bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration-Resistant Prostate Cancer
Authors: Sweeney Christopher J. , Petry Russell , Xu Chang , Childress Merrida , He Jie , Fabrizio David , Gjoerup Ole , Morley Samantha , Catlett Timothy , Assaf Zoe J. , Yuen Kobe , Wongchenko Matthew , Shah Kalpit , Gupta Pratyush , Hegde Priti , Pasquina Lincoln W. , Mariathasan Sanjeev , Graf Ryon P. , Powles Thomas
Published: July 2024

Purpose:

Enzalutamide after abiraterone progression is commonly used in metastatic castration-resistant prostate cancer despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide.

Experimental Design:

ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing. Baseline ctDNA TF, changes in ctDNA TF from baseline to cycle 3 day 1 (C3D1), and detection at C3D1 alone were compared with overall response rate, radiographic progression-free survival (rPFS), median OS (mOS), and 50% reduction in PSA.

Results:

ctDNA TF detection at baseline and/or C3D1 was associated with shorter rPFS and OS in 494 evaluable patients. Detection of ctDNA TF at C3D1, with or without detection at cycle 1 day 1, was associated with worse rPFS and mOS than lack of detection. When ctDNA TF and PSA response at C3D1 were discordant, patients with (ctDNA TF undetected/PSA not reduced) had more favorable outcomes than (ctDNA TF detected/PSA reduced; mOS 22.1 vs. 16 months; P < 0.001).

Conclusions:

In a large cohort of patients with metastatic castration-resistant prostate cancer receiving enzalutamide after abiraterone, we demonstrate the utility of a new tissue-agnostic assay for monitoring molecular response based on ctDNA TF detection and dynamics. ctDNA TF provides a minimally invasive, complementary biomarker to PSA testing and may refine personalized treatment approaches.
Unveiling the Culprit: IL17 Signaling in the Pancreatic Epithelium Drives Tumorigenesis
Authors: Lee Kyoung Eun , Pasca di Magliano Marina
Published: July 2024

IL17 signaling promotes pancreatic cancer development, yet the cell compartment responsible for the protumorigenic function of IL17 has not been defined. In this article, Castro-Pando and colleagues demonstrate that IL17/IL17 receptor A signaling in the pancreatic epithelium is critical for pancreatic cancer initiation and for establishing immunosuppression, whereas its signaling in the immune compartment is dispensable. This work provides an important mechanistic insight on the role of IL17 signaling and identifies a potential new immune checkpoint as a target in pancreatic cancer.

See related article by Castro-Pando et al., p. 1170
Supplementary Figure 3 from PTP4A2 Promotes Glioblastoma Progression and Macrophage Polarization under Microenvironmental Pressure
Authors: Chouleur Tiffanie , Emanuelli Andrea , Souleyreau Wilfried , Derieppe Marie-Alix , Leboucq Téo , Hardy Serge , Mathivet Thomas , Tremblay Michel L. , Bikfalvi Andreas
Published: July 2024

PTP4As expression in patients and cell lines
IL-1β Induces LDL Transcytosis by a Novel Pathway Involving LDLR and Rab27a
Authors: Jang Erika , Ho Tse Wing Winnie , Brumell John H. , Lefebvre François , Wang Changsen , Lee Warren L.
Published: July 2024

BACKGROUND:

In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) treated advanced atherosclerosis using a blocking antibody for IL-1β (interleukin-1β); this significantly reduced cardiovascular events. However, whether IL-1β regulates early disease, particularly LDL transcytosis, remains unknown.

METHODS:

We used total internal reflection fluorescence microscopy to quantify transcytosis by human coronary artery endothelial cells exposed to IL-1β. To investigate transcytosis in vivo, we injected wild-type and knockout mice with IL-1β and LDL to visualize acute LDL deposition in the aortic arch.

RESULTS:

Exposure to picomolar concentrations of IL-1β induced transcytosis of LDL but not of albumin by human coronary artery endothelial cells. Surprisingly, expression of the 2 known receptors for LDL transcytosis, ALK-1 (activin receptor-like kinase-1) and SR-BI (scavenger receptor BI), was unchanged or decreased. Instead, IL-1β increased the expression of the LDLR (LDL receptor); this was unexpected because LDLR is not required for LDL transcytosis. Overexpression of LDLR had no effect on basal LDL transcytosis. However, knockdown of LDLR abrogated the effect of IL-1β on transcytosis rates while the depletion of Cav-1 (caveolin-1) did not. Since LDLR was necessary but overexpression had no effect, we reasoned that another player must be involved. Using public RNA sequencing data to curate a list of Rab (Ras-associated binding) GTPases affected by IL-1β, we identified Rab27a. Overexpression of Rab27a alone had no effect on basal transcytosis, but its knockdown prevented induction by IL-1β. This was phenocopied by depletion of the Rab27a effector JFC1 (synaptotagmin-like protein 1). In vivo, IL-1β increased LDL transcytosis in the aortic arch of wild-type but not
Ldlr

−/−

or Rab27a-deficient mice. The JFC1 inhibitor nexinhib20 also blocked IL-1β–induced LDL accumulation in the aorta.

CONCLUSIONS:

IL-1β induces LDL transcytosis by a distinct pathway requiring LDLR and Rab27a; this route differs from basal transcytosis. We speculate that induction of transcytosis by IL-1β may contribute to the acceleration of early disease.
Multimodal Imaging-Assisted Intravascular Theranostic Photoactivation on Atherosclerotic Plaque
Authors: Kim Jin Hyuk , Song Joon Woo , Kim Yeon Hoon , Kim Hyun Jung , Kim Ryeong Hyun , Park Ye Hee , Nam Hyeong Soo , Kang Dong Oh , Yoo Hongki , Park Kyeongsoon , Kim Jin Won
Published: July 2024

BACKGROUND:

Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution.

METHODS:

We fabricated a Dectin-1–targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence–emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks.

RESULTS:

The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway.

CONCLUSIONS:

Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1–targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β–dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy.
Early and Late Aortic-Related Mortality and Rupture After Fenestrated-Branched Endovascular Aortic Repair of Thoracoabdominal Aortic Aneurysms: A Prospective Multicenter Cohort Study
Authors: Oderich Gustavo S. , Huang Ying , Harmsen William S. , Tenorio Emanuel R. , Schanzer Andres , Timaran Carlos H. , Schneider Darren B. , Mendes Bernardo C. , Eagleton Matthew J. , Farber Mark A. , Gasper Warren J. , Beck Adam W. , Sweet Matthew P. , Lee W. Anthony , Mendes Bernardo C. , Parodi F. Ezequiel , Tenorio Emanuel R. , Zettervall Sara L.
Published: July 2024

BACKGROUND:

Fenestrated-branched endovascular aortic repair (FB-EVAR) has been used as a minimally invasive alternative to open surgical repair to treat patients with thoracoabdominal aortic aneurysms (TAAAs). The aim of this study was to evaluate aortic-related mortality (ARM) and aortic aneurysm rupture after FB-EVAR of TAAAs.

METHODS:

Patients enrolled in 8 prospective, nonrandomized, physician-sponsored investigational device exemption studies between 2005 and 2020 who underwent elective FB-EVAR of asymptomatic intact TAAAs were analyzed. Primary end points were ARM, defined as any early mortality (30 days or in hospital) or late mortality from aortic rupture, dissection, organ or limb malperfusion attributable to aortic disease, complications of reinterventions, or aortic rupture. Secondary end points were early major adverse events, TAAA life-altering events (defined as death, permanent spinal cord injury, permanent dialysis, or stroke), all-cause mortality, and secondary interventions.

RESULTS:

A total of 1109 patients were analyzed; 589 (53.1%) had extent I–III and 520 (46.9%) had extent IV TAAAs. Median age was 73.4 years (interquartile range, 68.1–78.3 years); 368 (33.2%) were women. Early mortality was 2.7% (n=30); congestive heart failure was associated with early mortality (odds ratio, 3.30 [95% CI, 1.22–8.02];
P
=0.01). Incidence of early aortic rupture was 0.4% (n=4). Incidence of early major adverse events and TAAA life-altering events was 20.4% (n=226) and 7.7% (n=85), respectively. There were 30 late ARMs; 5-year cumulative incidence was 3.8% (95% CI, 2.6%–5.4%); older age and extent I–III TAAAs were independently associated with late ARM (each
P
<0.05). Fourteen late aortic ruptures occurred; 5-year cumulative incidence was 2.7% (95% CI, 1.2%–4.3%); extent I–III TAAAs were associated with late aortic rupture (hazard ratio, 5.85 [95% CI, 1.31–26.2];
P
=0.02). Five-year all-cause mortality was 45.7% (95% CI, 41.7%–49.4%). Five-year cumulative incidence of secondary intervention was 40.3% (95% CI, 35.8%–44.5%).

CONCLUSIONS:

ARM and aortic rupture are uncommon after elective FB-EVAR of asymptomatic intact TAAAs. Half of the ARMs occurred early, and most of the late deaths were not aortic related. Late all-cause mortality rate and the need for secondary interventions were 46% and 40%, respectively, 5 years after FB-EVAR.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifiers: NCT02089607, NCT02050113, NCT02266719, NCT02323581, NCT00583817, NCT01654133, NCT00483249, NCT02043691, and NCT01874197.
Identification of Noncoding Functional Regulatory Variants of
STIM1
Gene in Idiopathic Pulmonary Arterial Hypertension
Authors: Liu Bingxun , Wen Cen-Jin , Zhou Guangyuan , Wei Yun-Peng , Wu Zeang , Zhang Ting , Zhou Yudan , Qiu Shuyi , Wang Tao , Ruiz Matthieu , Dupuis Jocelyn , Yuan Ping , Liu Jinming , Zhu Liping , Jing Zhi-Cheng , Hu Qinghua
Published: July 2024

BACKGROUND:

STIM1 (stromal interaction molecule 1) regulates store-operated calcium entry and is involved in pulmonary artery vasoconstriction and pulmonary artery smooth muscle cell proliferation, leading to pulmonary arterial hypertension (PAH).

METHODS:

Bioinformatics analysis and a 2-stage matched case-control study were conducted to screen for noncoding variants that may potentially affect
STIM1
transcriptional regulation in 242 patients with idiopathic PAH and 414 healthy controls. Luciferase reporter assay, real-time quantitative polymerase chain reaction, western blot, 5-ethynyl-2’-deoxyuridine (EdU) assay, and intracellular Ca
2+
measurement were performed to study the mechanistic roles of those
STIM1
noncoding variants in PAH.

RESULTS:

Five noncoding variants (rs3794050, rs7934581, rs3750996, rs1561876, and rs3750994) were identified and genotyped using Sanger sequencing. Rs3794050, rs7934581, and rs1561876 were associated with idiopathic PAH (recessive model, all
P
<0.05). Bioinformatics analysis showed that these 3 noncoding variants possibly affect the enhancer function of
STIM1
or the microRNA (miRNA) binding to
STIM1
. Functional validation performed in HEK293 and pulmonary artery smooth muscle cells demonstrated that the noncoding variant rs1561876-G (
STIM1
mutant) had significantly stronger transcriptional activity than the wild-type counterpart, rs1561876-A, by affecting the transcriptional regulatory function of both hsa-miRNA-3140-5p and hsa-miRNA-4766-5p. rs1561876-G enhanced intracellular Ca
2+
signaling in human pulmonary artery smooth muscle cells secondary to calcium-sensing receptor activation and promoted proliferation of pulmonary artery smooth muscle cells under both normoxia and hypoxia conditions, suggesting a possible contribution to PAH development.

CONCLUSIONS:

The potential clinical implications of the 3 noncoding variants of
STIM1
, rs3794050, rs7934581, and rs1561876, are 2-fold, as they may help predict the risk and prognosis of idiopathic PAH and guide investigations on novel therapeutic pathway(s).
Skillful Long-Lead Seasonal Predictions in the Summertime Northern Hemisphere Midlatitudes
Authors: Lin Hai , Muncaster Ryan , Derome Jacques , Merryfield William J. , Diro Gulilat
Published: July 2024

In contrast to boreal winter when extratropical seasonal predictions benefit greatly from ENSO-related teleconnections, our understanding of forecast skill and sources of predictability in summer is limited. Based on 40 years of hindcasts of the Canadian Seasonal to Interannual Prediction System, version 3 (CanSIPSv3), this study shows that predictions for the Northern Hemisphere summer surface air temperature are skillful more than 6 months in advance in several midlatitude regions, including eastern Europe–Middle East, central Siberia–Mongolia–North China, and the western United States. These midlatitude regions of statistically significant predictive skill appear to be connected to each other through an upper-tropospheric circumglobal wave train. Although a large part of the forecast skill for the surface air temperature and 500-hPa geopotential height is attributable to the linear trend associated with global warming, there is significant long-lead seasonal forecast skill related to interannual variability. Two additional idealized hindcast experiments are performed to help shed light on sources of the long-lead forecast skill using one of the CanSIPSv3 models and its uncoupled version. It is found that tropical ENSO-related sea surface temperature (SST) anomalies contribute to the forecast skill in the western United States, while land surface conditions in winter, including snow cover and soil moisture, in the Siberian and western U.S. regions have a delayed or long-lasting impact on the atmosphere, which leads to summer forecast skill in these regions. This implies that improving land surface initial conditions and model representation of land surface processes is crucial for the further development of a seasonal forecasting system.

Significance Statement

Useful seasonal predictions in the boreal summer midlatitude regions are of great value. In this study, we show that predictions for the boreal summer season are skillful more than 6 months in advance in several midlatitude regions, including eastern Europe–Middle East, central Siberia–Mongolia–North China, and the western United States. The forecast skill in these regions is associated with a circumglobal teleconnection atmospheric circulation pattern. Sources of the long-lead forecast skill include the global warming–related trend and anomalies in the ocean and land surface initial conditions. It is found that the wintertime snow cover and soil moisture in the Siberian and western U.S. regions have a delayed or long-lasting impact on the atmosphere, which leads to summer forecast skill.
Defining Optimal Cobalamin Status for Neonates and Infants
Authors: Bjørke-Monsen Anne-Lise
Published: July 2024

Background:

An optimal cobalamin status is necessary for normal neurodevelopment.

Objective:

To give a description of the epidemiology, pathophysiology and diagnostic challenges related to cobalamin insufficiency in neonates and infants in order to prevent its occurence.

Results:

Inadequate cobalamin status is prevalent among neonates and young infants, due to a high prevalence of maternal cobalamin deficiency, exclusive breastfeeding for extended periods and late introduction of animal food. Cobalamin insufficiency is associated with delayed neurodevelopment and subtle clinical symptoms like feeding difficulties, regurgitations and constipation in young infants. Early diagnosis and treatment of impaired cobalamin status is important to prevent neurologic damage.

Conclusion:

Clinical suspicion of cobalamin insufficiency in infants should infer immediate biochemical testing and a plasma total homocysteine > 5.0 µmol/L indicate cobalamin insufficiency in need of intramuscular treatment with hydroxycobalamin, followed by introduction of animal food after 4 months of age.
Evaluating the impact of laboratory-based eligibility criteria by race/ethnicity in first-line clinical trials of DLBCL
Authors: Khurana Arushi , Mwangi Raphael , Nastoupil Loretta J. , Reagan Patrick M. , Farooq Umar , Romancik Jason T. , McDonnell Timothy J. , Riska Shaun M. , Lossos lzidore S. , Kahl Brad S. , Martin Peter , Witzig Thomas E. , Cerhan James R. , Flowers Christopher R. , Nowakowski Grzegorz S. , Maurer Matthew J.
Published: July 2024

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 laboratory-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression, suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Using data from the prospectively enrolled Lymphoma Epidemiology Outcomes cohort study, with demographics broadly similar to the US patients diagnosed with lymphoma, we evaluated the impact of laboratory eligibility criteria from recent first-line DLBCL trials across various racial and ethnic backgrounds. There were significant differences in the baseline laboratory values by race/ethnicity with Black/African American (AA) patients having the lowest mean hemoglobin and highest creatinine clearance. Based on recent clinical trial eligibility criteria, AA and Hispanic patients had higher rates of laboratory-based ineligibility than non-Hispanic White patients. The largest gap in the clinical outcomes between eligible and noneligible patients was noted within AA patients with an overall survival hazard ratio based on POLARIX clinical trial criteria of 4.09 (95% confidence interval, 1.83-9.14). A thoughtful approach to the utility of each criterion and cutoffs for eligibility needs to be evaluated in the context of its differential impact across various racial/ethnic groups.
COVID-19 mRNA vaccination responses in individuals with sickle cell disease: an ASH RC Sickle Cell Research Network Study
Authors: Anderson Alan R. , Strouse John J. , Manwani Deepa , Brandow Amanda M. , Vichinsky Elliott , Campbell Andrew , Leavey Patrick J. , Nero Alecia , Ibrahim Ibrahim F. , Field Joshua J. , Baer Amanda , Soto-Calderon Haideliza , Vincent Lauren , Zhao Yan , Santos Jefferson J. S. , Hensley Scott E. , Mortier Nicole , Lanzkron Sophie , Neuberg Donna , Abrams Charles S.
Published: July 2024

Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The American Society of Hematology Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether messenger RNA (mRNA) vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received 2 doses of the Pfizer-BioNTech vaccine and provided baseline blood samples before vaccination and 2 months after the initial vaccination for analysis of immunoglobulin G (IgG) reactivity against the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Six-month IgG reactivity against the viral RBD was also available in 37 patients. Postvaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2 to 3 days of first or second vaccination was reported by 5 participants (12%) including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 initially seronegative participants (34%) converted to seropositive after vaccination. Overall, mRNA vaccination had a good risk-benefit profile in individuals with SCD. This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with SCD. This trial was registered at www.ClinicalTrials.gov as #NCT05139992.
Treatment of sleep apnoea early after myocardial infarction with adaptive servo-ventilation: a proof-of-concept randomised controlled trial
Authors: Arzt Michael , Fox Henrik , Stadler Stefan , Hetzenecker Andrea , Oldenburg Olaf , Hamer Okka W. , Poschenrieder Florian , Wiest Clemens , Tanacli Radu , Kelle Sebastian , Bruch Leonhard , Seidel Mirko , Koller Michael , Zeman Florian , Buchner Stefan
Published: July 2024

Background

Sleep disordered breathing (SDB) has been associated with less myocardial salvage and smaller infarct size reduction after acute myocardial infarction (AMI). The Treatment of sleep apnoea Early After Myocardial infarction with Adaptive Servo-Ventilation (TEAM-ASV I) trial investigated the effects of adding adaptive servo-ventilation (ASV) for SDB to standard therapy on the myocardial salvage index (MSI) and change in infarct size within 12 weeks after AMI.

Methods

In this multicentre, randomised, open-label trial, patients with AMI and successful percutaneous coronary intervention within 24 h after symptom onset plus SDB (apnoea–hypopnoea index ≥15 events·h−1) were randomised to standard medical therapy alone (control) or plus ASV (starting 3.6±1.4 days post-AMI). The primary outcome was the MSI at 12 weeks post-AMI. Cardiac magnetic resonance (CMR) imaging was performed at ≤5 days and 12 weeks after AMI.

Results

76 individuals were enrolled from February 2014 to August 2020; 39 had complete CMR data for analysis of the primary end-point. The MSI was significantly higher in the ASVversuscontrol group (difference 14.6% (95% CI 0.14–29.1%); p=0.048). At 12 weeks, absolute (6.6 (95% CI 4.8–8.5)versus2.8 (95% CI 0.9–4.8) % of left ventricular mass; p=0.003) and relative (44 (95% CI 30–57)versus21 (95% CI 6–35) % of baseline; p=0.013) reductions in infarct size were greater in the ASVversuscontrol group. No serious treatment-related adverse events occurred.

Conclusions

Early treatment of SDB with ASV improved the MSI and decreased infarct size at 12 weeks after AMI. Larger randomised trials are required to confirm these findings.
Extracellular vesicles in sputum of children with cystic fibrosis pulmonary exacerbations
Authors: Ben-Meir Elad , Antounians Lina , Eisha Shafinaz , Ratjen Felix , Zani Augusto , Grasemann Hartmut
Published: July 2024

Background

The aim of this study was to quantify mediators of neutrophilic inflammation within airway extracellular vesicles (EVs) of children treated for a cystic fibrosis (CF) pulmonary exacerbation (PEx).

Methods

EVs were isolated from stored sputum samples collected before and after antibiotic therapy for PEx between 2011 and 2013, and characterised by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Western blot analysis of EV protein extracts was used for EV canonical protein markers CD63, CD9 and flotillin-1 (FLOT1), as well as neutrophil elastase (NE), myeloperoxidase (MPO) and interleukin-8. The EV content of NE and MPO were expressed as ratios of NE/FLOT1 and MPO/FLOT1 protein band densities.

Results

Sputum samples from 21 children aged 13.3 (range 8.0–17.0) years were analysed. NTA showed high concentrations of particles at the size of small EVs (50–200 nm), and typical EV morphology was confirmed by TEM. CD63, CD9 and FLOT1 were detectable in all samples. Median (interquartile range (IQR)) NE/FLOT1 increased from 2.46 (1.68–5.25) before to 6.83 (3.89–8.89, p<0.001) after PEx therapy, and median (IQR) MPO/FLOT1 increased from 2.30 (1.38–4.44) before to 5.76 (3.45–6.94, p<0.01) after, while EV size remained unchanged. Improvement in lung function (percent predicted forced expiratory volume in 1 s (ppFEV1)) with PEx therapy correlated with NE EV content (r=0.657, p=0.001).

Conclusions

Airways of children with CF contain EVs that carry NE and MPO as cargo. The lower NE and MPO content at the time of PEx, compared with after therapy, and the correlation with pulmonary function suggest both a functional role of EVs in CF airway inflammation and the potential of EVs as a biomarker to monitor CF lung disease.
Coronavirus disease 2019 vaccination acceptance and associated factors among residents of Dire Dawa Administration, Eastern Ethiopia: a community-based cross-sectional study
Authors: Jidha Tafese Dejene , Deginet Endayen , Tefera Bereket , Amenu Demisew , Beressa Girma , Hailu Mickiale
Published: July 2024

Background

Corona virus disease 2019 (COVID-19) is an extremely contagious viral infection caused by the severe acute respiratory syndrome coronavirus 2. Understanding the willingness of the community to receive the COVID-19 vaccine will help in the development and implementation of effective COVID-19 vaccination promotion programs. Therefore, we aimed to assess the level of COVID-19 vaccine acceptance and associated factors among residents of Dire Dawa Administration, Eastern Ethiopia.

Methods

A community-based cross-sectional study was conducted among 840 residents in Dire Dawa Administration from May 18th to June 18th, 2021. Multistage cluster sampling followed by systematic random sampling was used to select respondents. A pretested interviewer-administered structured questionnaire was used to collect the data from respondents. Bivariable and multivariable logistic regression were used to identify predictors of COVID-19 vaccine acceptance. The odds ratio (OR), along with a 95% confidence interval (CI), was used to estimate the strength of the association.

Results

Out of 840 respondents recruited, the proportion of COVID-19 vaccine acceptance was found to be 54.4% (457/840); (95% CI: 51.0%, 57.7%) Being male [AOR = 1.85, 95% CI: (1.35, 2.54), P < 0.001], not having a current habit of substance use [AOR = 2.38, 95% CI: (1.73, 3.26), P < 0.001], having a monthly income of less than 51.31 USD [AOR = 0.19, 95% CI: (0.04, 0.88), P = 0.001]; and not having a prior history of vaccination experience [AOR = 0.40, 95% CI: (0.29, 0.54), P < 0.001] were significantly associated with COVID-19 vaccine acceptance.

Conclusion

This study reveals that the proportion of COVID-19 vaccine acceptance among residents of Dire Dawa Administration, Eastern Ethiopia, was 54.4%. Factors like being male and not having a current habit of substance use were positively associated, whereas having a monthly income of less than 51.31 USD and not having a prior history of vaccination experience were negatively associated with COVID-19 vaccine acceptance. Health information dissemination and economic empowerment are crucial to improving COVID-19 vaccine acceptance among the community. This study provides valuable data for policymakers to plan early vaccination programs and tackle the challenges identified in the study.
Association between triglyceride glucose-waist height ratio index and cardiovascular disease in middle-aged and older Chinese individuals: a nationwide cohort study
Authors: Ren Qiushi , Huang Yang , Liu Quan , Chu Tongxin , Li Gang , Wu Zhongkai
Published: July 2024

Background

The triglyceride-glucose (TyG) index and its combination with obesity indicators can predict cardiovascular diseases (CVD). However, there is limited research on the relationship between changes in the triglyceride glucose-waist height ratio (TyG-WHtR) and CVD. Our study aims to investigate the relationship between the change in the TyG-WHtR and the risk of CVD.

Methods

Participants were from the China Health and Retirement Longitudinal Study (CHARLS). CVD was defined as self-reporting heart disease and stroke. Participants were divided into three groups based on changes in TyG-WHtR using K-means cluster analysis. Multivariable binary logistic regression analysis was used to examine the association between different groups (based on the change of TyG-WHtR) and CVD. A restricted cubic spline (RCS) regression model was used to explore the potential nonlinear association of the cumulative TyG-WHtR and CVD events.

Results

During follow-up between 2015 and 2020, 623 (18.8%) of 3312 participants developed CVD. After adjusting for various potential confounders, compared to the participants with consistently low and stable TyG-WHtR, the risk of CVD was significantly higher in participants with moderate and increasing TyG-WHtR (OR 1.28, 95%CI 1.01–1.63) and participants with high TyG-WHtR with a slowly increasing trend (OR 1.58, 95%CI 1.16–2.15). Higher levels of cumulative TyG-WHtR were independently associated with a higher risk of CVD events (per SD, OR 1.27, 95%CI 1.12–1.43).

Conclusions

For middle-aged and older adults, changes in the TyG-WHtR are independently associated with the risk of CVD. Maintaining a favorable TyG index, effective weight management, and a reasonable waist circumference contribute to preventing CVD.
Dietary patterns and hepatocellular carcinoma risk: a systematic review and meta-analysis of cohort and case–control studies
Authors: Shu Wenxi , Liu Ling , Jiang Jiaojiao , Yao Qinghua
Published: July 2024

Background

Globally, HCC presents a significant health burden, characterized by high incidence and mortality rates. Epidemiological studies have increasingly suggested a link between dietary patterns and the risk of hepatocellular carcinoma (HCC), yet consensus on this relationship remains elusive.

Objective

This study aims to synthesize existing literature and provide a comprehensive analysis of the association between dietary patterns and HCC risk through meta-analytical methods.

Methods

A systematic search of PubMed, Embase, and the Cochrane Library databases was conducted to identify studies examining common dietary patterns in relation to HCC, published up to August 2023. Study quality was rigorously evaluated using the Newcastle–Ottawa Scale. We employed a random effects model to synthesize effect sizes, calculating hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

We identified 13 papers, of these 10 investigating a priori dietary patterns(index-based dietary patterns) and 3 focusing on a posterior dietary patterns (data-driven dietary patterns). Analysis of a priori dietary patterns revealed that higher scores in the Healthy Eating Index (HEI) & alternative HEI (HR = 0.67, 95% CI: 0.54–0.85), Dietary Approaches to Stop Hypertension (DASH) (HR = 0.77, 95% CI: 0.66–0.91), and the Mediterranean diet (HR = 0.65, 95% CI: 0.56–0.75) were associated with a reduced risk of HCC. Conversely, pro-inflammatory dietary patterns were linked with an increased risk (HR = 2.21, 95% CI: 1.58–3.09). In a posterior dietary patterns, a vegetable-based diet was negatively correlated with HCC risk (HR = 0.63, 95% CI: 0.49–0.81).

Conclusion

This meta-analysis underscores a significant association between dietary patterns and the risk of HCC. Adherence to healthy dietary patterns characterized by high in vegetables, whole grains, legumes, nuts, and low in red and processed meats may confer a protective effect against HCC, whereas inflammatory diets appear to elevate risk.
RETRACTED ARTICLE: N6-methyladenosine modification of circMARK2 enhances cytoplasmic export and stabilizes LIN28B, contributing to the progression of Wilms tumor
Authors: Shu Guannan , Zhao Zhang , Zhao Tianxin , Deng Changmi , Zhu Jiangquan , Han Yufeng , Chen Minyu , Jing Jiajia , Bai Gaochen , Li Dian , Li Feng , He Jing , Fu Wen , Liu Guochang
Published: July 2024

Background

The potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression.

Methods

We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining.

Results

CircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates.

Conclusions

Our study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.
The development of a set of key points to aid clinicians and researchers in designing and conducting n-of-1 trials
Authors: Chatters Robin , Hawksworth Olivia , Julious Steven , Cook Andrew
Published: July 2024

Introduction

n-of-1 trials are undertaken to optimise the evaluation of health technologies in individual patients. They involve a single patient receiving treatments, both interventional and control, consecutively over set periods of time, the order of which is decided at random. Although n-of-1 trials are undertaken in medical research it could be argued they have the utility to be undertaken more frequently. We undertook the National Institute for Health Research (NIHR) commissioned DIAMOND (Development of generalisable methodology for n-of-1 trials delivery for very low volume treatments) project to develop key points to assist clinicians and researchers in designing and conducting n-of-1 trials.

Methods

The key points were developed by undertaking a stakeholder workshop, followed by a discussion within the study team and then a stakeholder dissemination and feedback event. The stakeholder workshop sought to gain the perspectives of a variety of stakeholders (including clinicians, researchers and patient representatives) on the design and use of n-of-1 trials. A discussion between the study team was held to reflect on the workshop and draft the key points. Lastly, the stakeholders from the workshop were invited to a dissemination and feedback session where the proposed key points were presented and their feedback gained.

Results

A set of 22 key points were developed based on the insights from the workshop and subsequent discussions. They provide guidance on when an n-of-1 trial might be a viable or appropriate study design and discuss key decisions involved in the design of n-of-1 trials, including determining an appropriate number of treatment periods and cycles, the choice of comparator, recommended approaches to randomisation and blinding, the use of washout periods and approaches to analysis.

Conclusions

The key points developed in the project will support clinical researchers to understand key considerations when designing n-of-1 trials. It is hoped they will support the wider implementation of the study design.
Positive parental history of diabetes is associated with early diagnosis, better dietary compliance, and glycemic control among type 2 diabetes patients in southern Sri Lanka
Authors: De Zoysa Warsha , Weerarathna Thilak Priyantha , Wasana Keddagoda Gamage Piyumi , Weerarathna Miyuru Kavinda , Senadeera Vidarsha
Published: July 2024

Background

Parental history of diabetes is an established risk factor for type 2 diabetes mellitus (T2DM). There is limited data on the association of parental history with the prevalence of T2DM in Sri Lanka. The study aims to examine the prevalence and correlation of parental history and factors such as the onset age, glycaemic control, and self-reported dietary compliance among T2DM patients. With a rising incidence of T2DM in Sri Lanka, understanding the impact of parental history on age at diagnosis and glycemic control can aid in targeted screening and interventions.

Methods

A cross-sectional study was carried out on 500 T2DM patients attending a diabetes clinic in Galle, the capital of Southern Sri Lanka with a multiethnic population. Convenient sampling strategy was followed in the recruitment process and a questionnaire-based method was used to collect the data. All the collected data was analysed using SPSS V 25.0.

Results

51.2% had a parental history of T2DM, and those with a positive parental history were diagnosed six years earlier than those with a negative parental history (p < 0.001). A significant correlation between parental history and gestational diabetes mellitus (GDM) was observed (p < 0.001). Patients with a parental history reported better dietary adherence (p < 0.001). Binary logistic regression analysis revealed patients with positive parental history had significantly lower HbA1C (p = 0.003, OR = 0.748).

Conclusion

T2DM patients with a parental history showed significant association with early diabetes onset, GDM, better glycemic control, and dietary adherence.
Predictors and pathways of in-hospital mortality in active vascular contrast extravasation detected on abdominopelvic CT
Authors: Kaewlai Rathachai , Chomchalerm Gun , Tongsai Sasima , Chatpuwaphat Jitti , Chatkaewpaisal Anchisa , Khamman Pramuk , Thamtorawat Somrach , Praditsuktavorn Banjerd , Maitriwong Worapat , Matsumoto Junichi
Published: July 2024

Objectives

This study aimed to identify factors influencing in-hospital mortality in adult patients with active vascular contrast extravasation (AVCE) on abdominopelvic computed tomography (CT).

Methods

All consecutive patients with AVCE detected on CT between January 2019 and May 2022 were retrospectively included. Their data were compared through uni- and multivariable analyses between patients with and without in-hospital mortality. Path analysis was utilized to clarify the relationships among factors affecting mortality.

Results

There were 272 patients (60.2 ± 19.4 years, 150 men) included, of whom 70 experienced in-hospital mortality. Multivariable analysis revealed nonsurgery, chronic kidney disease (CKD) stage 4–5 or dialysis, prolonged partial thromboplastin time (PTT), minimum AVCE length > 8 mm, and a lower rate of packed red cell (PRC) transfusion were identified as independent predictors of in-hospital mortality (p = 0.005–0.048). Path analysis demonstrated direct influences of CKD4-5 or dialysis, prolonged PTT, and minimum AVCE length on mortality (coefficients 0.525–0.616; p = 0.009 to < 0.001). PRC transfusion impacted mortality through nonsurgery (coefficient 0.798, p = 0.003) and intensive care unit (ICU) admission (coefficients 0.025, p = 0.016), leading to subsequent death. Three AVCE spaces (free, loose, and tight) defined on CT were not directly associated with in-hospital mortality.

Conclusion

In adults with AVCE on CT, AVCE size had a direct independent influence on mortality, highlighting the critical role of radiologists in detecting and characterizing this finding. Additionally, CKD4-5 or dialysis and prolonged PTT also directly influenced mortality, while the lower rate of PRC transfusion impacted mortality through nonsurgery and ICU admission.

Clinical relevance statement

In patients with active vascular contrast extravasation (AVCE) on abdominopelvic CT, larger AVCE directly increased in-hospital mortality. Radiologists’ detection and characterization of this finding is crucial, along with recognizing factors like CKD4-5, dialysis, and prolonged PTT to improve patient outcomes.

Key Points

Several factors independently predicted in-hospital mortality in patients with abdominopelvic AVCE.

Extravasation length > 8 mm was the only imaging marker predictive of in-hospital mortality.

Non-imaging factors correlated with in-hospital mortality, and PRC transfusion impacted mortality through nonsurgery and ICU admission pathways.

Graphical Abstract
Modified mesenchymal stromal cells by in vitro transcribed mRNA: a therapeutic strategy for hepatocellular carcinoma
Authors: Cantero María José , Bueloni Barbara , Gonzalez Llamazares Lucrecia , Fiore Esteban , Lameroli Lucia , Atorrasagasti Catalina , Mazzolini Guillermo , Malvicini Mariana , Bayo Juan , García Mariana G.
Published: July 2024

Background

Mesenchymal stromal cells (MSCs) tropism for tumours allows their use as carriers of antitumoural factors and in vitro transcribed mRNA (IVT mRNA) is a promising tool for effective transient expression without insertional mutagenesis risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with antitumor properties by stimulating the specific immune response. The aim of this work was to generate modified MSCs by IVT mRNA transfection to overexpress GM-CSF and determine their therapeutic effect alone or in combination with doxorubicin (Dox) in a murine model of hepatocellular carcinoma (HCC).

Methods

DsRed or GM-CSF IVT mRNAs were generated from a cDNA template designed with specific primers followed by reverse transcription. Lipofectamine was used to transfect MSCs with DsRed (MSC/DsRed) or GM-CSF IVT mRNA (MSC/GM-CSF). Gene expression and cell surface markers were determined by flow cytometry. GM-CSF secretion was determined by ELISA. For in vitro experiments, the J774 macrophage line and bone marrow monocytes from mice were used to test GM-CSF function. An HCC model was developed by subcutaneous inoculation (s.c.) of Hepa129 cells into C3H/HeN mice. After s.c. injection of MSC/GM-CSF, Dox, or their combination, tumour size and mouse survival were evaluated. Tumour samples were collected for mRNA analysis and flow cytometry.

Results

DsRed expression by MSCs was observed from 2 h to 15 days after IVT mRNA transfection. Tumour growth remained unaltered after the administration of DsRed-expressing MSCs in a murine model of HCC and MSCs expressing GM-CSF maintained their phenotypic characteristic and migration capability. GM-CSF secreted by modified MSCs induced the differentiation of murine monocytes to dendritic cells and promoted a proinflammatory phenotype in the J774 macrophage cell line. In vivo, MSC/GM-CSF in combination with Dox strongly reduced HCC tumour growth in C3H/HeN mice and extended mouse survival in comparison with individual treatments. In addition, the tumours in the MSC/GM-CSF + Dox treated group exhibited elevated expression of proinflammatory genes and increased infiltration of CD8 + T cells and macrophages.

Conclusions

Our results showed that IVT mRNA transfection is a suitable strategy for obtaining modified MSCs for therapeutic purposes. MSC/GM-CSF in combination with low doses of Dox led to a synergistic effect by increasing the proinflammatory tumour microenvironment, enhancing the antitumoural response in HCC.
Numerical simulation of high-frequency induction welding in longitudinal welded tubes
Authors: Asperheim John Inge , Das Prerana , Grande Bjørnar , Hömberg Dietmar , Petzold Thomas
Published: July 2024

In the present paper the high-frequency induction welding process is studied numerically. The mathematical model comprises a harmonic vector potential formulation of the Maxwell equations and a quasi-static, convection dominated heat equation coupled through the Joule heat term and nonlinear constitutive relations. Its main novelties are a new analytic approach which permits to compute a spatially varying feed velocity depending on the angle of the Vee-opening and additional spring-back effects. Moreover, a numerical stabilization approach for the finite element discretization allows to consider realistic weld-line speeds and thus a fairly comprehensive three-dimensional simulation of the tube welding process.
Machine learning to optimize literature screening in medical guideline development
Authors: Harmsen Wouter , de Groot Janke , Harkema Albert , van Dusseldorp Ingeborg , de Bruin Jonathan , van den Brand Sofie , van de Schoot Rens
Published: July 2024

Objectives

In a time of exponential growth of new evidence supporting clinical decision-making, combined with a labor-intensive process of selecting this evidence, methods are needed to speed up current processes to keep medical guidelines up-to-date. This study evaluated the performance and feasibility of active learning to support the selection of relevant publications within medical guideline development and to study the role of noisy labels.

Design

We used a mixed-methods design. Two independent clinicians’ manual process of literature selection was evaluated for 14 searches. This was followed by a series of simulations investigating the performance of random reading versus using screening prioritization based on active learning. We identified hard-to-find papers and checked the labels in a reflective dialogue.

Main outcome measures

Inter-rater reliability was assessed using Cohen’s Kappa (ĸ). To evaluate the performance of active learning, we used the Work Saved over Sampling at 95% recall (WSS@95) and percentage Relevant Records Found at reading only 10% of the total number of records (RRF@10). We used the average time to discovery (ATD) to detect records with potentially noisy labels. Finally, the accuracy of labeling was discussed in a reflective dialogue with guideline developers.

Results

Mean ĸ for manual title-abstract selection by clinicians was 0.50 and varied between − 0.01 and 0.87 based on 5.021 abstracts. WSS@95 ranged from 50.15% (SD = 17.7) based on selection by clinicians to 69.24% (SD = 11.5) based on the selection by research methodologist up to 75.76% (SD = 12.2) based on the final full-text inclusion. A similar pattern was seen for RRF@10, ranging from 48.31% (SD = 23.3) to 62.8% (SD = 21.20) and 65.58% (SD = 23.25). The performance of active learning deteriorates with higher noise. Compared with the final full-text selection, the selection made by clinicians or research methodologists deteriorated WSS@95 by 25.61% and 6.25%, respectively.

Conclusion

While active machine learning tools can accelerate the process of literature screening within guideline development, they can only work as well as the input given by human raters. Noisy labels make noisy machine learning.