compared white blood cell (WBC) count, C-reactive protein (CRP) level, serum albumin level, and CRP/albumin ratio (CAR) between LDP and ODP. Complications, especially postoperative pancreatic fistula (POPF), recovery program, and hospital stay period, were also compared. Results: POPF (17.1% vs. 38.7%, p = 0.039) and surgical morbidity (≥Clavien-Dindo grade III, 12.2% vs. 32.3%, p = 0.038) were significantly lower in LDP than in ODP, as for the difference in postoperative inflammatory response, including CRP and CAR, was just temporary. By multivariate analysis, CAR ≥6.94 on POD 3 was significant predictor of POPF (42.1% vs. 13.2%, odds ratio 4.828, p = 0.030). Conclusion: LDP has lower POPF and earlier postoperative recovery. CAR could be a predictor of POPF.
Sex Differences in Skeletal Muscle Pathology in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Wood Nathanael , Critchlow Annabel , Cheng Chew W. , Straw Sam , Hendrickse Paul W. , Pereira Marcelo G. , Wheatcroft Stephen B. , Egginton Stuart , Witte Klaus K. , Roberts Lee D. , Bowen T. Scott
Published: October 2024

BACKGROUND:

Women with heart failure and reduced ejection fraction (HFrEF) have greater symptoms and a lower quality of life compared with men; however, the role of noncardiac mechanisms remains poorly resolved. We hypothesized that differences in skeletal muscle pathology between men and women with HFrEF may explain clinical heterogeneity.

METHODS:

Muscle biopsies from both men (n=22) and women (n=16) with moderate HFrEF (New York Heart Association classes I–III) and age- and sex-matched controls (n=18 and n=16, respectively) underwent transcriptomics (RNA-sequencing), myofiber structural imaging (histology), and molecular signaling analysis (gene/protein expression), with serum inflammatory profiles analyzed (enzyme-linked immunosorbent assay). Two-way ANOVA was conducted (interaction sex and condition).

RESULTS:

RNA-sequencing identified 5629 differentially expressed genes between men and women with HFrEF, with upregulated terms for catabolism and downregulated terms for mitochondria in men. mRNA expression confirmed an effect of sex (
P
<0.05) on proatrophic genes related to ubiquitin proteasome, autophagy, and myostatin systems (higher in all men versus all women), whereas proanabolic
IGF1
expression was higher (
P
<0.05) in women with HFrEF only. Structurally, women compared with men with HFrEF showed a pro-oxidative phenotype, with smaller but higher numbers of type I fibers, alongside higher muscle capillarity (
P
interaction
<0.05) and higher type I fiber areal density (
P
interaction
<0.05). Differences in gene/protein expression of regulators of muscle phenotype were detected between sexes, including
HIF1α
,
ESR1
,
VEGF
(vascular endothelial growth factor), and PGC1α expression (
P
<0.05), and for upstream circulating factors, including VEGF, IL (interleukin)-6, and IL-8 (
P
<0.05).

CONCLUSIONS:

Sex differences in muscle pathology in HFrEF exist, with men showing greater abnormalities compared with women related to the transcriptome, fiber phenotype, capillarity, and circulating factors. These preliminary data question whether muscle pathology is a primary mechanism contributing to greater symptoms in women with HFrEF and highlight the need for further investigation.
Abstract Mo014: Cardioactive molecules identified by functional in vivo screening prevent anthracycline cardiotoxicity
Authors: Bortolotti Francesca , Mura Antonio , Riccio Matteo Maria , Dal Ferro Matteo , Zentilin Lorena , Giacca Mauro
Published: October 2024

Introduction:
Promotion of cardiomyocyte survival upon insult is mandatory to allow maintenance of ventricular function and dam development of severe heart dysfunction. Recently, through an in vivo functional screening of the mouse secretome we identified potent mediators of cardiomyocyte survival among 1200 soluble factors expressed by AAV vectors. The cardiac overexpression of the most effective cytokines (Chrdl1, Fam3c and Fam3b) maintained cardiac function after myocardial infarction by blunting oxidative damage, decreasing cell death, promoting autophagy, and inhibiting myofibroblast activation (Ruozi, Bortolotti
et al.
2022. Sci Transl Med 14, eabo0699)

Aim:
We investigated the effect of cardioactive proteins in a mouse anthracycline model of cardiotoxicity.

Material and Methods:
Mimicking clinical chronic therapeutic regimens, doxorubicin (24 mg/kg) was administered to C57/BL6 female mice one week after AAV9-driven cardiac overexpression of Chrdl1, Fam3b or Fam3c. Echocardiography was performed after 6 and 8 weeks and was followed by histology and molecular analysis. Apoptosis, autophagy and mitochondrial function was analysed in primary cardiomyocytes along with pathway investigation.

Results:
AAV9-mediated overexpression of Chrdl1, Fam3b and Fam3c markedly improved animal survival. Echocardiographic assessment revealed significant reduction of left ventricular ejection fraction and marked heart dilatation in control animals, while all treated animals maintained functional and anatomical parameters. Treated mice showed normal cardiac mass and cardiomyocyte cross-sectional area, reduced interstitial collagen deposition and decreased expression of profibrotic genes. In both rodents and human cardiomyocytes, Chrdl1, Fam3b and Fam3c factors decreased doxorubicin induced apoptosis, induced protective macroautophagy and preserved mitochondrial morphology. Chrdl1 prevented doxorubicin-mediated BMP upregulation and autophagy engulfment through the inhibition of a detrimental molecular pathway downstream the BMP receptor.

Conclusions:
The development of biotherapeutics that act as pro-survival factors for cardiomyocytes offers significant translational perspectives in cardio-oncology.
Abstract Tu074: A Potential Link Between Stress Kinase JNK2 and AKAP-1 in Catecholamine-Induced Acute Heart Failure
Authors: Kohli Aaryan , Yan Jiajie , Cao Yuanyuan , Bare Dan , Ai Xun
Published: October 2024

Takotsuba Syndrome (TTS) is a type of emotional/physical stress-induced heart failure (HF). Stress-elevated catecholamines activate adrenergic signaling. Cardiac A-Kinase Anchoring Protein-1 (AKAP1) is known to regulate the adrenergic signaling via protein complex formation and phosphorylation. We recently discovered that activation of the stress response kinase JNK2 is critical in HF onset. Whether AKAP1 is involved with stress-activated JNK2 and HF onset remains completely unknown.

Isoproterenol (Iso; synthetic catecholamine) effects on JNK2 activation were assessed in left ventricles (LV) from Iso-treated wildtype (WT) mice (67 mg/kg i.p., 2 days) and in heterologous HEK-RyR2 cells (inducible cardiac ryanodine receptor-2; myocyte mimic; 5 mM Iso, 24 h). A JNK2 effect on cardiac function was reflected by cardiac output (CO) using echocardiography in cardiac-specific MKK7D (inducible overexpression of active MKK7D; a JNK upstream activator) and MKK7D-JNK2KD (50% JNK2 knockdown in MKK7D) mice. The AKAP1-JNK2 link was assessed using immunoprecipitation (IP) and immunoblotting in
tGFP
-JNK2 and/or
FLAG
-AKAP1 transfected HEK293 cells.

Iso-WT LV had increased JNK phosphorylation (JNK-p, activated) and reduced SERCA2 (a hallmark of HF) vs controls. Likely, MKK7-induction in MKK7D LV increased JNK2 and JNK-p (vs WT-littermates; p<0.05, n=5,4), which led to reduced CO by 68% (n=5,6, p<0.01) and downregulated SERCA2 by 79% (p<0.01, n=4,8), also evidenced by preserved CO and SERCA2 in MKK7D-JNK2KD mice (50% ablated JNK2; n=9). Moreover, Iso treatment in HEK-RyR2 cells activated JNK2, but not JNK1, compared to sham controls. Intriguingly, we found that JNK2 was associated with AKAP1, given the co-IP of
tGFP
-JNK2 with anti-
FLAG
antibody pulldown of
FLAG
-AKAP1 co-transfected HEK293 cells (n=3). Further, overexpressed
FLAG
-AKAP1 increased the phosphorylation of co-transfected
tGFP
-JNK2 as well as endogenous JNK (p<0.01 & p<0.001, n=3,3), while the notable JNK downstream target c-Jun also showed increased phosphorylation (c-Jun-p; p<0.05, n=3,3), supporting a previously unrecognized role for AKAP1 in JNK2 activation.

In total, our findings suggest that stress activates JNK2 via an adrenergic-AKAP1 activation pathway to drive HF/TTS onset.
Abstract Tu149: FDA-Approved Antidepressant Trazodone Potentially Increases the Risk of Dyslipidemia
Authors: Ramirez Naara , Sui Yipeng
Published: October 2024

Cardiovascular disease is the leading cause of death. Many cardiovascular health problems, such as atherosclerosis, are caused by dyslipidemia. One xenobiotic nuclear receptor, Pregnane X Receptor (PXR), plays a significant role in atherosclerosis and dyslipidemia, and is activated by various environmental chemicals, including endocrine-disrupting chemicals (EDCs). EDCs are found in common household items such as plastics, medications, and food. Trazodone is a clinically used medication to treat depression by aiding in restoring the balance of serotonin in the brain. But it is unclear if Trazodone has possible impacts on cardiovascular risk factors such as dyslipidemia. Our preliminary data suggested that Trazodone activated human PXR in both intestinal (LS180) and hepatic (HepG2) cells. We hypothesize that Trazodone could regulate the cholesterol uptake mediated by PXR signaling. In this study we use cell-based transfection assay to evaluate the underlying mechanisms by which Trazodone activates PXR. We found that Trazodone was a more potent agonist of human PXR than mouse PXR. Trazodone could activate PXR more intensely in human liver cells compared with human intestinal cells. Our data suggested that Trazodone was a selective PXR agonist and promoted the dissociation between PXR and its nuclear corepressors. Next, we are to identify the key amino acid residues within PXR ligand binding pocket that interact with Trazodone by using computational docking study along with site-mutagenesis assay. Furthermore, we plan to estimate if Trazodone altered cholesterol uptake by human intestinal cells using fluorescence-labeled cholesterol. In conclusion, we explore the potential molecular mechanisms of how FDA-approved antidepressant Trazodone activates human PXR and increases the possible risk of dyslipidemia, which provides potential evidence on future cardiovascular disease risk assessment for Trazodone as well as other antidepressant drugs.
Abstract We035: PTMA-MBD3 axis is a core heart regenerative driver in mammals
Authors: Liu Ning , Jianqiu Pei , Xie Yifan , Nie Yu
Published: October 2024

Introduction:
The adult mammalian heart has an extremely limited ability for regeneration after injury, whereas the fetal heart can steadily regenerate. Uncovering the molecular underpinnings of proliferative cardiomyocytes and manipulating the core genes activate cardiomyocyte proliferation may provide new insight into adult heart regrowth and functional repair post-injury.

Methods and Results:
We performed single-cell RNA-sequencing of mouse embryonic hearts from various developmental stages (E8.5-E17.5), and identified a cardiomyocyte population in proliferative phase with 120 highly expressed feature genes. Combining with our bulk RNA-seq data on isolated cardiomyocytes from different heart developmental periods (E14.5, P1-P56), we screened and demonstrated that Ptma is the core conservative factor in promoting mouse, rat and human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) proliferation. Cardiac specifically knocking out Ptma blocked cardiomyocyte proliferation and neonatal mouse heart regeneration after apical resection injury. AAV9-delivered Ptma overexpression extended neonatal heart regenerative time window and showed therapeutic benefit in driving adult cardiomyocyte proliferation and cardiac repair. As PTMA is a polypeptide, we further validated that PTMA derived conservative peptide Tα1 displayed more effective in treating adult cardiac injury compared to Decapeptide. PTMA is an unstructured, intrinsically disordered nuclear protein that functions by binding to target proteins. Using Co-IP, IP and Native PAGE, we found PTMA promoted cardiomycyte proliferaton by binding to MBD3, which decreases the formation of MBD3-HDAC1 NuRD complex . We further decreased MBD3-HDAC1 NuRD complex formation by inhibiting MBD3, boosting both rat and mouse cardiomyocyte proliferation.

Conclusions:
We identified the PTMA-MBD3 axis as an effective target for promoting mammalian heart regeneration and provided a new insight into cardiomyocyte proliferation through blocking MBD3-HDAC1 NuRD complex.
Abstract We062: Characterization of Transcriptional Responses to Streptococcus pneumoniae Infection in the Heart versus Sterile Cardiac Injury
Authors: Minassian Daniel , Wilson Garrett , Weaver Casey , Orihuela Carlos
Published: October 2024

Background:
Streptococcus pneumoniae
(
Spn
) remains the leading cause of community-acquired pneumonia (CAP). As many as 30% of patients hospitalized for CAP experience a major adverse cardiac event (MACE). Importantly, the elevated risk for MACE is not only limited to the time of acute infection but also extends several years post-hospitalization.

Research Question:
Is the host response to
Spn-
mediated injury in the heart different from the response to sterile injury?

Goals:
To identify defining features of the host response to
Spn
in the heart via differences in gene expression.

Methods:
We performed a bioinformatic analysis of bulk RNAseq data collected from hearts of mice acutely infected with
Spn
and compared this to publicly available data sets of mice that received experimental myocardial infarction, i.e. ischemia reperfusion and permanent ligation. Using DeSeq2, we identified 2,971 genes with differential expression between the infected and infarcted conditions. To identify gene expression differences that might be relevant to human patients, we subsequently used the Reactome GSA software to map our differential expression results onto predicted human pathways.

Results:
Categorization of the gene roles identified those in the classical antibody-mediated complement activation as the dominant pathway with differential expression. Reactome analysis of the top 5 differentially expressed genes (p < 0.05) at the individual level identified
BAIAP2L1
,
CXCL9
,
IRF7
,
IL18BP
,
RPL12
, and
PSMB10
as significantly upregulated in
Spn
infected hearts versus infarcted hearts. As one feature of Spn mediated damage is the recruitment of immune cells to the affected sites and cardiac remodeling, we validated upregulation of CXCL9 as well as CXCL10, potent recruiters of T-cells, as enhanced during
Spn
infection.

Conclusions:
Our analyses provide information on how the host response to disseminated pneumococcal infection in the heart is distinct from sterile injury and identified mediators that may be contributing to adverse cardiac remodeling.
Abstract We100: Altering cardiac impulse propagation and generation by local flash photolysis of caged Ca
2+
Authors: Mochizuki Kentaro , Tamura Shoko , Morishita Yuma , Harada Yoshinori , Tanaka Hideo
Published: October 2024

Calcium ion (Ca
2+
) is one of key components in the heart excitation and conduction, and its overload is known to induce abnormal impulse propagation and generation, enabling to lead lethal arrhythmias. However, unknown is how large area of Ca
2+
-overload in a cardiac tissue is required to provoke such abnormalities.

By utilizing UV-photolysis of caged Ca
2+
, we investigated whether the increase of Ca
2+
concentration ([Ca
2+
]) at the local on a cardiomyocytes monolayer alters its spatiotemporal impulse patterns, and also assessed its dependence on area-sizes of the Ca
2+
-overload. The monolayers of cardiomyocytes isolated from neonatal rats were prepared on quartz-substrates (φ27 mm) with 2 days incubation, then treated with a fluorescent indicator of Ca
2+
(Fluo-8/AM: 5 µM) and a caged Ca
2+
(DMNPE-4/AM: 5 - 50 µM). Its excitation manner and impulse propagation were monitored as fluorescence images by a macro-zoom microscope (image size: ~1,500 mm
2
, frame rate: 400 frame/s). Under monitoring, UV light (λ: 365 nm) for flash photolysis of caged Ca
2+
was irradiated to a limited area (diameters of 3 - 9 mm) on the cell layer, with and without electrical pacing.

Under periodical excitation by pacing, the delay of impulse propagation was detected at UV-irradiated area on the monolayer. The delay was enhanced with an increase of [Ca
2+
] under the photolysis, but gradually dissolved with a decay of [Ca
2+
] after stopping UV irradiation. Under non-pacing, on the other hand, it was found that abnormal impulses were generated from the UV-irradiated area as a result of increase of [Ca
2+
]. Probabilities about the abnormal impulses showed a linear relationship with the area size of UV-photolysis. Also, we confirmed that the abnormal impulses by the UV-photolysis provoked a reentry-like excitation manner when the electrical conductivity of cardiomyocytes was further degraded by an administration of carbenoxolone.

In conclusion, we demonstrated altering impulse propagation/generation of cardiomyocytes monolayer by the local frash photolysis of caged Ca
2+
, and investigated its dependence on spatial conditions of the overload region. The target of this study will be shifted to whole hearts as one on next steps in order to provide the statistical insight in arrhythmogenesis.

This research was partially supported by JSPS(18K19459, 22K18174) and JST-CREST(JPMJCR 1925).
Abstract We105: cBIN1 Gene Therapy Improves Left Ventricular Filling Pressure in a Canine Model of Ischemic Dilated Cardiomyopathy
Authors: Khan Muhammad , Yazaki Kyoichiro , Ishidoya Yuki , Offei Emmanuel , Ruizcastillo Sofia , Shah Ankur , Li Jing , palatinus Joseph , Hong Tingting , Shaw Robin , Dosdall Derek
Published: October 2024

Introduction:
In heart failure patients, increased left ventricular end diastolic pressure (LVEDP) is pathognomonic of myocardial dysfunction. Previously, we presented that gene therapy with exogeneous cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein that organizes T-tubule microdomains and is decreased in failing hearts, recovers systolic function in a canine model of chronic ischemic dilated cardiomyopathy (IDCM). The effect of catheter-based delivery of cBIN1 gene therapy on increased LVEDP is unclear.

Hypothesis:
We tested the hypothesis that cBIN1 gene therapy improves LVEDP in a canine model of IDCM.

Methods:
Twelve healthy dogs (30±2 kg) underwent left anterior descending artery ligation and developed IDCM with LVEF <40% and NT-proBNP >900 pmol/L over 3–4 months. Animals received a single application at 20 subendocardial LV sites of either AAV9-GFP (control, n=6) or AAV9-cBIN1 (n=6) using a MyoStar catheter-based injection. Pressure-volume loops were acquired in vivo, including measurement of LVEDP, end-systolic pressure-volume relation (ESPVR), isovolumic relaxation time (IVRT) and isovolumetric contraction time (IVCT). Measurements were performed on the day prior to administering the therapy (
pre-therapy
) and 5–8 weeks post-intramyocardial injection (
post-therapy
). For statistics, student t-test was used, and p<0.05 refers as significant. Results are reported as mean±SD.

Results:
In AAV9-GFP control-treated dogs, compared with pre-therapy, post-therapy LVEDP elevated significantly (13±1 vs. 17±1 mmHg, p=0.002,
Figure A
), whereas in the cBIN1-treated cohort, elevated LVEDP improved significantly (13±4 vs. 11±3 mmHg, p=0.042). With control therapy, ESPVR exhibited a significant decrease in contractility (1.40±0.44 vs. 1.81±0.49 mmHg/mL, p=0.001,
Figure B
), whereas cBIN1 therapy caused a substantial improvement in ESPVR (1.54±0.71 vs. 1.34±0.43 mmHg/mL, p=0.022,
Figure B
). At the post-therapy time-point, compared with control therapy, cBIN1 therapy improved IVRT (96±10 vs. 72±8 ms, p<0.001,
Figure C
) and IVCT (49±4 vs. 40±3 ms, p=0.009,
Figure D
).

Conclusion:
cBIN1 gene therapy reduces elevated LV filling pressure and improves overall hemodynamics in a canine model of chronic IDCM.
Evidence of the Double Amplification of Traveling Planetary Waves during the January 2021 Sudden Stratospheric Warming
Authors: Rhodes C. Todd , Barton Cory , Eckermann Stephen , Kuhl David , Ma Jun
Published: October 2024

The in situ generation and characteristics of planetary waves (PWs) in the mesosphere and lower thermosphere (MLT) during the January 2021 sudden stratospheric warming (SSW) are investigated using the Navy Global Environmental Model. During SSW, upward-propagating PWs can be absorbed, refracted, or amplified, the latter implying in situ PW generation. Additionally, asymmetric dissipation of gravity wave (GW) drag in the MLT due to varying stratospheric winds may also seed PW generation. Ultimately, the interaction of waves with instability can enhance three components of PWs [westward-propagating PWs (WPWs), quasi-stationary PWs (QSPWs), and eastward-propagating PWs (EPWs)]. The propagation pathway of a wave is diagnosed by its refractive index and is dependent on factors such as the baroclinic/barotropic stability of the atmosphere, the wave’s relative phase velocity, and the wavenumber. Through these pathways, waves are able to transfer heat and momentum throughout the atmosphere. Under particular conditions, the waves can amplify in situ by extracting energy from the background wind. Our study identifies two scenarios in which WPWs and EPWs were amplified successively. Amplified WPWs propagated upward and influenced the MLT, while amplified EPWs propagated downward and influenced the upper troposphere.
Clinical effectiveness of a fracture liaison service for geriatric hip fracture patients in Hong Kong
Authors: Siu Sheung Kan , Wan Yue Ting Ophelia
Published: October 2024

Introduction: Fragility hip fracture has become a huge public health burden with ageing population. Yet workup and treatment of osteoporosis following a fragility fracture remain under-utilised in clinical practice. The purpose of this study was to evaluate the clinical effectiveness of Fracture Liaison Service (FLS) in preventing future fractures and mortality rate following hip fracture in Hong Kong. Investigation and treatment rate of osteoporosis were also assessed. Methods: A retrospective single-centre cohort study was conducted to study patients aged over 65 years admitted to our hospital for fragility hip fracture before and after FLS implementation. Patients who were recruited in the FLS programme following hospital admission from October 2020 to September 2021 were regarded as the intervention group, whereas those admitted from April 2019 to March 2020 were regarded as historical control. The follow up time was 15 months for both groups. Results: A total of 139 patients were included in the study, with 68 in the intervention group and 71 in the control group. The refracture rate dropped from 5.6% to 0% after FLS implementation, while the 15-month mortality rate increased slightly from 0% to 2.9%, both of which did not show statistical significance, with a p-value of .120 and .238 respectively. Post-injury bone density investigation rate increased from 8.5% to 60.3%, and antiosteoporotic treatment initiation rate increased from 19.7% to 97.1%. Both of them showed statistical significance ( p < .001). Treatment discontinuation rate decreased from 14.3% to 7.8%, with a p-value of .603. Conclusions: FLS implementation in Hong Kong was an effective tool to increase investigation and treatment rate of osteoporosis in geriatric hip fracture patients. Its impact on refracture and mortality rate remained insignificant in this cohort of patients. Further study with a longer follow up time and more delicate selection of participants may demonstrate a better outcome.
Surgeon-administered ultrasound-guided combined popliteal sciatic nerve and adductor canal block in fixation of trimalleolar fracture
Authors: Chow Chun Lok , Siu Yuk Chuen , Ma Chun Man , Lui Tun Hing
Published: October 2024

Introduction: Combined popliteal sciatic nerve and adductor canal block under ultrasound guidance has been described as a safe and effective mean of regional anesthesia for foot and ankle surgery. Limited studies have shown its effectiveness while performed by surgeons. This study aims to assess the effectiveness and safety for this mode of regional anesthesia while carried out by orthopedic surgeons. Method: Patients presented to our unit with trimalleolar fracture of ankle who underwent operation under surgeon-administered ultrasound-guided combined popliteal sciatic nerve and adductor canal block were evaluated in this study. A total of 13 patients with mean age of 57.8 were included. Data regarding the diagnosis, pattern of injuries, comorbidities in American Society of Anesthesiologists Classification, duration of operation, blood loss, intraoperative pain control in visual analog scale (VAS), degree of motor blockage, postoperative pain control and hospital length of stay were collected and evaluated. Result: All patients experienced complete anesthesia with VAS 0 and complete motor blockage throughout the operation. Average operative time was 179 min. Postoperative pain control was satisfactory. There was no regional anesthesia related complication arise. Conclusion: Surgeon-administered ultrasound-guided combined popliteal sciatic nerve and adductor canal block is a safe and effective mean to provide anesthesia for trimalleolar fracture fixation according to our experience.
Risk Factors for High Repair Tension During Rotator Cuff Repair
Authors: Miyake Satoshi , Shibata Terufumi , Kobayashi Shunsuke , Matsunaga Kei , Hata Naofumi , Shibata Yozo , Izaki Teruaki , Yamamoto Takuaki
Published: October 2024

Background:

Excessively high repair tension, especially tension ≥10 N, can lead to unsuccessful rotator cuff repair.

Purpose/Hypothesis:

The purpose of this study was to identify the preoperative risk factors for high repair tension in rotator cuff repair. It was hypothesized was that older age, longer symptom duration, nontraumatic (ie, degenerative) tear onset, progressive fatty degeneration, and larger tear size would be among the risk factors.

Study Design:

Cross-sectional study; Level of evidence, 3.

Methods:

This retrospective study involved 80 patients (80 shoulders) diagnosed with rotator cuff tears by magnetic resonance imaging between July 2018 and August 2020. Repair tension was measured intraoperatively using a digital tension meter. Risk factors for high repair tension (≥10 N) were evaluated. The t test was used to assess the relationship of repair tension with patient characteristics and surgical parameters. Parameters with a P value of <.05 in the univariate analysis were entered into a multivariate logistic regression model to determine their relationship with repair tension ≥10 N.

Results:

Symptom duration of ≥4 months, nontraumatic tear onset, large/massive tears, mediolateral (ML) tear length of ≥20 mm, and anteroposterior (AP) tear length of ≥18 mm were associated with high odds of repair tension ≥10 N ( P≤ .013 for all). Multivariate analysis showed that nontraumatic onset, ML tear length of ≥20 mm, and AP tear length of ≥18 mm were independent risk factors for repair tension ≥10 N ( P≤ .035 for all).

Conclusion:

The independent risk factors for high repair tension (≥10 N) during rotator cuff repair were nontraumatic tear onset, ML tear length of ≥20 mm, and AP tear length of ≥18 mm. Symptom duration of ≥4 months and large/massive tears were associated with high odds of repair tension ≥10 N, although they were not considered independent risk factors. Prospective cohort studies with larger sample sizes are needed to confirm the clinical value of the risk factors identified in this study.
Surgical Treatment of Insertional Achilles Tendinopathy Augmented With Human Acellular Dermal Matrix: A Retrospective Case Series
Authors: Corlee Bryce , Bloomquist Mitchell , Brantley Branden , Hamilton Curtis , Ringus Vytautas
Published: October 2024

Background:

Insertional Achilles tendinopathy (IAT) is often surgically treated with Achilles tendon partial or total detachment, debridement and repair of the Achilles tendon, excision of retrocalcaneal exostosis, and suture anchor reattachment. To date, there is no report that examines the use of acellular dermal matrix (ADM) augmentation in this procedure without the use of suture anchor reattachment.

Methods:

Thirty-two female and 10 male patients (mean age 52 years) with IAT underwent surgical treatment including partial detachment of the Achilles tendon, excision of the retrocalcaneal exostosis, debridement and repair of the Achilles tendon, and augmentation with human acellular dermal matrix allograft. Outcomes measured were the visual analog scale (VAS) score, time to weightbearing, major and minor complications.

Results:

Forty-two patients were followed for a mean of 20.8 months. The VAS score improved from a mean of 5.1 to 1.9 at final follow-up. The mean time to weightbearing was 4.4 weeks. Eleven patients (26.2%) experienced complications. One patient (2.4%) suffered a rupture of the Achilles in the early postoperative period. Three patients (7.1%) had delayed wound healing, with 1 (2.4%) requiring surgical debridement. Two (4.8%) experienced continued pain requiring further surgical treatment.

Conclusion:

This protocol for surgical treatment of IAT with the use of human ADM allograft augmentation resulted in improved VAS scores and was associated with a low risk of postoperative infection without a prolonged nonweightbearing period.

Level of Evidence:

Level IV, retrospective case series.
Association of dietary inflammatory index and dietary oxidative balance score with gastrointestinal cancers in NHANES 2005–2018
Authors: Chang Yu , Yu Chanjiao , Dai Xianyu , Sun Haibo , Tang Tongyu
Published: October 2024

Background&Aims

Gastrointestinal (GI) cancers, including gastric, liver, esophageal, pancreatic, and colorectal cancers, represent significant global health burdens. Emerging evidence suggests that dietary patterns, particularly their inflammatory and oxidative properties, may influence cancer risk. The Dietary Inflammatory Index (DII) and Dietary Oxidative Balance Score (DOBS) assess the inflammatory and oxidative effects of diets, respectively. This study aims to explore the association between DII, DOBS, and the combined risk of GI cancers, and investigates the potential mediating roles of serum albumin and red cell distribution width (RDW).

Methods

Data from 26,320 participants in the NHANES 2005–2018 cycles were analyzed. DII was calculated based on 28 dietary components, and DOBS included 17 nutrients (3 pro-oxidants and 14 antioxidants). Logistic regression models assessed the associations between DII, DOBS, and GI cancers. Restricted cubic spline (RCS) models examined dose-response relationships. Mediation analysis evaluated the roles of serum albumin and RDW. Subgroup analyses explored interactions with demographic and health-related factors.

Results

Higher DII was associated with increased GI cancer risk (OR: 1.26, 95% CI: 1.07–1.49 per unit increase), while higher DOBS was associated with reduced risk (OR: 0.90, 95% CI: 0.76–0.99 per unit increase). RCS analysis indicated a significant nonlinear relationship between DII and GI cancer risk. Serum albumin and RDW partially mediated the associations between DII, DOBS, and GI cancers. Subgroup analyses showed stronger associations for DII among certain demographics, and significant interactions were found between DII and BMI. For DOBS, significant interactions were observed with age and BMI.

Conclusion

This study reveals significant associations between dietary inflammatory and oxidative balance scores and GI cancer risk. Higher DII is linked to increased risk, while higher DOBS is protective. The mediating roles of serum albumin and RDW provide insights into underlying mechanisms. These findings underscore the potential of dietary modifications in GI cancer prevention and management, emphasizing the importance of anti-inflammatory and antioxidant-rich diets.
Tezepelumab for severe asthma: elevating current practice to recognize epithelial driven profiles
Authors: Caminati Marco , Vatrella A. , Rogliani P. , Carpagnano E. , Spanevello A. , Senna G.
Published: October 2024

Background

An increasing amount of evidence supports the relevance of epithelium across the wide spectrum of asthma pathobiology. On a clinical ground tezepelumab, selectively binding TSLP, a major epithelial cytokine, has demonstrated to be effective in asthma patients regardless their specific phenotype. In order to avoid the risk of considering tezepelumab as a not-specific option, the present perspective aims to sketch the tezepelumab best eligible patient profile and to propose some hallmarks of epithelial-driven disease by reviewing the published evidence on the drug mechanism of action and efficacy data.

Main body

Although it cannot rely on standardised or exclusive “markers”, the relationship between environment and poor asthma control might suggest a major relevance of the epithelial barrier dysfunction. In that light, allergy and asthma exacerbations concomitant with specific exposures (pathogens, pollutants, chemicals), as well as increased susceptibility to infections can be considered as the hallmark of an impaired epithelial immune response. Tezepelumab is effective in allergic patients, being able to reduce asthma exacerbations precipitated by the exposure to seasonal or perennial aeroallergens, including fungi. In addition, tezepelumab reduced the incidence of co-occurring respiratory illness and asthma exacerbations. In terms of inflammation, epithelial immune response has been related to an impaired mucus hypersecretion and plugging. A placebo-controlled trial demonstrated a significant reduction of mucus plugging in treated patient. Airways hyperreactivity (AHR), airways obstruction and remodelling have been described as an expression of epithelial orchestrated immunological activation. Of note, a significantly higher incidence of mannitol negative test in patients treated with tezepelumab when compared to placebo group has been observed. In addition, A 130 mL improvement in pre-BD FEV1 has been described in patients assuming Tezepelumab. The above-mentioned data suggest that bronchial reversibility and AHR can be considered “functional biomarkers” supporting patients’ phenotyping and the identification of tezepelumab best responders.

Conclusion

Integrating “functional biomarkers” to the inflammatory ones and a better characterization of asthma exacerbations might pave the way to a different and more transversal phenotyping, which overcomes the “restrictive” labels including T2 high, allergic/atopic or T2 low asthma. Precisely defining the disease characteristics and potential targets for a better control even in tezepelumab eligible subjects is essential to avoid the block buster temptation and optimize the personalized medicine approach according to each patient’s individuality.
24-hour Movement Questionnaire (QMov24h) for adults: development process and measurement properties
Authors: Rodrigues Bruno , Júdice Pedro B. , Marques Adilson , Carraça Eliana V. , Lopes Luís , Sousa-Sá Eduarda , Encantado Jorge , Videira-Silva António , Cliff Dylan P. , Mendes Romeu , Santos Rute ,   on behalf of the QMov24h working group, Silva Analiza M. , Palmeira António L. , Machado-Rodrigues Aristides M. , Sampaio Arnaldina , Moreira Carla , Agostinis-Sobrinho César , Lima Diogo , Biscoito Filipe , Rocha João , Martins Raul , Abreu Sandra , Vale Susana , Figueiras Teresa , Pereira Teresa , Simões Vera
Published: October 2024

Background

Sleep, sedentary behaviour, and physical activity are essential components within the 24-hour time frame. Existing questionnaires used to measure these behaviours have insufficient measurement properties and are unsuitable for assessing compliance with the WHO Physical Activity and 24-hour Movement Guidelines. To describe the development process of the 24-hour Movement Questionnaire (QMov24h) and its testing. The QMov24h was developed to gather detailed information on sleep, sedentary behaviour, and physical activity.

Methods

The sample comprised 117 participants (58% women), aged 30.95 ± 13.56 years. The development process of the QMov24h followed the COSMIN guidelines: (i) Construction of items; (ii) Face validity with end-users; (iii) Content validity with experts; (iv) Criterion validity against accelerometry and convergent validity against diary assessments; and (v) 7-day test-retest reliability.

Results

The QMov24h presented adequate content and face validity. The QMov24h showed moderate criterion validity for sleep (rho=0.343;p<0.001), light physical activity (rho=0.31;p=0.002) and total aerobic physical activity (rho=0.343;p<0.001), as well as strong criterion validity for sedentary behaviour (rho=0.428;p<0.001) and aerobic moderate-to-vigorous physical activity (rho=0.534;p<0.001). Reliability varied from poor to excellent (ICC from 0.38 to 0.962;p<0.001) for all questionnaire variables. Regarding compliance of the 24-hour movement guidelines, the questionnaire also showed a strong to almost perfect percentage of agreement with accelerometry (from 69% to 94.3%), and minimal to strong reliability (k from 0.38 to 0.87) between the first and second administrations of the QMov24h.

Conclusions

The QMov24h questionnaire is a valid and reliable tool for assessing levels of movement behaviours and compliance with guidelines in adults. Its measurement properties are comparable to, or even better than, those of existing questionnaires, while posing a similar burden to participants. The QMov24h is useful for research, clinical practice, and public health surveillance. The QMov24h has strong psychometric properties, making it suitable for translation, cultural adaptation, and testing in diverse populations for broader international use.