bluuebunny/crossref_metadata_2025 huggingface dataset:
Cause analysis of expressway traffic accidents based on accident statistics of Hunan provincial expressway in 2012–2018
Authors: Liu Xinyu , Huang Shengjun , Chen Qun
Published: February 2023

Based on the 2012–2018 accident statistics on the Hunan Provincial Expressway in China, this paper analyses the proportion to which various factors contribute to accidents, as well as the trends over time. From 2012 to 2018, the total number of general procedure handling accidents (i.e. major accidents) increased first and then decreased, while the number of accidents and deaths per 1000 kilometres decreased year by year. The total number of simple procedure handling accidents (i.e. minor accidents) increased year by year, but the number of accidents per 1000 kilometres remained relatively stable. Speeding, fatigued driving, improper driving operation, failure to maintain a safe distance from the preceding vehicle and pedestrians entering the expressway are the main causes of general procedure handling accidents. Failure to maintain a safe distance from the preceding vehicle as required and improper driving operation accounted for approximately 2/3 of the simple procedure handling accidents. In view of the accidents caused by these factors, how to use law enforcement, education, science and technology and facilities construction to further reduce the occurrence of expressway traffic accidents is discussed.
Phylogeographic and Phylogenomic Structure of the Quarantine Plant Pathogen Colletotrichum liriopes, Including New Reports in the United States
Authors: Chaverri Priscila , Romberg Megan K. , Montero-Vargas Maripaz , McKemy John M. , Rane Karen K. , Balbalian Clarissa J. , Castlebury Lisa A.
Published: February 2023

Global agricultural trade has accelerated the emergence and re-emergence of new plant pathogens. In the United States, the fungal pathogen Colletotrichum liriopes is still considered a foreign quarantine pathogen that affects ornamental plants (i.e., Liriope spp.). Even though this species has been reported in East Asia on various asparagaceous hosts, its first and only report in the United States was in 2018. However, that study used only ITS nrDNA for identification, and no available culture or voucher specimen was maintained. The main objective of the present study was to determine the geographic and host distribution of specimens identified as C. liriopes. To accomplish this, new and existing isolates, sequences, and genomes obtained from various hosts and geographic locations (i.e., China, Colombia, Mexico, and the United States) were compared with the ex-type of C. liriopes. Multilocus phylogenetic (ITS, Tub2, GAPDH, CHS-1, and HIS3), phylogenomic, and splits tree analyses revealed that all the studied isolates/sequences form a well-supported clade with little intraspecific variation. Morphological characterizations support these findings. The minimum spanning network, low nucleotide diversity, and negative Tajima’s D from both multilocus and genomic data suggest that there was a recent movement/invasion of a few East Asian genotypes to other countries where the ornamental plants are produced (e.g., South America) and subsequently to the importing countries, such as the United States. The study reveals that the geographic and host distribution of C. liriopes sensu stricto is expanded to the United States (i.e., at least Maryland, Mississippi, and Tennessee) and on various hosts in addition to Asparagaceae and Orchidaceae. The present study produces fundamental knowledge that can be used in efforts to reduce costs or losses from agricultural trade and to expand our understanding of pathogen movement.
Assessment of Fungicide Resistance via Molecular Assay in Populations of Podosphaera leucotricha, Causal Agent of Apple Powdery Mildew, in New York
Authors: Strickland David A. , Spychalla Jamie P. , van Zoeren Janet E. , Basedow Michael R. , Donahue Daniel J. , Cox Kerik D.
Published: February 2023

Podosphaera leucotricha, causal agent of apple powdery mildew, is a pathogen endemic worldwide where apples are produced. In the absence of durable host resistance, the disease is most effectively managed in conventional orchards with single-site fungicides. In New York State, increasingly erratic precipitation patterns and warmer temperatures due to climate change may create a regional environment more conducive to apple powdery mildew development and spread. In this scenario, outbreaks of apple powdery mildew may supplant the apple diseases of current management concern: apple scab and fire blight. Presently, there have been no reports from producers of fungicide control failures for apple powdery mildew, though increased disease incidence has been reported to and observed by the authors. As such, action was needed to assess the fungicide resistance status of populations of P. leucotricha to ensure key classes of single-site fungicides (FRAC 3, demethylation inhibitors, DMI; FRAC 11, quinone outside inhibitors, QoI; and FRAC 7, succinate dehydrogenase inhibitors, SDHI) remain effective. In a 2-year survey (2021 to 2022), we collected 160 samples of P. leucotricha from 43 orchards, representing conventional, organic, low-input, and unmanaged orchards from New York’s primary production regions. Samples were screened for mutations in the target genes (CYP51, cytb, and sdhB) historically known to confer fungicide resistance in other fungal pathogens to the DMI, QoI, and SDHI fungicide classes, respectively. Across all samples, no nucleotide sequence mutations that translated into problematic amino acid substitutions were found in the target genes, suggesting that New York populations of P. leucotricha remain sensitive to the DMI, QoI, and SDHI fungicide classes, provided no other fungicide resistance mechanism is at play in the population.
Postoperative Dural Sac Cross-Sectional Area as an Association for Outcome After Surgery for Lumbar Spinal Stenosis
Authors: Hermansen Erland , Myklebust Tor Å. , Weber Clemens , Brisby Helena , Austevoll Ivar M. , Hellum Christian , Storheim Kjersti , Aaen Jørn , Banitalebi Hasan , Brox Jens I. , Grundnes Oliver , Rekeland Frode , Solberg Tore , Franssen Eric , Indrekvam Kari
Published: February 2023

Study Design.

Prospective cohort study.

Objective.

The aim was to investigate the association between postoperative dural sac cross-sectional area (DSCA) after decompressive surgery for lumbar spinal stenosis and clinical outcome. Furthermore, to investigate if there is a minimum threshold for how extensive a posterior decompression needs to be to achieve a satisfactory clinical result.

Summary of Background Data.

There is limited scientific evidence for how extensive lumbar decompression needs to be to obtain a good clinical outcome in patients with symptomatic lumbar spinal stenosis.

Materials and Methods.

All patients were included in the Spinal Stenosis Trial of the NORwegian Degenerative spondylolisthesis and spinal STENosis (NORDSTEN)-study. The patients underwent decompression according to three different methods. DSCA measured on lumbar magnetic resonance imaging at baseline and at three months follow-up, and patient-reported outcome at baseline and at two-year follow-up were registered in a total of 393 patients. Mean age was 68 (SD: 8.3), proportion of males were 204/393 (52%), proportion of smokers were 80/393 (20%), and mean body mass index was 27.8 (SD: 4.2).

The cohort was divided into quintiles based on the achieved DSCA postoperatively, the numeric, and relative increase of DSCA, and the association between the increase in DSCA and clinical outcome were evaluated.

Results.

At baseline, the mean DSCA in the whole cohort was 51.1 mm2 (SD: 21.1). Postoperatively the area increased to a mean area of 120.6 mm2 (SD: 46.9). The change in Oswestry disability index in the quintile with the largest DSCA was −22.0 (95% CI: −25.6 to −18), and in the quintile with the lowest DSCA the Oswestry disability index change was −18.9 (95% CI: −22.4 to −15.3). There were only minor differences in clinical improvement for patients in the different DSCA quintiles.

Conclusion.

Less aggressive decompression performed similarly to wider decompression across multiple different patient-reported outcome measures at two years following surgery.
Hypoalbuminemia as a Predictor of Mortality, Disability, and Readmission in Patients Undergoing Spine Surgery
Authors: Randell Zane , Martin Brook , Hendrickson Nathan , Brodke Darrel , Spiker Ryan , Lawrence Brandon , Spina Nicholas
Published: February 2023

Study Design.

Retrospective Cohort Study

Objective.

To clarify the association between preoperative albumin status and mortality and morbidity in lumbar spine surgery.

Summary of Background Data.

Hypoalbuminemia is a known marker of inflammation and is associated with frailty. Hypoalbuminemia is an identified risk factor for mortality following spine surgery for metastases, yet has not been well studied among spine surgical cohorts outside of metastatic cancer.

Methods.

We identified patients with preoperative serum albumin lab values who underwent lumbar spine surgery at a US public university health system between 2014 and 2021. Demographic, comorbidity, and mortality data were collected along with pre- and postoperative Oswestry Disability Index (ODI) scores. Any cause readmission within one year of surgery was recorded. Hypoalbuminemia was defined as <3.5 g/dL in serum. We examined Kaplan-Meier survival plots based on serum albumin. Multivariable regression models were used to identify the association between preoperative hypoalbuminemia with mortality, readmission and ODI, while controlling for age, sex, race, ethnicity, procedure and Charlson Comorbidity Index.

Results.

Of 2,573 patients, 79 were identified as hypoalbuminemic. Hypoalbuminemic patients had significantly greater adjusted risk of mortality through 1 year (OR 10.2; 95% CI 3.1 - 33.5; P<0.001), and 7 years (HR 4.18; 95% CI 2.29 – 7.65; P<0.001). Hypoalbuminemic patients had ODI scores 13.5 points higher (95%CI 5.7 – 21.4; P<0.001) at baseline. Adjusted readmission rates were not different between groups through 1 year (OR 1.15; 0.5 – 2.62; P=0.75) or through full surveillance (HR 0.82; 95%CI 0.44 – 1.54; P=0.54).

Conclusion.

Preoperative hypoalbuminemia was strongly associated with postoperative mortality. Hypoalbuminemic patients did not have demonstrably worse outcomes in their functional disability beyond 6 months. Within the first 6 months following surgery, the hypoalbuminemic group improved at a similar rate to the normoalbuminemic group despite having greater preoperative disability. However, causal inference is limited in this retrospective study.
Generating universal chimeric antigen receptor expressing cell products from induced pluripotent stem cells: beyond the autologous CAR-T cells
Authors: Deng Xinyue , Zhou Jianfeng , Cao Yang
Published: February 2023

Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achieved in intractable lymphoma treatments. Currently, well-explored approaches focus on autologous cells due to their low immunogenicity, but they are highly restricted by the high costs, time consumption of processing, and the insufficiency of primary cells in some patients. Induced pluripotent stem cells (iPSCs) are cell sources that can theoretically produce indefinite well-differentiated immune cells. Based on the above facts, it may be reasonable to combine the iPSC technology and the CAR design to produce a series of highly controllable and economical “live” drugs. Manufacturing hypoimmunogenic iPSCs by inactivation or over-expression at the genetic level and then arming the derived cells with CAR have emerged as a form of “off-the-shelf” strategy to eliminate tumor cells efficiently and safely in a broader range of patients. This review describes the reasonability, feasibility, superiority, and drawbacks of such approaches, summarizes the current practices and relevant research progress, and provides insights into the possible new paths for personalized cell-based therapies.
Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca2+-dependent gap junction intercellular communication
Authors: Li Xiaoping , Xiao Yunshuo , Wang Xiaoqi , Huang Ruihao , Wang Rui , Deng Yi , Rao Jun , Gao Qiangguo , Yang Shijie , Zhang Xi
Published: February 2023

Background:

Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown.

Methods:

Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca2+-related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance.

Results:

Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca2+ is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments.

Conclusions:

Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.
Screening costs associated with donor selection for fecal microbiota transplantation for treatment of PD-1 refractory melanoma patients
Authors: Fortman Dylan , Avellan Maria G. Pazan , Hurd Drew , Schwartz Marc , Dubner Howard , Hewitt Corey , Berton Samantha , Ernst Scarlett , Rose Amy , Zarour Hong Wangd, Hassane , Davar Diwakar
Published: February 2023

The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness.
Neuropathy, Ataxia, and Retinitis Pigmentosa Syndrome
Authors: Finsterer Josef
Published: February 2023

Objectives:

To provide an overview about the phenotype, genotype, treatment, and outcome of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.

Methods:

Systematic review by application of appropriate search terms.

Results:

NARP syndrome is a syndromic mitochondrial disorder due to pathogenic variants inMT-ATP6. The canonical phenotypic features of NARP syndrome include proximal muscle weakness, axonal neuropathy, cerebellar ataxia, and retinitis pigmentosa. Noncanonical phenotypic features in NARP include epilepsy, cerebral or cerebellar atrophy, optic atrophy, cognitive impairment, dementia, sleep apnea syndrome, hearing impairment, renal insufficiency, and diabetes. So far, 10 pathogenic variants inMT-ATP6have been associated with NARP, NARP-like syndrome, or NARP/maternally inherited Leigh overlap syndrome. Most pathogenicMT-ATP6variants are missense, but a few truncating pathogenic variants have been reported. The most common variant responsible for NARP is the transversion m.8993T>G. Only symptomatic treatment for NARP syndrome is available. In most of the cases, patients die prematurely. Patients with late-onset NARP survive longer.

Conclusions:

NARP is a rare, syndromic, monogenic mitochondrial disorder due to pathogenic variants inMT-ATP6.The nervous system and the eyes are most commonly affected. Although only symptomatic treatment is available, the outcome is usually fair.
What Is in the Myopathy Literature?
Authors: Lacomis David
Published: February 2023

This update begins with the results of a positive trial of intravenous immunoglobulin in dermatomyositis and a study of molecular and morphologic patterns in inclusion body myositis that may explain treatment refractoriness. Single center reports of muscular sarcoidosis and immune-mediated necrotizing myopathy follow. There is also a report of caveolae-associated protein 4 antibodies as a potential biomarker and cause of immune rippling muscle disease. The remainder covers updates on muscular dystrophies as well as congenital and inherited metabolic myopathies with an emphasis on genetic testing. Rare dystrophies, including one involving ANXA11 mutations and a series on oculopharyngodistal myopathy, are discussed.
Earlobe Rejuvenation: A Review of Current Treatment Modalities
Authors: Azzawi Soraya , Aigen Alyx Rosen
Published: February 2023

BACKGROUND

As one of the defining features of the face, the ear influences perceptions of beauty. Despite its significance, comparatively little is known about rejuvenation options for the ear.

OBJECTIVE

To provide a comprehensive review of minimally invasive options for earlobe rejuvenation.

METHODS

& Materials: Cochrane, Embase, and PubMed were used to identify articles exploring minimally invasive treatments for ear rejuvenation.

RESULTS

Topical medications, peels, fillers, lasers, photodynamic therapy, and dermabrasion are safe and efficacious for managing a variety of concerns related to earlobe aesthetics.

CONCLUSION

Numerous minimally invasive treatment modalities are available for earlobe rejuvenation; further investigation is needed to design a grading system and treatment algorithm.
Variable ventilation versus stepwise lung recruitment manoeuvres for lung recruitment
Authors: Vivona Luigi , Huhle Robert , Braune Anja , Scharffenberg Martin , Wittenstein Jakob , Kiss Thomas , Kircher Michael , Herzog Paul , Herzog Moritz , Millone Marco , Gama de Abreu Marcelo , Bluth Thomas
Published: February 2023

BACKGROUND

Variable ventilation recruits alveoli in atelectatic lungs, but it is unknown how it compares with conventional recruitment manoeuvres.

OBJECTIVES

To test whether mechanical ventilation with variable tidal volumes and conventional recruitment manoeuvres have comparable effects on lung function.

DESIGN

Randomised crossover study.

SETTING

University hospital research facility.

ANIMALS

Eleven juvenile mechanically ventilated pigs with atelectasis created by saline lung lavage.

INTERVENTIONS

Lung recruitment was performed using two strategies, both with an individualised optimal positive-end expiratory pressure (PEEP) associated with the best respiratory system elastance during a decremental PEEP trial: conventional recruitment manoeuvres (stepwise increase of PEEP) in pressure-controlled mode) followed by 50 min of volume-controlled ventilation (VCV) with constant tidal volume, and variable ventilation, consisting of 50 min of VCV with random variation in tidal volume.

MAIN OUTCOME MEASURES

Before and 50 min after each recruitment manoeuvre strategy, lung aeration was assessed by computed tomography, and relative lung perfusion and ventilation (0% = dorsal, 100% = ventral) were determined by electrical impedance tomography.

RESULTS

After 50 min, variable ventilation and stepwise recruitment manoeuvres decreased the relative mass of poorly and nonaerated lung tissue (percent lung mass: 35.3 ± 6.2 versus 34.2 ± 6.6, P = 0.303); reduced poorly aerated lung mass compared with baseline (−3.5 ± 4.0%, P = 0.016, and −5.2 ± 2.8%, P < 0.001, respectively), and reduced nonaerated lung mass compared with baseline (−7.2 ± 2.5%, P < 0.001; and −4.7 ± 2.8%, P < 0.001 respectively), while the distribution of relative perfusion was barely affected (variable ventilation: −0.8 ± 1.1%, P = 0.044; stepwise recruitment manoeuvres: −0.4 ± 0.9%, P = 0.167). Compared with baseline, variable ventilation and stepwise recruitment manoeuvres increased P
aO2 (172 ± 85mmHg, P = 0.001; and 213 ± 73 mmHg, P < 0.001, respectively), reduced P
aCO2 (−9.6 ± 8.1 mmHg, P = 0.003; and −6.7 ± 4.6 mmHg, P < 0.001, respectively), and decreased elastance (−11.4 ± 6.3 cmH2O, P < 0.001; and −14.1 ± 3.3 cmH2O, P < 0.001, respectively). Mean arterial pressure decreased during stepwise recruitment manoeuvres (−24 ± 8 mmHg, P = 0.006), but not variable ventilation.

CONCLUSION

In this model of lung atelectasis, variable ventilation and stepwise recruitment manoeuvres effectively recruited lungs, but only variable ventilation did not adversely affect haemodynamics.

TRIAL REGISTRATION

This study was registered and approved by Landesdirektion Dresden, Germany (DD24-5131/354/64).
Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium
Authors: Pydyn Natalia , Kadluczka Justyna , Major Piotr , Hutsch Tomasz , Belamri Kinga , Malczak Piotr , Radkowiak Dorota , Budzynski Andrzej , Miekus Katarzyna , Jura Jolanta , Kotlinowski Jerzy
Published: February 2023

Background and Aims:

NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity.

Methods:

In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients’ PBMCs there were no differences in the expression of genes regulating β-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG).

Conclusion:

We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.
Rates of employment after liver transplant: A nationwide cohort study
Authors: Henson Jacqueline B. , Cabezas Melanie , McElroy Lisa M. , Muir Andrew J.
Published: February 2023

Background:

Employment outcomes after liver transplant (LT) over the past decade have not been described.

Methods:

LT recipients ages 18–65 from 2010-2018 were identified in Organ Procurement and Transplantation Network data. Employment within two years post-transplant was assessed.

Results:

Of 35,340 LT recipients, 34.2% were employed post-LT, including 70.4% who were working pre-transplant, compared to only 18.2% not working preLT. Younger age, male sex, educational attainment, and functional status were associated with returning to employment.

Conclusion:

Returning to employment is an important goal for many LT candidates and recipients, and these findings can be used to guide their expectations.
Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease
Authors: Yu Lei , Yousuf Sarim , Yousuf Shahrukh , Yeh Jeffrey , Biggins Scott W. , Morishima Chihiro , Shyu Irene , O’Shea-Stone Galen , Eilers Brian , Waldum Annie , Copié Valérie , Burkhead Jason
Published: February 2023

Background and Aim:

Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways.

Methods:

We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men.

Results:

The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%, p=0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18–9.82, p=0.023).

Conclusions:

In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.
Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-β/SMAD signaling
Authors: Song Yu , Wei Jiayi , Li Rong , Fu Ruifeng , Han Pei , Wang Heming , Zhang Guangcong , Li Shuyu , Chen Sinuo , Liu Zhiyong , Zhao Yicheng , Zhu Changfeng , Zhu Jimin , Zhang Shuncai , Pei Hao , Cheng Jiefei , Wu Jian , Dong Ling , Song Guangqi , Shen Xizhong , Yao Qunyan
Published: February 2023

Background and Aims:

Liver fibrosis is a leading indicator for increased mortality and long-term comorbidity in NASH. Activation of HSCs and excessive extracellular matrix production are the hallmarks of liver fibrogenesis. Tyrosine kinase receptor (TrkB) is a multifunctional receptor that participates in neurodegenerative disorders. However, paucity of literature is available about TrkB function in liver fibrosis. Herein, the regulatory network and therapeutic potential of TrkB were explored in the progression of hepatic fibrosis.

Methods and Results:

The protein level of TrkB was decreased in mouse models of CDAHFD feeding or carbon tetrachloride-induced hepatic fibrosis. TrkB suppressed TGF-β-stimulated proliferation and activation of HSCs in 3-dimensional liver spheroids and significantly repressed TGF-β/SMAD signaling pathway either in HSCs or in hepatocytes. The cytokine, TGF-β, boosted Nedd4 family interacting protein-1 (Ndfip1) expression, promoting the ubiquitination and degradation of TrkB through E3 ligase Nedd4-2. Moreover, carbon tetrachloride intoxication-induced hepatic fibrosis in mouse models was reduced by adeno-associated virus vector serotype 6 (AAV6)–mediated TrkB overexpression in HSCs. In addition, in murine models of CDAHFD feeding and Gubra-Amylin NASH (GAN), fibrogenesis was reduced by adeno-associated virus vector serotype 8 (AAV8)–mediated TrkB overexpression in hepatocytes.

Conclusion:

TGF-β stimulated TrkB degradation through E3 ligase Nedd4-2 in HSCs. TrkB overexpression inhibited the activation of TGF-β/SMAD signaling and alleviated the hepatic fibrosis both in vitro and in vivo. These findings demonstrate that TrkB could be a significant suppressor of hepatic fibrosis and confer a potential therapeutic target in hepatic fibrosis.
Unmet Clinical Needs and Management Recommendations for Blastic Plasmacytoid Dendritic Cell Neoplasm: A Consensus-based Position Paper From an Ad Hoc International Expert Panel
Authors: Pagano Livio , Zinzani Pier Luigi , Pileri Stefano , Quaglino Pietro , Cuglievan Branko , Berti Emilio , Pemmaraju Naveen , Onida Francesco , Willemze Rein , Orfao Alberto , Barosi Giovanni
Published: February 2023

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with overall survival. The rarity of the disease results in a few large-scale studies, a lack of controlled clinical trials for its management, and a lack of evidence-based guidelines. Here, we present a review of unmet clinical needs on the management of BPDCN by a panel of eleven experts involved in the research and clinical practice of BPDCN. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. The panel analyzed the critical issues of diagnostic pathway, prognostic stratification, therapy for young and fit patients and elderly and unfit patients, indication for allotransplant and for autotransplant, indication for central nervous system prophylaxis, and management of pediatric BPDCN patients. For each of these issues, consensus opinions were provided and, when appropriate, proposals for advancement in clinical practice were addressed. The hope is that this comprehensive overview will serve to improve the practice of BPDCN and inform the design and implementation of new studies in the field.
Operational nuclear research reactors in the Asia-Pacific with potential for medical radionuclide production
Authors: Tan Hun Yee , Wong Yin How , Kasbollah Azahari , Md Shah Mohammad Nazri , Perkins Alan Christopher , Yeong Chai Hong
Published: February 2023

Personalised cancer treatment is of growing importance and can be achieved via targeted radionuclide therapy. Radionuclides with theranostic properties are proving to be clinically effective and are widely used because diagnostic imaging and therapy can be accomplished using a single formulation that avoids additional procedures and unnecessary radiation burden to the patient. For diagnostic imaging, single photon emission computed tomography (SPECT) or positron emission tomography (PET) is used to obtain functional information noninvasively by detecting the gamma (γ) rays emitted from the radionuclide. For therapeutics, high linear energy transfer (LET) radiations such as alpha (α), beta (β-) or Auger electrons are used to kill cancerous cells in close proximity, whereas sparing the normal tissues surrounding the malignant tumour cells.

One of the most important factors that lead to the sustainable development of nuclear medicine is the availability of functional radiopharmaceuticals. Nuclear research reactors play a vital role in the production of medical radionuclides for incorporation into clinical radiopharmaceuticals. The disruption of medical radionuclide supplies in recent years has highlighted the importance of ongoing research reactor operation. This article reviews the current status of operational nuclear research reactors in the Asia-Pacific region that have the potential for medical radionuclide production. It also discusses the different types of nuclear research reactors, their operating power, and the effects of thermal neutron flux in producing desirable radionuclides with high specific activity for clinical applications.
Wnt/β-catenin modulating drugs regulate somatostatin receptor expression and internalization of radiolabelled octreotide in neuroendocrine tumor cells
Authors: Weich Alexander , Rogoll Dorothea , Peschka Melissa , Weich Wolfgang , Pongracz Judit , Brand Markus , Fröhlich Matthias , Serfling Sebastian E. , Rowe Steven P. , Kosmala Aleksander , Reiter Florian P. , Meining Alexander , Werner Rudolf A. , Scheurlen Michael
Published: February 2023

Background

Differentiated neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs), targets for therapy with either unlabeled or radioactively labeled somatostatin analogs (SSA). Associated with worse prognosis, dedifferentiated NET loose SSTR expression, which may be linked to deregulation of Wnt/β-catenin signaling on an intracellular level. The aim of the present study was to investigate the effect of Wnt/β-catenin signaling pathway alterations on SSTR expression and its function in NET.

Methods

The NET cell lines BON-1 and QGP-1 were incubated with the Wnt-inhibitors 5-aza-2′-deoxycytidine (5-aza-CdR), Quercetin, or Niclosamide, or the Wnt activator lithium chloride (LiCl). Expression of SSTR1, SSTR2, and SSTR5 was determined by quantitative RT-PCR (qRT-PCR), immunocytomicroscopy and western blot. Changes in the Wnt pathway were analyzed by qRT-PCR of selected target genes and the TaqMan Array Human WNT Pathway. Receptor-associated function was determined by measuring the cellular uptake of [125I-Tyr3] octreotide.

Results

The mRNAs of SSTRs 1–5 were expressed in both cell lines. Wnt inhibitors caused downregulation of Wnt target genes, while 5-aza-CdR had the highest inhibitory effect. LiCl lead to an upregulation of Wnt genes, which was more marked in QGP-1 cells. SSTR expression increased in both cell lines upon Wnt inhibition. All three Wnt inhibitors lead to a marked increase in the specific uptake of [125I-Tyr3]octreotide, with 5-aza-CdR showing the greatest effect (increase by more than 50% in BON-1 cells), while a decreased uptake of [125I-Tyr3]octreotide was seen upon activation of Wnt signaling by LiCl.

Conclusions

We demonstrate here that Wnt signaling orchestrates SSTR expression and function in a preclinical NET model. Wnt inhibition increases [125I-Tyr3]octreotide uptake offering an opportunity to enhance the efficacy of SSTR-targeted theranostic approaches.
DECREASE IN THE PLATELET-TO-LYMPHOCYTE RATIO IN DAYS AFTER ADMISSION FOR SEPSIS CORRELATES WITH IN-HOSPITAL MORTALITY
Authors: Zheng Rui , Shi Yi-Yi , Pan Jing-Ye , Qian Song-Zan
Published: February 2023

Background: A previous study has linked an increase in platelet-to-lymphocyte ratio (PLR) to a poor prognosis; however, the relationship between early change in PLR and outcomes in sepsis patients is unclear. Methods: The Medical Information Mart for Intensive Care IV database was for this retrospective cohort analysis on patients meeting the Sepsis-3 criteria. All the patients meet the Sepsis-3 criteria. The platelet-to-lymphocyte ratio (PLR) was calculated by dividing the platelet count by the lymphocyte count. We collected all PLR measurements that were available within 3 days of admission for analysis of longitudinal changes over time. Multivariable logistic regression analysis was used to determine the relationship between the baseline PLR and in-hospital mortality. After correcting for possible confounders, the generalized additive mixed model was used to examine the trends in PLR over time among survivors and nonsurvivors. Results: Finally, 3,303 patients were enrolled, and both low and high PLR levels were significantly associated with higher in-hospital mortality in the multiple logistic regression analysis (tertile 1: odds ratio, 1.240; 95% confidence interval, 0.981–1.568 and tertile 3: odds ratio, 1.410; 95% confidence interval, 1.120–1.776, respectively). The generalized additive mixed model results revealed that the PLR of the nonsurvival group declined faster than that of the survival group within 3 days after intensive care unit admission. After controlling for confounders, the difference between the two groups steadily decreased and increased by an average of 37.38 daily. Conclusions: There was a U-shaped relationship between the baseline PLR and in-hospital mortality of sepsis patients, and there was a significant difference between the nonsurvival and survival groups in the change in PLR over time. The early decrease in PLR was related to an increase in in-hospital mortality.
EARLY INITIATION OF RENAL REPLACEMENT THERAPY IN INTENSIVE CARE UNIT PATIENTS WITH BOTH ACUTE RESPIRATORY DISTRESS SYNDROME AND SEPSIS WITH OR WITHOUT RENAL FAILURE: A RETROSPECTIVE COHORT STUDY BASED ON PROPENSITY SCORE MATCHING
Authors: Li Ziping , Zhang Haoyue , Xie Keliang , Zhang Ying , Zhang Zhen , Zheng Weiqiang , Yang Tianqi , Zhang Linlin , Yu Yonghao
Published: February 2023

Background: It is unknown whether early renal replacement therapy (RRT) initiation strategy in intensive care unit (ICU) patients with both acute respiratory distress syndrome (ARDS) and sepsis with or without renal failure is clinically beneficial. Patients and methods: A total of 818 patients with both ARDS and sepsis admitted to the ICU of Tianjin Medical University General Hospital were included in the analysis. Early RRT was defined as initiating the RRT strategy within 24 h of admission. The relationship between early RRT and clinical outcomes, including primary (30-day mortality) and secondary (90-day mortality, serum creatinine, Pao
2/Fio
2, duration of invasive mechanical ventilation, cumulative fluid output, and cumulative fluid balance) outcomes, was compared using propensity score matching (PSM). Results: A total of 277 patients (33.9% of the total population) underwent an early RRT initiation strategy before PSM. After PSM, a cohort of 147 patients with early RRT and 147 patients without early RRT with matched baseline characteristics (including serum creatinine at admission) were constructed. Early RRT was not significantly associated with 30- (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.85-1.85; P = 0.258) or 90-day mortality (HR, 1.30; 95% CI, 0.91–1.87, P = 0.150). At each time point within 72 h after admission, there was no significant difference in serum creatinine, Pao
2/Fio
2 and duration of mechanical ventilation between the early and the no early RRT groups. Early RRT significantly increased total output at all time points within 72 h of admission and reached a statistically significant negative fluid balance at 48 h. Conclusions: Early RRT initiation strategies had no statistically significant survival benefit in ICU patients with both ARDS and sepsis, with or without renal failure, nor did they significantly improve serum creatinine and oxygenation or shorten the duration of mechanical ventilation. The use and timing of RRT in such patients should be thoroughly investigated.
Bariatric Surgery and Suicide Risk in Patients With Obesity
Authors: Hung Anna , Maciejewski Matthew L. , Berkowitz Theodore S.Z. , Arterburn David E. , Mitchell James E. , Bradley Katharine A. , Kimbrel Nathan A. , Smith Valerie A.
Published: February 2023

Objective:

In a large multisite cohort of Veterans who underwent Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy, we compared the 5-year suicidal ideation and attempt rates with matched nonsurgical controls.

Background:

Bariatric surgery has significant health benefits but has also been associated with adverse mental health outcomes.

Methods:

Five-year rates of suicidal ideation and suicide attempts of Veterans who underwent Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy from the fiscal year 2000–2016 to matched nonsurgical controls using sequential stratification using cumulative incidence functions (ideation cohort: n=38,199; attempt cohort: n=38,661 after excluding patients with past-year outcome events). Adjusted differences in suicidal ideation and suicide attempts were estimated using a Cox regression with a robust sandwich variance estimator.

Results:

In the matched cohorts for suicidal ideation analyses, the mean age was 53.47 years and the majority were males (78.7%) and White (77.7%). Over 40% were treated for depression (41.8%), had a nonrecent depression diagnosis (40.9%), and 4.1% had past suicidal ideation or suicide attempts >1 year before index. Characteristics of the suicide attempt cohort were similar. Regression results found that risk of suicidal ideation was significantly higher for surgical patients (adjusted hazard ratio=1.21, 95% CI: 1.03–1.41), as was risk of suicide attempt (adjusted hazard ratio=1.62, 95% CI: 1.22–2.15).

Conclusions:

Bariatric surgery appears to be associated with a greater risk of suicidal ideation and attempts than nonsurgical treatment of patients with severe obesity, suggesting that patients need careful monitoring for suicidal ideation and additional psychological support after bariatric surgery.
Understanding Disparities in Receipt of Complex Gastrointestinal Cancer Surgery at a Small Geographic Scale
Authors: Dong Weichuan , Kucmanic Matthew , Winter Jordan , Pronovost Peter , Rose Johnie , Kim Uriel , Koroukian Siran M. , Hoehn Richard
Published: February 2023

Objective:

To define neighborhood-level disparities in the receipt of complex cancer surgery.

Background:

Little is known about the geographic variation of receipt of surgery among patients with complex gastrointestinal (GI) cancers, especially at a small geographic scale.

Methods:

This study included individuals diagnosed with 5 invasive, nonmetastatic, complex GI cancers (esophagus, stomach, pancreas, bile ducts, liver) from the Ohio Cancer Incidence Surveillance System during 2009 and 2018. To preserve patient privacy, we combined US census tracts into the smallest geographic areas that included a minimum number of surgery cases (n=11) using the Max-p-regions method and called these new areas “MaxTracts.” Age-adjusted surgery rates were calculated for MaxTracts, and the Hot Spot analysis identified clusters of high and low surgery rates. US Census and CDC PLACES were used to compare neighborhood characteristics between the high- and low-surgery clusters.

Results:

This study included 33,091 individuals with complex GI cancers located in 1006 MaxTracts throughout Ohio. The proportion in each MaxTract receiving surgery ranged from 20.7% to 92.3% with a median (interquartile range) of 48.9% (42.4–56.3). Low-surgery clusters were mostly in urban cores and the Appalachian region, whereas high-surgery clusters were mostly in suburbs. Low-surgery clusters differed from high-surgery clusters in several ways, including higher rates of poverty (23% vs. 12%), fewer married households (40% vs. 50%), and more tobacco use (25% vs. 19%; all P<0.01).

Conclusions:

This improved understanding of neighborhood-level variation in receipt of potentially curative surgery will guide future outreach and community-based interventions to reduce treatment disparities. Similar methods can be used to target other treatment phases and other cancers.
Modulation of cellular autophagy by genotype 1 hepatitis E virus ORF3 protein
Authors: Srivastava Manjita , Bhukya Prudhvi Lal , Barman Muneesh Kumar , Bhise Neha , Lole Kavita S.
Published: February 2023

Hepatitis E virus (HEV) egresses from infected hepatocytes as quasienveloped particles containing open reading frame 3 (ORF3) protein. HEV ORF3 (small phosphoprotein) interacts with host proteins to establish a favourable environment for virus replication. It is a functional viroporin that plays an important role during virus release. Our study provides evidence that pORF3 plays a pivotal role in inducing Beclin1-mediated autophagy that helps HEV-1 replication as well as its exit from cells. The ORF3 interacts with host proteins involved in regulation of transcriptional activity, immune response, cellular and molecular processes, and modulation of autophagy, by interacting with proteins, DAPK1, ATG2B, ATG16L2 and also several histone deacetylases (HDACs). For autophagy induction, the ORF3 utilizes non-canonical NF-κB2 pathway and sequesters p52NF-κB and HDAC2 to upregulate DAPK1 expression, leading to enhanced Beclin1 phosphorylation. By sequestering several HDACs, HEV may prevent histone deacetylation to maintain overall cellular transcription intact to promote cell survival. Our findings highlight a novel crosstalk between cell survival pathways participating in ORF3-mediated autophagy