bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected
Authors: Gynn Liana E , Anderson Elizabeth , Robinson Gareth , Wexler Sarah A , Upstill-Goddard Gillian , Cox Christine , May Jennifer E
Published: September 2021

Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one-third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.
Screening by deep sequencing reveals mediators of microRNA tailing in C. elegans
Authors: Vieux Karl-Frédéric , Prothro Katherine P , Kelley Leanne H , Palmer Cameron , Maine Eleanor M , Veksler-Lublinsky Isana , McJunkin Katherine
Published: September 2021

microRNAs are frequently modified by addition of untemplated nucleotides to the 3′ end, but the role of this tailing is often unclear. Here we characterize the prevalence and functional consequences of microRNA tailing in vivo, using Caenorhabditis elegans. MicroRNA tailing in C. elegans consists mostly of mono-uridylation of mature microRNA species, with rarer mono-adenylation which is likely added to microRNA precursors. Through a targeted RNAi screen, we discover that the TUT4/TUT7 gene family member CID-1/CDE-1/PUP-1 is required for uridylation, whereas the GLD2 gene family member F31C3.2—here named GLD-2-related 2 (GLDR-2)—is required for adenylation. Thus, the TUT4/TUT7 and GLD2 gene families have broadly conserved roles in miRNA modification. We specifically examine the role of tailing in microRNA turnover. We determine half-lives of microRNAs after acute inactivation of microRNA biogenesis, revealing that half-lives are generally long (median = 20.7 h), as observed in other systems. Although we observe that the proportion of tailed species increases over time after biogenesis, disrupting tailing does not alter microRNA decay. Thus, tailing is not a global regulator of decay in C. elegans. Nonetheless, by identifying the responsible enzymes, this study lays the groundwork to explore whether tailing plays more specialized context- or miRNA-specific regulatory roles.
Recent advances and new discoveries in the pipeline of the treatment of primary spinal tumors and spinal metastases: a scoping review of registered clinical studies from 2000 to 2020
Authors: Furlan Julio C , Wilson Jefferson R , Massicotte Eric M , Sahgal Arjun , Fehlings Michael G
Published: September 2021

The field of spinal oncology has substantially evolved over the past decades. This review synthesizes and appraises what was learned and what will potentially be discovered from the recently completed and ongoing clinical studies related to the treatment of primary and secondary spinal neoplasms. This scoping review included all clinical studies on the treatment of spinal neoplasms registered in the ClinicalTrials.gov website from February 2000 to December 2020. The terms “spinal cord tumor,” “spinal metastasis,” and “metastatic spinal cord compression” were used. Of the 174 registered clinical studies on primary spinal tumors and spinal metastasis, most of the clinical studies registered in this American registry were interventional studies led by single institutions in North America (n = 101), Europe (n = 43), Asia (n = 24), or other continents (n = 6). The registered clinical studies mainly focused on treatment strategies for spinal neoplasms (90.2%) that included investigating stereotactic radiosurgery (n = 33), radiotherapy (n = 21), chemotherapy (n = 20), and surgical technique (n = 11). Of the 69 completed studies, the results from 44 studies were published in the literature. In conclusion, this review highlights the key features of the 174 clinical studies on spinal neoplasms that were registered from 2000 to 2020. Clinical trials were heavily skewed toward the metastatic population as opposed to the primary tumors which likely reflects the rarity of the latter condition and associated challenges in undertaking prospective clinical studies in this population. This review serves to emphasize the need for a focused approach to enhancing translational research in spinal neoplasms with a particular emphasis on primary tumors.
Glutamine anaplerosis is required for amino acid biosynthesis in human meningiomas
Authors: Ijare Omkar B , Hambarde Shashank , Brasil da Costa Fabio Henrique , Lopez Sophie , Sharpe Martyn A , Helekar Santosh A , Hangel Gilbert , Bogner Wolfgang , Widhalm Georg , Bachoo Robert M , Baskin David S , Pichumani Kumar
Published: September 2021

Background

We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unraveling their metabolic phenotypes provide new therapeutic insights. Glutamine catabolism is key to the growth and proliferation of tumors. Here, we investigated the metabolomics of freshly resected meningiomas and glutamine metabolism in patient-derived meningioma cells.

Methods

1H NMR spectroscopy of tumor tissues from meningioma patients was used to differentiate the metabolite profiles of grade-I and grade-II meningiomas. Glutamine metabolism was examined using 13C/15N glutamine tracer, in 5 patient-derived meningioma cells.

Results

Alanine, lactate, glutamate, glutamine, and glycine were predominantly elevated only in grade-II meningiomas by 74%, 76%, 35%, 75%, and 33%, respectively, with alanine and glutamine levels being statistically significant (P ≤ .02). 13C/15N glutamine tracer experiments revealed that both grade-I and -II meningiomas actively metabolize glutamine to generate various key carbon intermediates including alanine and proline that are necessary for the tumor growth. Also, it is shown that glutaminase (GLS1) inhibitor, CB-839 is highly effective in downregulating glutamine metabolism and decreasing proliferation in meningioma cells.

Conclusion

Alanine and glutamine/glutamate are mainly elevated in grade-II meningiomas. Grade-I meningiomas possess relatively higher glutamine metabolism providing carbon/nitrogen for the biosynthesis of key nonessential amino acids. GLS1 inhibitor (CB-839) is very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.
A pH-response chemotherapy synergistic photothermal therapy for tumor suppression and bone regeneration by mussel-inspired Mg implant
Authors: Shao Hongwei , Cheng Shi , Yao Mengyu , Ji Xiongfa , Zhong Hua , Wang Donghui , Fan Xiujuan , Li Qian , Zhou Jielong , Zhang Yu , Peng Feng
Published: September 2021

Primary malignant bone tumors can be life-threatening. Surgical resection of tumor plus chemotherapy is the standard clinical treatment. However, postoperative recovery is hindered due to tumor recurrence caused by residual tumor cells and bone defect caused by resection of tumor tissue. Herein, a multifunctional mussel-inspired film was fabricated on Mg alloy, that is, an inner hydrothermal-treated layer, a middle layer of polydopamine, and an outer layer of doxorubicin. The modified Mg alloy showed excellent photothermal effect and thermal/pH-controlled release of doxorubicin. The synergistic effect of chemotherapy and photothermal therapy enabled the modified Mg alloy to kill bone tumor in vitro and inhibit tumor growth in nude mice. Moreover, because of the controlled release of Mg ions and biocompatibility of polydopamine, the modified Mg alloy supported extracellular matrix mineralization, alkaline phosphatase activity, and bone-related gene expression in C3H10T1/2. Bone implantation model in rats verified that the modified Mg showed excellent osteointegration. These findings prove that the use of mussel-inspired multifunction film on Mg alloy offers a promising strategy for the therapy of primary malignant bone tumor.
CORRELATION BETWEEN ANTERIOR–POSTERIOR AND LATERAL DIMENSIONS WITH THE EFFECTIVE AND WATER-EQUIVALENT DIAMETERS IN AXIAL IMAGES FROM HEAD COMPUTED TOMOGRAPHY EXAMINATIONS
Authors: Dewi Winda Kusuma , Anam Choirul , Hidayanto Eko , Wati Annisa Lidia , Dougherty Geoff
Published: September 2021

The study aims to correlate the effective diameter (Deff) and water-equivalent diameter (Dw) parameters with anterior–posterior (AP), lateral (LAT) and AP + LAT dimensions in order to estimate the patient dose in head CT examinations. Seventy-four patient datasets from head CT examinations were retrospectively collected. The patient’s sizes were calculated from the middle slice using a software of IndoseCT. Dw and Deff were plotted as functions of AP, LAT and AP + LAT dimensions. The best trendline fit for LAT and AP functions was a second order polynomial, which resulted in R2 of 0.89 for Deff vs LAT, 0.88 for Dw vs LAT, 0.92 for Deff vs AP and 0.91 for Dw vs AP. A linear correlation was found for Deff vs AP + LAT, Dw vs AP + LAT and Dw vs Deff with R2 of 0.97, 0.96 and 0.98, respectively.
University students’ fully digital study of mathematics: an identification of student-groups via their resources usage and a characterization by personal and affective characteristics
Authors: Kempen Leander , Liebendörfer Michael
Published: September 2021

We investigated university students’ study of mathematics in the digital setting context of the COVID-19 pandemic. We gathered data from a survey of 89 students enrolled in a ‘Linear Algebra 1’ course including affective variables, learning strategies, social relatedness and resources considered useful. The results indicate students’ high effort and self-regulation and a high variation in affective characteristics and social relatedness. All the traditional aspects of mathematics teaching (lecture, tutorials and lecture notes) were rated as particularly useful. In addition, the videos from external resources were rated as equally useful as the teaching team’s videos. In contrast, traditional literature such as textbooks was rarely considered useful. The most useful resource rated was communication with peers, underlining the important role of social learning despite fully digital learning environments. Finally, a cluster analysis based on students’ rated usefulness of the resources led to three different user-types. Whereas the ‘digitals’ find the external digital resources very useful (videos, webpages, etc.), the ‘traditionalists’ rate the digitalized traditional resources best (lecture, tutorials, etc.). All resources receive uniformly good ratings from a third group (‘all resource users’). We reflect on our findings in light of the pandemic and describe directions for future research.
Dolutegravir Impairs Stem Cell-Based 3D Morphogenesis Models in a Manner Dependent on Dose and Timing of Exposure: An Implication for Its Developmental Toxicity
Authors: Kirkwood-Johnson Lauren , Katayama Nana , Marikawa Yusuke
Published: September 2021

Dolutegravir (DTG) is an antiretroviral drug of the integrase strand transfer inhibitor (INSTI) class used to treat human immunodeficiency virus infection. It is the recommended first-line regimen for most people, including women of childbearing age. However, some human and animal studies have suggested that DTG causes birth defects, although its developmental toxicity remains controversial. Here, we investigated the adverse effects of DTG using pluripotent stem cell-based in vitro morphogenesis models that have previously been validated as effective tools to assess the developmental toxicity of various chemicals. DTG diminished the growth and axial elongation of the morphogenesis model of mouse pluripotent stem cells at exposures of 2 μM and above in a concentration-dependent manner. Concomitantly, DTG altered the expression profiles of developmental regulator genes involved in embryonic patterning. The adverse effects were observed when the morphogenesis model was exposed to DTG at early stages of development, but not at later stages. The potency and molecular impact of DTG on the morphogenesis model were distinct from other INSTIs. Last, DTG altered the growth and gene expression profiles of the morphogenesis model of human embryonic stem cells at 1 μM and above. These studies demonstrate that DTG impairs morphological and molecular aspects of the in vitro morphogenesis models in a manner dependent on dose and timing of exposure through mechanisms that are unrelated to its action as an INSTI. This finding will be useful for interpreting the conflicting outcomes regarding the developmental toxicity of DTG in human and animal studies.
Small understorey trees have greater capacity than canopy trees to adjust hydraulic traits following prolonged experimental drought in a tropical forest
Authors: Giles A L , Rowland L , Bittencourt P R L , Bartholomew D C , Coughlin I , Costa P B , Domingues T , Miatto R C , Barros F V , Ferreira L V , Groenendijk P , Oliveira A A R , da Costa A C L , Meir P , Mencuccini M , Oliveira R S
Published: September 2021

Future climate change predictions for tropical forests highlight increased frequency and intensity of extreme drought events. However, it remains unclear whether large and small trees have differential strategies to tolerate drought due to the different niches they occupy. The future of tropical forests is ultimately dependent on the capacity of small trees (<10 cm in diameter) to adjust their hydraulic system to tolerate drought. To address this question, we evaluated whether the drought tolerance of neotropical small trees can adjust to experimental water stress and was different from tall trees. We measured multiple drought resistance-related hydraulic traits across nine common neotropical genera at the world’s longest-running tropical forest throughfall-exclusion experiment and compared their responses with surviving large canopy trees. Small understorey trees in both the control and the throughfall-exclusion treatment had lower minimum stomatal conductance and maximum hydraulic leaf-specific conductivity relative to large trees of the same genera, as well as a greater hydraulic safety margin (HSM), percentage loss of conductivity and embolism resistance, demonstrating that they occupy a distinct hydraulic niche. Surprisingly, in response to the drought treatment, small trees increased specific hydraulic conductivity by 56.3% and leaf:sapwood area ratio by 45.6%. The greater HSM of small understorey trees relative to large canopy trees likely enabled them to adjust other aspects of their hydraulic systems to increase hydraulic conductivity and take advantage of increases in light availability in the understorey resulting from the drought-induced mortality of canopy trees. Our results demonstrate that differences in hydraulic strategies between small understorey and large canopy trees drive hydraulic niche segregation. Small understorey trees can adjust their hydraulic systems in response to changes in water and light availability, indicating that natural regeneration of tropical forests following long-term drought may be possible.
5Religion and Representation
Authors: Rzepa Joanna
Published: September 2021

In recent years, the relationship between religion and representation has been examined with particular intensity in the field of modernist studies, to which all books reviewed in this chapter have contributed. It is telling that three of them are devoted to Virginia Woolf, whose firm rejection of patriarchal Christianity and the established church has for years been considered a prime example of modernism’s hostility to religion. New scholarship on Woolf, religion, and spirituality offers a much more nuanced view of her engagement with Christian culture and illustrates the wealth of new methodological developments in the field of modernist studies. The review opens with a discussion of the recent religious turn in modernist studies, situating it within the expansion of the field connected to the emergence of the new modernist studies. Subsequently, it examines four new books that contribute to scholarship on modernism and religion. The chapter is divided into five sections: 1. The New Modernist Studies and Religion; 2. Jane de Gay, Virginia Woolf and Christian Culture; 3. Stephanie Paulsell, Religion Around Virginia Woolf; 4. Religion, Secularism, and the Spiritual Paths of Virginia Woolf, edited by Kristina K. Groover; 5. Martin Lockerd, Decadent Catholicism and the Making of Modernism. The books reviewed illustrate the scope and depth of new research into modernism and religion, offering a fresh critical perspective that challenges the widely accepted view of modernism as a purely secular movement.
XVII New Literatures
Authors: Batra Kanika , Lorre-Johnston Christine , Manzo Kerry , McNeill Dougal , Miller Benjamin , Naruse Cheryl Narumi , Niblett Michael , Sharrad Paul , Uraizee Joya , Zarranz Libe Garcia
Published: September 2021

This chapter has seven sections: 1. Africa; 2. Australia; 3. Canada; 4. The Caribbean; 5. South Asia: The Indian Subcontinent and Sri Lanka; 6. New Zealand and Pacific; 7. Southeast Asia. Section 1 is by Kanika Batra, Kerry Manzo, and Joya Uraizee; coverage of West Africa will resume in 2022; section 2 is by Benjamin Miller and Paul Sharrad; section 3 is by Christine Lorre-Johnston and Libe García Zarranz; section 4 is by Michael Niblett; section 5 will resume in 2022; section 6 is by Dougal McNeill; section 7 is by Cheryl Narumi Naruse.
A Review of the ‘Candidatus Liberibacter africanus’ Citrus Pathosystem in Africa
Authors: da Graça John V. , Cook Glynnis , Ajene Inusa J. , Grout Tim G. , Pietersen Gerhard , Roberts Ronel , Bester Rachelle , Pretorius Mathys C. , Maree Hans J.
Published: September 2021

It has been nearly 100 years since citrus growers in two distinct regions in the northern provinces of South Africa noticed unusual symptoms in their citrus trees, causing significant crop losses. They had no idea that these symptoms would later become part of an almost global pandemic of a disease called greening or huanglongbing (HLB). The rapid spread of the disease indicated that it might be caused by a transmissible pathogen, but it took >50 years to identify the causative agent as ‘Candidatus Liberibacter africanus’. Recently, the disease appeared in more African countries, spreading by both infected planting material and Trioza erytreae. To date, five ‘Ca. L. africanus’ subspecies have been identified in various rutaceous species, with ‘Ca. L. africanus subsp. clausenae’ the only subspecies for which a biovar was detected in citrus. Efforts to detect and differentiate HLB-causing Liberibacter species are ongoing, and recent developments are discussed here. This review focuses on aspects of the African form of HLB, including its specific bacterial species and subspecies, its main insect vector, its geographic distribution, and current management strategies.
The Utility of the Hyperinlet View in Posterior Fixation of Pelvic Ring Injuries
Authors: Gosselin Michelle M. , Dennis Garret S. , Gary Joshua L.
Published: September 2021

Percutaneous pelvic fixation has evolved into a widely used, safe, and effective treatment option in the management of pelvic ring injuries. Proper preoperative and intraoperative radiographic evaluation of these injuries is critical to ensure safe placement of fixation of the pelvis. Traditional intraoperative views for posterior pelvic ring fixation include the pelvic inlet and outlet views. We propose that the intraoperative use of a hyperinlet view, which uses additional cranial tilt relative to the traditional inlet view, is helpful to better delineate the spinal canal and thereby better define the posterior limit of the osseous fixation pathway of the upper sacral segments. This study illustrates the use of this novel radiographic view and presents a patient cohort in which it was effectively used.
Smoking Is Associated With Lower Satisfaction in Nondiabetic Patients Undergoing Minimally Invasive Single-level Transforaminal Lumbar Interbody Fusion
Authors: Gatot Cheryl , Liow Ming Han Lincoln , Goh Graham S. , Mohan Niraj , Yongqiang Chen Jerry , Ling Zhixing Marcus , Soh Reuben C.C. , Yue Wai-Mun , Guo Chang-Ming , Tan Seang-Beng , Chen John Li-Tat
Published: September 2021

Study Design:

This was a retrospective review of prospectively collected registry data.

Objective:

The objective of this study was to investigate the effect of smoking on 2 years postoperative functional outcomes, satisfaction, and radiologic fusion in nondiabetic patients undergoing minimally invasive transforaminal lumbar interbody fusion (TLIF) for degenerative spine conditions.

Summary of Background Data:

There is conflicting data on the effect of smoking on long-term functional outcomes following lumbar fusion. Moreover, there remains a paucity of literature on the influence of smoking within the field of minimally invasive spine surgery.

Methods:

Prospectively collected registry data of nondiabetic patients who underwent primary single-level minimally invasive TLIF in a single institution was reviewed. Patients were stratified based on smoking history. All patients were assessed preoperatively and postoperatively using the Numerical Pain Rating Scale for back pain and leg pain, Oswestry Disability Index, Short-Form 36 Physical and Mental Component Scores. Satisfaction was assessed using the North American Spine Society questionnaire. Radiographic fusion rates were compared.

Results:

In total, 187 patients were included, of which 162 were nonsmokers, and 25 had a positive smoking history. In our multivariate analysis, smoking history was insignificant in predicting for minimal clinically important difference attainment rates in Physical Component Score and fusion grading outcomes. However, in terms of satisfaction score, positive smoking history remained a significant predictor (odds ratio=4.7, 95% confidence interval: 1.10–20.09,P=0.036).

Conclusions:

Nondiabetic patients with a positive smoking history had lower satisfaction scores but comparable functional outcomes and radiologic fusion 2 years after single-level TLIF. Thorough preoperative counseling and smoking cessation advice may help to improve patient satisfaction following minimally invasive spine surgery.

Level of Evidence:

Level III—nonrandomized cohort study.
Disseminated Coccidioidomycosis as the First Presentation of a C-Terminal NFKB2 Pathogenic Variant: A Case Report and Review of the Literature
Authors: Pérez Cavazos Samantha , De la Cruz Cruz Rodrigo A. , Castillo Bejarano José Iván , Vaquera Aparicio Denisse Natalie , Mascareñas de los Santos Abiel Homero , Zárate Hernández Mariá del Carmen
Published: September 2021

Introduction:

Although most cases of coccidioidomycosis are subclinical or self-limited respiratory disease, 1% lead to extrathoracic dissemination and become fatal, especially in patients with an associated immunodeficiency. Up to 30%–50% of patients with defects in cell-mediated immunity, those with AIDS and recipients of solid-organ transplants, may develop disseminated coccidioidomycosis (DC). Within the primary immunodeficiencies, an uncommon group is caused by C-terminal NFKB2 pathogenic variants.

Materials and Methods:

We performed a literature search of core databases. Written informed consent for the study and for publication was obtained.

Case Presentation:

A 7-year-old Mexican girl, eldest of 3 sisters, no relevant family history, and a history of recurrent upper respiratory infections and alopecia totalis was admitted with DC involving pulmonary, soft tissue, skin, bone and joint compromise. The immunodeficiency assessment showed low IgM and NK cells. We found an NFKB2 de novo heterozygous nonsense mutation of c.2611C>T (p.Gln871*). She was treated with liposomal amphotericin B and itraconazole with surgical debridement. The clinical phenotype of this primary immunodeficiency is characterized by antibody deficiency and associated broncho-pulmonary predisposition to infection, but moreover also opportunistic infections and autoimmunity, most recognizable alopecia and adrenocorticotropic hormone-deficiency. After 1 year of her discharge, she continues under surveillance with antifungal therapy with itraconazole and replacement intravenous immunoglobulin until today

Conclusion:

This is the first case report of DC in a patient with an NFKB2 pathogenic variant and it illustrates the importance of screening for primary immunodeficiencies in patients with disseminated fungal infections.
Machine Learning Used to Compare the Diagnostic Accuracy of Risk Factors, Clinical Signs and Biomarkers and to Develop a New Prediction Model for Neonatal Early-onset Sepsis
Authors: Stocker Martin , Daunhawer Imant , van Herk Wendy , el Helou Salhab , Dutta Sourabh , Schuerman Frank A. B. A. , van den Tooren-de Groot Rita K. , Wieringa Jantien W. , Janota Jan , van der Meer-Kappelle Laura H. , Moonen Rob , Sie Sintha D. , de Vries Esther , Donker Albertine E. , Zimmerman Urs , Schlapbach Luregn J. , de Mol Amerik C. , Hoffmann-Haringsma Angelique , Roy Madan , Tomaske Maren , Kornelisse René F. , van Gijsel Juliette , Plötz Frans B. , Wellmann Sven , Achten Niek B. , Lehnick Dirk , van Rossum Annemarie M. C. , Vogt Julia E.
Published: September 2021

Background:

Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs.

Study Design:

Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier.

Results:

One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random.

Conclusions:

Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.
Bronchoscopy in Patients With Known or Suspected COVID-19
Authors: Cumbo-Nacheli Gustavo , Colt Henri , Agrawal Abhinav , Cicenia Joseph , Corbetta Lorenzo , Goel Akhil D. , Goga Ameena , Lee Hans J. , Murgu Septimiu , Pannu Jasleen , Senitko Michal , Tarantini Francesco , Vujacich Patricia , Williamson Jonathan , Yap Elaine , Lentz Robert J.
Published: September 2021

Background:

Amid the Coronavirus Disease 2019 (COVID-19) pandemic, the benefits and risks of bronchoscopy remain uncertain. This study was designed to characterize bronchoscopy-related practice patterns, diagnostic yields, and adverse events involving patients with known or suspected COVID-19.

Methods:

An online survey tool retrospectively queried bronchoscopists about their experiences with patients with known or suspected COVID-19 between March 20 and August 20, 2020. Collected data comprised the Global Pandemic SARS-CoV-2 Bronchoscopy Database (GPS-BD). All bronchoscopists and patients were anonymous with no direct investigator-to-respondent contact.

Results:

Bronchoscopy procedures involving 289 patients from 26 countries were analyzed. One-half of patients had known COVID-19. Most (82%) had at least 1 pre-existing comorbidity, 80% had at least 1 organ failure, 51% were critically ill, and 37% were intubated at the time of the procedure. Bronchoscopy was performed with diagnostic intent in 166 (57%) patients, yielding a diagnosis in 86 (52%). and management changes in 80 (48%). Bronchoscopy was performed with therapeutic intent in 71 (25%) patients, mostly for secretion clearance (87%). Complications attributed to bronchoscopy or significant clinical decline within 12 hours of the procedure occurred in 24 (8%) cases, with 1 death.

Conclusion:

Results from this international database provide a widely generalizable characterization of the benefits and risks of bronchoscopy in patients with known or suspected COVID-19. Bronchoscopy in this setting has reasonable clinical benefit, with diagnosis and/or management change resulting from about half of the diagnostic cases. However, it is not without risk, especially in patients with limited physiological reserve.
Increased FIO2 influences SvO2 interpretation and accuracy of Fick-based cardiac output assessment in cardiac surgery patients
Authors: Lin Sheng-Yi , Chang Feng-Cheng , Lin Jr-Rung , Chou An-Hsun , Tsai Yung-Fong , Liao Chia-Chih , Tsai Hsin-I. , Chen Chun-Yu
Published: September 2021

Introduction:

The study aimed to reveal how the fraction of inspired oxygen (FIO2) affected the value of mixed venous oxygen saturation (SvO2) and the accuracy of Fick-equation-based cardiac output (Fick-CO).

Methods:

Forty two adult patients who underwent elective cardiac surgery were enrolled and randomly divided into 2 groups: FIO2 < 0.7 or >0.85. Under stable general anesthesia, thermodilution-derived cardiac output (TD-CO), SvO2, venous partial pressure of oxygen, hemoglobin, arterial oxygen saturation, arterial partial pressure of oxygen, and blood pH levels were recorded before surgical incision.

Results:

Significant differences in FIO2 values were observed between the 2 groups (0.56 ± 0.08 in the <70% group and 0.92 ± 0.03 in the >0.85 group; P < .001). The increasing FIO2 values lead to increases in SvO2, venous partial pressure of oxygen, and arterial partial pressure of oxygen, with little effects on cardiac output and hemoglobin levels. When comparing to TD-CO, the calculated Fick-CO in both groups had moderate Pearson correlations and similar linear regression results. Although the FIO2 <0.7 group presented a less mean bias and a smaller limits of agreement, neither group met the percentage error criteria of <30% in Bland-Altman analysis.

Conclusion:

Increased FIO2 may influence the interpretation of SvO2 and the exacerbation of Fick-CO estimation, which could affect clinical management.

Trial Registration:

ClinicalTrials.gov ID number: NCT04265924, retrospectively registered (Date of registration: February 9, 2020).
Neuron - specific enolase predicts the prognosis in advanced small cell lung cancer patients treated with first-line PD-1/PD-L1 inhibitors
Authors: Li Lingling , Zhang Zhibo , Hu Yi
Published: September 2021

There has been no effective biomarker for small cell lung cancer (SCLC) patients with first-line immune checkpoint inhibitors (ICIs) treatment. The predictive value of neuron-specific enolase (NSE) in this cohort remains unclear.

The medical records of 254 consecutive SCLC patients receiving programmed cell death receptor-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors were compiled from January 2015 to October 2020 in Chinese PLA General Hospital. Survival analysis was performed to explore the prognostic role of NSE at baseline and 3 weeks post treatment.

One hundred two advanced SCLC patients treated with first-line PD-1/PD-L1 inhibitors were enrolled in this study. Normal baseline NSE levels were correlated with significantly prolonged progression-free survival (PFS, median: 8.7 vs 4.7 months, P = .006) and overall survival (OS, median: 23.8 vs 15.2 months, P = .014) compared with elevated baseline NSE levels, so as for normal NSE levels at 3 weeks with prolonged PFS (median PFS: 8.4 vs 4.5 months, P = .0002) and OS (median OS: 23.3 vs 7.4 months, P < .0001). Intriguingly, elevated NSE levels at 3 weeks were associated with shorter PFS (median PFS: 4.5 vs 5.8 months, P = .04) and OS (median OS: 5.5 vs 14.7 months, P < .0001) compared with normal NSE levels in the elevated baseline NSE subgroup. Most subgroup analyses stratified by clinical characteristics confirmed the prognostic value of baseline NSE level.

Elevated NSE levels at baseline and 3 weeks were associated with worse prognosis in advanced SCLC patients receiving first-line ICIs treatment. NSE level might be applied as a useful prognostic tool for SCLC patients with immunotherapy.
Clinical efficacy and safety of Huachansu injection combination with platinum-based chemotherapy for advanced non-small cell lung cancer
Authors: Tan Xinmei , Liang Xueyan , Xi Jiaxi , Guo Sitong , Meng Mingyu , Chen Xiaoyu , Li Yan
Published: September 2021

Background:

Huachansu injection (HCS) is a widely used traditional Chinese medicine for advanced non-small cell lung cancer (NSCLC) to alleviate the adverse drug reactions (ADRs) and enhance the clinical efficacy of chemotherapy.

Objective:

To evaluate the efficacy and safety of HCS as an adjunctive treatment to platinum-based chemotherapy (PBC) for advanced NSCLC.

Methods:

A systematic review and meta-analysis were conducted according to PRISMA guidelines. A total of nine databases were searched to select randomized controlled trials (RCTs) of HCS plus PBC to treat NSCLC from inception to October 10, 2020. RCTs on HCS plus PBC vs PBC alone for advanced NSCLC were included. Dichotomous data were pooled as risk ratio (RR) with 95% confidence intervals. RCTs compared to HCS plus PBC vs PBC alone were included. Primary outcomes were objective response rate (ORR) and disease control rate (DCR), and secondary outcomes were survival rate, quality of life (QOL), and adverse drug reactions (ADRs). GRADE software was used to access the quality of evidence.

Results:

A total of 32 RCTs, including 2753 patients, were included. Compared to PBC alone, HCS plus PBC improved the ORR, DCR, 1- and 2-year survival rates, and QOL and alleviated neutropenia, thrombocytopenia, nausea, vomiting, anemia, liver injury, renal injury, and alopecia.

Conclusions:

Compared to PBC alone, HCS plus PBC improved the clinical efficacy and alleviated the ADRs in advanced NSCLC patients. Considering the limitations of the included RCTs, high-quality trials with longer follow-ups are needed to further confirm the results.
An association between electronic nicotine delivery systems use and a history of stroke using the 2016 behavioral risk factor surveillance system
Authors: Bricknell Ryan A.T. , Ducaud Christobal , Figueroa Alejandra , Schwarzman Logan S. , Rodriguez Pura , Castro Grettel , Zevallos Juan Carlos , Barengo Noël C.
Published: September 2021

Electronic nicotine delivery systems (ENDS) are growing in use and many of the health implications with these devices remain unknown. This study aims to assess, using a survey representative of the USA general population, if an association exists between a history of ENDS use and a history of stroke.

This cross-sectional study was a secondary data analysis using the 2016 behavioral risk factor surveillance system survey. The main exposure variable of the study was a self-reported history of ENDS use. The main outcome was a self-reported history of stroke. Covariates included sex, race, traditional cigarette use, smokeless tobacco use, chronic kidney disease, diabetes, myocardial infarction, and coronary artery disease. Unadjusted and adjusted logistic regression analyses were done. Adjusted odds ratios (AOR) and their corresponding 95% confidence intervals (CI) were calculated.

Of the 486,303 total behavioral risk factor surveillance system survey participants, 465,594 met the inclusion criteria for this study of ENDS use and stroke. This study shows that current ENDS use was positively associated with a history of stroke. AOR of some daily ENDS use with stroke was 1.28 (95% CI: 1.02–1.61) and AOR of current daily ENDS use with stroke was 1.62 (95% CI: 1.18–2.31). The majority (55.9%) of current daily ENDS users reported former traditional cigarette smoking. Female sex, non-white ethnicity, elderly age, chronic kidney disease, coronary artery disease, diabetes, and traditional cigarette use characteristics were all also associated with increased odds of reporting a stroke.

This study found a statistically significant and positive association between ENDS use and a history of stroke. Further research is warranted to investigate the reproducibility and temporality of this association. Nevertheless, this study contributes to the growing body of knowledge about the potential cardiovascular concerns related to ENDS use and the need for large cohort studies.
The Role of Cognitive Impairment on Physical Therapy Attendance and Outcomes in Multiple Sclerosis
Authors: Gomes Kayla E. , Ruiz Jennifer A. , Raskin Sarah A. , Turner Aaron P. , DelMastro Heather M. , Neto Lindsay O. , Gromisch Elizabeth S.
Published: September 2021

Background and Purpose:

Many persons with multiple sclerosis (PwMS) experience cognitive impairments, which may affect their ability to engage in physical therapy. There is limited information on how cognitive impairments are associated with PwMS' ability to participate and improve their functional outcomes. This study aimed to assess the relationship between cognitive functioning and PwMS' attendance, total goal attainment, and functional improvement following physical therapy intervention.

Methods:

Participants (n = 45) were PwMS who participated in a larger self-management study and enrolled in physical therapy within the past 2 years. Objective cognitive functioning was examined using tests of prospective memory, retrospective memory, working memory, and processing speed, along with a self-report measure. Bivariate analyses were conducted to examine the relationship between cognitive functioning and each physical therapy outcome (session attendance, attaining goals, and changes in functional outcome measures), followed by logistic regressions with age, education, gender, and disability level as covariates.

Results:

Difficulty learning new verbal information was associated with a greater likelihood of “no showing” one or more of their physical therapy sessions. Reductions in working memory and processing speed were associated with PwMS not meeting all their rehabilitation goals. Despite deficits in new learning, memory, and processing speed, 85.2% of those with pre-/postscores showed improvements in at least one functional outcome measure following physical therapy intervention.

Discussion and Conclusions:

These findings demonstrate the ability for PwMS to make functional motor gains despite the presence of cognitive impairments and highlight the potential contributions of cognitive functioning on attendance and goal attainment of physical therapy intervention.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A362, which includes background, methods, results, and discussion in the authors' own voices).
Claudin-18 Immunohistochemical Staining Facilitates the Identification of Metastatic Carcinoma of Gastric or Pancreatic Origin in Effusion Specimens
Authors: Yang Yu-Jou , Jeng Yung-Ming , Yang Ching-Yao , Hu Hsiang-Wei
Published: September 2021

Determining the primary origin of a malignant effusion remains a common challenge for cytopathologists. Although immunohistochemical (IHC) markers are available for most primary sites, ideal IHC markers for metastatic gastric adenocarcinoma and pancreatic ductal adenocarcinoma are lacking, and related interpretation is often hindered by mesothelial cells. We recently revealed that claudin-18 IHC staining is useful for identifying the stomach and pancreas as the primary sites of metastatic adenocarcinoma. Thus, we assessed the use of claudin-18 IHC staining in 111 cell blocks obtained from various metastatic cancers and specimens negative for malignancy. Positive membranous claudin-18 staining was noted in all 10 (100%) metastatic pancreatic ductal adenocarcinomas, 9 (90%) of 10 gastric adenocarcinomas, and 1 (9%) of 11 nonmucinous lung adenocarcinomas. The cases of metastatic mucinous carcinomas of lung origin (1 case) and ovarian origin (1 case) were also positive for claudin-18. The other remaining 89 cases showed variable cytoplasmic staining on some cells (73 cases) or complete absence of staining (16 cases). After normalization to the tumor frequency, the sensitivity and specificity for identifying the stomach or pancreas as primary tumor sites in ascites were 95% (confidence interval: 0.83-0.99) and 99% (confidence interval: 0.94-1), respectively. In conclusion, membranous claudin-18 staining is a useful marker for metastatic gastric adenocarcinoma and pancreatic ductal adenocarcinoma in effusion specimens.
Amyloid Arthropathy: A Review
Authors: Diaz-Perez Julio A. , Conway Sheila A. , Zuo Yiqin , Nielsen Gunnlaugur Petur , Selig Martin , Rosenberg Andrew E.
Published: September 2021

Amyloid arthropathy is a joint disease associated with systemic amyloidosis. Herein, we present a model case and review the clinicopathologic features and pathophysiology of this disorder. Amyloid arthropathy results from elevation of serum amyloidogenic proteins and their deposition as aggregates in synovial fluid and articular tissues. The most common proteins are beta-2-microglobulin in the context of long-term hemodialysis therapy and immunoglobulin light chains associated with plasma cell proliferations. We provide a comprehensive update on the pathogenesis, clinical manifestations, and pathologic features of amyloid arthropathy. We provide detailed insights on amyloid protein deposition and aggregation in joints and proper details for diagnosis.
When Anger Remains Unspoken: Anger and Accelerated Epigenetic Aging Among Stress-Exposed Black Americans
Authors: McKenna Brooke G. , Mekawi Yara , Katrinli Seyma , Carter Sierra , Stevens Jennifer S. , Powers Abigail , Smith Alicia K. , Michopoulos Vasiliki
Published: September 2021

Objective

Race-related lifetime stress exposure (LSE) including racial discrimination, trauma, and stressful life events have been shown to contribute to racial health disparities. However, little is known about associations between race-related stressors and premature biological aging that confer the risk of adverse health outcomes. Even less is known about the mechanisms through which race-related stressors may be associated with accelerated aging. Early evidence suggests psychological processes such as anger, and particularly the internalization of anger, may play a role.

Methods

In a community sample of predominantly low-income Black adults (n = 219; age = 45.91 [12.33] years; 64% female), the present study examined the association of race-related LSE (as defined by exposure to racial discrimination, trauma, and stressful life events) and epigenetic age acceleration through anger expression.

Results

Internalized and externalized anger expression were each significantly associated with LSE and age acceleration. Although LSE was not directly associated with age acceleration (ΔR
2 = 0.001, p = .64), we found that greater LSE was indirectly associated with age acceleration through increases in internalized, but not externalized, anger (indirect effect: β = 0.03, standard error = 0.02, 95% confidence interval = 0.003 to 0.08; total effect: β = 0.02, 95% confidence interval = −0.25 to 0.31).

Conclusions

These results suggest race-related LSE may elicit the internalization of anger, which, along with the externalization of anger, may initiate detrimental epigenetic alterations that confer the risk of adverse health outcomes. These findings lay the groundwork for longitudinal studies of the association between race-related stress and racial health disparities.
β-Adrenergic Contributions to Emotion and Physiology During an Acute Psychosocial Stressor
Authors: MacCormack Jennifer K. , Armstrong-Carter Emma L. , Gaudier-Diaz Monica M. , Meltzer-Brody Samantha , Sloan Erica K. , Lindquist Kristen A. , Muscatell Keely A.
Published: September 2021

Objective

β-Adrenergic receptor signaling, a critical mediator of sympathetic nervous system influences on physiology and behavior, has long been proposed as one contributor to subjective stress. However, prior findings are surprisingly mixed about whether β-blockade (e.g., propranolol) blunts subjective stress, with many studies reporting no effects. We reevaluated this question in the context of an acute psychosocial stressor with more comprehensive measures and a larger-than-typical sample. We also examined the effects of β-blockade on psychophysiological indicators of sympathetic and parasympathetic nervous system reactivity, given that β-blockade effects for these measures specifically under acute psychosocial stress are not yet well established.

Methods

In a double-blind, randomized, placebo-controlled study, 90 healthy young adults received 40 mg of the β-blocker propranolol or placebo. Participants then completed the Trier Social Stress Test, which involved completing an impromptu speech and difficult arithmetic in front of evaluative judges. Self-reported emotions and appraisals as well as psychophysiology were assessed throughout.

Results

Propranolol blunted Trier Social Stress Test preejection period reactivity (b = 9.68, p = .003), a marker of sympathetic nervous system activity, as well as salivary α-amylase reactivity (b = −0.50, p = .006). Critically, propranolol also blunted negative, high arousal emotions in response to the stressor (b = −0.22, p = .026), but cognitive appraisals remained intact (b values < −0.17, p values > .10).

Conclusions

These results provide updated experimental evidence that β-adrenergic blockade attenuates negative, high arousal emotions in response to a psychosocial stressor while also blunting sympathetic nervous system reactivity. Together, these findings shed light on the neurophysiological mechanisms by which stressors transform into the subjective experience we call “stress.”

Trial Registration: ClinicalTrials.gov Identifier: NCT02972554.