bluuebunny/crossref_metadata_2025 huggingface dataset:
Cumulative methotrexate dose is not associated with liver fibrosis in patients with a history of moderate-to-severe psoriasis
Authors: Babakinejad Parastoo , Lapsley Rebecca , Forster Lara , McPherson Stuart , Pearce Mark S , Reynolds Nick J , Slack Emma , Weatherhead Sophie C , Hampton Philip J
Published: February 2024

Background

There are established risk factors for liver fibrosis (LF), but data on the impact of methotrexate on LF in patients with psoriasis are lacking.

Objectives

This cross-sectional study aimed to determine the prevalence of LF in patients with psoriasis and to evaluate the relationship between LF, cumulative methotrexate dose and other LF risk factors.

Methods

Adults with a history of moderate-to-severe chronic plaque psoriasis were recruited between June 2020 and March 2021. Patients underwent transient elastography to evaluate LF. Three values for liver stiffness measurement (LSM) were assessed, indicating mild or worse LF (≥ 7 kPa), moderate or worse LF (≥ 7.9 kPa) and advanced LF (≥ 9.5kPa). Cumulative methotrexate dose and other potential risk factors for LF were assessed.

Results

Overall, 240 patients were recruited and 204 participants with valid LSM values were included in the analysis [median age 48 years [interquartile range (IQR) 37–57]; 51% female sex; 56% body mass index (BMI) ≥ 30 (kg m−2) and a median Alcohol Use Disorders Identification Test (AUDIT) score of 4 (IQR 1–7, 23% score ≥ 8)]. In total, 91% had received methotrexate [median duration 36 months (IQR 14–78)]. Prevalence of LF was 36%, 25% and 17% using LSM ≥ 7 kPa, ≥ 7.9 kPa and ≥ 9.5 kPa, respectively. There was no association between cumulative methotrexate dose [median 2.16 (IQR 0.93–5.2)] and continuous LSM values [unstandardized coefficient 0.16, 95% confidence interval (CI) −0.49 to 0.82, P = 0.626] or using the categorical LSM cutoff values: ≥ 7 kPa [unadjusted odds ratio 1.06 (95% CI 0.97–1.15), P = 0.192], ≥ 7.9 kPa [unadjusted odds ratio 1.03 (95% CI 0.94–1.12), P = 0.577] and ≥ 9.5 kPa (unadjusted odds ratio 1.01, 95% CI 0.91–1.12; P = 0.843). The following risk factors were associated with higher LSM values: BMI (P ≤ 0.001), waist circumference (P ≤ 0.001), metabolic syndrome (P ≤ 0.001), AUDIT score (P = 0.020) and FIB-4 score (P = 0.03). BMI ≥ 28, diabetes and metabolic syndrome were shown to be better predictors of LF compared with FIB-4 score.

Conclusions

This study confirms a high prevalence of significant LF in patients with psoriasis. Cumulative methotrexate dose was not associated with LF. Patients with BMI ≥ 28, metabolic syndrome and diabetes are at higher risk for LF. These risk factors may help to identify when a more detailed liver health assessment is needed.
Thick endothelialization of the self-expandable valve causes delayed coronary obstruction
Authors: Samura Takaaki , Fujimoto Eiki , Ise Takayuki , Hata Hiroki
Published: February 2024

Delayed coronary obstruction is a rare complication occurring after transcatheter aortic valve replacement (TAVR). Although TAVR has become popular, in some cases, the therapeutic strategy should be carefully selected depending on the patient’s anatomical and/or functional restrictions. We report a rare case of delayed coronary obstruction in which coronary obstruction was caused by thick endothelialization of the nitinol frame of the prosthetic valve. A 79-year-old female who had undergone TAVR 4 months before presented with mild chest pain and was admitted to our institution. Computed tomography and coronary angiography revealed that the space from the sinus of Valsalva to the nitinol frame was narrow and separated from the inside of the nitinol frame because of critical endothelialization. Therefore, an emergency surgical aortic valve replacement was performed. The patient had an uneventful postoperative course and was discharged 20 days postoperatively without any complications.
A quantitative survey of the blueberry (Vacciniumspp.) culturable nectar microbiome: variation between cultivars, locations, and farm management approaches
Authors: Rering Caitlin C , Rudolph Arthur B , Li Qin-Bao , Read Quentin D , Muñoz Patricio R , Ternest John J , Hunter Charles T
Published: February 2024

Microbes in floral nectar can impact both their host plants and floral visitors, yet little is known about the nectar microbiome of most pollinator-dependent crops. In this study, we examined the abundance and composition of the fungi and bacteria inhabiting Vaccinium spp. nectar, as well as nectar volume and sugar concentrations. We compared wild V. myrsinites with two field-grown V. corymbosum cultivars collected from two organic and two conventional farms. Differences in nectar traits and microbiomes were identified between V. corymbosum cultivars but not Vaccinium species. The microbiome of cultivated plants also varied greatly between farms, whereas management regime had only subtle effects, with higher fungal populations detected under organic management. Nectars were hexose-dominant, and high cell densities were correlated with reduced nectar sugar concentrations. Bacteria were more common than fungi in blueberry nectar, although both were frequently detected and co-occurred more often than would be predicted by chance. “Cosmopolitan” blueberry nectar microbes that were isolated in all plants, including Rosenbergiella sp. and Symmetrospora symmetrica, were identified. This study provides the first systematic report of the blueberry nectar microbiome, which may have important implications for pollinator and crop health.
From peacekeeping missions to global peacekeeping assemblages
Authors: Albrecht Peter , Patey Luke , Abrahamsen Rita , Williams Paul D
Published: February 2024

How does the experience of peacekeeping shape the countries that contribute troops and the troops themselves, individually and collectively? Most of the peacekeeping literature's focus has traditionally been on field missions, the countries that host them and the challenges of attracting sufficient and appropriately trained troops. We suggest that more emphasis should be put not only on the locations where missions deploy, but also on the individuals, countries and institutions that make up the missions. To analytically capture this more comprehensive understanding of what peacekeeping is—its multiple effects across space—we suggest drawing on the concept of assemblages to make an analytical shift from peacekeeping missions to global peacekeeping assemblages. First, this approach abandons the prior analytical separation of field mission, host country and contributing state/organization as discrete or isolated analytical focus points. Second, it encourages a detailed empirical methodology that focuses on how multiplicities of different actors, knowledges, technologies, norms and values through power struggles and negotiations constitute assemblages in geographically dispersed locations. Third, we suggest treating peacekeeping as flexible social facts, as outcomes of the co-functioning of heterogenous actors with diverse motivations and objectives that cannot be traced back to a single, but rather multiple point(s) of origin(s).
Extracorporeal Membrane Oxygenation in a Patient with Severe Inhalation Injury: Multidisciplinary Burn Team Care
Authors: Peters Rachael A , Cancio Jill M , Glenn Keith , Cancio Leopoldo C
Published: February 2024

Introduction

Inhalation injury is a major risk factor for mortality in burn patients via 3 primary mechanisms: airway edema and obstruction, hypoxemic respiratory failure, and pneumonia. Currently, the mainstay of treatment is supportive care to include early intubation, lung-protective or high-frequency-percussive mechanical ventilation, nebulized heparin, and aggressive pulmonary toilet. Despite these treatments, a subset of these patients progress to severe acute respiratory distress syndrome (ARDS) for which rescue options are limited.

Case Presentation

A 31-year-old woman was found down in a house fire. On admission to the burn intensive care unit, she was diagnosed with grade 3 smoke inhalation injury. Cutaneous thermal injury was absent. By hospital day 2, she developed worsening hypoxemia and hypercapnia despite maximal ventilatory support. She was placed on veno-venous extracorporeal membrane oxygenation (ECMO). She received an average of 2.2 hours of direct rehabilitation a day and completed out-of-bed modalities over 90% of total hospital days. After 159 hours, she was decannulated, and by hospital day 18, she was discharged home on supplemental oxygen.

Conclusion

Current literature regarding ECMO in inhalation injury is limited, but a growing body of evidence suggests that treatment of severe smoke inhalation injury should include ECMO for those who fail conventional therapy.
Cyclones and flooding in tropical Northern Australia increase the risk of exposure to melioidosis
Authors: Bauer Irmgard L
Published: February 2024

Due to two recent cyclones in North Queensland, leading to widespread flooding, working holiday visa holders, typically backpackers, are now permitted to assist in cleanup efforts. Melioidosis, endemic in tropical Northern Australia, is a rare but potentially fatal bacterial infection. Travel health advice for backpackers to Australia should include appropriate information.
Bone marrow findings post allogeneic transplant for myeloproliferative neoplasms and chronic myelomonocytic leukemia with increased fibrosis
Authors: Gupta Srishti , Courville Elizabeth L
Published: February 2024

Background

Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease.

Methods

In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record.

Results

Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular.

Conclusions

Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease.
Interim FDG-PET improves treatment failure prediction in primary central nervous system lymphoma: An LOC network prospective multicentric study
Authors: Rozenblum Laura , Houillier Caroline , Baptiste Amandine , Soussain Carole , Edeline Véronique , Naggara Philippe , Soret Marine , Causse-Lemercier Valérie , Willems Lise , Choquet Sylvain , Ursu Renata , Galanaud Damien , Belin Lisa , Hoang-Xuan Khê , Kas Aurélie
Published: February 2024

Background

The purpose of our study was to assess the predictive and prognostic role of 2-18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/MRI during high-dose methotrexate-based chemotherapy (HD-MBC) in de novo primary central nervous system lymphoma (PCNSL) patients aged 60 and above.

Methods

This prospective multicentric ancillary study included 65 immunocompetent patients who received induction HD-MBC as part of the BLOCAGE01 phase III trial. FDG-PET/MRI were acquired at baseline, post 2 cycles (PET/MRI2), and posttreatment (PET/MRI3). FDG-PET response was dichotomized with “positive” indicating persistent tumor uptake higher than the contralateral mirroring brain region. Performances of FDG-PET and International PCNSL Collaborative Group criteria in predicting induction response, progression-free survival (PFS), and overall survival (OS) were compared.

Results

Of the 48 PET2 scans performed, 9 were positive and aligned with a partial response (PR) on MRI2. Among these, 8 (89%) progressed by the end of the induction phase. In contrast, 35/39 (90%) of PET2-negative patients achieved complete response (CR). Among the 18 discordant responses at interim (PETCR/MRIPR), 83% ultimately achieved CR. Eighty-seven percent of the PET2-negative patients were disease free at 6 months versus 11% of the PET2-positive patients (P < .001). The MRI2 response did not significantly differentiate patients based on their PFS, regardless of whether they were in CR or PR. Both PET2 and MRI2 independently predicted OS in multivariate analysis, with PET2 showing a stronger association.

Conclusions

Our study highlights the potential of interim FDG-PET for early management of PCNSL patients. Response-driven treatment based on PET2 may guide future clinical trials.

Trial

LOCALYZE, NCT03582254, ancillary of phase III clinical trial BLOCAGE01, NCT02313389 (Registered July 10, 2018—retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT03582254?term=LOCALYZE&draw=2&rank=1.
Understanding the heterogeneity of childhood allergic sensitization and its relationship with asthma
Authors: Custovic Adnan , Custovic Darije , Fontanella Sara
Published: February 2024

Purpose of review

To review the current state of knowledge on the relationship between allergic sensitization and asthma; to lay out a roadmap for the development of IgE biomarkers that differentiate, in individual sensitized patients, whether their sensitization is important for current or future asthma symptoms, or has little or no relevance to the disease.

Recent findings

The evidence on the relationship between sensitization and asthma suggests that some subtypes of allergic sensitization are not associated with asthma symptoms, whilst others are pathologic. Interaction patterns between IgE antibodies to individual allergenic molecules on component-resolved diagnostics (CRD) multiplex arrays might be hallmarks by which different sensitization subtypes relevant to asthma can be distinguished. These different subtypes of sensitization are associated amongst sensitized individuals at all ages, with different clinical presentations (no disease, asthma as a single disease, and allergic multimorbidity); amongst sensitized preschool children with and without lower airway symptoms, with different risk of subsequent asthma development; and amongst sensitized patients with asthma, with differing levels of asthma severity.

The use of machine learning-based methodologies on complex CRD data can help us to design better diagnostic tools to help practising physicians differentiate between benign and clinically important sensitization.
Is allergen immunotherapy a model of personalized treatment in pediatric respiratory allergy?
Authors: Wandalsen Gustavo Falbo , Aarestrup Fernando Monteiro , Solé Dirceu
Published: February 2024

Purpose of review

To review recent evidence on allergen immunotherapy (AIT) as a model of personalized medicine in the treatment of children and adolescents with respiratory allergies.

Recent findings

Meta-analysis and systematic review studies continue to point out that AIT is an effective treatment for children with respiratory allergies. Molecular allergy allows the understanding of patient sensitization profiles that frequently change the prescription of AIT. There is still a lack of evidence showing that this personalized prescription of AIT is associated with better clinical outcomes. The nasal allergen challenge has extended the indications of AIT for a new group of subjects with local allergic rhinitis. Patient selection of allergens involved in the increasingly personalized composition of extracts to be used in AIT increasingly characterizes it as personalized medicine.

Despite the numerous studies carried out to identify the best biomarker to evaluate the response to AIT, there is still much disagreement, and clinical assessment (symptoms, quality of life, among others) continues to be the best way to evaluate the therapeutic success of AIT.
Regional anaesthesia via parasternal catheters inserted preoperatively and postoperative delirium after cardiac surgery
Authors: Elhadjene Nory , Grand Nathalie , Azarnoush Kasra , Petrosyan Andranik , Raissouni Khalil , Campisi Salvatore , Sandri Fabrizio , Palao Jean Charles , Awad Sahar , Magand Clément , Molliex Serge , Ollier Edouard , Morel Jérôme , Lanoiselee Julien ,   Investigators of the Opioid Reduced Anaesthesia with parasternal CATheters on postoperative delirium after cardiac surgery (ORACAT) study
Published: February 2024

Visual Abstract:

http://links.lww.com/EJA/A927
Pharmacogenomic allele coverage of genome-wide genotyping arrays: a comparative analysis
Authors: Lenz Courtney , Narang Ankita , Bousman Chad A.
Published: February 2024

The use of genome-wide genotyping arrays in pharmacogenomics (PGx) research and clinical implementation applications is increasing but it is unclear which arrays are best suited for these applications. Here, we conduct a comparative coverage analysis of PGx alleles included on genome-wide genotyping arrays, with an emphasis on alleles in genes with PGx-based prescribing guidelines. Genomic manifest files for seven arrays including the Axiom Precision Medicine Diversity Array (PMDA), Axiom PMDA Plus, Axiom PangenomiX, Axiom PangenomiX Plus, Infinium Global Screening Array, Infinium Global Diversity Array (GDA) and Infinium GDA with enhanced PGx (GDA-PGx) Array, were evaluated for coverage of 523 star alleles across 19 pharmacogenes included in prescribing guidelines developed by the Clinical Pharmacogenetic Implementation Consortium and Dutch Pharmacogenomics Working Group. Specific attention was given to coverage of the Association of Molecular Pathology’s Tier 1 and Tier 2 allele sets for CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, NUDT15, TPMT and VKORC1. Coverage of the examined PGx alleles was highest for the Infinium GDA-PGx (88%), Axiom PangenomiX Plus (77%), Axiom PangenomiX (72%) and Axiom PMDA Plus (70%). Three arrays (Infinium GDA-PGx, Axiom PangenomiX Plus and Axiom PMDA Plus) fully covered the Tier 1 alleles and the Axiom PangenomiX array provided full coverage of Tier 2 alleles. In conclusion, PGx allele coverage varied by gene and array. A superior array for all PGx applications was not identified. Future comparative analyses of genotype data produced by these arrays are needed to determine the robustness of the reported coverage estimates.
The role of sinusoidal endothelial cells and TIMP1 in the regulation of fibrosis in a novel human liver 3D NASH model
Authors: van Riet Sander , Julien Anais , Atanasov Andrea , Nordling Åsa , Ingelman-Sundberg Magnus
Published: February 2024

Background:

The prevalence of NAFLD is rapidly increasing. NAFLD can progress to NASH, fibrosis, cirrhosis, and HCC, which will soon become the main causes of liver transplantation. To date, no effective drug for NASH has been approved by the Food and Drug Administration. This is partly due to the lack of reliable human in vitro models. Here, we present a novel human liver spheroid model that can be used to study the mechanisms underlying liver fibrosis formation and degradation.

Methods and Results:

Such spheroids, which contain hepatocytes, stellate cells, KC, and LSECs, spontaneously develop fibrosis that is exacerbated by treatment with free fatty acids. Conditioned medium from activated LSECs caused similar activation of fibrosis in spheroids containing primary human hepatocyte and NPCs, indicating the action of soluble mediators from the LSECs. Spheroids containing LSECs treated with free fatty acids produced tissue inhibitor of metalloproteinases inhibitor 1, a matrix metalloproteinases inhibitor important for fibrosis progression. Tissue inhibitor of metalloproteinases inhibitor 1 knockdown using siRNA led to a reduction in collagen and procollagen accumulation, which could be partially rescued using a potent matrix metalloproteinases inhibitor. Interestingly, tissue inhibitor of metalloproteinases inhibitor 1 was found to be expressed at higher levels, specifically in a subtype of endothelial cells in the pericentral region of human fibrotic livers, than in control livers.

Conclusion:

Potential anti-NASH drugs and compounds were evaluated for their efficacy in reducing collagen accumulation, and we found differences in specificity between spheroids with and without LSECs. This new human NASH model may reveal novel mechanisms for the regulation of liver fibrosis and provide a more appropriate model for screening drugs against NASH.
The clinical value of β-D-glucan testing and next-generation metagenomic sequencing for the diagnosis of fungal endophthalmitis
Authors: Li Yuxin , Qian Zhuyun , Chen Huagui , Zhang Shuguang , Wang Ruifeng , Yu Shuhuan , Chen Li , Wang Lu , Xu Songtao , Tao Yong
Published: February 2024

Purpose:

To explore the clinical value of β-D-glucan (BDG) testing and next-generation metagenomic sequencing (mNGS) for detecting the pathogens of fungal endophthalmitis (FE).

Methods:

This study included 32 cases (32 eyes) with FE and 20 cases (20 eyes) with intraocular inflammation caused by other etiologies. All patients underwent extraction of aqueous humor or vitreous fluid samples for BDG testing and mNGS. The diagnostic performance and total clinical concordance rate (TCCR) of BDG testing and mNGS for FE were evaluated and calculated based on the results of the clinical diagnosis.

Results:

Among the clinically diagnosed FE, the positivity rates of BDG testing and mNGS (90.63%) were both significantly higher (P<0.001) than that of microbial cultures (53.13%). There was 100% consistency in pathogen identification using mNGS and culture identification for culture-positive cases. The area under the curve (AUC) was 0.927 for BDG testing and 0.853 for mNGS. When the 2 tests were combined, the sensitivity (93.75%), specificity (100.00%), and TCCR (96.15%) were all improved compared with the single tests.

Conclusions:

The positive rates of BDG test and mNGS were markedly higher than those of cultures in FE identification. The combination of these 2 tests showed improved performance when compared with individual tests.
Behavioral Problems and Family Impact in Congenital Cytomegalovirus Infection
Authors: Rodríguez-Molino Paula , Alarcón Ana , Martínez-Biarge Miriam , Cabrera-Lafuente Marta , Aldecoa Victoria , Fernández-Sánchez Aránzazu , Fernández-Jiménez Eduardo , Baquero-Artigao Fernando , García-Alix Alfredo
Published: February 2024

We examined behavior (Child Behavior Checklist) and family functioning (Family Impact Questionnaire) in 65 children with congenital cytomegalovirus. Behavioral problems were present in 30.8%. Parents of children with moderate/severe outcomes reported strain on all areas of family functioning. Behavioral problems were associated with negative impact on parental feelings and marital/partnership relationship. Our findings inform planning support services.
Association Between Intimate Partner Violence (IPV) and Physical, Psychological, and Social Health Outcomes for Women in Bangladesh
Authors: Nipa Shamima Islam , Islam Asma , Disha Fabiha Alam , Raigangar Veena
Published: February 2024

Background:

Intimate partner violence (IPV) is a global issue impacting 1 in 3 women worldwide. IPV has been shown to have direct impact on the physical, psychological, and social aspects of life and overall well-being.

Objective:

The purpose of this study was to explore associations between report of IPV and physical, psychological, and social health outcomes with special emphasis on relationship of IPV to pelvic floor, pelvic pain, and urinary incontinence for Bangladeshi women.

Study Design:

A cross-sectional study was conducted using purposive sampling.

Methods:

Married women between 18 and 50 years were recruited in the study. IPV was measured using the Hurt-Insult-Threaten-Scream (HITS) screening tool and complex trauma was measured utilizing the Complex Trauma Inventory (CTI) Scale. Data were analyzed through SPSS version 21.0, and reported as descriptive statistics.

Results:

The total number of the respondents was n = 100. The mean age of respondents was 36.57 years (standard deviation ± 9.66). According to the HITS screening tool 27% respondents reported IPV. There was a significant, strong correlation between HITS scores for IPV and negative health outcomes of chronic disease and disability (r = 0.8; P ≤ .05). There was a direct association between HITS scores and (1) CTI scores for complex trauma, (2) pelvic floor dysfunction, and (3) duration of marriage.

Conclusion:

High prevalence of IPV was reported for this cohort of women living in Bangladesh. HITS scores for IPV were direct significant associations with severity and intensity of posttraumatic stress disorder on the CTI, and with low back pain, pelvic floor dysfunction, postpartum complications, and cardiac problems.
Severe thrombocytopenia associated to bevacizumab in a patient with scleroderma, gastrointestinal angiodysplasias and refractory gastrointestinal bleeding
Authors: Perez Lloveras Eugenia , Michelangelo Juan Manuel , Videla Carlos Gustavo , Gonzalez Maria Laura , Privitera Veronica , Serra Marcelo Martin , Vazquez Carolina
Published: February 2024

This case report discusses the medical history of a 64-year-old woman diagnosed with scleroderma and diffuse gastrointestinal angiodysplasia. The patient received bevacizumab (BVZ) therapy to address gastrointestinal bleeding that was unresponsive to endoscopic treatment. Subsequently, she developed severe thrombocytopenia. Although there were suspicions of an immune-mediated mechanism resulting from BVZ treatment, the laboratory results did not provide conclusive evidence. The patient underwent transfusions, received gamma globulin, and was treated with Romiplostim. Over time, her platelet levels gradually improved, and the bleeding was successfully controlled. It's worth noting that BVZ-induced thrombocytopenia is a relatively rare yet severe adverse effect. Recognizing and understanding the mechanisms behind thrombocytopenia is essential for developing safer treatment approaches. Further research is required to identify potential risk factors associated with this condition.
Hematopoietic stem cell collection for sickle cell disease gene therapy
Authors: Leonard Alexis , Weiss Mitchell J.
Published: February 2024

Purpose of review

Gene therapy for sickle cell disease (SCD) is advancing rapidly, with two transformative products recently approved by the US Food and Drug Administration and numerous others under study. All current gene therapy protocols require ex vivo modification of autologous hematopoietic stem cells (HSCs). However, several SCD-related problems impair HSC collection, including a stressed and damaged bone marrow, potential cytotoxicity by the major therapeutic drug hydroxyurea, and inability to use granulocyte colony stimulating factor, which can precipitate severe vaso-occlusive events.

Recent findings

Peripheral blood mobilization of HSCs using the CXCR4 antagonist plerixafor followed by apheresis collection was recently shown to be safe and effective for most SCD patients and is the current strategy for mobilizing HSCs. However, exceptionally large numbers of HSCs are required to manufacture an adequate cellular product, responses to plerixafor are variable, and most patients require multiple mobilization cycles, increasing the risk for adverse events. For some, gene therapy is prohibited by the failure to obtain adequate numbers of HSCs.

Here we review the current knowledge on HSC collection from individuals with SCD and potential improvements that may enhance the safety, efficacy, and availability of gene therapy for this disorder.
Cholangioscopy with Spyglass DS using percutaneous transhepatic cholangiography access: a retrospective cohort study
Authors: Solstad Trygve Ulvund , Thorsteinsson Morten , Schultz Nicolai , Larsen Peter Nørgaard , Taudorf Mikkel , Achiam Michael
Published: February 2024

Background:

Conventional peroral methods to visualize biliary strictures are not feasible in some patients with altered anatomy or biliary obstruction, and percutaneous transhepatic cholangioscopy can be used as an alternative procedure. This study aimed to retrospectively review the use of percutaneous transhepatic cholangiography using the SpyGlass DS technology (S-PTCS) during a 5-year period at a Danish tertiary referral center.

Materials and Methods:

All patients who underwent S-PTCS at a single Danish tertiary referral center between 2016 and 2021 were retrospectively analyzed. The visual, technical, and overall success rates of S-PTCS were analyzed, as well as the complication rate. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of S-PTCS were calculated.

Results:

Twenty-two patients were included in the study. Visual, technical, and overall success of S-PTCS was achieved in 17/22, 22/22, and 21/22 patients, respectively. S-PTCS yielded a sensitivity of 83.3%, a specificity of 100%, a PPV of 100%, a NPV of 94.1%, and an accuracy of 95.4%. Complications occurred in 1/22 patients.

Conclusion:

S-PTCS is a safe modality, with high success rates, high predictive values, and a low rate of complications. This study suggests that S-PTCS is an alternative to conventional methods in patients with indeterminate biliary strictures where conventional methods were unfeasible.
Prevalence of Low-Acuity Pediatric Emergency Medical Services (EMS) Transports to a Pediatric Emergency Department (ED) in an Urban Area
Authors: Ward Caleb E. , Badolato Gia M. , Taylor Michael F. , Brown Kathleen M. , Simpson Joelle N. , Chamberlain James M.
Published: February 2024

Objectives

Many patients transported by Emergency Medical Services (EMS) do not have emergent resource needs. Estimates for the proportion of pediatric EMS calls for low-acuity complaints, and thus potential candidates for alternative dispositions, vary widely and are often based on physician judgment. A more accurate reference standard should include patient assessments, interventions, and dispositions. The objective of this study was to describe the prevalence and characteristics of low-acuity pediatric EMS calls in an urban area.

Methods

This is a prospective observational study of children transported by EMS to a tertiary care pediatric emergency department. Patient acuity was defined using a novel composite measure that included physiologic assessments, resources used, and disposition. Bivariable and multivariable logistic regression were conducted to assess for factors associated with low-acuity status.

Results

A total of 996 patients were enrolled, of whom 32.9% (95% confidence interval, 30.0–36.0) were low acuity. Most of the sample was Black, non-Hispanic with a mean age of 7 years. When compared with adolescents, children younger than 1 year were more likely to be low acuity (adjusted odds ratio, 3.1 [1.9–5.1]). Patients in a motor vehicle crash were also more likely to be low acuity (adjusted odds ratio, 2.4 [1.2–4.6]). All other variables, including race, insurance status, chief complaint, and dispatch time, were not associated with low-acuity status.

Conclusions

One third of pediatric patients transported to the pediatric emergency department by EMS in this urban area are for low-acuity complaints. Further research is needed to determine low-acuity rates in other jurisdictions and whether EMS providers can accurately identify low-acuity patients to develop alternative EMS disposition programs for children.
In Search of the Truth: Choice of Ground Truth for Predictive Modeling of Trauma Team Activation in Pediatric Trauma
Authors: Chacon Miranda , Liu Catherine W , Crawford Loralai , Polydore Hadassah , Ting Tiffany , Wakeman Derek , Wilson Nicole A
Published: February 2024

BACKGROUND:

Assigning trauma team activation (TTA) levels for trauma patients is a classification task that machine learning models can help optimize. However, performance is dependent on the “ground-truth” labels used for training. Our purpose was to investigate 2 ground truths, the Cribari matrix and the Need for Trauma Intervention (NFTI), for labeling training data.

STUDY DESIGN:

Data were retrospectively collected from the institutional trauma registry and electronic medical record, including all pediatric patients (age <18 years) who triggered a TTA (January 2014 to December 2021). Three ground truths were used to label training data: (1) Cribari (Injury Severity Score >15 = full activation), (2) NFTI (positive for any of 6 criteria = full activation), and (3) the union of Cribari+NFTI (either positive = full activation).

RESULTS:

Of 1,366 patients triaged by trained staff, 143 (10.47%) were considered undertriaged using Cribari, 210 (15.37%) using NFTI, and 273 (19.99%) using Cribari+NFTI. NFTI and Cribari+NFTI were more sensitive to undertriage in patients with penetrating mechanisms of injury (p = 0.006), specifically stab wounds (p = 0.014), compared with Cribari, but Cribari indicated overtriage in more patients who required prehospital airway management (p < 0.001), CPR (p = 0.017), and who had mean lower Glasgow Coma Scale scores on presentation (p < 0.001). The mortality rate was higher in the Cribari overtriage group (7.14%, n = 9) compared with NFTI and Cribari+NFTI (0.00%, n = 0, p = 0.005).

CONCLUSIONS:

To prioritize patient safety, Cribari+NFTI appears best for training a machine learning algorithm to predict the TTA level.
DEEP LEARNING APPROACH FOR RENAL CELL CARCINOMA DETECTION, SUBTYPING, AND GRADING
Authors: Aziz Maroof Abdul , Javadian Fatemeh , Mathew Sherin Susheel , Gopal Avinash , Stegmaier Johannes , Jose Abin
Published: February 2024

We propose a comprehensive end-to-end pipeline designed for the detection, subtyping, and grading of tumors. Our proposed method-ology initiates the generation of a heat map, indicating the severity of the tumor. Subsequently, the identification of the most critical patches is conducted based on the probability scores. These identified patches are then directed to a grade prediction network. A distinctive aspect of our research lies in being the first to explore an end-to-end pipeline for both heat map generation and grading prediction. Our experiments were conducted leveraging the public, The Cancer Genome Atlas (TCGA) repository, focusing specifically on renal cancer. We introduced additional patch-level labels to improve the model performance. The generation of tumor heat maps targeted three primary cancer subtypes: clear cell, papillary, and chromophobe. To enhance our approach, we implemented center-loss and introduced a method aimed at refining the quality of patches. The experimental outcomes highlight superior performance compared to state-of-the-art method. This research contributes to the advancement of tumor detection and grading, emphasizing the significance of an integrated approach for heat map generation and grading pre-diction.
Evaluation of a novel Tc-24 recombinant antigen ELISA for serologic testing forTrypanosoma cruziin dogs
Authors: Mejia Rojelio , Verocai Guilherme G. , Mosley Ilana A. , Zhan Bin , Vongthavaravat Lindsey , Busselman Rachel E. , Hamer Sarah A.
Published: February 2024

Chagas disease is a parasitic infection caused byTrypanosoma cruzi. Diagnosis of chroni Chagas disease in dogs relies on limited serological test options. This study used a new Tc-24 recombinant antigen ELISA on an archival set of 70 dog serum samples from multi-dog kennel environments in Texas subjected to three existing Chagas serological tests. Tc-24 ELISA produced a quantitative result and could detect anti-T. cruziantibodies in dogs with high sensitivity and specificity. Comparing individual tests to Tc-24 ELISA resulted in strong associations and correlations, which suggest that Tc-24 ELISA is a reliable and accurate diagnostic tool for dogs with a single test.
Hyperactivity Induced By Vapor Inhalation of Nicotine in Male and Female Rats
Authors: Javadi-Paydar Mehrak , Kerr Tony M. , Taffe Michael A.
Published: February 2024

Rationale

Preclinical models of electronic nicotine delivery system (ENDS; “e-cigarette”) use have been rare, so there is an urgent need to develop experimental approaches to evaluate their effects.

Objective

To contrast the impact of inhaled nicotine across sex.

Methods

Male and female Wistar rats were exposed to vapor from a propylene glycol vehicle (PG), nicotine (NIC; 1-30 mg/mL in PG), or were injected with NIC (0.1-0.8 mg/kg, s.c.), and then assessed for changes in temperature and activity. The antagonist mecamylamine (2 mg/kg) was administered prior to NIC to verify pharmacological specificity. Plasma levels of nicotine and cotinine were determined after inhalation and injection.

Results

Activity increased in females for ∼60 minutes after nicotine inhalation, and this was blocked by mecamylamine. A similar magnitude of hyperlocomotion was observed after s.c. administration. Body temperature was reduced after nicotine inhalation by female rats but mecamylamine increased this hypothermia. Increased locomotor activity was observed in male rats if inhalation was extended to 40 minutes or when multiple inhalation epochs were used per session. The temperature of male rats was not altered by nicotine. Plasma nicotine concentrations were slightly lower in male rats than in female rats after 30-minute nicotine vapor inhalation and slightly higher after nicotine injection (1.0 mg/kg, s.c.).

Conclusions

Nicotine inhalation increases locomotor activity in male and female rats to a similar or greater extent than by subcutaneous injection. Sex differences were observed, which may be related to lower nicotine plasma levels, lower baseline activity and/or a higher vehicle response in males.
Development of a novelin silicoclassification model to assess reactive metabolite formation in the cysteine trapping assay and investigation of important substructures
Authors: Umemori Yuki , Handa Koichi , Yoshimura Saki , Kageyama Michiharu , Iijima Takeshi
Published: February 2024

Predicting whether a compound can cause drug-induced liver injury (DILI) is difficult due to the complexity of its mechanism. The production of reactive metabolites is one of the major causes of DILI, particularly idiosyncratic DILI. The cysteine trapping assay is one of the methods to detect reactive metabolites which bind to microsomes covalently. However, it is cumbersome to use 35S isotope-labeled cysteine for this assay. Therefore, we constructed anin silicoclassification model for predicting a positive/negative outcome in the cysteine trapping assay to accelerate the drug discovery process. In this study, we collected 475 compounds (436 in-house compounds and 39 publicly available drugs). Using a Message Passing Neural Network (MPNN) and Random Forest (RF) with extended connectivity fingerprint (ECFP) 4, we built machine learning models to predict the covalent binding risk of compounds. The 5-fold cross-validation (CV) and hold-out test were evaluated in random- and time-split trials. Additionally, we investigated the substructures that contributed to positive results in the cysteine trapping assay through the framework of the MPNN model. In the random-split dataset, the AUC-ROC of MPNN and RF were 0.698 and 0.811 in the 5-fold CV, and 0.742 and 0.819 in the hold-out test, respectively. In the time-split dataset, AUC-ROC of MPNN and RF were 0.729 and 0.617 in the 5-fold CV, and 0.625 and 0.559 in the hold-out test, restrictively. This result suggests that the MPNN model has a higher predictivity than RF in the time-split dataset. Hence, we conclude that thein silicoMPNN classification model for the cysteine trapping assay have better predictive power. Furthermore, most of the substructures that contributed positively to the cysteine trapping assay were consistent with previous reports such as propranolol, verapamil, and imipramine. This is a new machine learning model that can determine the outcome of the cysteine trapping assay, namely accurately predicting the covalent binding risk as the one of factors of idiosyncratic DILI. We believe that this can contribute to mitigating DILI risk for reactive metabolites at the early stages of drug discovery.
Leaf abaxial and adaxial surfaces differentially affect plant-fungal pathogen interactions
Authors: Caseys Celine , Muhich Anna Jo , Vega Josue , Ahmed Maha , Hopper Aleshia , Kelly David , Kim Sydney , Madrone Matisse , Plaziak Taylor , Wang Melissa , Kliebenstein Daniel J.
Published: February 2024

Eudicot plant species have bifacial leaves with each surface varying in a diversity of components, resulting in potentially different microhabitats for pathogens. We tested howBotrytis cinerea,a necrotroph fungal pathogen, interacts with the two different leaf surfaces across 16 crop species and 20 Arabidopsis genotypes. This showed that the abaxial surface is generally more susceptible to the pathogen than the adaxial surface. In Arabidopsis, the differential lesion area between leaf surfaces was associated to jasmonic acid (JA) and salicylic acid (SA) signaling and differential induction of defense chemistry. When infecting the adaxial surface, leaves mounted stronger defenses by producing more glucosinolates and camalexin defense compounds, partially explaining the differential susceptibility across surfaces. Testing a collection of 96B. cinereastrains showed genetic heterogeneity of growth patterns, with a few strains preferring the adaxial surface while most are more virulent on the abaxial surface. Overall, we show that leaf-Botrytis interactions are complex with host-specific, surface-specific, and strain-specific behaviors. Within Arabidopsis, this mechanistically links to potential variation in JA/SA signaling across the two surfaces.
The interplay of trophic interactions and game dynamics gives rise to life-history trade-offs, consistent personalities, and predator-prey and aggression power laws
Authors: Salahshour Mohammad
Published: February 2024

By introducing a simple model of ecological interactions where individuals interact trophically, and through a game dynamic, I show that the dissipative flow of resources can derive evolution and lead to the emergence of a scale-invariant ecosystem exhibiting a wide range of mean and fluctuation scaling laws that govern trophic interactions and game dynamics. The eco-evolutionary approach suggests life history trade-offs are a natural consequence of ecological dynamics and, combined with the non-equilibrium dynamic, lead to the evolution of consistent personalities. Aggressiveness and personality consistency depend on trophic position, and predators evolve a higher aggressiveness and starker personality differences.

Author summary

Throughout the history of life, the flow of energy across ecosystems has contributed to the evolution of complex forms of life and strikingly universal patterns on a large scale. However, it is not clear what factors lead to such universal patterns and how they relate to evolution. Simple mathematical models suggest that the dissipative flow of resources through ecosystems leads to self-organization in a critical state with scale-invariant avalanches of activity. The scale-invariant structure of ecosystems results in a complex set of scaling laws governing the structure and dynamics of populations. The same non-equilibrium ecological dynamics derive evolution and account for the evolution of individuals’ behavioral differences and consistent personalities.
Thyroid Hormone Suppresses Medulloblastoma Progression Through Promoting Terminal Differentiation of Tumor Cells
Authors: Yang Yijun , Valdés-Rives Silvia Anahi , Liu Qing , Li Yuzhe , Tan Jun , Tan Yinfei , Koch Christian A , Rong Yuan , Houser Steven R. , Wei Shuanzeng , Cai Kathy Q , Cheng Sheue-yann , Curran Tom , Wechsler-Reya Robert , Yang Zeng-jie
Published: February 2024

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). A possible link between thyroid hormone (TH) signaling and MB pathogenicity has not been reported. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.
The atypical antipsychotic aripiprazole alters the outcome of disseminatedCandida albicansinfections
Authors: Reitler Parker , Regan Jessica , DeJarnette Christian , Srivastava Ashish , Carnahan Jen , Tucker Katie M. , Meibohm Bernd , Peters Brian M , Palmer Glen E.
Published: February 2024

Invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. For many IFIs, ≥ 30% of patients fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 approved medications that antagonize azole activity. While gain-of-function mutants resulting in antifungal resistance are often associated with reduced fitness and virulence, it is currently unknown how exposure to azole antagonistic drugs impactC. albicansphysiology, fitness, or virulence. In this study, we examined how exposure to azole antagonists affectedC. albicansphenotype and capacity to cause disease. We discovered that most of the azole antagonists had little impact on fungal growth, morphology, stress tolerance, or gene transcription. However, aripiprazole had a modest impact onC. albicanshyphal growth and increased cell wall chitin content. It also worsened the outcome of disseminated infections in mice at human equivalent concentrations. This effect was abrogated in immunosuppressed mice, indicating an additional impact of aripiprazole on host immunity. Collectively, these data provide proof-of-principle that unanticipated drug-fungus interactions have the potential to influence the incidence and outcomes of invasive fungal disease.

Importance

As natural inhabitants of the gastrointestinal and reproductive tracts,Candidasp. are routinely exposed to medications consumed by their human host. This study provides new insight into how drugs can modulate the physiology, fitness, and pathogenicity ofCandida albicans- one of the most important human fungal pathogens. These results provide a proof of principle that co-administered medications consumed by at-risk patients may influence the initiation and/or outcome of life-threatening fungal disease.