bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of maternal intrahepatic cholestasis during pregnancy on the growth trajectory of offspring: a population-based nested case‒control cohort study
Authors: Li Xueqi , Kong Yao , Ren Yuxin , Li Yaqian , Xu Jinfeng , Zhan Yongchi , Zhou Shu , Yang Fan , Xu Tingting , Wang Xiaodong
Published: June 2024

Background

Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse fetal outcomes, yet its influence on offspring growth remains unclear. Our study dynamically tracks growth rates in children from ICP and healthy mothers and investigates the link between maternal liver function and developmental abnormalities in offspring.

Method

Our case‒control study involved 97 women with ICP and 152 with uncomplicated pregnancies nested in a cohort of their offspring, including 50 from the ICP group and 87 from the uncomplicated pregnancy group. We collected pediatric growth and development data, with a maximum follow-up duration of 36 months. Stratified analyses of children's height, weight, and head circumference were conducted, and Spearman's rank correlation was applied to examine the relationships between maternal serological markers and pediatric growth metrics.

Result

Maternal liver and renal functions, along with serum lipid profiles, significantly differed between the ICP and normal groups. In the ICP group, the offspring showed elevated alanine aminotransferase (ALT), direct bilirubin (DBIT), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (APOB) levels. Notably, the length-for-age z score (LAZ), weight-for-age z score (WAZ), and head circumference-for-age z score (HCZ) were lower in ICP offspring compared with those from normal pregnancies within the 1- to 12-month age range (P < 0.05). However, no significant differences in LAZ, weight-for-length z score (WLZ), BMI-for-age z score (BAZ), or HCZ were observed between groups in the 13- to 36-month age range. Maternal maximum lactate dehydrogenase (LDH) and total bile acids (TBA) levels during pregnancy were inversely correlated with LAZ and WAZ in the first year. Furthermore, offspring of mothers with ICP exhibited a greater incidence of stunting (24% vs. 6.9%, P = 0.004) and abnormal HCZ (14% vs. 3.7%, P = 0.034).

Conclusions

Growth disparities in offspring of ICP-affected pregnancies were most significant within the 1- to 12-month age range. During this period, maximum maternal LDH and TBA levels were negatively correlated with LAZ and WAZ values of offspring. The observation of similar growth rates between ICP and control group offspring from 13 to 36 months suggested catch-up growth in the ICP group.
Association between decision-to-delivery time and neonatal outcomes: a systematic review and meta-analysis
Authors: Shen Jiali , Shi Minmin
Published: June 2024

Background

Decision-to-delivery time (DDT), a crucial factor during the emergency caesarean section, may potentially impact neonatal outcomes. This study aims to assess the association between DDT and various neonatal outcomes.

Methods

A comprehensive search of PubMed, Scopus, Cochrane Library, and Google Scholar databases was conducted. A total of 32 eligible studies that reported on various neonatal outcomes, such as Apgar score, acidosis, neonatal intensive unit (NICU) admissions and mortality were included in the review. Studies were selected based on predefined eligibility criteria, and a random-effects inverse-variance model with DerSimonian-Laird estimate of tau² was used for meta-analysis. Heterogeneity and publication bias were assessed using I² statistics and Egger’s test, respectively.

Results

The meta-analysis revealed a significant association between DDT < 30 min and increased risk of Apgar score < 7 (OR 1.803, 95% CI: 1.284–2.533) and umbilical cord pH < 7.1 (OR 4.322, 95% CI: 2.302–8.115), with substantial heterogeneity. No significant association was found between DDT and NICU admission (OR 0.982, 95% CI: 0.767–1.258) or neonatal mortality (OR 0.983, 95% CI: 0.565–1.708), with negligible heterogeneity. Publication bias was not detected for any outcomes.

Conclusions

This study underscores the association between shorter DDT and increased odds of adverse neonatal outcomes such as low Apgar scores and acidosis, while no significant association was found in terms of NICU admissions or neonatal mortality. Our findings highlight the complexity of DDT’s impact, suggesting the need for nuanced clinical decision-making in cases of emergency caesarean sections.
Radiomics model based on contrast-enhanced computed tomography imaging for early recurrence monitoring after radical resection of AFP-negative hepatocellular carcinoma
Authors: Yan Xuanzhi , Li Yicheng , Qin Wanying , Liao Jiayi , Fan Jiaxing , Xie Yujin , Wang Zewen , Li Siming , Liao Weijia
Published: June 2024

Background

Although radical surgical resection is the most effective treatment for hepatocellular carcinoma (HCC), the high rate of postoperative recurrence remains a major challenge, especially in patients with alpha-fetoprotein (AFP)-negative HCC who lack effective biomarkers for postoperative recurrence surveillance. Emerging radiomics can reveal subtle structural changes in tumors by analyzing preoperative contrast-enhanced computer tomography (CECT) imaging data and may provide new ways to predict early recurrence (recurrence within 2 years) in AFP-negative HCC. In this study, we propose to develop a radiomics model based on preoperative CECT to predict the risk of early recurrence after surgery in AFP-negative HCC.

Patients and methods

Patients with AFP-negative HCC who underwent radical resection were included in this study. A computerized tool was used to extract radiomic features from the tumor region of interest (ROI), select the best radiographic features associated with patient’s postoperative recurrence, and use them to construct the radiomics score (RadScore), which was then combined with clinical and follow-up information to comprehensively evaluate the reliability of the model.

Results

A total of 148 patients with AFP-negative HCC were enrolled in this study, and 1,977 radiographic features were extracted from CECT, 2 of which were the features most associated with recurrence in AFP-negative HCC. They had good predictive ability in both the training and validation cohorts, with an area under the ROC curve (AUC) of 0.709 and 0.764, respectively. Tumor number, microvascular invasion (MVI), AGPR and radiomic features were independent risk factors for early postoperative recurrence in patients with AFP-negative HCC. The AUCs of the integrated model in the training and validation cohorts were 0.793 and 0.791, respectively. The integrated model possessed the clinical value of predicting early postoperative recurrence in patients with AFP-negative HCC according to decision curve analysis, which allowed the classification of patients into subgroups of high-risk and low-risk for early recurrence.

Conclusion

The nomogram constructed by combining clinical and imaging features has favorable performance in predicting the probability of early postoperative recurrence in AFP-negative HCC patients, which can help optimize the therapeutic decision-making and prognostic assessment of AFP-negative HCC patients.
The carcinogenic PAHs in breads, amount, analytical method and mitigation strategy, a systematic review study
Authors: Tavoosidana Gholamreza , Abdolhosseini Mansoreh , Mazaheri Yeghaneh , Basaran Burhan , Shavali-gilani Parisa , Sadighara Parisa
Published: June 2024

Bread is one of the most consumed foods all over the world. Several contaminants are identified in bread. Polycyclic aromatic hydrocarbons (PAHs) is one of these contaminants. This systematic study evaluates the amount of four carcinogenic PAHs (PAH4) in various types of breads. To conduct this study, a comprehensive search was carried out using keywords of polycyclic aromatic hydrocarbons, PAHs, PAH4, and bread, with no time limitations. 17 articles were selected and fully evaluated. The observed range of PAH4 concentrations in bread varied from non-detected (ND) to 20.66 µg/kg. In the sample preparation process for analysis, an ultrasonic bath was predominantly utilized. Most chromatographic methods are able to measure PAHs in food, but the GC-MS method has been used more. To mitigate PAH levels in bread, it is suggested to incorporate antioxidants during the bread-making process. Furthermore, the type of bread, the type of fuel used to bake the bread, the temperature and the cooking time were some of the factors affecting the amount of PAH. Restricting these factors could significantly reduce PAH content. Regarding the risk assessment conducted in the manuscript, it was determined that industrial breads are usually considered safe. However, some traditional breads may pose risks in terms of their potential PAH content.
Associations between smoking, sex steroid hormones, trouble sleeping, and depression among U.S. adults: a cross-sectional study from NHANES (2013–2016)
Authors: Huang Jing , Shi Peiwen , Zhao Yuan , Zhang Huinan , Gao Tian , Wang Xing
Published: June 2024

Background

Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear.

Methods

Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression.

Results

With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (β = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (Ptrend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (Pmodification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (Pmediation >0.05).

Conclusion

Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications.
Spatial distribution and determinants of Early sexual initiation in Ethiopia
Authors: Kebede Shimels Derso , Kebede Natnael , Mihiretu Mengistu Mera , Enyew Ermias Bekele , Ayele Kokeb , Asmare Lakew , Bayou Fekade Demeke , Arfaynie Mastewal , Walle Agmasie Damtew , Tsega Yawkal , Endawkie Abel
Published: June 2024

Introduction

: Early sexual initiation has negative health, social, and economic consequences for both women and future generations. The trend of early sexual initiation is increasing globally, leading to higher rates of sexually transmitted diseases and unplanned pregnancies. Ethiopia has been challenged various disasters that makes women vulnerable and position them at heightened risk of early sexual initiation in the last four years. The spatial patterns and factors of early sexual initiation in the post-conflict-post pandemic settings is not well understood. Hence this research aimed at mapping Spatial Patterns and identifying determinant factors in the Post-COVID-Post-Conflict Settings.

Methods

The study was conducted on secondary data from the PMA 2021 cross-sectional survey which conducted nationally from November 2021 to January 2022 which is in the post pandemic and post-war period. Total weighted sample of 6,036 reproductive age women were included in the analysis. ArcGIS Pro and SaTScan software were used to handle spatial analysis. Multilevel logistic regression model was used to estimate the effects of independent variables on early sexual initiation at individual and community level factors. Adjusted odds ratio with the 95% confidence interval was reported to declare the strength and statistical significance of the association.

Result

The spatial distribution of early sexual initiation was clustered in Ethiopia with a global Moran’s I index value of 0.09 and Z-score 6.01 (p-value < 0.001).Significant hotspots were detected in East Gojjam zone of Amhara region, Bale, Arsi, West Hararge, East Wellega and Horo Gudru Wellega zones of Oromia region. The odds of having early sexual initiation was higher in women with primary education (AOR = 1.23, 95%CI: 1.03, 1.47), secondary or above education (AOR = 4.36, 95%CI: 3.49, 5.44), Women aged 26 to 25 (AOR = 1.91, 95%CI: 1.61, 2.26), women aged 36 to 49(AOR = 1.51, 95%CI: 1.24, 1.84). However, there was a significant lower likelihood of early sexual initiation in rural resident women (AOR = 0.53, 95%CI: 0.35, 0.81) and women living in 5 to 7 family size (AOR = 0.79, 95%CI: 0.68, 0.92), and more than 7 members (AOR = 0.63, 95%CI: 0.49, 0.81).

Conclusions

The spatial distribution of early sexual initiation was clustered in Ethiopia. Interventions should be taken to eliminate the observed variation by mobilizing resources to high-risk areas. Policies and interventions targeted to this problem may also take the identified associated factors into account for better results.
Development and validation of a prediction model for postoperative urinary retention after prolapse surgery: A retrospective cohort study
Authors: Kim Min Ju , Lee Sungyoung , Lee So Yeon , Oh Sumin , Jeon Myung Jae
Published: June 2024

Background

Postoperative urinary retention (POUR), a common condition after prolapse surgery with potential serious sequelae if left untreated, lacks a clearly established optimal timing for catheter removal. This study aimed to develop and validate a predictive model for postoperative urinary retention lasting > 2 and > 4 days after prolapse surgery.

Methods

We conducted a retrospective review of 1,122 patients undergoing prolapse surgery. The dataset was divided into training and testing cohorts. POUR was defined as the need for continuous intermittent catheterization resulting from a failed spontaneous voiding trial, with passing defined as two consecutive voids ≥ 150 mL and a postvoid residual urine volume ≤ 150 mL. We performed logistic regression and the predicted model was validated using both training and testing cohorts.

Results

Among patients, 31% and 12% experienced POUR lasting > 2 and > 4 days, respectively. Multivariable logistic model identified 6 predictors. For predicting POUR, internal validation using cross-validation approach showed good performance, with accuracy lasting > 2 (area under the curve [AUC] 0.73) and > 4 days (AUC 0.75). Split validation using pre-separated dataset also showed good performance, with accuracy lasting > 2 (AUC 0.73) and > 4 days (AUC 0.74). Calibration curves demonstrated that the model accurately predicted POUR lasting > 2 and > 4 days (from 0 to 80%).

Conclusions

The proposed prediction model can assist clinicians in personalizing postoperative bladder care for patients undergoing prolapse surgery by providing accurate individual risk estimates.
Presence of pathogen DNA in milk harvested from quarters is associated to changes in cows’ milk yield and composition
Authors: Magro Silvia , Visentin Elena , Costa Angela , Penasa Mauro , Cendron Filippo , Moroni Paolo , Chiarin Elena , Cassandro Martino , Santinello Matteo , De Marchi Massimo
Published: June 2024

Background

Intramammary infection is the result of invasion and multiplication of microorganisms in the mammary gland and commonly leads to mastitis in dairy animals. Although much has been done to improve cows’ udder health, mastitis remains a significant and costly health issue for dairy farmers, especially if subclinical. In this study, quarter milk samples from clinically healthy cows were harvested to detect pathogens via quantitative PCR (qPCR) and evaluate changes in individual milk traits according to the number of quarters infected and the type of microorganism(s). A commercial qPCR kit was used for detection of Mycoplasma bovis, Mycoplasma spp., Staphylococcus aureus, coagulase-negative staphylococci (CNS), Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis, Prototheca spp., Escherichia coli, Klebsiella spp., Enterococcus spp. and Lactococcus lactis ssp. lactis. Quarter and pooled milk information of 383 Holstein, 132 Simmental, 129 Rendena, and 112 Jersey cows in 9 Italian single-breed herds was available.

Results

Among the cows with pathogen(s) present in at least 1 quarter, CNS was the most commonly detected DNA, followed by Streptococcus uberis, Mycoplasma bovis, and Streptococcus agalactiae. Cows negative to qPCR were 206 and had the lowest milk somatic cell count. Viceversa, cows with DNA isolated in ≥ 3 quarters were those with the highest somatic cell count. Moreover, when major pathogens were isolated in ≥ 3 quarters, milk had the lowest casein index and lactose content. In animals with pathogen(s) DNA isolated, the extent with whom milk yield and major solids were impaired did not significantly differ between major and minor pathogens.

Conclusions

The effect of the number of affected quarters on the pool milk quality traits was investigated in clinically healthy cows using a commercial kit. Results remark the important negative effect of subclinical udder inflammations on milk yield and quality, but more efforts should be made to investigate the presence of untargeted microorganisms, as they may be potentially dangerous for cows. For a smarter use of antimicrobials, analysis of milk via qPCR is advisable – especially in cows at dry off - to identify quarters at high risk of inflammation and thus apply a targeted/tailored treatment.
Nasal carriage of Staphylococcus aureus in healthy dairy cows in Algeria: antibiotic resistance, enterotoxin genes and biofilm formation
Authors: Titouche Yacine , Akkou Madjid , Djaoui Yasmina , Mechoub Donia , Fatihi Abdelhak , Campaña-Burguet Allelen , Bouchez Pascal , Bouhier Laurence , Houali Karim , Torres Carmen , Nia Yacine , Hennekinne Jacques-Antoine
Published: June 2024

Background

Staphylococcus aureus can colonize and infect a variety of animal species. In dairy herds, it is one of the leading causes of mastitis cases. The objective of this study was to characterize the S. aureus isolates recovered from nasal swabs of 249 healthy cows and 21 breeders of 21 dairy farms located in two provinces of Algeria (Tizi Ouzou and Bouira).

Methods

The detection of enterotoxin genes was investigated by multiplex PCRs. Resistance of recovered isolates to 8 antimicrobial agents was determined by disc-diffusion method. The slime production and biofilm formation of S. aureus isolates were assessed using congo-red agar (CRA) and microtiter-plate assay. Molecular characterization of selected isolates was carried out by spa-typing and Multi-Locus-Sequence-Typing (MLST).

Results

S. aureus was detected in 30/249 (12%) and 6/13 (28.6%) of nasal swabs in cows and breeders, respectively, and a total of 72 isolates were recovered from positive samples (59 isolates from cows and 13 from breeders). Twenty-six of these isolates (36.1%) harbored genes encoding for staphylococcal enterotoxins, including 17/59 (28.8%) isolates from cows and 9/13 (69.2%) from breeders. Moreover, 49.1% and 92.3% of isolates from cows and breeders, respectively, showed penicillin resistance. All isolates were considered as methicillin-susceptible (MSSA). Forty-five (76.3%) of the isolates from cows were slime producers and 52 (88.1%) of them had the ability to form biofilm in microtiter plates. Evidence of a possible zoonotic transmission was observed in two farms, since S. aureus isolates recovered in these farms from cows and breeders belonged to the same clonal lineage (CC15-ST15-t084 or CC30-ST34-t2228).

Conclusions

Although healthy cows in this study did not harbor methicillin-resistant S. aureus isolates, the nares of healthy cows could be a reservoir of enterotoxigenic and biofilm producing isolates which could have implications in human and animal health.
‘It was like coming back from the clouds’: a qualitative analysis of the lived experience of overdose consequent to drug use among a cohort of people who use drugs in Scotland
Authors: Byrne Christopher J. , Sani Fabio , Flynn Teresa , Malaguti Amy
Published: June 2024

Background

Globally, non-fatal overdose (NFOD) rates consequent to drug use, typically opioids, continue increasing at a startling rate. Existing quantitative research has revealed myriad factors and characteristics linked to experiencing NFOD, but it is critically important to explore the lived context underlying these associations. In this qualitative study, we sought to understand the experiences of NFOD among people who use drugs in a Scottish region in order to: enhance public policy responses; inform potential intervention development to mitigate risk; and contribute to the literature documenting the lived experience of NFOD.

Methods

From June to July 2021, two peer researchers conducted face-to-face semi-structured interviews with people who use drugs who had experienced recent NFOD attending harm reduction services in Tayside, Scotland. These were transcribed verbatim and evaluated using thematic analysis with an inductive approach which had an experiential and essentialist orientation.

Results

Twenty people were interviewed across two sites. Of those, 15 (75%) were male and mean age was 38.2 (7.7) years. All had experienced at least one NFOD in the prior six months, and all reported polydrug use. Five themes were identified, within which 12 subthemes were situated. The themes were: social context; personal risk-taking triggers; planned and impulsive consumption; risk perception; and overdose reversal. The results spoke to the environmental, behavioural, cognitive, economic, and marketplace, factors which influence the context of NFOD in the region.

Conclusions

A complex interplay of behavioural, psychological, and situational factors were found to impact the likelihood of experiencing NFOD. Structural inequities which policy professionals and civic leaders should seek to remedy were identified, while service providers may seek to reconfigure healthcare provision for people who use drugs to account for the interpersonal, psychological, and social factors identified, which appear to precipitate NFOD.

Trial registration

Not applicable.
Effects of fruit and vegetable intake on memory and attention: a systematic review of randomized controlled trials
Authors: Khor Khai Ling , Kumarasuriar Vashnarekha , Tan Kok Wei , Ooi Pei Boon , Chia Yook-Chin
Published: June 2024

Background

Memory and attention are important for daily functioning, and their function deteriorates due to aging. However, fruit and vegetable consumption are one of the protective factors against deterioration in memory and attention. This systematic review of randomized controlled trials (RCTs) aims to identify the effects of fruit and vegetable consumption on memory and attention.

Methods

We conducted a systematic search in EBSCOhost, ProQuest, PubMed, Embase, and Web of Science from inception up to 06/09/2022. The inclusion criteria were peer-reviewed articles, fruit and vegetable intake measured using randomized controlled trials, and the outcome measures that showed the results of memory and attention scores. Two researchers independently extracted articles that met the selection criteria and evaluated the quality of each study.

Results

There were 70 articles identified from the databases, of which 13 articles met the inclusion criteria and were included in this systematic review. There were 493 participants in total. The results show that consumption of fruit and vegetable intake improved memory and attention in longitudinal studies (10 to 12 weeks). Children showed improvement in immediate recall after supplementation with blueberries. Older adults required a higher dose of fruit and vegetable intake consumption to achieve significant improvement compared with children and younger adults. Furthermore, the effect of fruits and vegetables on memory showed better immediate memory recall than delayed recall.

Conclusion

This systematic review showed that there is an improvement in memory and attention with fruit and vegetable intake consumption. Hence, awareness of fruit and vegetable intake consumption is important to maintain cognitive health.
Association between anxiety, depression symptoms, and academic burnout among Chinese students: the mediating role of resilience and self-efficacy
Authors: Liu Wanqing , Zhang Ruiyun , Wang Huan , Rule Andrew , Wang Min , Abbey Cody , Singh Manpreet K. , Rozelle Scott , She Xinshu , Tong Lian
Published: June 2024

Background

To explore the associations between anxiety and depression symptoms and academic burnout among children and adolescents in China, and to examine the role of resilience and self-efficacy in addressing academic burnout.

Methods

A total of 2,070 students in grades 4–8 were recruited from two primary and three middle schools in Shanghai, completed the Elementary School Student Burnout Scale (ESSBS), the Multidimensional Anxiety Scale for Children-Chinese (MASC-C), the Center for Epidemiological Studies Depression Scale (CES-D), the Connor-Davidson Resilience Scale (CD-RISC), and the General Self-Efficacy Scale (GSES), with 95.04% effective response rate. Multivariable regression analyses examining the associations between anxiety / depression symptoms and academic burnout (as well as the associations between resilience / self-efficacy and academic burnout) were performed using STATA 16.0 and SmartPLS 3.0.

Results

Anxiety symptoms (β = 0.124, p < 0.01) and depression symptoms (β = 0.477, p < 0.01) were positively correlated with academic burnout. Resilience partially mediated the association between depression symptoms and academic burnout (β = 0.059, p < 0.01), with a mediation rate of 12.37%. Self-efficacy partially mediated the associations between anxiety symptoms and academic burnout (β = 0.022, p < 0.01) and between depression symptoms and academic burnout (β = 0.017, p < 0.01), with mediation rates of 17.74% and 3.56%, respectively. Resilience and self-efficacy together (β = 0.041, p < 0.01) formed a mediating chain between depression symptoms and academic burnout, with a mediation rate of 8.6%.

Conclusions

Anxiety and depression symptoms were positively associated with academic burnout. Resilience and self-efficacy were found to mediate the associations partially.
Inhibition changes across the lifespan: experimental evidence from the Stroop task
Authors: Forte Giuseppe , Troisi Giovanna , Favieri Francesca , Casagrande Maria
Published: June 2024

Individuals constantly exert inhibitory control over their thoughts and behaviors to plan actions that compete with habits and impulses. Cognitive inhibition enhances the selection of task-relevant stimuli and is closely related to neural changes that occur across the lifespan. Since few studies have focused on the entire lifespan, this study aimed to assess cognitive inhibition abilities in a sample of 425 healthy participants (age range: 7–88 years) using the Stroop task. The participants were grouped according to age into children, adolescents, young adults, adults, middle-aged adults, and older adults. A series of ANOVAs considered Group as the independent variable and Performance indices as the dependent variables. The children did not show an interference effect (Stroop effect), likely due to the lack of an automated reading process as a consequence of ongoing brain maturation. Adolescents and young adults performed significantly faster than older adults did. The results indicate that response speed reaches its peak during adolescence and young adulthood and then slightly decreases until older age. Nevertheless, when compared with the other groups, only older adults showed significant differences in the Stroop effect, suggesting that inhibitory abilities remain relatively consistent throughout adulthood but rapidly worsen in recent years due to the physiological decline in cognitive and brain functioning associated with aging.
Hypoxia within tumor microenvironment characterizes distinct genomic patterns and aids molecular subtyping for guiding individualized immunotherapy
Authors: Shi Run , Sun Jing , Zhou Hanyu , Hu Tong , Gao Zhaojia , Wang Xin , Li Minglun , Zhou Zhaokai , Shu Yongqian
Published: June 2024

Assessing the hypoxic status within the tumor microenvironment (TME) is crucial for its significant clinical relevance in evaluating drug resistance and tailoring individualized strategies. In this study, we proposed a robust pan-cancer hypoxic quantification method utilizing multiple public databases, diverse bioinformatics, and statistical methods. All tumor samples were classified into four subtypes: non-hypoxic/TMEhigh (C1), hypoxic/TMEhigh (C2), non-hypoxic/TMElow (C3), and hypoxic/TMElow (C4). We systematically analyzed multi-omics data and single-cell RNA-sequencing (scRNA-seq) data to reveal distinct immune landscape patterns and genomic characteristics among the four subtypes across pan-cancer. Furthermore, we employed multiple machine learning approaches to construct a hypoxic-TME model to enhance the predictive accuracy of immunotherapy response. Additionally, drug repositioning was implemented for cancer patients predicted as non-responders to immunotherapy. A pan-cancer analysis identified PDK1 as a hub gene linking tumor hypoxia, glycolysis, and immunotherapy resistance. In vivo experimental validation further confirmed that targeting PDK1 could improve the response to immunotherapy. Overall, our study may offer valuable insights for integrating hypoxic-TME classification into tumor staging and providing personalized strategies for cancer patients.
Inhibition of circulating dipeptidyl-peptidase 3 by procizumab in experimental septic shock reduces catecholamine exposure and myocardial injury
Authors: Garcia Bruno , ter Schiphorst Benoit , Santos Karine , Su Fuhong , Dewachter Laurence , Vasques-Nóvoa Francisco , Rocha-Oliveira Estela , Roncon-Albuquerque Roberto , Uba Theo , Hartmann Oliver , Picod Adrien , Azibani Feriel , Callebert Jacques , Goldman Serge , Annoni Filippo , Favory Raphaël , Vincent Jean-Louis , Creteur Jacques , Taccone Fabio Silvio , Mebazaa Alexandre , Herpain Antoine
Published: June 2024

Background

Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock.

Methods

In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65–75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin–angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples.

Results

PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression.

Conclusions

In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.

Graphical Abstract
Risk factors for mortality in post-myocardial infarction patients: insights from the improve SCA bridge study
Authors: Kumar Dileep , Bardooli Fawaz , Chen Wen-Jone , Huang Dejia , Sankardas Mullasari Ajit , Ahmed Waqar Habib , Liew Houng-Bang , Gwon Hyeon-Cheol , Van Dorn Brian , Holmes Thomas , Thompson Amy , Zhang Shu
Published: June 2024

Background

Underutilization of implantable cardioverter defibrillators (ICD) to prevent sudden cardiac death (SCD) in post-myocardial infarction (MI) patients remains an issue across several geographies. A better understanding of risk factors for SCD in post-MI patients from regions with low ICD adoption rates will help identify those who will benefit from an ICD. This analysis assessed risk factors for all-cause and cardiovascular-related mortality in post-MI patients from the Improve Sudden Cardiac Arrest (SCA) Bridge Trial.

Results

For the entire cohort, the overall 1-year mortality rate was 5.9% (88/1491) and 3.4% (51/1491) for all-cause and cardiovascular mortality, respectively, with 76.5% of all cardiac deaths being from SCD. A multivariate model determined increased age, reduced left ventricular ejection fraction (LVEF), increased time from myocardial infarction to hospital admission, being female, being from Southeast Asia (SEA), and having coronary artery disease to be significant risk factors for all-cause mortality. The risk factors for cardiovascular-related mortality revealed increased age, reduced LVEF, and being from SEA as significant risk factors.

Conclusions

We show several characteristics as being predictors of cardiovascular-related mortality in post-MI patients from the Improve SCA Bridge study. Patients who experience an MI and present with these characteristics would benefit from a referral to an electrophysiologist for further SCD risk stratification and management and possible subsequent ICD implantation to reduce unnecessary death.
Primary sinonasal chondroid chordoma in a pediatric patient: a diagnostic challenge
Authors: Mann Prachi , Arya Ayush , Disawal Amit , Anand Aarti
Published: June 2024

Background

Chordomas are rare, malignant tumors typically centered in midline structures such as the clivus and sacrum, with peak prevalence in the fourth decade. Clival chordomas may secondarily extend to involve the nasopharynx and nasal cavity; however, primary extra-osseous chordomas are even more uncommon. We present an unusual case of a primary sinonasal chondroid chordoma arising from the maxillary sinus in a 5-year-old child. This is the second case of primary sinonasal chordoma reported in the literature so far, after Tao ZZ et al. and the first case of the chondroid variant.

Case presentation

A 5-year-old male presented with right-sided nasal obstruction, nasal congestion, and snoring for 2 months. Physical examination showed a reddish polypoidal mass in the right nasal cavity obstructing the choana with nasal septal deviation toward left side. Radiological examination with CT confirmed the presence of a well-defined, heterogeneously hyperdense lobulated mass in right maxillary sinus extending into right nasal cavity with intralesional coarse calcifications. MRI revealed expansile solid altered signal intensity mass, which appears to be isointense on T1-weighted imaging (T1WI) and heterogeneously hyperintense on T2-weighted imaging (T2WI) with a heterogeneous honeycomb pattern of enhancement. Differentials considered were rhabdomyosarcoma, nasopharyngeal carcinoma, and neuroblastoma metastasis. However, the lesion was pathologically proven as a chondroid chordoma. No association with skull base or clival lesion was found on review.

Conclusions

Primary sinonasal chordomas are rare in occurrence but should be considered a differential for sinonasal masses in the presence of characteristic MRI features, despite their uncommon location.
Mini-MEndR: a miniaturized 96-well predictive assay to evaluate muscle stem cell-mediated repair
Authors: Gulati Nitya , Davoudi Sadegh , Xu Bin , Rjaibi Saifedine T. , Jacques Erik , Pham Justin , Fard Amir , McGuigan Alison P. , Gilbert Penney M.
Published: June 2024

Background

Functional evaluation of molecules that are predicted to promote stem cell mediated endogenous repair often requires in vivo transplant studies that are low throughput and hinder the rate of discovery. To offer greater throughput for functional validation studies, we miniaturized, simplified and expanded the functionality of a previously developed muscle endogenous repair (MEndR) in vitro assay that was shown to capture significant events of in vivo muscle endogenous repair.

Methods

The mini-MEndR assay consists of miniaturized cellulose scaffolds designed to fit in 96-well plates, the pores of which are infiltrated with human myoblasts encapsulated in a fibrin-based hydrogel to form engineered skeletal muscle tissues. Pre-adsorbing thrombin to the cellulose scaffolds facilitates in situ tissue polymerization, a critical modification that enables new users to rapidly acquire assay expertise. Following the generation of the 3D myotube template, muscle stem cells (MuSCs), enriched from digested mouse skeletal muscle tissue using an improved magnetic-activated cell sorting protocol, are engrafted within the engineered template. Murine MuSCs are fluorescently labeled, enabling co-evaluation of human and mouse Pax7+ cell responses to drug treatments. A regenerative milieu is introduced by injuring the muscle tissue with a myotoxin to initiate endogenous repair “in a dish”. Phenotypic data is collected at endpoints with a high-content imaging system and is analyzed using ImageJ-based image analysis pipelines.

Results

The miniaturized format and modified manufacturing protocol cuts reagent costs in half and hands-on seeding time ~ threefold, while the image analysis pipelines save 40 h of labour. By evaluating multiple commercially available human primary myoblast lines in 2D and 3D culture, we establish quality assurance metrics for cell line selection that standardizes myotube template quality. In vivo outcomes (enhanced muscle production and Pax7+ cell expansion) to a known modulator of MuSC mediated repair (p38/β MAPK inhibition) are recapitulated in the miniaturized culture assay, but only in the presence of stem cells and the regenerative milieu.

Discussion

The miniaturized predictive assay offers a simple, scaled platform to co-investigate human and mouse skeletal muscle endogenous repair molecular modulators, and thus is a promising strategy to accelerate the muscle endogenous repair discovery pipeline.
A Hybrid Type III Effectiveness-Implementation Trial to Optimize Medication Safety With Oral Antitumor Therapy in Real-World: The AMBORA Competence and Consultation Center
Authors: Cuba Lisa , Dürr Pauline , Gessner Katja , Häcker Babette , Fietkau Rainer , Siebler Jürgen , Pavel Marianne , Neurath Markus F. , Berking Carola , Wullich Bernd , Brückl Valeska , Beckmann Matthias W. , Fromm Martin F. , Dörje Frank
Published: June 2024

PURPOSE

Implementation science endeavors to facilitate the translation of evidence-based research into clinical routine. The clinical pharmacological/pharmaceutical care program evaluated in the randomized AMBORA trial on medication safety with oral antitumor therapeutics (OAT) optimizes care delivery and provides significant benefits for patients, treatment teams, and health care systems. Thus, we aimed to investigate the implementation of this care program within the AMBORA Competence and Consultation Center (AMBORA Center).

METHODS

The AMBORA Center within a University Comprehensive Cancer Center offered several services (eg, patient consultations) and was evaluated according to the RE-AIM framework. This multicenter hybrid type III trial focused on implementation outcomes (eg, patient recruitment, referring units, evaluation of services) while concurrently investigating effectiveness (eg, side effects, medication errors). Quantitative and qualitative assessments were combined.

RESULTS

The AMBORA Center conducted over 800 consultations with 420 patients in seven institutions. The primary end point of counseling 70% of patients treated with OAT was not reached. Patients were referred by 15 treatment units compared with 11 units in the AMBORA trial. On the basis of heterogeneous referral rates and characteristics across the institutions, barriers and facilitators of the implementation process were derived. Several survey results (eg, stakeholder interviews, online/paper-based questionnaires) reflected a high appreciation of services by patients and health care professionals. The severity of 60.1% (178 of 296) of detected side effects improved, and 86.3% (297 of 344) of medication errors were resolved.

CONCLUSION

Despite not reaching the primary implementation outcome, the AMBORA Center included more treatment units and demonstrated patient benefit of the AMBORA care program by meeting all effectiveness outcomes. We outlined quantitative and qualitative implementation characteristics to enhance outreach and foster further dissemination of centers to optimize medication safety with OAT.
Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma
Authors: Andrews Miles C. , Li Gerald , Graf Ryon P. , Fisher Virginia A. , Mitchell Jerry , Aboosaiedi Ali , O'Rourke Harriet , Shackleton Mark , Iddawela Mahesh , Oxnard Geoffrey R. , Huang Richard S.P.
Published: June 2024

PURPOSE

The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known.

METHODS

Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti–PD-1 (n = 240) or dual anti–PD-1 and anti–CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score.

RESULTS

TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P < .001; HR, 0.61 [95% CI, 0.41 to 0.90]; P = .01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P = .009; HR, 0.61 [95% CI, 0.42 to 0.88]; P = .007, respectively) patients. Dual ICI offered no significant advantage in BRAFwt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAFmut patient subgroup for whom mono ICI may be preferable.

CONCLUSION

TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice.
Serial Cell-Free DNA Sequencing in ROS1 Fusion–Positive Lung Cancers During Treatment With Entrectinib
Authors: Choudhury Noura J. , Jun Woo Hyung , Chen Monica , Shah Ronak , Donoghue Mark , Berger Michael , Drilon Alexander
Published: June 2024

PURPOSE

Patients with metastatic ROS1 fusion–positive non–small cell lung cancer (NSCLC) are effectively treated with entrectinib, a multikinase inhibitor. Whether serial targeted gene panel sequencing of cell-free DNA (cfDNA) can identify response and progression along with mechanisms of acquired resistance to entrectinib is underexplored.

METHODS

In patients with ROS1 fusion–positive NSCLC, coclinical trial plasma samples were collected before treatment, after two cycles, and after progression on entrectinib (global phase II clinical trial, ClinicalTrials.gov identifier: NCT02568267 ). Samples underwent cfDNA analysis using MSK-ACCESS. Variant allele frequencies of detectable alterations were correlated with objective response per RECIST v1.1 criteria.

RESULTS

Twelve patients were included, with best response as partial response (n = 9, 75%), stable disease (n = 2, 17%), and progressive disease (PD; n = 1, 8%). A ROS1 fusion was variably detected in cfDNA; however, patients without a ROS1 fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling ROS1 fusion or concurrent non- ROS1 alterations ( TP53, CDH1, NF1, or ARID1A mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a ROS1 fusion or non- ROS1 alterations. On-target resistance was rare; only one patient acquired ROS1 G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in NF1.

CONCLUSION

Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion–positive lung cancers in addition to detecting putative resistance mechanisms on progression.
Perioperative Primary Care Utilization and Postoperative Readmission, Emergency Department Use, and Mortality in Older Surgical Patients
Authors: Ron Donna , Abess Alexander T. , Boone Myles D. , Martinez-Camblor Pablo , Deiner Stacie G.
Published: June 2024

BACKGROUND:

Postdischarge primary care follow-up is associated with lower readmission rates after medical hospitalizations. However, the effect of primary care utilization on readmission has not been studied in surgical patients.

METHODS:

Retrospective cohort study of Medicare beneficiaries aged 65 and older undergoing major inpatient diagnostic or therapeutic procedures (n = 3,552,906) from 2017 through 2018, examining the association between postdischarge primary care visits within 14 days of discharge (primary exposure), and Annual Wellness Visits in the year prior (secondary exposure), with 30-day unplanned readmission (primary outcome), emergency department visits, and mortality (secondary outcomes).

RESULTS:

Overall, 9.5% (n = 336,837) had postdischarge visits within 14 days, 2.9% (n = 104,571) had Annual Wellness Visits in the year preceding the procedure, 9.5% (n = 336,401) were readmitted, 9% (n = 319,054) had emergency department visits, and 0.6% (n = 22,103) of the cohort died within 30 days. Our fully adjusted propensity-matched proportional hazards Cox regression analysis showed that postdischarge visits were associated with a 5% lower risk of readmission (hazard ratio [HR], 0.95, 95% confidence interval [CI], 0.93–0.97), 43% higher risk of emergency department use (HR, 1.43, 95% CI, 1.40–1.46) and no difference in mortality risk (HR, 0.98, 95% CI, 0.90–1.06), compared with not having a visit within 14 days of discharge. In a separate set of regression models, Annual Wellness Visits were associated with a 9% lower risk of readmission (HR, 0.91, 95% CI, 0.88–0.95), 45% higher risk of emergency department utilization (HR, 1.45, 95% CI, 1.40–1.49) and an 18% lower mortality risk (HR, 0.82, 95% CI, 0.75–0.89) compared with no Annual Wellness Visit in the year before the procedure.

CONCLUSIONS:

Both postdischarge visits and the Medicare Annual Wellness Visit appear to be extremely underutilized among the older surgical population. In those patients who do utilize primary care, compared with propensity-matched patients who do not, our study suggests primary care use is associated with modestly lower readmission rates. Prospective studies are needed to determine whether targeted primary care involvement can reduce readmission.