bluuebunny/crossref_metadata_2025 huggingface dataset:
Na+-preferential ion transporter HKT1;1 mediates salt tolerance in blueberry
Authors: Song Huifang , Cao Yibo , Zhao Xinyan , Zhang Lingyun
Published: September 2023

Soil salinity is a major environmental factor constraining growth and productivity of highbush blueberry (Vaccinium corymbosum). Leaf Na+ content is associated with variation in salt tolerance among blueberry cultivars; however, the determinants and mechanisms conferring leaf Na+ exclusion are unknown. Here, we observed that the blueberry cultivar ‘Duke’ was more tolerant than ‘Sweetheart’ and accumulated less Na+ in leaves under salt stress conditions. Through transcript profiling, we identified a member of the high-affinity K+ transporter (HKT) family in blueberry, VcHKT1;1, as a candidate gene involved in leaf Na+ exclusion and salt tolerance. VcHKT1;1 encodes a Na+-preferential transporter localized to the plasma membrane and is preferentially expressed in the root stele. Heterologous expression of VcHKT1;1 in Arabidopsis (Arabidopsis thaliana) rescued the salt hypersensitivity phenotype of the athkt1 mutant. Decreased VcHKT1;1 transcript levels in blueberry plants expressing antisense-VcHKT1;1 led to increased Na+ concentrations in xylem sap and higher leaf Na+ contents compared with wild-type plants, indicating that VcHKT1;1 promotes leaf Na+ exclusion by retrieving Na+ from xylem sap. A naturally occurring 8-bp insertion in the promoter increased the transcription level of VcHKT1;1, thus promoting leaf Na+ exclusion and blueberry salt tolerance. Collectively, we provide evidence that VcHKT1;1 promotes leaf Na+ exclusion and propose natural variation in VcHKT1;1 will be valuable for breeding Na+-tolerant blueberry cultivars in the future.
C-terminally encoded peptides act as signals to increase cotton root nitrate uptake under nonuniform salinity
Authors: Li Chenyang , Hu Qiuyue , Luo Zhen , Wang Xiaowen , Tang Wei , Lu Hequan , Ma Changle , Kong Xiangqiang
Published: September 2023

Soil salinity is often heterogeneous in saline fields. Nonuniform root salinity increases nitrate uptake into cotton (Gossypium hirsutum) root portions exposed to low salinity, which may be regulated by root portions exposed to high salinity through a systemic long-distance signaling mechanism. However, the signals transmitted between shoots and roots and their precise molecular mechanisms for regulating nitrate uptake remain unknown. Here, we showed that nonuniform root salinity treatment using split-root systems increases the expression of C-TERMINALLY ENCODED PEPTIDE (GhCEP) genes in high-saline-treated root portions. GhCEP peptides originating in high-saline-treated root portions act as ascending long-distance mobile signals transported to the shoots to promote the expression of CEP DOWNSTREAM (GhCEPD) genes by inducing the expression of CEP receptor (GhCEPR) genes. The shoot-derived GhCEPD polypeptides act as descending mobile signals transported to the roots through the phloem, increasing the expression of nitrate transport genes NITRATE TRANSPORTER 1.1 (GhNRT1.1), GhNRT2.1, and GhNRT1.5 in nonsaline-treated root portions, thereby increasing nitrate uptake in the nonsaline-treated root portions. This study indicates that GhCEP and GhCEPD signals are transported between roots and shoots to increase nitrate uptake in cotton, and the transport from the nonsaline root side is in response to nonuniform root salinity distribution.
Sensory neuron activation from topical treatments modulates the sensorial perception of human skin
Authors: Bennett-Kennett Ross , Pace Joseph , Lynch Barbara , Domanov Yegor , Luengo Gustavo S , Potter Anne , Dauskardt Reinhold H
Published: September 2023

Neural signaling of skin sensory perception from topical treatments is often reported in subjective terms such as a sensation of skin “tightness” after using a cleanser or “softness” after applying a moisturizer. However, the mechanism whereby cutaneous mechanoreceptors and corresponding sensory neurons are activated giving rise to these perceptions has not been established. Here, we provide a quantitative approach that couples in vitro biomechanical testing and detailed computational neural stimulation modeling along with a comprehensive in vivo self-assessment survey to demonstrate how cutaneous biomechanical changes in response to treatments are involved in the sensorial perception of the human skin. Strong correlations are identified between reported perception up to 12 hours post treatment and changes in the computed neural stimulation from mechanoreceptors residing deep under the skin surface. The study reveals a quantitative framework for understanding the biomechanical neural activation mechanism and the subjective perception by individuals.
Low-rate smartphone videoscopy for microsecond luminescence lifetime imaging with machine learning
Authors: Wang Yan , Sadeghi Sina , Velayati Alireza , Paul Rajesh , Hetzler Zach , Danilov Evgeny , Ligler Frances S , Wei Qingshan
Published: September 2023

Time-resolved techniques have been widely used in time-gated and luminescence lifetime imaging. However, traditional time-resolved systems require expensive lab equipment such as high-speed excitation sources and detectors or complicated mechanical choppers to achieve high repetition rates. Here, we present a cost-effective and miniaturized smartphone lifetime imaging system integrated with a pulsed ultraviolet (UV) light-emitting diode (LED) for 2D luminescence lifetime imaging using a videoscopy-based virtual chopper (V-chopper) mechanism combined with machine learning. The V-chopper method generates a series of time-delayed images between excitation pulses and smartphone gating so that the luminescence lifetime can be measured at each pixel using a relatively low acquisition frame rate (e.g. 30 frames per second [fps]) without the need for excitation synchronization. Europium (Eu) complex dyes with different luminescent lifetimes ranging from microseconds to seconds were used to demonstrate and evaluate the principle of V-chopper on a 3D-printed smartphone microscopy platform. A convolutional neural network (CNN) model was developed to automatically distinguish the gated images in different decay cycles with an accuracy of >99.5%. The current smartphone V-chopper system can detect lifetime down to ∼75 µs utilizing the default phase shift between the smartphone video rate and excitation pulses and in principle can detect much shorter lifetimes by accurately programming the time delay. This V-chopper methodology has eliminated the need for the expensive and complicated instruments used in traditional time-resolved detection and can greatly expand the applications of time-resolved lifetime technologies.
Broadening the public health approach to policing
Authors: Sidebottom Aiden , Tilley Nick
Published: September 2023

There is growing interest in a public health approach to policing. In Britain, it has attracted major government investment and is advocated as a way to improve understanding and prevention of violence. We largely support efforts better to integrate public health and policing. We do, however, argue in this paper that the current conception of public health is unduly narrow, focussing overwhelmingly on early intervention and paying little attention to situational measures directed at more immediate causes of crime. We argue that the neglect of situational intervention rests on a partial interpretation of the public health literature, and ignores a long history of situational measures being effectively used to reduce harmful behaviours. If a public health approach is to generate improvements in policing and crime prevention, we argue that a broader conception of public health is needed.
Long-term in vivo chimeric cells tracking in non-human primate
Authors: Wu Junmo , Kang Yu , Luo Xiang , Dai Shaoxing , Shi Yuxi , Li Zhuoyao , Tang Zengli , Chen Zhenzhen , Zhu Ran , Yang Pengpeng , Li Zifan , Wang Hong , Chen Xinglong , Zhao Ziyi , Ji Weizhi , Niu Yuyu
Published: September 2023

Non-human primates (NHPs) are increasingly used in preclinical trials to test the safety and efficacy of biotechnology therapies. Nonetheless, given the ethical issues and costs associated with this model, it would be highly advantageous to use NHP cellular models in clinical studies. However, developing and maintaining the naïve state of primate pluripotent stem cells (PSCs) remains difficult as does in vivo detection of PSCs, thus limiting biotechnology application in the cynomolgus monkey. Here, we report a chemically defined, xeno-free culture system for culturing and deriving monkey PSCs in vitro. The cells display global gene expression and genome-wide hypomethylation patterns distinct from monkey-primed cells. We also found expression of signaling pathways components that may increase the potential for chimera formation. Crucially for biomedical applications, we were also able to integrate bioluminescent reporter genes into monkey PSCs and track them in chimeric embryos in vivo and in vitro. The engineered cells retained embryonic and extra-embryonic developmental potential. Meanwhile, we generated a chimeric monkey carrying bioluminescent cells, which were able to track chimeric cells for more than 2 years in living animals. Our study could have broad utility in primate stem cell engineering and in utilizing chimeric monkey models for clinical studies.
“Ethnic Cleansing”: An Analysis of Conceptual and Empirical Ambiguity
Authors: Garrity Meghan M
Published: September 2023

Despite significant scholarly disagreement about its definition, core meaning, and corresponding cases, ethnic cleansing has escaped careful conceptual examination. This article identifies five key areas of conceptual confusion that undermine the integrity and utility of the concept. These include discrepancies over the core meaning of ethnic cleansing; tension between ethnic cleansing as a practice and a policy; the lack of boundedness between ethnic cleansing and other related concepts; the universe of cases that belong together; and disparate subtype classification criteria. This conceptual confusion undermines effective comparative analysis and, in turn, our understanding of the causes of ethnic cleansing and associated policy recommendations. The solution is to abandon the social science usage of ethnic cleansing in favor of alternative concepts defined by the distinct intent of the perpetrator(s): massacre (to annihilate), mass expulsion (to remove), coercive assimilation (to eliminate a unique cultural identity), and control (to subjugate). This eliminates ambiguity, improves theoretical precision, and opens a promising new research agenda.
Aberrant single-subject morphological brain networks in first-episode, treatment-naive adolescents with major depressive disorder
Authors: Qiu Xiaofan , Li Junle , Pan Fen , Yang Yuping , Zhou Weihua , Chen Jinkai , Wei Ning , Lu Shaojia , Weng Xuchu , Huang Manli , Wang Jinhui
Published: September 2023

Background

Neuroimaging-based connectome studies have indicated that major depressive disorder (MDD) is associated with disrupted topological organization of large-scale brain networks. However, the disruptions and their clinical and cognitive relevance are not well established for morphological brain networks in adolescent MDD.

Objective

To investigate the topological alterations of single-subject morphological brain networks in adolescent MDD.

Methods

Twenty-five first-episode, treatment-naive adolescents with MDD and 19 healthy controls (HCs) underwent T1-weighted magnetic resonance imaging and a battery of neuropsychological tests. Single-subject morphological brain networks were constructed separately based on cortical thickness, fractal dimension, gyrification index, and sulcus depth, and topologically characterized by graph-based approaches. Between-group differences were inferred by permutation testing. For significant alterations, partial correlations were used to examine their associations with clinical and neuropsychological variables in the patients. Finally, a support vector machine was used to classify the patients from controls.

Results

Compared with the HCs, the patients exhibited topological alterations only in cortical thickness-based networks characterized by higher nodal centralities in parietal (left primary sensory cortex) but lower nodal centralities in temporal (left parabelt complex, right perirhinal ectorhinal cortex, right area PHT and right ventral visual complex) regions. Moreover, decreased nodal centralities of some temporal regions were correlated with cognitive dysfunction and clinical characteristics of the patients. These results were largely reproducible for binary and weighted network analyses. Finally, topological properties of the cortical thickness-based networks were able to distinguish the MDD adolescents from HCs with 87.6% accuracy.

Conclusion

Adolescent MDD is associated with disrupted topological organization of morphological brain networks, and the disruptions provide potential biomarkers for diagnosing and monitoring the disease.
Variability in the expression and perception of positive affect in human infancy
Authors: Grossmann Tobias , Wood Adrienne
Published: September 2023

Positive emotions play a critical role in guiding human behavior and social interactions. This study examined whether and how genetic variability in the oxytocin system is linked to individual differences in expressing positive affect in human infants. Our results show that genetic variation in CD38 (rs3796863), previously linked to increased release of oxytocin, was associated with higher rates of positive affective displays among a sample of 7-month-old infants, using established parent-report measures. Moreover, infants displaying increased levels of positive affect (smiling and laughter) also showed enhanced brain responses in the right inferior frontal cortex, a brain region previously linked to perception–action coupling, when viewing others smile at them. These findings suggest that, from early in development, genetic variation in the oxytocin system is associated with individual differences in expressed positive affect, which in turn are linked to differences in perceiving positive affect. This helps uncover the neurobiological processes accounting for variability in the expression and perception of positive affect in infancy.
Learning from in-group and out-group models induces separative effects on human mate copying
Authors: Xie Jiajia , Li Lin , Lu Yang , Zhuang Jinying , Wu Yuyan , Li Peng , Zheng Li
Published: September 2023

Mate copying is a social learning process in which individuals gather public information about potential mates by observing models’ choices. Previous studies have reported that individual attributes of female models affect mate copying, yet little is known about whether and how the group attributes of models influence mate copying. In the current behavioral and functional magnetic resonance imaging studies, female participants were asked to rate their willingness to choose the depicted males as potential romantic partners before and after observing in-group or out-group female models accepting, rejecting or being undecided (baseline) about the males. Results showed that participants changed their ratings to align with the models’ acceptance or rejection choices. Compared to rejection copying, the effect of acceptance copying was stronger and regulated by in- and out-group models, manifesting a discounting copying effect when learning from out-group models. At the neural level, for acceptance copying, stronger temporoparietal junction (TPJ) activity and connectivity between TPJ and anterior medial prefrontal cortex (amPFC) were observed when female models belonged to out-group members; meanwhile, the functional connection of TPJ and amPFC positively predicted the rating changes when learning from out-group models. The results indicated that participants might need more resources to infer out-group members’ intentions to overcome the in-group bias during acceptance copying.
Coming of Age on the Margins: A Life Course Perspective on the Time Use of Australian Adolescents with Disabilities
Authors: O’Flaherty Martin , King Tania , Kavanagh Anne
Published: September 2023

People with disabilities experience persistent, multifaceted disadvantage across the life course. The origins of life course disadvantage among people with disabilities may stem, in part, from exclusion during developmentally sensitive periods in childhood. Time use among adolescents represents a potentially important mechanism implicated in the emergence of disability-related disadvantage, but previous research has largely neglected the time use of school age adolescents with disabilities. Utilizing nationally representative time diary data, this study investigated disability-related differences in adolescents’ time use, and how these gaps vary by sex and age. Results indicated that disability-related differences in time use are widespread and substantial in magnitude. Adolescents with disabilities spend more time in screen-based leisure, alone, and with mothers, and less time in educational activities than non-disabled adolescents. Boys with disabilities additionally spend less time in structured leisure and with peers than non-disabled boys. Differences in time alone, with peers, and in screen-based leisure increase in magnitude at older ages. We conclude that differential time use in adolescence may contribute to multiple persistent disadvantages experienced by people with disabilities over the life course.
“There’s theology and then there’s the people I love. . .”: Authority and Ambivalence in Seminarians’ Attitudes Toward Same-Sex Relationships, Marriage, and Ordination
Authors: Johnston Erin , Holleman Anna , Krull Laura
Published: September 2023

Drawing from 102 in-depth interviews conducted with first-year Master of Divinity (M.Div.) students at a Mainline Protestant seminary, this paper examines how students describe and account for their positions on homosexuality, same-sex marriage, and the ordination of gay and lesbian clergy. We found that students on “both sides”—i.e., those who lean affirming and those who lean non-affirming—invoked three primary authorities in their accounts: Biblical authority, Godly authority, and the authority of lived experience, as demonstrated in the lives of gay and lesbian people. We also found that nearly one-third of the students in our sample expressed uncertainty, ambivalence, and/or contradictions in their responses. Through a close analysis of these accounts, we show that ambivalence and uncertainty are rooted in attempts to navigate and “reconcile” the pulls of these different authorities and that attitudinal certainty is often accomplished by privileging one authority over others.
Fullerene C60 protects against 7,12-dimethylbenz [a] anthracene (DMBA) induced-pancreatic damage via NF-κB and Nrf-2/HO-1 axis in rats
Authors: Beyaz Seda , Aslan Abdullah , Gok Ozlem , Ozercan Ibrahim Hanifi , Agca Can Ali
Published: September 2023

The objective of this investigation was to investigate the protective effects of fullerene C60 nanoparticle against pancreatic damage experimentally induced by 7,12-dimethylbenz [a] anthracene (DMBA) in female rats. Fullerene C60 nanoparticle was administered to rats 5 times a week by oral gavage (o.g) at 1.7 mg/kg bw 7 days after DMBA administration. 60 Wistar albino female rats divided to four groups; Groups: (1) Control group: Fed with standard diet; (2) Fullerene C60 group: Fullerene C60 (1.7 mg/kg bw); (3) DMBA group: DMBA (45 mg/kg bw); (4) Fullerene C60 + DMBA group: Fullerene C60 (1.7 mg/kg bw) and DMBA (45 mg/kg bw). Lipid peroxidation malondialdehyde (MDA), catalase activity (CAT) and glutathione (GSH) levels in pancreatic tissue were determined by spectrophotometer. Protein expression levels of p53, HO-1, p38-α (MAPK), Nrf-2, NF-κB and COX-2 in pancreatic tissue were determined by western blotting technique. In our findings, compared to the group given DMBA, MDA levels and p38-α, NF-κB and COX-2 levels decreased, CAT activity, GSH level, total protein density and p53, HO-1, Nrf-2 levels in the groups given fullerene C60 nanoparticle an increase in expression levels was observed. Our results showed that fullerene C60 nanoparticle may be more beneficial in preventing pancreatic damage.
Revealing a new eyelessNereis(Nereididae: Annelida) clade from deep-sea organic falls
Authors: Bergamo Gilberto , Carrerette Orlemir , Shimabukuro Mauricio , Santos Cinthya S G , Sumida Paulo Y G
Published: September 2023

Three new eyeless species of Nereis from organic falls (whale bones and wood parcels) in the Southwestern Atlantic from depths between 550 and 3285 m are described, and the eyeless species Neanthes shinkai is transferred to Nereis. All new species and Nereis shinkai comb. nov. can be distinguished from the majority of Nereis species by the absence of eyes and by the presence of small and delicate paragnaths. Interestingly, the species Nereis anoculepitoka sp. nov. presents epitoky, with sexual dimorphism and the morphological variations described herein. This is the first description of an eyeless epitoke form from organic falls in the deep ocean. We conducted molecular phylogenetic analyses using COI and 16S mitochondrial genes, confirmed the morphological identification and established an eyeless clade within Nereis including the three new species and Nereis shinkai comb. nov. The presence of different species in a relatively small geographical area can be explained, in part, by the action of different water masses in each sampling site and suggests that organic islands are potential hotspots for specialization of Nereis in the deep sea.
Automatic Scoring of Rhizoctonia Crown and Root Rot Affected Sugar Beet Fields from Orthorectified UAV Images Using Machine Learning
Authors: Ispizua Yamati Facundo Ramón , Günder Maurice , Barreto Abel , Bömer Jonas , Laufer Daniel , Bauckhage Christian , Mahlein Anne-Katrin
Published: September 2023

Rhizoctonia crown and root rot (RCRR), caused by Rhizoctonia solani, can cause severe yield and quality losses in sugar beet. The most common strategy to control the disease is the development of resistant varieties. In the breeding process, field experiments with artificial inoculation are carried out to evaluate the performance of genotypes and varieties. The phenotyping process in breeding trials requires constant monitoring and scoring by skilled experts. This work is time demanding and shows bias and heterogeneity according to the experience and capacity of each individual person. Optical sensors and artificial intelligence have demonstrated great potential to achieve higher accuracy than human raters and the possibility to standardize phenotyping applications. A workflow combining red–green–blue and multispectral imagery coupled to an unmanned aerial vehicle (UAV), as well as machine learning techniques, was applied to score diseased plants and plots affected by RCRR. Georeferenced annotation of UAV-orthorectified images was carried out. With the annotated images, five convolutional neural networks were trained to score individual plants. The training was carried out with different image analysis strategies and data augmentation. The custom convolutional neural network trained from scratch together with pretrained MobileNet showed the best precision in scoring RCRR (0.73 to 0.85). The average per plot of spectral information was used to score the plots, and the benefit of adding the information obtained from the score of individual plants was compared. For this purpose, machine learning models were trained together with data management strategies, and the best-performing model was chosen. A combined pipeline of random forest and k-nearest neighbors has shown the best weighted precision (0.67). This research provides a reliable workflow for detecting and scoring RCRR based on aerial imagery. RCRR is often distributed heterogeneously in trial plots; therefore, considering the information from individual plants of the plots showed a significant improvement in UAV-based automated monitoring routines.
Current treatment approach to ANCA-associated vasculitis
Authors: Yazici Yusuf
Published: September 2023

Purpose of review

This review will attempt to summarize the most potentially impactful new data on the way ANCA-associated vasculitis (AAV) is diagnosed, treated, and monitored.

Recent findings

The newly developed classification criteria for AAV have serious methodological issues that need to be addressed before they are widely adopted. The newly approved drugs and studies into both achieving remission and maintaining it have added to our overall knowledge of managing AAV and should hopefully contribute to improving outcomes in AAV.

The diagnosis, treatment and monitoring of AAV have seen major improvements in the last two years. The remaining issues outlined in this review still need to be addressed to best serve AAV patients.
Current Evidence for Hybrid Constructs
Authors: Lee Nathan J. , Lehman Ronald A.
Published: September 2023

It is not surprising that the utilization of hybrid constructs, combining cervical disc arthroplasty with anterior cervical disc arthroplasty, has steadily increased over the last decade. Known limitations exist with multi-level anterior cervical disc arthroplasty and cervical disc arthroplasty procedures. Hybrid surgery offers the possibility to address patient-specific pathology in a more tailored manner by restoring functional mobility and promoting fusion where appropriate. This review discusses the current evidence, both biomechanical and clinical, of hybrid surgery for 2-level and 3-level cervical disease.
Short-term and Long-term Complications of Cervical Disk Arthroplasty
Authors: Nguyen Austin Q. , Credille Kevin , Saifi Comron
Published: September 2023

Study Design:

A narrative review.

Objective:

This review discusses the short and long-term complications associated with cervical disk arthroplasty (CDA).

Summary of Background Data:

CDA is a safe and effective motion-sparing alternative to fusion for the treatment of cervical disk pathology in patients with cervical radiculopathy or myelopathy. Although CDA offers advantages over fusion within a narrower set of indications, it introduces new technical challenges and potential complications.

Methods:

A systematic search of several large databases, including Cochrane Central, PubMed, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry, was conducted from January 2005 to August 2023 to identify published studies and clinical trials evaluating cervical disk replacement complications and outcomes.

Results:

Short-term complications are primarily related to surgical approach and include dysphagia reported as high as ~70%, laryngeal nerve injury ~0%–1.25%, Horner syndrome ~0.06%, hematoma ~0.01%, gross device extrusion ~0.3%, whereas long-term complications include adjacent segment disease reported at ~3.8%, osteolysis ~44%–64%, heterotopic ossification ~7.3%–69.2%, implant failure ~3.3%–3.7%, and implant wear, which varies depending on design.

Conclusions:

Approaches for mitigating complications broadly include meticulous dissection, intraoperative techniques, and diligent postoperative follow-up. This review emphasizes the need for a comprehensive understanding and management of complications to enhance the safety, reproducibility, and success of CDA. As CDA continues to evolve, there remains a critical need for ongoing research to delve deeper into evaluating risk for complications and long-term patient outcomes.
Mortality Risk Factors in Pediatric Onco-Critical Care Patients and Machine Learning Derived Early Onco-Critical Care Phenotypes in a Retrospective Cohort
Authors: Flerlage Tim , Fan Kimberly , Qin Yidi , Agulnik Asya , Arias Anita V. , Cheng Cheng , Elbahlawan Lama , Ghafoor Saad , Hurley Caitlin , McArthur Jennifer , Morrison R. Ray , Zhou Yinmei , Park H.J. , Carcillo Joseph A. , Hines Melissa R.
Published: September 2023

OBJECTIVES:

To use supervised and unsupervised statistical methodology to determine risk factors associated with mortality in critically ill pediatric oncology patients to identify patient phenotypes of interest for future prospective study.

DESIGN:

This retrospective cohort study included nonsurgical pediatric critical care admissions from January 2017 to December 2018. We determined the prevalence of multiple organ failure (MOF), ICU mortality, and associated factors. Consensus k-means clustering analysis was performed using 35 bedside admission variables for early, onco-critical care phenotype development.

SETTING:

Single critical care unit in a subspeciality pediatric hospital.

INTERVENTION:

None.

PATIENTS:

There were 364 critical care admissions in 324 patients with underlying malignancy, hematopoietic cell transplant, or immunodeficiency reviewed.

MEASUREMENTS:

Prevalence of multiple organ failure, ICU mortality, determination of early onco-critical care phenotypes.

MAIN RESULTS:

ICU mortality was 5.2% and was increased in those with MOF (18.4% MOF, 1.7% single organ failure [SOF], 0.6% no organ failure; p ≤ 0.0001). Prevalence of MOF was 23.9%. Significantly increased ICU mortality risk was associated with day 1 MOF (hazards ratio [HR] 2.27; 95% CI, 1.10–6.82; p = 0.03), MOF during ICU admission (HR 4.16; 95% CI, 1.09–15.86; p = 0.037), and with invasive mechanical ventilation requirement (IMV; HR 5.12; 95% CI, 1.31–19.94; p = 0.018). Four phenotypes were derived (PedOnc1–4). PedOnc1 and 2 represented patient groups with low mortality and SOF. PedOnc3 was enriched in patients with sepsis and MOF with mortality associated with liver and renal dysfunction. PedOnc4 had the highest frequency of ICU mortality and MOF characterized by acute respiratory failure requiring invasive mechanical ventilation at admission with neurologic dysfunction and/or severe sepsis. Notably, most of the mortality in PedOnc4 was early (i.e., within 72 hr of ICU admission).

CONCLUSIONS:

Mortality was lower than previously reported in critically ill pediatric oncology patients and was associated with MOF and IMV. These findings were further validated and expanded by the four derived nonsynonymous computable phenotypes. Of particular interest for future prospective validation and correlative biological study was the PedOnc4 phenotype, which was composed of patients with hypoxic respiratory failure requiring IMV with sepsis and/or neurologic dysfunction at ICU admission.
Teaching Bundle Care Approach to Intensive Care Nurses to Prevent Ventilator Associated Pneumonia with a Stratified Validated Module
Authors: Tatikonda Chandra Mouli , Prasad Katuri Rama Krishna , Rout Nibedita , Panda Sagarika , Mishra Shakti Bedanta , Dash Abhilash , Samal Samir , Roy Cherian
Published: September 2023

Background

Module-based teaching of ventilator-associated pneumonia (VAP) with a systematic, stratified approach is expected to have a promising role in teaching. We hypothesized it to improve the skill and knowledge of intensive care unit nurses.

Objectives

The aim of this study was to determine the efficacy of the teaching module with debriefing sessions on the VAP bundle care approach, and the secondary objective was to estimate the improvement in individual components of the VAP bundle.

Methods

A total of 200 paramedical staff were exposed to a teaching module consisting of pretest didactic lectures, debriefing sessions, reflection by participants, and feedback. Posttest analysis was done to assess knowledge. Skill assessment was done with directly observed procedural skills (DOPS) assessment, and feedback was taken from participants. Follow-up was done at 6 months to assess decay in knowledge and skills.

Results

Preworkshop and postworkshop DOPS scores were analyzed using the Mann-Whitney U test. Subgroup analysis was performed using the paired t test. Median pretest and posttest scores were 6 (interquartile range, 4-8) and 13 (interquartile range, 11-15), respectively (P < .001). Comparing DOPS scores before and after exposure to the teaching module, the number of subjects with scores that were below expectations was 24 and 4; meeting expectations was 94 and 24; borderline expectations were 36 and 104; and above expectations was 46 and 58, respectively, between the groups (P < .001). A decay in knowledge and skills was noted in the follow-up.

Conclusion

A validated teaching module with debriefing sessions is useful in training bundle care approaches to intensive care unit nurses.
Validation of Parent-reported Gestational Age Categories for Children Less Than 6 Years of Age
Authors: Palumbo Alexandra M. , Kirkwood David , Borkhoff Cornelia M. , Keown-Stoneman Charles D. G. , Muraca Giulia M. , Fuller Anne , Birken Catherine S. , Maguire Jonathon L. , Brown Hilary K. , Anderson Laura N. ,   on behalf of the TARGet Kids! Collaboration
Published: September 2023

Background:

Preterm birth is an important outcome or exposure in epidemiologic research. When administrative data on measured gestational age is not available, parent-reported gestational age can be obtained from questionnaires, which is subject to potential bias. To our knowledge, few studies have assessed the validity of parent-reported gestational age categories, including commonly defined categories of preterm birth.

Methods:

We used linked data from primarily healthy children <6 years of age in TARGet Kids! in Toronto, Canada, and ICES administrative healthcare data from April 2011 to March 2020. We assessed the criterion validity of questionnaire-based parent-reported gestational age by calculating sensitivity and specificity for term (≥37 weeks), late preterm (34–36 weeks), and moderately preterm (32–33 weeks) gestational age categories, using administrative healthcare records of gestational age as the criterion standard. We conducted subgroup analyses for various parent and socioeconomic factors that may influence recall.

Results:

Of the 4684 participants, 97.3% correctly classified the gestational age category according to administrative healthcare data. Parent-reported gestational age sensitivity ranged from 83.7% to 98.5% and specificity ranged from 88.3% to 99.8%, depending on category. For each subgroup characteristic, sensitivity and specificity were all ≥70%. Lower educational attainment, lower family income, father reporting, ≥1 year since birth, ≥2 children, lower parent age, and reported gestational diabetes and/or hypertension were associated with slightly lower sensitivity and/or specificity.

Conclusions:

In this linked cohort, parent-reported gestational age categories had high accuracy. Criterion validity varied minimally among some parent and socioeconomic factors. Our findings can inform future quantitative bias analyses.
Ambient Air Quality and Fatal Asthma Exacerbations among Children in North Carolina
Authors: Mirabelli Maria C. , Flanders W. Dana , Vaidyanathan Ambarish , Beavers Daniel P. , Gower W. Adam
Published: September 2023

Background:

Little is known about the role of air quality in fatal asthma exacerbations among children.

Methods:

We collected information about 80 deaths that occurred in North Carolina from 2001 through 2016, among children aged 5–17 years, with asthma identified as the primary cause of death. We linked information about each death with county-level estimates of particulate matter ≤2.5 µm (PM2.5) and ozone (O3). Using the linked data, we conducted a case–crossover analysis of associations between PM2.5 and O3 lagged by 3–5 days with the odds of fatal asthma exacerbations.

Results:

In the highest tertile of PM2.5 lag(3–5), the odds of a fatal exacerbation of asthma were more than twice the odds in the lowest tertile (odds ratio = 2.2; 95% confidence interval = 1.1, 4.6).

Conclusion:

These findings from North Carolina provide evidence to support the hypothesis that ambient air pollution increases the risk of fatal exacerbations of asthma among children.
Comparative Effectiveness of Dynamic Treatment Strategies for Medication Use and Dosage: Emulating a Target Trial Using Observational Data
Authors: Birnie Kate , Tomson Charles , Caskey Fergus J. , Ben-Shlomo Yoav , Nitsch Dorothea , Casula Anna , Murray Eleanor J. , Sterne Jonathan A. C.
Published: September 2023

Background:

Availability of detailed data from electronic health records (EHRs) has increased the potential to examine the comparative effectiveness of dynamic treatment strategies using observational data. Inverse probability (IP) weighting of dynamic marginal structural models can control for time-varying confounders. However, IP weights for continuous treatments may be sensitive to model choice.

Methods:

We describe a target trial comparing strategies for treating anemia with darbepoetin in hemodialysis patients using EHR data from the UK Renal Registry 2004 to 2016. Patients received a specified dose (microgram/week) or did not receive darbepoetin. We compared 4 methods for modeling time-varying treatment: (A) logistic regression for zero dose, standard linear regression for log dose; (B) logistic regression for zero dose, heteroscedastic linear regression for log dose; (C) logistic regression for zero dose, heteroscedastic linear regression for log dose, multinomial regression for patients who recently received very low or high doses; and (D) ordinal logistic regression.

Results:

For this dataset, method (C) was the only approach that provided a robust estimate of the mortality hazard ratio (HR), with less-extreme weights in a fully weighted analysis and no substantial change of the HR point estimate after weight truncation. After truncating IP weights at the 95th percentile, estimates were similar across the methods.

Conclusions:

EHR data can be used to emulate target trials estimating the comparative effectiveness of dynamic strategies adjusting treatment to evolving patient characteristics. However, model checking, monitoring of large weights, and adaptation of model strategies to account for these is essential if an aspect of treatment is continuous.
The Joint Effect of Education and Alcohol Use on 100% Alcohol-attributable Hospitalization or Death in Canada
Authors: Smith Brendan T. , Warren Christine M. , Andreacchi Alessandra T. , Schwartz Naomi , Hobin Erin
Published: September 2023

Background:

Individuals with low socioeconomic position (SEP) experience disproportionately greater alcohol-attributable harm than individuals with high SEP despite similar or less alcohol use (i.e., the alcohol harm paradox). We examined the sex/gender- specific independent and joint effects of education and heavy drinking or volume of alcohol use on 100% alcohol-attributable hospitalization or death.

Methods:

We conducted a cohort study among 199,125 current and former alcohol users aged 15–64 years from population-representative Canadian Community Health Surveys (2000–2008) linked to hospitalization and mortality records through 2017. We estimated the sex/gender-specific associations between education and heavy drinking or volume of alcohol use and incident 100% alcohol-attributable hospitalization or death using multivariable Fine and Gray subdistribution hazard models with competing risk (non-100% alcohol-attributable deaths), assessing additive interactions using the Synergy Index (S).

Results:

Overall, heavy drinking prevalence and volume of alcohol use were similar or lower in individuals with lower education compared with higher education. Lower education levels compared with a bachelor’s degree or above were associated with increased 100% alcohol-attributable hospitalization or death [e.g., less than high school, men: hazard ratio (HR) = 2.78; 95% CI = 2.17, 3.56; women: HR = 2.98; 95% CI = 2.00, 4.44]. We found superadditive joint effects between low education and heavy drinking (men: S = 1.22; 95% CI = 1.14, 1.30; women: S = 1.34; 95% CI = 0.88, 2.04) and low education and higher volume of alcohol use (e.g., excess volume, men: S = 1.30; 95% CI = 1.05, 1.62; women: S = 1.41; 95% CI = 0.77, 2.58), with larger inequities in women than men with similar alcohol use.

Conclusions:

Our study is consistent with the hypothesis that increased vulnerability to alcohol use among individuals with lower education partially explains the alcohol harm paradox in Canada.
Regional changes in intestinal permeability in cirrhosis are associated with mucosal bacteria
Authors: Bloom Patricia P. , Rao Krishna , Bassis Christine , Nojkov Borko , Young Vincent B. , Lok Anna SF
Published: September 2023

Background:

Several complications of cirrhosis are theorized to result from the translocation of bacteria or their products across the intestinal epithelium. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with cirrhosis.

Approach and Results:

We collected 247 duodenum, ileum, and colon biopsies from 58 consecutive patients with cirrhosis and 33 controls during clinically indicated endoscopies. Patients with cirrhosis were similarly aged to controls (60 vs. 58 y) and had a median Model for End-stage Liver Disease of 8 (interquartile range 7, 10). Biopsies underwent 16S rRNA-encoding gene amplicon sequencing to determine mucosal bacteria composition and transepithelial electrical resistance (TEER) to determine epithelial permeability. In the entire cohort, there were regional differences in TEER with the lowest TEER (ie, more permeable) in the ileum; duodenum TEER was 43% higher and colon TEER 20% higher than ileum TEER (ANOVA p = 0.0004). When comparing patients with cirrhosis and controls, both TEER (26% lower in cirrhosis, p = 0.006) and alpha diversity differed in the duodenum (27% lower in cirrhosis, p = 0.01) but not ileum or colon. A beta-binomial model found that 26 bacteria were significantly associated with TEER. Bifidobacteriaceae Bifidobacterium in duodenal mucosa was protective of epithelial permeability and future hospitalization for hepatic decompensation.

Conclusions:

Duodenal epithelial permeability was higher, and mucosal bacteria alpha diversity was lower in cirrhosis compared to controls, while no such differences were seen in the ileum or colon. Specific bacteria were associated with epithelial permeability and future hepatic decompensation.
Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model
Authors: Tsutsui Yuriko , Mori Taizo , Yoshio Sachiyo , Sato Miku , Sakata Toshihiro , Yoshida Yuichi , Kawai Hironari , Yoshikawa Shiori , Yamazoe Taiji , Matsuda Michitaka , Kakazu Eiji , Osawa Yosuke , Oyama Chinatsu , Tamura-Nakano Miwa , Kawaguchi Takumi , Yoshizumi Tomoharu , Kanto Tatsuya
Published: September 2023

Background:

NASH is an increasingly common cause of chronic liver disease and can progress to cirrhosis and HCC. Although exercise suppresses inflammation during acute hepatitis, its impact on the progression of chronic liver disease remains unclear. Here, we investigated the effects of exercise on disease progression and intrahepatic immune cell composition in a mouse model of NASH.

Method:

Mice were assigned to 4 groups: 2 control groups (normal diet) and 2 NASH groups (western diet and low-dose carbon tetrachloride injection). One of each group remained sedentary and one was exercised on a treadmill for 12 weeks (60 min/d, 5 times/wk). All mice were then analyzed for liver histomorphology, steatosis, inflammation, and fibrosis; liver, adipose tissue, and skeletal muscle expression of genes related to metabolism and inflammation; and intrahepatic immune cell composition.

Result:

Compared with the normal diet mice, NASH mice exhibited enhanced liver steatosis, inflammation, and fibrosis; upregulated expression of liver lipogenesis-related and inflammation-related genes; and increased frequencies of intrahepatic F4/80int CD11bhi bone marrow-derived macrophages and programmed death receptor-1 (PD-1)+ CD8+ T cells. Expression of inflammatory cytokines and the frequencies of bone marrow-derived macrophages and PD-1+ CD8+ T cells correlated positively with liver steatosis, inflammation, and fibrosis. Exercise was shown to reduce NASH-induced hepatic steatosis, liver inflammation, and fibrosis; induce alterations in metabolism-related genes and inflammatory cytokines in the liver; and suppress accumulation of liver bone marrow-derived macrophages and PD-1+ CD8+ T cells. In addition, we showed that exercise induced increased expression of IL-15 in muscle and its deficiency exacerbated the pathology of NASH.

Conclusions:

Exercise alters the intrahepatic immune cell profile and protects against disease progression in a mouse model of NASH.
Serum levels of fibrogenesis biomarkers reveal distinct endotypes predictive of response to weight loss in advanced nonalcoholic fatty liver disease
Authors: Karsdal Morten A. , Hallsworth Kate , Scragg Jadine , Leeming Diana J. , Villesen Ida F. , Avery Leah , Haigh Laura , Govaere Olivier , Wichmann Sarah , Taylor Guy , Cassidy Sophie , McPherson Stuart , Anstee Quentin M.
Published: September 2023

Background:

NAFLD is associated with activation of fibroblasts and hepatic fibrosis. Substantial patient heterogeneity exists, so it remains challenging to risk-stratify patients. We hypothesized that the amount of fibroblast activity, as assessed by circulating biomarkers of collagen formation, can define a “high-risk, high-fibrogenesis” patient endotype that exhibits greater fibroblast activity and potentially more progressive disease, and this endotype may be more amendable to dietary intervention.

Methods:

Patients with clinically confirmed advanced NAFLD were prescribed a very low-calorie diet (VLCD) intervention (∼800 kcal/d) to induce weight loss, achieved using total diet replacement. Serum markers of type III (PRO-C3) and IV collagen (PRO-C4) fibrogenesis were assessed at baseline every second week until the end of the VLCD, and 4 weeks post-VLCD and at 9 months follow-up.

Results:

Twenty-six subjects had a mean weight loss of 9.7% with VLCD. This was associated with significant improvements in liver biochemistry. When stratified by baseline PRO-C3 and PRO-C4 into distinct fibrosis endotypes, these predicted substantial differences in collagen fibrogenesis marker dynamics in response to VLCD. Patients in the high activity group (PRO-C3 >11.4 ng/mL and/or PRO-C4 >236.5 ng/mL) exhibited a marked reduction of collagen fibrogenesis, ranging from a 40%–55% decrease in PRO-C3 and PRO-C4, while fibrogenesis remained unchanged in the low activity group. The biochemical response to weight loss was substantially greater in patients a priori exhibiting a high fibroblast activity endotype in contrast to patients with low activity.

Conclusions:

Thus, the likelihood of treatment response may be predicted at baseline by quantification of fibrogenesis biomarkers.