bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular taxonomy of myelodysplastic syndromes and its clinical implications
Authors: Bernard Elsa , Hasserjian Robert P. , Greenberg Peter L. , Arango Ossa Juan E. , Creignou Maria , Tuechler Heinz , Gutierrez-Abril Jesus , Domenico Dylan , Medina-Martinez Juan S. , Levine Max , Liosis Konstantinos , Farnoud Noushin , Sirenko Maria , Jädersten Martin , Germing Ulrich , Sanz Guillermo , van de Loosdrecht Arjan A. , Nannya Yasuhito , Kosmider Olivier , Follo Matilde Y. , Thol Felicitas , Zamora Lurdes , Pinheiro Ronald F. , Pellagatti Andrea , Elias Harold K. , Haase Detlef , Ganster Christina , Ades Lionel , Tobiasson Magnus , Palomo Laura , Della Porta Matteo Giovanni , Fenaux Pierre , Belickova Monika , Savona Michael R. , Klimek Virginia M. , Santos Fabio P. S. , Boultwood Jacqueline , Kotsianidis Ioannis , Santini Valeria , Solé Francesc , Platzbecker Uwe , Heuser Michael , Valent Peter , Finelli Carlo , Voso Maria Teresa , Shih Lee-Yung , Fontenay Michaela , Jansen Joop H. , Cervera José , Gattermann Norbert , Ebert Benjamin L. , Bejar Rafael , Malcovati Luca , Ogawa Seishi , Cazzola Mario , Hellström-Lindberg Eva , Papaemmanuil Elli
Published: July 2024

Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research.
Gut microbiota Parabacteroides distasonis enchances the efficacy of immunotherapy for bladder cancer by activating anti-tumor immune responses
Authors: Wang Benlin , Qiu Yifeng , Xie Ming , Huang Pengcheng , Yu Yao , Sun Qi , Shangguan Wentai , Li Weijia , Zhu Zhangrui , Xue Jingwen , Feng Zhengyuan , Zhu Yuexuan , Yang Qishen , Wu Peng
Published: July 2024

Objective

Bladder cancer(BCa) was a disease that seriously affects patients’ quality of life and prognosis. To address this issue, many researches suggested that the gut microbiota modulated tumor response to treatment; however, this had not been well-characterized in bladder cancer. In this study, our objective was to determine whether the diversity and composition of the gut microbiota or the density of specific bacterial genera influence the prognosis of patients with bladder cancer.

Methods

We collected fecal samples from a total of 50 bladder cancer patients and 22 matched non-cancer individuals for 16S rDNA sequencing to investigate the distribution of Parabacteroides in these two groups. Further we conducted follow-up with cancer patients to access the impact of different genera of microorganisms on patients survival. We conducted a Fecal Microbiota Transplantation (FMT) and mono-colonization experiment with Parabacteroides distasonis to explore its potential enhancement of the efficacy of anti-PD-1 immunotherapy in MB49 tumor-bearing mice. Immunohistochemistry, transcriptomics and molecular experiment analyses were employed to uncover the underlying mechanisms.

Results

The 16S rDNA showed that abundance of the genus Parabacteroides was elevated in the non-cancer control group compared to bladder cancer group. The results of tumor growth curves showed that a combination therapy of P. distasonis and ICIs treatment significantly delayed tumor growth and increased the intratumoral densities of

both CD4+T and CD8+T cells. The results of transcriptome analysis demonstrated that the pathways associated with antitumoral immune response were remarkably upregulated in the P. distasonis gavage group.

Conclusion

P. distasonis delivery combined with α-PD-1 mAb could be a new strategy to enhance the effect of anti-PD-1 immunotherapy. This effect might be achieved by activating immune and antitumor related pathways.
Biofilm-producing ability of methicillin-resistant Staphylococcus aureus clinically isolated in China
Authors: Yu Jingyi , Han Weihua , Xu Yanlei , Shen Li , Zhao Huilin , Zhang Jiao , Xiao Yanghua , Guo Yinjuan , Yu Fangyou
Published: July 2024

Background

Staphylococcus aureus, a commensal bacterium, colonizes the skin and mucous membranes of approximately 30% of the human population. Apart from conventional resistance mechanisms, one of the pathogenic features of S. aureus is its ability to survive in a biofilm state on both biotic and abiotic surfaces. Due to this characteristic, S. aureus is a major cause of human infections, with Methicillin-Resistant Staphylococcus aureus (MRSA) being a significant contributor to both community-acquired and hospital-acquired infections.

Results

Analyzing non-repetitive clinical isolates of MRSA collected from seven provinces and cities in China between 2014 and 2020, it was observed that 53.2% of the MRSA isolates exhibited varying degrees of ability to produce biofilm. The biofilm positivity rate was notably high in MRSA isolates from Guangdong, Jiangxi, and Hubei. The predominant MRSA strains collected in this study were of sequence types ST59, ST5, and ST239, with the biofilm-producing capability mainly distributed among moderate and weak biofilm producers within these ST types. Notably, certain sequence types, such as ST88, exhibited a high prevalence of strong biofilm-producing strains. The study found that SCCmec IV was the predominant type among biofilm-positive MRSA, followed by SCCmec II. Comparing strains with weak and strong biofilm production capabilities, the positive rates of the sdrD and sdrE were higher in strong biofilm producers. The genetic determinants ebp, icaA, icaB, icaC, icaD, icaR, and sdrE were associated with strong biofilm production in MRSA. Additionally, biofilm-negative MRSA isolates showed higher sensitivity rates to cefalotin (94.8%), daptomycin (94.5%), mupirocin (86.5%), teicoplanin (94.5%), fusidic acid (81.0%), and dalbavancin (94.5%) compared to biofilm-positive MRSA isolates. The biofilm positivity rate was consistently above 50% in all collected specimen types.

Conclusions

MRSA strains with biofilm production capability warrant increased vigilance.
Accuracy of oscillometric noninvasive blood pressure at the ankle in the lateral position during general anesthesia
Authors: Farag Ahmed , Mostafa Maha , Hasanin Ahmed , Sobh Lamis , Raafat Heba , Obayah Gihan , Youssef Maha
Published: July 2024

Background

This study aimed to evaluate the accuracy of ankle blood pressure measurements in relation to invasive blood pressure in the lateral position.

Methods

This prospective observational study included adult patients scheduled for elective non-cardiac surgery under general anesthesia in the lateral position. Paired radial artery invasive and ankle noninvasive blood pressure readings were recorded in the lateral position using GE Carescape B650 monitor. The primary outcome was the ability of ankle mean arterial pressure (MAP) to detect hypotension (MAP < 70 mmHg) using area under the receiver operating characteristic curve (AUC) analysis. The secondary outcomes were the ability of ankle systolic blood pressure (SBP) to detect hypertension (SBP > 140 mmHg) as well as bias (invasive measurement – noninvasive measurement), and agreement between the two methods using the Bland-Altman analysis.

Results

We analyzed 415 paired readings from 30 patients. The AUC (95% confidence interval [CI]) of ankle MAP for detecting hypotension was 0.88 (0.83–0.93). An ankle MAP of ≤ 86 mmHg had negative and positive predictive values (95% CI) of 99 (97–100)% and 21 (15–29)%, respectively, for detecting hypotension. The AUC (95% CI) of ankle SBP to detect hypertension was 0.83 (0.79–0.86) with negative and positive predictive values (95% CI) of 95 (92–97)% and 36 (26–46)%, respectively, at a cutoff value of > 144 mmHg. The mean bias between the two methods was − 12 ± 17, 3 ± 12, and − 1 ± 11 mmHg for the SBP, diastolic blood pressure, and MAP, respectively.

Conclusion

In patients under general anesthesia in the lateral position, ankle blood pressure measurements are not interchangeable with the corresponding invasive measurements. However, an ankle MAP > 86 mmHg can exclude hypotension with 99% accuracy, and an ankle SBP < 144 mmHg can exclude hypertension with 95% accuracy.
Multimorbidity and associated informal care receiving characteristics for US older adults: a latent class analysis
Authors: Liu Ruotong , Nagel Corey L. , Chen Siting , Newsom Jason T. , Allore Heather G. , Quiñones Ana R.
Published: July 2024

Background

Older adults with varying patterns of multimorbidity may require distinct types of care and rely on informal caregiving to meet their care needs. This study aims to identify groups of older adults with distinct, empirically-determined multimorbidity patterns and compare characteristics of informal care received among estimated classes.

Methods

Data are from the 2011 National Health and Aging Trends Study (NHATS). Ten chronic conditions were included to estimate multimorbidity patterns among 7532 individuals using latent class analysis. Multinomial logistic regression model was estimated to examine the association between sociodemographic characteristics, health status and lifestyle variables, care-receiving characteristics and latent class membership.

Results

A four-class solution identified the following multimorbidity groups: some somatic conditions with moderate cognitive impairment (30%), cardiometabolic (25%), musculoskeletal (24%), and multisystem (21%). Compared with those who reported receiving no help, care recipients who received help with household activities only (OR = 1.44, 95% CI 1.05–1.98), mobility but not self-care (OR = 1.63, 95% CI 1.05–2.53), or self-care but not mobility (OR = 2.07, 95% CI 1.29–3.31) had greater likelihood of being in the multisystem group versus the some-somatic group. Having more caregivers was associated with higher odds of being in the multisystem group compared with the some-somatic group (OR = 1.09, 95% CI 1.00-1.18), whereas receiving help from paid helpers was associated with lower odds of being in the multisystem group (OR = 0.36, 95% CI 0.19–0.77).

Conclusions

Results highlighted different care needs among persons with distinct combinations of multimorbidity, in particular the wide range of informal needs among older adults with multisystem multimorbidity. Policies and interventions should recognize the differential care needs associated with multimorbidity patterns to better provide person-centered care.
Association of selected adipokines with vitamin D deficiency in children with inflammatory bowel disease
Authors: Geryk Milos , Kucerova Veronika , Velganova-Veghova Maria , Foltenova Hana , Bouchalova Katerina , Karasek David , Radvansky Martin , Karaskova Eva
Published: July 2024

Background

Adipose tissue is significantly involved in inflammatory bowel disease (IBD). Vitamin D can affect both adipogenesis and inflammation. The aim of this study was to compare the production of selected adipokines, potentially involved in the pathogenesis of IBD - adiponectin, resistin, retinol binding protein 4 (RBP-4), adipocyte fatty acid binding protein and nesfatin-1 in children with IBD according to the presence of 25-hydroxyvitamin D (25(OH)D) deficiency.

Methods

The study was conducted as a case-control study in pediatric patients with IBD and healthy children of the same sex and age. In addition to adipokines and 25(OH)D, anthropometric parameters, markers of inflammation and disease activity were assessed in all participants.

Results

Children with IBD had significantly higher resistin levels regardless of 25(OH)D levels. IBD patients with 25(OH)D deficiency only had significantly lower RBP-4 compared to healthy controls and also compared to IBD patients without 25(OH)D deficiency. No other significant differences in adipokines were found in children with IBD with or without 25(OH)D deficiency. 25(OH)D levels in IBD patients corelated with RBP-4 only, and did not correlate with other adipokines.

Conclusions

Whether the lower RBP-4 levels in the 25(OH)D-deficient group of IBD patients directly reflect vitamin D deficiency remains uncertain. The production of other adipokines does not appear to be directly related to vitamin D deficiency.
The impact of regional disparities on the availability of meningococcal vaccines in the US
Authors: Schley Katharina , Jodar Eva , Presa Jessica V. , Willis Sarah J. , Prener Christopher G.
Published: July 2024

Background

In the United States (US), three types of vaccines are available to prevent invasive meningococcal disease (IMD), a severe and potentially fatal infection: quadrivalent conjugate vaccines against serogroups A, C, W, Y (MenACWY), and monovalent vaccines against serogroup B (MenB) as well as a newly licensed pentavalent vaccine (MenABCWY) protecting against serogroup A, B, C, W, and Y. The CDC’s Advisory Committee on Immunization Practices (ACIP) routinely recommends MenACWY vaccine for all 11- to 12-year-olds with a booster dose at 16 years. MenB vaccination is recommended based on shared clinical decision-making (SCDM) for 16- to 23-year-olds. Recently, the pentavalent meningococcal vaccine (MenABCWY) was recommended by the ACIP. Meningococcal vaccine uptake is suboptimal across the country, particularly among individuals with lower socioeconomic status (SES), despite these recommendations. The objective of the spatial analyses was to assess the relationship between stocking of MenACWY and MenB vaccines, area-level SES, and state-level policies.

Methods

The number of MenACWY and MenB doses stocked by vaccinators was obtained from IQVIA and the CDC’s Vaccine for Children (VFC) program and compiled into a county-level dataset from 2016 to 2019. SES, as measured using the CDC’s Social Vulnerability Index (SVI), state-level school recommendations, and universal purchasing programs were among the main county-level covariates included to control for factors likely influencing stocking. Data were stratified by public and private market. Bayesian spatial regression models were developed to quantify the variations in rates of stocking and the relative rates of stocking of both vaccines.

Results

After accounting for county-level characteristics, lower SES counties tended to have fewer doses of MenB relative to MenACWY on both public and private markets. Lower SES counties tended to have more supply of public vs. private doses. Universal purchasing programs had a strong effect on the markets for both vaccines shifting nearly all doses to the public market. School vaccination strategy was key for improving stocking rates.

Conclusions

Overall, the results show that MenACWY has greater stock relative to MenB across the US. This difference is exacerbated in vulnerable areas without school entry requirements for vaccination and results in inequity of vaccine availability. Beyond state-level policy and SES differences, SCDM recommendations may be a contributing factor, although this was not directly assessed by our model.
Knowledge of Alzheimer’s disease and associated factors among adults in Zhuhai, China: a cross-sectional analysis
Authors: Sun Ya-Jun , Song Jie , Li Xu-Ping , Wang Xiao-Hui , Wu Yi-Xuan , Huang Jia-Ju , Wang Shi-Bin , Teng Yong-Yong
Published: July 2024

Background

This study aimed to assess the public knowledge regarding Alzheimer’s Disease (AD) in Zhuhai, China, focusing on identifying knowledge gaps and the influence of demographic and health factors.

Methods

A cross-sectional study was conducted in Zhuhai, China, from October to November 2022. A total of 1986 residents from 18 communities were selected employing stratified multi-stage equi-proportional sampling. Questionnaires covering general information and the Alzheimer’s Disease Knowledge Scale (ADKS) were investigated face-to-face. Ordinal multiclass logistic regression was applied to assess the relationship between AD awareness and demographic and health characteristics.

Results

The average ADKS score was 18.5 (SD = 3.36) in Zhuhai. The lowest awareness rates were observed in the “Symptoms” and “Caregiving” subdomains of ADKS, with rates of 51.01% and 43.78%, respectively. The correct rates for the 30 ADKS questions ranged from 16.62 to 92.6%, showing a bimodal pattern with clusters around 80% and 20%. Women (OR = 1.203, 95% CI: 1.009–1.435), individuals aged 60 years or older (OR = 2.073, 95% CI: 1.467–2.932), those living in urban areas (OR = 1.361, 95% CI: 1.117–1.662), higher average monthly household income per capita (OR = 1.641, 95% CI: 1.297–2.082), and without any neurological or mental disorders (OR = 1.810, 95% CI: 1.323–2.478) were more likely to have higher levels of awareness about Alzheimer’s disease.

Conclusions

Adults in Zhuhai show a limited knowledge of AD, particularly in the ‘Symptoms’ and ‘Caregiving’ subdomains. Upcoming health campaigns must focus on bridging the knowledge gaps in different subdomains of AD, especially among subgroups with lower awareness, as identified in our study.
Total hip arthroplasty with porous tantalum trabecular metal pads in patients with Crowe IV developmental dysplasia of the hip: a midterm followup study
Authors: Yang Cheng , Li Donghai , Sun Shuo , Yang Zhouyuan , Kang Pengde
Published: July 2024

Purpose

Crowe IV developmental dysplasia of the hip (DDH) is a catastrophic hip disease. Moreover, obtaining ideal clinical efficacy in conventional total hip arthroplasty (THA) is often difficult. In this study, we aimed to assess the mid-term clinical results of THA with porous tantalum trabecular metal (TM) pads for acetabular reconstruction in the treatment of Crowe IV DDH.

Methods

A cohort of 28 patients (32 hips) diagnosed with Crowe type IV DDH who underwent acetabular reconstruction during THA using TM pads with scheduled follow-up between 2011 and 2018, were included in this study. Eight cases were men and 24 were women, with a mean age of 48.4 years (range, 36–72 years) and a mean follow-up was 74.3 months (range, 42–132 months). All patients underwent acetabular reconstruction using TM pads and total hip replacement with subtrochanteric osteotomy.

Results

At the final follow-up, 28 hips (87.5%) demonstrated mild or no postoperative limping. The Harris Hip Score improved from 58.4 ± 10.6 preoperatively to 85.6 ± 8.9. The mean pain, stiffness, and function scores on the Western Ontario and McMaster University Osteoarthritis index were 86.5 ± 10.2, 87.3 ± 12.4 and 85.4 ± 11.6 respectively. The mean score of patient satisfaction was 90.4 ± 7.6. Additionally, the SF-12 physical summary score was 41.8 ± 5.6 and the SF-12 mental summary score was 51.6 ± 5.4. TM construct survivorship due to all-cause failure was 90.6% at 5 years with 3 hips at risk, 87.5% at 10 years with 4 hips at risk. The survivorship due to failure from aseptic loosening was 96.9% at 5 years with 1hips at risk and 93.75% at 10 years with 2 hips at risk.

Conclusion

This study demonstrated satisfactory mid-term clinical and radiological results with the application of TM pads for acetabular reconstruction combined with THA in patients with Crowe IV DDH.

Trial registration number

ChiCTR1800014526, Date: 18/01/2018.
Test-reduced teaching for stimulation of intrinsic motivation (TRUST): a randomized controlled intervention study
Authors: Faure Theresa , Weyers Imke , Voltmer Jan-Bennet , Westermann Jürgen , Voltmer Edgar
Published: July 2024

Background

The anatomy dissection course is a major part of the first two years of the traditional medical curriculum in Germany. The vast amount of content to be learned and the repeated examination is unanimously perceived by students and teachers as a major stress factor that contributes to the increase of psychosocial stress during the first two years of the course of study. Published interventions for specific stress reduction are scarce.

Methods

In a randomized, controlled design two intervention groups were compared with a control group (CG) over the whole dissection course (nine measuring points before, during and after first and second semester). The ‘Stress Management intervention (IVSM)’ targeted at the setting of personal standards, the ‘Friendly Feedback intervention (IVFF)’ at the context of frequent testing. Quantitative surveys were distributed at nine measuring points. The questionnaire comprised validated instruments and self-developed items regarding stress, positive and negative affect, anxiety, intrinsic and extrinsic motivation, self-efficacy, and perceived performance.

Results

Out of 195 students inscribed in the dissection course, 166 (85%) agreed to participate in the study. The experience of stress during the dissection course was significantly higher in the CG than in the IVFF. Anxiety and negative affect were lower in students of the IVFF while positive affect, intrinsic motivation, and self-efficacy were higher than in the CG. For anxiety and negative affect in the IVSM this was especially seen at the end of the second semester. The self-perceived increase in both knowledge and preparedness for the first big oral and written examination did not differ between the study groups. About three quarters of the participants would choose the intervention ‘Friendly Feedback’ if given the choice.

Conclusions

Replacing formal tests with friendly feedback has proven to be an effective measure to reduce stress and negative affect and foster positive affect, self-efficacy, and intrinsic motivation, while it did not impair self-perceived academic performance.
Carbohydrate antigen 125 on epicardial fat and its association with local inflammation and fibrosis-related markers
Authors: Eiras Sonia , de la Espriella Rafael , Fu Xiaoran , Iglesias-Álvarez Diego , Basdas Rumeysa , Núñez-Caamaño J. R. , Martínez-Cereijo J. M. , Reija L. , Fernández A. L. , Sánchez-López David , Miñana Gema , Núñez Julio , González-Juanatey José R.
Published: July 2024

Background

Carbohydrate antigen 125 (CA125) is a proteolytic fragment of MUC-16 that is increased in heart failure (HF) and associated with inflammation, fluid overload, and worse adverse events. Our main objective was to study the expression of CA125 on epicardium and its association with inflammation, adipogenesis, and fibrosis.

Methods

Epicardial fat biopsies and blood were obtained from 151 non-selected patients undergoing open heart surgery. Immunohistochemistry, ELISA, or real-time PCR were used for analyzing protein or mRNA expression levels of CA125 and markers of inflammatory cells, fibroblasts, and adipocytes. Epithelial or stromal cells from epicardium were isolated and cultured to identify CA125 and its association with the adipogenesis and fibrosis pathways, respectively.

Results

The median age was 71 (63–74) years, 106 patients (70%) were male, and 62 (41%) had an established diagnosis of HF before surgery. The slice of epicardial fat biopsy determined a positive and colorimetric staining on the epithelial layer after incubating with the CA125 M11 antibody, providing the first description of CA125 expression in the human epicardium. Epicardial CA125 showed a strong and positive correlation with markers of inflammation and fibrosis in the epicardial fat tissue while exhibiting a negative correlation with markers of the adipogenesis pathway. This relationship remained significant after adjusting for potential confounders such as a prior HF diagnosis and plasma CA125 levels.

Conclusion

Epicardial cells express CA125, which is positively associated with inflammatory and fibroblast markers in epicardial adipose tissue. These results suggest that CA125 may be biologically involved in HF progression (transition from adipogenesis to fibrosis).

Graphical Abstract
Accumulation of liposomes in metastatic tumor sites is not necessary for anti-cancer drug efficacy
Authors: Kalra Jessica , Baker Jennifer , Sun XuXin , Kyle Alastair , Minchinton Andrew , Bally Marcel B.
Published: July 2024

Background

The tumor microenvironment is profoundly heterogeneous particularly when comparing sites of metastases. Establishing the extent of this heterogeneity may provide guidance on how best to design lipid-based drug delivery systems to treat metastatic disease. Building on our previous research, the current study employs a murine model of metastatic cancer to explore the distribution of ~ 100 nm liposomes.

Methods

Female NCr nude mice were inoculated with a fluorescently labeled, Her2/neu-positive, trastuzumab-resistant breast cancer cell line, JIMT-1mkate, either in the mammary fat pad to create an orthotopic tumor (OT), or via intracardiac injection (IC) to establish tumors throughout the body. Animals were dosed with fluorescent and radio-labeled liposomes. In vivo and ex vivo fluorescent imaging was used to track liposome distribution over a period of 48 h. Liposome distribution in orthotopic tumors was compared to sites of tumor growth that arose following IC injection.

Results

A significant amount of inter-vessel heterogeneity for DiR distribution was observed, with most tumor blood vessels showing little to no presence of the DiR-labelled liposomes. Further, there was limited extravascular distribution of DiR liposomes in the perivascular regions around DiR-positive vessels. While all OT tumors contained at least some DiR-positive vessels, many metastases had very little or none. Despite the apparent limited distribution of liposomes within metastases, two liposomal drug formulations, Irinophore C and Doxil, showed similar efficacy for both the OT and IC JIMT-1mkate models.

Conclusion

These findings suggest that liposomal formulations achieve therapeutic benefits through mechanisms that extend beyond the enhanced permeability and retention effect.
Redefining the ontogeny of hyalocytes as yolk sac-derived tissue-resident macrophages of the vitreous body
Authors: Rosmus Dennis-Dominik , Koch Jana , Hausmann Annika , Chiot Aude , Arnhold Franz , Masuda Takahiro , Kierdorf Katrin , Hansen Stefanie Marie , Kuhrt Heidrun , Fröba Janine , Wolf Julian , Boneva Stefaniya , Gericke Martin , Ajami Bahareh , Prinz Marco , Lange Clemens , Wieghofer Peter
Published: July 2024

Background

The eye is a highly specialized sensory organ which encompasses the retina as a part of the central nervous system, but also non-neural compartments such as the transparent vitreous body ensuring stability of the eye globe and a clear optical axis. Hyalocytes are the tissue-resident macrophages of the vitreous body and are considered to play pivotal roles in health and diseases of the vitreoretinal interface, such as proliferative vitreoretinopathy or diabetic retinopathy. However, in contrast to other ocular macrophages, their embryonic origin as well as the extent to which these myeloid cells might be replenished by circulating monocytes remains elusive.

Results

In this study, we combine transgenic reporter mice, embryonic and adult fate mapping approaches as well as parabiosis experiments with multicolor immunofluorescence labeling and confocal laser-scanning microscopy to comprehensively characterize the murine hyalocyte population throughout development and in adulthood. We found that murine hyalocytes express numerous well-known myeloid cell markers, but concomitantly display a distinct immunophenotype that sets them apart from retinal microglia. Embryonic pulse labeling revealed a yolk sac-derived origin of murine hyalocytes, whose precursors seed the developing eye prenatally. Finally, postnatal labeling and parabiosis established the longevity of hyalocytes which rely on Colony Stimulating Factor 1 Receptor (CSF1R) signaling for their maintenance, independent of blood-derived monocytes.

Conclusion

Our study identifies hyalocytes as long-living progeny of the yolk sac hematopoiesis and highlights their role as integral members of the innate immune system of the eye. As a consequence of their longevity, immunosenescence processes may culminate in hyalocyte dysfunction, thereby contributing to the development of vitreoretinal diseases. Therefore, myeloid cell-targeted therapies that convey their effects through the modification of hyalocyte properties may represent an interesting approach to alleviate the burden imposed by diseases of the vitreoretinal interface.
Impaired ATP hydrolysis in blood plasma contributes to age-related neutrophil dysfunction
Authors: Ledderose Carola , Valsami Eleftheria-Angeliki , Elevado Mark , Liu Qing , Giva Brennan , Curatolo Julian , Delfin Joshua , Abutabikh Reem , Junger Wolfgang G.
Published: July 2024

Background

The function of polymorphonuclear neutrophils (PMNs) decreases with age, which results in infectious and inflammatory complications in older individuals. The underlying causes are not fully understood. ATP release and autocrine stimulation of purinergic receptors help PMNs combat microbial invaders. Excessive extracellular ATP interferes with these mechanisms and promotes inflammatory PMN responses. Here, we studied whether dysregulated purinergic signaling in PMNs contributes to their dysfunction in older individuals.

Results

Bacterial infection of C57BL/6 mice resulted in exaggerated PMN activation that was significantly greater in old mice (64 weeks) than in young animals (10 weeks). In contrast to young animals, old mice were unable to prevent the systemic spread of bacteria, resulting in lethal sepsis and significantly greater mortality in old mice than in their younger counterparts. We found that the ATP levels in the plasma of mice increased with age and that, along with the extracellular accumulation of ATP, the PMNs of old mice became increasingly primed. Stimulation of the formyl peptide receptors of those primed PMNs triggered inflammatory responses that were significantly more pronounced in old mice than in young animals. However, bacterial phagocytosis and killing by PMNs of old mice were significantly lower than that of young mice. These age-dependent PMN dysfunctions correlated with a decrease in the enzymatic activity of plasma ATPases that convert extracellular ATP to adenosine. ATPases depend on divalent metal ions, including Ca2+, Mg2+, and Zn2+, and we found that depletion of these ions blocked the hydrolysis of ATP and the formation of adenosine in human blood, resulting in ATP accumulation and dysregulation of PMN functions equivalent to those observed in response to aging.

Conclusions

Our findings suggest that impaired hydrolysis of plasma ATP dysregulates PMN function in older individuals. We conclude that strategies aimed at restoring plasma ATPase activity may offer novel therapeutic opportunities to reduce immune dysfunction, inflammation, and infectious complications in older patients.
Surgical treatment of atrial fibrillation in elderly patients undergoing high risk cardiac surgery
Authors: Uzzaman Mohammed Mohsin , Manoly Imthiaz , Pannikkar Mohini , Caruso Vincenzo , Matuszewski Maciej , Nikolaidis Nicolas , Billing Stephen
Published: July 2024

Background

Evaluating outcomes of concurrent Cox-Maze procedures in elderly patients undergoing high-risk cardiac surgery.

Mehods

We retrospectively identified patients aged over 70 years with Atrial Fibrillation (AF) from 2011 to 2017 who had two or more other cardiac procedures. They were subdivided into two groups: 1. Cox-Maze IV AF ablation. 2. No-Surgical AF treatment. A propensity match score was used to generate a homogeneous cohort and to eliminate confounding variables. Heart rhythm was assessed from Holter reports or 12-lead ECG. Follow-up data was collected through telephone consultations and medical records.

Results

There were 239 patients. Median follow up was 61 months. 70 patients had Cox-Maze IV procedures (29.3%). Demographic, intra- and post-operative outcomes were similar between groups although duration of pre-operative AF was shorter in Cox-Maze group (p = 0.001). There was no significant 30-day mortality difference in propensity matched cohorts (n = 84. P = 0.078). Sinus rhythm at annual and latest follow-up was 84.9% and 80.0% respectively in Maze group – 160 patients (66.9%) were alive at long-term follow-up with good survival outcomes in Cox Maze group. There was a high proportion of patients in NYHA 1 status in Cox-Maze group. No differences observed in freedom from stroke (p = 0.80) or permanent pacemaker (p = 0.33) between the groups.

Conclusions

Surgical ablation is beneficial in elderly patients undergoing high-risk surgery - promoting excellent long-term freedom from AF and symptomatic / prognostic benefits, without added risk. Therefore, surgical risk should not be reason to deny benefits of concomitant AF-ablation.

Clinical trial registration

Not required.
Long-term outcomes following mitral valve replacement in children at heart center Leipzig: a 20-year analysis
Authors: Schumacher Katja , Marin-Cuartas Mateo , Aydin Muhammed Ikbal , de la Cuesta Manuela , Meier Sabine , Borger Michael Andrew , Dähnert Ingo , Kostelka Martin , Vollroth Marcel
Published: July 2024

Background

Although mitral valve repair is the preferred surgical strategy in children with mitral valve disease, there are cases of irreparable severe dysplastic valves that require mitral valve replacement. The aim of this study is to analyze long-term outcomes following mitral valve replacement in children in a tertiary referral center.

Methods

A total of 41 consecutive patients underwent mitral valve replacement between February 2001 and February 2021. The study data was prospectively collected and retrospectively analyzed. Primary outcomes were in-hospital mortality, long-term survival, and long-term freedom from reoperation.

Results

Median age at operation was 23 months (IQR 5–93), median weight was 11.3 kg (IQR 4.8–19.4 kg). One (2.4%) patient died within the first 30 postoperative days. In-hospital mortality was 4.9%. Four (9.8%) patients required re-exploration for bleeding, and 2 (4.9%) patients needed extracorporeal life support. Median follow-up was 11 years (IQR 11 months − 16 years). Long-term freedom from re-operation after 1, 5, 10 and 15 years was 97.1%, 93.7%, 61.8% and 42.5%, respectively. Long-term survival after 1, 5, 10 and 15 years was 89.9%, 87%, 87% and 80.8%, respectively.

Conclusion

If MV repair is not feasible, MV replacement offers a good surgical alternative for pediatric patients with MV disease. It provides good early- and long-term outcomes.
Extent of magnitude representation deficit and relationship with arithmetic skills in children with 22q11.2DS
Authors: Favre Emilie , Piveteau Margot , Babinet Marie-Noelle , Demily Caroline
Published: July 2024

Background

Previous studies have produced conflicting results concerning the extent of magnitude representation deficit and its relationship with arithmetic achievement in children with 22q11.2 deletion syndrome. More specifically, it remains unclear whether deficits are restricted to visuospatial content or are more general and whether they could explain arithmetical impairment.

Methods

Fifteen 5- to 12-year-old children with 22q11.2 deletion syndrome and 23 age-matched healthy controls performed a non-symbolic magnitude comparison task. Depending on the trial, participants had to compare stimuli with high or low visuospatial load (visuospatial stimuli or temporal sequence of visual stimuli). The participants also completed a battery of arithmetic skills (ZAREKI-R) and a battery of global cognitive functioning (WISC-V or WPPSI-IV), from which working memory and visuospatial indices were derived.

Results

Children with 22q11.2DS responded as fast as healthy controls did but received fewer correct responses, irrespective of visuospatial load. In addition, their performance in the non-symbolic magnitude comparison task did not correlate with the ZAREKI total score, while the working memory index did.

Conclusion

Children with 22q11.2DS might suffer from a global magnitude representation deficit rather than a specific deficit due to visuospatial load. However, this deficit alone does not seem to be related to arithmetic achievement. Working memory might be a better concern of interest in favoring arithmetic skills in patients with 22q11.2 deletion syndrome.

Trial registration

Clinicaltrials, NCT04373226. Registered 16 September 2020.
Oncologists Must Consider Participant Data When Using Large-Scale Cancer Data Sets
Authors: Avila Santiago , Roberson Mya L. , Rajagopal Padma Sheila
Published: July 2024

Primer that helps clarify large-scale clinical data sets and participant demographics for oncologists.
Financial Toxicity in Cancer Supportive Care: An International Survey
Authors: Chan Alexandre , Ke Yu , Tanay Mary , Dagsi Mary , Bergerot Cristiane , Dixit Niharika , Eng Lawson , Cardeña Gutiérrez Ana , Jiang Changchuan , Velázquez Ana I. , Islami Farhad , Soto-Perez-de-Celis Enrique
Published: July 2024

PURPOSE

The study aims to explore unmet social needs and sources of financial toxicities in patients as noted by health care professionals and researchers in cancer supportive care, shedding light on potential health disparities.

METHODS

In this cross-sectional survey, we anonymously surveyed active members of the Multinational Association of Supportive Care in Cancer (MASCC). The survey, structured in three sections, included questions regarding the routine assessment of social needs during patient consultations, sociodemographic aspects, factors influencing financial toxicity (FT), perceived support for managing FT, and available/desirable resources.

RESULTS

A total of 218 MASCC members were included, predominantly from high-income countries (HIC, 73.4%), with many age 41-60 years (56.5%) and female (56.9%). Drug/treatment cost and insurance coverage were the main sources for FT among the HIC, whereas participants from low-middle–income countries (LMIC) considered transportation cost, loss of employment because of cancer diagnosis, and unavailability of return-to-work services as the top three sources of FT. Respondents from LMIC (adjusted odds ratio [aOR], 3.01 [95% CI, 1.15 to 7.93]) and physicians (aOR, 2.67 [95% CI, 1.15 to 6.21]) were more likely to routinely assess financial coverages. Socioeconomic status was consistently ranked as one of the top three sources of financial toxicities by participants from LMIC (34%), HIC excluding the United States (38%), those who do not self-identify as racial/ethnic minority (36%), and physicians (40%).

CONCLUSION

This global survey of health care professionals and researchers in HIC and LMIC revealed varying approaches to assessing financial coverage and social needs. Socioeconomic status emerged as a consistent concern across countries, affecting financial toxicities. The study highlights the need for tailored approaches and improved resource visibility while emphasizing clinicians' pivotal role in addressing financial aspects of cancer care.
Genomics to select treatment for patients (pts) with metastatic cancer: Final analysis of Molecular Tumor Board (MTB) evaluations in the ROME trial.
Authors: Botticelli Andrea , Scagnoli Simone , Conte Pierfranco , Cremolini Chiara , Ascierto Paolo Antonio , Cappuzzo Federico , Aglietta Massimo , Mazzuca Federica , Capoluongo Ettore , Blandino Giovanni , Malapelle Umberto , Nuti Marianna , D'Amati Giulia , Cerbelli Bruna , Pruneri Giancarlo , Biffoni Mauro , Giannini Giuseppe , Cognetti Francesco , Curigliano Giuseppe , Marchetti Paolo ,   ROME Trial Investigators
Published: July 2024

3157

Background: The ROME trial (NCT04591431) investigates the efficacy of a tailored treatment (TT), driven by extensive genomic tests and Molecular Tumor Board (MTB) evaluation, compared to standard treatment (SoC) in patients (pts) with refractory metastatic cancer. Here we report the prevalence of actionable variants identified and the personalized treatment received by the patients enrolled. Methods: A centralized extensive NGS test (FoundationOne CDx and Liquid CDx) was performed on both tissue and blood samples. Pts with at least one potentially targetable alteration matched to the available drugs were discussed at the MTB. MTB evaluation criteria were: genomic variant type, tumor mutational burden (TMB), VAF, availability of preclinical or clinical data of efficacy and patients’ clinical characteristics. COSMIC, ClinVar, OncoKB and VarSome datasets were used to evaluate the clinical actionability of genomic alterations. MTB indications were: randomization to TT vs SoC, screening failure (SF), or indication to other trial/access to the drug. Results: From November 2020 to August 2023, 1794 pts were screened. A total of 127 weekly MTB meetings were conducted and 899 cases were discussed (7 cases/meeting on average). After MTB discussion, a targetable genomic alteration was identified in 425 pts, who received an indication to be randomized. MTB assigned ICIs to 190 pts (155 to ipilimumab plus nivolumab; 8 to nivolumab) due to high (≥10 mut/mb) TMB. 234 pts had indications to target therapy: 86 pts (37%) to PI3K/AKT/mTOR inhibitors(i), 59 (25%) anti-HER2 agents, 34 (15%) FGFRi, 31 (13%) BRAF/MEKi, 7 (3%) PARPi, 5 (2%) CDK4/6i, 4 (2%) ALKi, 2 (>1%) NTRKi, 2 (>1%) RETi, 2 (>1%) Hedgehog-i, 1 (>1%) JAKi, 1 (>1%) MEKi. 27 pts had indication to ICIs plus target therapy combinations. Additionally, 150 pts with potentially hereditary variants were addressed to genetic counselling and germline testing. Finally, according to the genomic evaluation, 63 pts were referred by MTB to other clinical trial even if considered SF for the ROME trial, 34 patients received from the MTB a modification of the initially proposed standard therapy and 4 had both suggestions. Overall, 652 pts (36%) received an indication following NGS test and MTB evaluation. Conclusions: Our study provides evidence that MTB discussion of comprehensive genomic profiling data identifies a personalized treatment in a large (36%) fraction of patients, thus outperforming the traditional histological approach. Clinical trial information: NCT04591431 .
Impact of obesity on immune-related adverse events and tyrosine kinase inhibitor side effects in patients with metastatic renal cell carcinoma (mRCC).
Authors: Alharbi Malak , Tariq Muhammad Junaid , Jatwani Karan , George Saby
Published: July 2024

4560

Background: A pooled data analysis from clinical trials, including various cancer subtypes, showed that obesity is associated with a heightened incidence of immune-related adverse events (irAEs). However, the heterogeneous patient population across different demographics calls for further investigation into the correlation between obesity and adverse effects from immune checkpoint inhibitors (ICI) in mRCC. Additionally, there is limited available data regarding the association of obesity with tyrosine kinase inhibitors (TKIs) toxicities. We hypothesize that obesity may be linked to an increased rate of irAEs and TKIs toxicities in mRCC patients (pts). Methods: We conducted a retrospective analysis of pts diagnosed with mRCC using TriNetX Research Network (TriNetX LLC., Cambridge, Massachusetts, USA). We searched two cohorts (ICI and TKIs) and toxicities using the ICD-10-CM codes. Pts were categorized into two groups based on body mass index (BMI): obese (BMI ≥30) and non-obese (BMI >19 - < 30). Characteristics of the cohorts were balanced using propensity score matching. Results: A total of 4526 pts with mRCC receiving treatment met the inclusion criteria. 40% of pts were in ICI cohort (n=1811), and 60% (n=2715) in TKI cohort. In the ICI cohort 53% were obese (959/1811), and 47% non-obese (852/1811). Among both cohorts, 50% were male, 30% females, 20% unknown and the average age was 69-72. In TKI cohort, Obese group had 57% (1549/2715) pts while non-obese group included 43% (1166/2715) pts. In ICI cohort, there was no statistically significant difference in risk of developing thyroid dysfunction, liver toxicity, type 1 diabetes, adrenal insufficiency/hypophysitis, skin toxicity, pneumonitis, cardiomyopathy, colitis or myositis/arthropathy between obese and non-obese groups (p>0.05). In TKI cohort, risk of thyroid dysfunction was higher among obese (0.177, n=187/1056) vs non-obese (0.131, n=102/781), p=0.007. Moreover, obese pts had a higher rate of diarrhea compared to non-obese (0.141 vs 0.109, p= 0.017). No significant difference was seen in the rate of developing other toxicities including liver dysfunction, mucositis, cardiovascular toxicities including hypertensive crisis or fatigue. (Table) Conclusions: The use of TKIs has shown an increased risk of developing thyroid dysfunction and diarrhea in obese pts. However, there is no difference in irAE with use of ICI between obese and non-obese pts. Further large studies are needed to support this observation and to study the mechanism by which obesity and metabolic syndromes influence the development of adverse effects. [Table: see text]