bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating and Optimizing Surface Soil Moisture Drydowns in the ORCHIDEE Land Surface Model at In Situ Locations
Authors: Raoult Nina , Ottlé Catherine , Peylin Philippe , Bastrikov Vladislav , Maugis Pascal
Published: March 2021

The rate at which land surface soils dry following rain events is an important feature of terrestrial models. It determines, for example, the water availability for vegetation, the occurrences of droughts, and the surface heat exchanges. As such, surface soil moisture (SSM) “drydowns,” i.e., the SSM temporal dynamics following a significant rainfall event, are of particular interest when evaluating and calibrating land surface models (LSMs). By investigating drydowns, characterized by an exponential decay time scale τ, we aim to improve the representation of SSM in the ORCHIDEE global LSM. We consider τ calculated over 18 International Soil Moisture Network sites found within the footprint of FLUXNET towers, covering different vegetation types and climates. Using the ORCHIDEE LSM, we compare τ from the modeled SSM time series to values computed from in situ SSM measurements. We then assess the potential of using τ observations to constrain some water, carbon, and energy parameters of ORCHIDEE, selected using a sensitivity analysis, through a standard Bayesian optimization procedure. The impact of the SSM optimization is evaluated using FLUXNET evapotranspiration and gross primary production (GPP) data. We find that the relative drydowns of SSM can be well calibrated using observation-based τ estimates, when there is no need to match the absolute observed and modeled SSM values. When evaluated using independent data, τ-calibration parameters were able to improve drydowns for 73% of the sites. Furthermore, the fit of the model to independent fluxes was only minutely changed. We conclude by considering the potential of global satellite products to scale up the experiment to a global-scale optimization.
Railway cyber safety: An intelligent threat perspective
Authors: Unwin Duncan , Sanzogni Louis
Published: March 2021

Cybersecurity threats to railways are increasing, both due to improvements in the techniques of hackers and the increasing merger of cyber and physical spheres. Accepted approaches to safety can be extended to consider the risks from cyber, however the nature of railways as complex cyber-physical systems of systems may require a broader approach beyond functional safety. This paper explores some of the cybersecurity hazards using a war gaming approach. The authors find that, while standard engineering approaches are effective in building new rail control system components, a broader and more creative consideration of attacks has benefits. In particular they identify the ability to cause mass disruption by targeting the fail-safes designed to ensure safety or auxiliary systems that are not directly classified within the scope of the ICS.
Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia
Authors: Murali Ishwarya , Kasar Siddha , Naeem Aishath , Tyekucheva Svitlana , Khalsa Jasneet K. , Thrash Emily M. , Itchaki Gilad , Livitz Dimitri , Leshchiner Ignaty , Dong Shuai , Fernandes Stacey M. , Getz Gad , Johnson Amy , Brown Jennifer R.
Published: March 2021

Inhibitors of Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase δ (PI3Kδ) that target the B-cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Mutations associated with resistance to BTK inhibitors have been identified, but limited data are available on mechanisms of resistance to PI3Kδ inhibitors. Here we present findings from longitudinal whole-exome sequencing of cells from patients with multiply relapsed CLL (N = 28) enrolled in trials of PI3K inhibitors. The nonresponder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF, and KRAS genes in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in nonresponder CLL cells with and without mutations, whereas treatment with a MEK inhibitor rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδ inhibitors in CLL and provide a rationale for therapy with a combination of PI3Kδ and ERK inhibitors.
Characterization of DLBCL with a PMBL gene expression signature
Authors: Duns Gerben , Viganò Elena , Ennishi Daisuke , Sarkozy Clementine , Hung Stacy S. , Chavez Elizabeth , Takata Katsuyoshi , Rushton Christopher , Jiang Aixiang , Ben-Neriah Susana , Woolcock Bruce W. , Slack Graham W. , Hsi Eric D. , Craig Jeffrey W. , Hilton Laura K. , Shah Sohrab P. , Farinha Pedro , Mottok Anja , Gascoyne Randy D. , Morin Ryan D. , Savage Kerry J. , Scott David W. , Steidl Christian
Published: March 2021

Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typically affects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas with gene expression features of PMBL have been described in nonmediastinal sites, raising questions about how these tumors should be classified. Here, we investigated whether these nonmediastinal lymphomas are indeed PMBLs or instead represent a distinct group within diffuse large B-cell lymphoma (DLBCL). From a cohort of 325 de novo DLBCL cases, we identified tumors from patients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature (nm-PMBLsig+; n = 16; 5%). A majority of these tumors expressed MAL and CD23, proteins typically observed in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig+ cases revealed close associations with DLBCL, and a majority displayed a germinal center B cell–like cell of origin (GCB). In contrast to patients with bf-PMBL, patients with nm-PMBLsig+ presented at an older age and did not show pleural disease, and bone/bone marrow involvement was observed in 3 cases. However, although clinically distinct from bf-PMBL, nm-PMBLsig+ tumors resembled bf-PMBL at the molecular level, with upregulation of immune response, JAK-STAT, and NF-κB signatures. Mutational analysis revealed frequent somatic gene mutations in SOCS1, IL4R, ITPKB, and STAT6, as well as CD83 and BIRC3, with the latter genes significantly more frequently affected than in GCB DLBCL or bf-PMBL. Our data establish nm-PMBLsig+ lymphomas as a group within DLBCL with distinct phenotypic and genetic features. These findings may have implications for gene expression– and mutation-based subtyping of aggressive B-cell lymphomas and related targeted therapies.
Osteocytes regulate neutrophil development through IL-19: a potent cytokine for neutropenia treatment
Authors: Xiao Min , Zhang Wuju , Liu Wen , Mao Linlin , Yang Jincheng , Hu Le , Zhang Sheng , Zheng Yaling , Liu Anling , Song Qiancheng , Li Yuhua , Xiao Guozhi , Zou Zhipeng , Bai Xiaochun
Published: March 2021

Osteocytes are the most abundant (90% to 95%) cells in bone and have emerged as an important regulator of hematopoiesis, but their role in neutrophil development and the underlying mechanisms remain unclear. Interleukin 19 (IL-19) produced predominantly by osteocytes stimulated granulopoiesis and neutrophil formation, which stimulated IL-19 receptor (IL-20Rβ)/Stat3 signaling in neutrophil progenitors to promote their expansion and neutrophil formation. Mice with constitutive activation of mechanistic target of rapamycin complex (mTORC1) signaling in osteocytes (Dmp1-Cre) exhibited a dramatic increase in IL-19 production and promyelocyte/myelocytic expansion, whereas mTORC1 inactivation in osteocytes reduced IL-19 production and neutrophil numbers in mice. We showed that IL-19 administration stimulated neutrophil development, whereas neutralizing endogenous IL-19 or depletion of its receptor inhibited the process. Importantly, low-dose IL-19 reversed chemotherapy, irradiation, or chloramphenicol-induced neutropenia in mice more efficiently than granulocyte colony-stimulating factor. This evidence indicated that IL-19 was an essential regulator of neutrophil development and a potent cytokine for neutropenia treatment.
Outcomes of a clinician-directed protocol for discontinuation of complement inhibition therapy in atypical hemolytic uremic syndrome
Authors: Chaturvedi Shruti , Dhaliwal Noor , Hussain Sarah , Dane Kathryn , Upreti Harshvardhan , Braunstein Evan M. , Yuan Xuan , Sperati C. John , Moliterno Alison R. , Brodsky Robert A.
Published: March 2021

Terminal complement inhibition is the standard of care for atypical hemolytic uremic syndrome (aHUS). The optimal duration of complement inhibition is unknown, although indefinite therapy is common. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 31 patients that started eculizumab for acute aHUS (and without a history of renal transplant). Twenty-five (80.6%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (interquartile range: 1.06, 9.70) months. Eighteen patients discontinued per protocol and 7 because of nonadherence. Of these, 5 (20%) relapsed; however, relapse rate was higher in the case of nonadherence (42.8%) vs clinician-directed discontinuation and monitoring (11.1%). Four of 5 patients who relapsed were successfully retreated without a decline in renal function. One patient died because of recurrent aHUS and hypertensive emergency in the setting of nonadherence. Nonadherence to therapy (odds ratio, 8.25; 95% confidence interval, 1.02-66.19; P = .047) was associated with relapse, whereas the presence of complement gene variants (odds ratio, 1.39; 95% confidence interval, 0.39-4.87; P = .598) was not significantly associated with relapse. Relapse occurred in 40% (2 of 5) with a CFH or MCP variant, 33.3% (2 of 6) with other complement variants, and 0% (0 of 6) with no variants (P = .217). There was no decline in mean glomerular filtration rate from the date of stopping eculizumab until end of follow-up. In summary, eculizumab discontinuation with close monitoring is safe in most patients, with low rates of aHUS relapse and effective salvage with eculizumab retreatment in the event of recurrence.
Tandem high-dose influenza vaccination is associated with more durable serologic immunity in patients with plasma cell dyscrasias
Authors: Branagan Andrew R. , Duffy Eamon , Gan Geliang , Li Fangyong , Foster Connor , Verma Rakesh , Zhang Lin , Parker Terri L. , Seropian Stuart , Cooper Dennis L. , Brandt Debra , Kortmansky Jeremy , Witt Davit , Ferencz Thomas M. , Dhodapkar Kavita M. , Dhodapkar Madhav V.
Published: March 2021

Patients with plasma cell dyscrasias (PCDs) experience an increased burden of influenza, and current practice of single-dose annual influenza vaccination yields suboptimal protective immunity in these patients. Strategies to improve immunity to influenza in these patients are clearly needed. We performed a randomized, double-blind, placebo-controlled clinical trial comparing tandem Fluzone High-Dose influenza vaccination with standard-of-care influenza vaccination. Standard-of-care vaccination was single-dose age-based vaccination (standard dose, <65 years; high dose, ≥65 years), and patients in this arm received a saline placebo injection at 30 days. A total of 122 PCD patients were enrolled; 47 received single-dose standard-of-care vaccination, and 75 received 2 doses of Fluzone High-Dose vaccine. Rates of hemagglutinin inhibition (HAI) titer seroprotection against all 3 strains (H1N1, H3N2, and influenza B) were significantly higher for patients after tandem high-dose vaccination vs control (87.3% vs 63.2%; P = .003) and led to higher seroprotection at the end of flu season (60.0% vs 31.6%; P = .04). These data demonstrate that tandem high-dose influenza vaccination separated by 30 days leads to higher serologic HAI titer responses and more durable influenza-specific immunity in PCD patients. Similar vaccine strategies may also be essential to achieve protective immunity against other emerging pathogens such as novel coronavirus in these patients. This trial was registered at www.clinicaltrials.gov as #NCT02566265.
Intracellular pH regulation: characterization and functional investigation of H+ transporters in Stylophora pistillata
Authors: Capasso Laura , Ganot Philippe , Planas-Bielsa Víctor , Tambutté Sylvie , Zoccola Didier
Published: March 2021

Background

Reef-building corals regularly experience changes in intra- and extracellular H+ concentrations ([H+]) due to physiological and environmental processes. Stringent control of [H+] is required to maintain the homeostatic acid-base balance in coral cells and is achieved through the regulation of intracellular pH (pHi). This task is especially challenging for reef-building corals that share an endosymbiotic relationship with photosynthetic dinoflagellates (family Symbiodinaceae), which significantly affect the pHi of coral cells. Despite their importance, the pH regulatory proteins involved in the homeostatic acid-base balance have been scarcely investigated in corals. Here, we report in the coral Stylophora pistillata a full characterization of the genomic structure, domain topology and phylogeny of three major H+ transporter families that are known to play a role in the intracellular pH regulation of animal cells; we investigated their tissue-specific expression patterns and assessed the effect of seawater acidification on their expression levels.

Results

We identified members of the Na+/H+ exchanger (SLC9), vacuolar-type electrogenic H+-ATP hydrolase (V-ATPase) and voltage-gated proton channel (HvCN) families in the genome and transcriptome of S. pistillata. In addition, we identified a novel member of the HvCN gene family in the cnidarian subclass Hexacorallia that has not been previously described in any species. We also identified key residues that contribute to H+ transporter substrate specificity, protein function and regulation. Last, we demonstrated that some of these proteins have different tissue expression patterns, and most are unaffected by exposure to seawater acidification.

Conclusions

In this study, we provide the first characterization of H+ transporters that might contribute to the homeostatic acid-base balance in coral cells. This work will enrich the knowledge of the basic aspects of coral biology and has important implications for our understanding of how corals regulate their intracellular environment.
The Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-15): translation, adaptation and validation of the Polish version for patients with multiple sclerosis and spinal cord injury
Authors: Przydacz Mikolaj , Golabek Tomasz , Dudek Przemyslaw , Chlosta Piotr
Published: March 2021

Background

Polish physicians and researchers lack an extensive and precise instrument in their native language for evaluating sexual dysfunction in individuals with neurogenic disorders. The aim of this study was to create a culturally adapted, validated, Polish language version of the Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-15) for persons with multiple sclerosis (MS) and spinal cord injury (SCI).

Methods

International recommendations and standardized methods for instrument validation were followed. Sexually active patients with MS and SCI completed the MSISQ-15, International Index of Erection Function (IIEF-15, men), and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-31, women). IIEF-15 and PISQ-31 were used as reference questionnaires. Responses were collected at baseline (test) and after 2 weeks (re-test).

Results

We recruited 299 Polish-speaking patients with MS or SCI. Interviews disclosed that the translated questionnaire had optimal content validity/cross-cultural adaptation. MSISQ-15 scores correlated significantly with the severity of sexual dysfunction as evaluated by IIEF-15 (r = − 0.487) and PISQ-31 (r = − 0.709). These correlations substantiated the high quality construct/criterion validity. An analysis of reliability presented good internal consistency (Cronbach’s alpha of 0.93 for the total score of MS patients and 0.86 for the total score of SCI patients) and reproducibility (intraclass correlation coefficients of 0.91 for the total score of MS patients and 0.92 for the total score of SCI patients). There were no ceiling or floor effects.

Conclusions

The Polish version of MSISQ-15 exhibited excellent measurement properties. It is a suitable and reliable instrument to assess sexual dysfunction in MS and SCI individuals. The Polish MSISQ-15 will enhance routine clinical practice and assist research for neurogenic patients in Poland.
A prognostic nomogram based on LASSO Cox regression in patients with alpha-fetoprotein-negative hepatocellular carcinoma following non-surgical therapy
Authors: Zhou Dongdong , Liu Xiaoli , Wang Xinhui , Yan Fengna , Wang Peng , Yan Huiwen , Jiang Yuyong , Yang Zhiyun
Published: March 2021

Background

Alpha-fetoprotein-negative hepatocellular carcinoma (AFP-NHCC) (< 8.78 ng/mL) have special clinicopathologic characteristics and prognosis. The aim of this study was to apply a new method to establish and validate a new model for predicting the prognosis of patients with AFP-NHCC.

Methods

A total of 410 AFP-negative patients with clinical diagnosed with HCC following non-surgical therapy as a primary cohort; 148 patients with AFP-NHCC following non-surgical therapy as an independent validation cohort. In primary cohort, independent factors for overall survival (OS) by LASSO Cox regression were all contained into the nomogram1; by Forward Stepwise Cox regression were all contained into the nomogram2. Nomograms performance and discriminative power were assessed with concordance index (C-index) values, area under curve (AUC), Calibration curve and decision curve analyses (DCA). The results were validated in the validation cohort.

Results

The C-index of nomogram1was 0.708 (95%CI: 0.673–0.743), which was superior to nomogram2 (0.706) and traditional modes (0.606–0.629). The AUC of nomogram1 was 0.736 (95%CI: 0.690–0.778). In the validation cohort, the nomogram1 still gave good discrimination (C-index: 0.752, 95%CI: 0.691–0.813; AUC: 0.784, 95%CI: 0.709–0.847). The calibration curve for probability of OS showed good homogeneity between prediction by nomogram1 and actual observation. DCA demonstrated that nomogram1 was clinically useful. Moreover, patients were divided into three distinct risk groups for OS by the nomogram1: low-risk group, middle-risk group and high-risk group, respectively.

Conclusions

Novel nomogram based on LASSO Cox regression presents more accurate and useful prognostic prediction for patients with AFP-NHCC following non-surgical therapy. This model could help patients with AFP-NHCC following non-surgical therapy facilitate a personalized prognostic evaluation.
A randomized phase II study of S-1 monotherapy versus cisplatin with vinorelbine for completely resected stage II/IIIA non-small cell lung cancer: rationale and study protocol design for the LOGIK1702 study
Authors: Tsuchiya Tomoshi , Matsumoto Keitaro , Miyazaki Takuro , Doi Ryoichiro , Tokunaga Shoji , Yamaguchi Hiroyuki , Tomoshige Koichi , Watanabe Hironosuke , Nagayasu Takeshi , Sugio Kenji
Published: March 2021

Background

The current standard postoperative treatment for stage II-IIIA non-small cell lung cancer (NSCLC) is a regimen of platinum doublet adjuvant chemotherapy. These regimens, which are the same as for solid NSCLC tumors, often cause severe adverse reactions in the treated patients. Therefore, an effective treatment regimen with fewer side effects is needed.

Methods/design

The purpose of this study is to evaluate the effectiveness and safety of S-1 monotherapy (80 mg/m2 orally administrated twice daily, at day 1–14, 16 cycles) and cisplatin with vinorelbine combination therapy (cisplatin 80 mg/m2 at day 1,vinorelbine 25 mg/m2 at day 1, 8, 4 cycles) in patients with II/IIIA stage non-small-cell lung cancer who underwent a total resection. In addition, we will also evaluate the level of treatment side effects by assessing quality of life (QOL), work productivity and activity performance. The primary endpoint is a 2-year relapse free survival (RFS) and the second primary endpoints are 2-year overall survival (OS), rate of treatment completion, safety, work productivity and activity, and quality of adjusted life years (QALY). At the same time, we aim to obtain precise information required to perform future phase 3 randomized controlled trials. The study is designed to estimate the primary endpoint with accuracy determined as the width of its 95% confidence interval to be less than 20%. Recruitment started in May 2017 and is ongoing.

Discussion

This study has been conceived to establish a superior regimen for completely resected NSCLC based on efficacy, safety and QOL.

Trial registration

Registry number: UMIN000027435. Registered May 22, 2017.
Factors associated with neurodevelopment in preterm infants with systematic inflammation
Authors: Lee Eun Sun , Kim Ee-Kyung , Shin Seung han , Choi Young-Hun , Jung Young Hwa , Kim Sae Yun , Koh Ji Won , Choi Eui Kyung , Cheon Jung-Eun , Kim Han-Suk
Published: March 2021

Background

Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment.

Methods

This prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight < 1250 g. Infants were grouped according to the presence of systemic inflammation: Control (no inflammation, n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months.

Results

The I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score − 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p < 0.05). Among the I group, the proportion of immature neutrophils (I/T ratios) and IL-1 beta levels in the CSF were associated with aEEG measures at the day of symptom onset (D0). Seizure spike on aEEG at D0 was significantly correlated with motor and social-emotional domains of Bayley-III (p < 0.05). The I/T ratio and CRP and TNF-α levels of blood at D0, white matter injury on MRI at discharge, head circumference and seizure spikes on aEEG at near-term age were associated with Bayley-III scores at a CA of 18 months.

Conclusions

Systemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.
The associations between maternal and child diet quality and child ADHD – findings from a large Norwegian pregnancy cohort study
Authors: Borge Tiril Cecilie , Biele Guido , Papadopoulou Eleni , Andersen Lene Frost , Jacka Felice , Eggesbø Merete , Caspersen Ida Henriette , Aase Heidi , Meltzer Helle Margrete , Brantsæter Anne Lise
Published: March 2021

Background

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder. Effective long-term treatment options are limited, which warrants increased focus on potential modifiable risk factors. The aim of this study was to investigate associations between maternal diet quality during pregnancy and child diet quality and child ADHD symptoms and ADHD diagnosis.

Methods

This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). We assessed maternal diet quality with the Prenatal Diet Quality Index (PDQI) and Ultra-Processed Food Index (UPFI) around mid-gestation, and child diet quality using the Diet Quality Index (CDQI) at 3 years. ADHD symptoms were assessed at child age 8 years using the Parent Rating Scale for Disruptive Behaviour Disorders. ADHD diagnoses were retrieved from the Norwegian Patient Registry.

Results

In total, 77,768 mother-child pairs were eligible for studying ADHD diagnoses and 37,787 for ADHD symptoms. Means (SD) for the PDQI, UPFI and CDQI were 83.1 (9.3), 31.8 (9.7) and 60.3 (10.6), respectively. Mean (SD) ADHD symptom score was 8.4 (7.1) and ADHD diagnosis prevalence was 2.9% (male to female ratio 2.6:1). For one SD increase in maternal diet index scores, we saw a change in mean (percent) ADHD symptom score of − 0.28 (− 3.3%) (CI: − 0.41, − 0.14 (− 4.8, − 1.6%)) for PDQI scores and 0.25 (+ 3.0%) (CI: 0.13, 0.38 (1.5, 4.5%)) for UPFI scores. A one SD increase in PDQI score was associated with a relative risk of ADHD diagnosis of 0.87 (CI: 0.79, 0.97). We found no reliable associations with either outcomes for the CDQI, and no reliable change in risk of ADHD diagnosis for the UPFI.

Conclusions

We provide evidence that overall maternal diet quality during pregnancy is associated with a small decrease in ADHD symptom score at 8 years and lower risk for ADHD diagnosis, with more robust findings for the latter outcome. Consumption of ultra-processed foods was only associated with increased ADHD symptom score of similar magnitude as for overall maternal diet quality, and we found no associations between child diet quality and either outcome. No causal inferences should be made based on these results, due to potential unmeasured confounding.
An analytical approach to aggregate patient inflows to a simulation model over the radiotherapy process
Authors: Lindberg Jesper , Holmström Paul , Hallberg Stefan , Björk-Eriksson Thomas , Olsson Caroline E.
Published: March 2021

Background

In meeting input data requirements for a system dynamics (SD) model simulating the radiotherapy (RT) process, the number of patient care pathways (RT workflows) needs to be kept low to simplify the model without affecting the overall performance. A large RT department can have more than 100 workflows, which results in a complex model structure if each is to be handled separately. Here we investigated effects on model performance by reducing the number of workflows for a model of the preparatory steps of the RT process.

Methods

We created a SD model sub-structure capturing the preparatory RT process. Real data for patients treated in 2015-2016 at a modern RT department in Sweden were used. RT workflow similarity was quantified by averaged pairwise utilization rate differences (%) and the size of corresponding correlation coefficients (r). Grouping of RT workflows was determined using two accepted strategies (80/20 Pareto rule; merging all data into one group) and a customized algorithm with r≥0.75:0.05:0.95 as criteria for group inclusion by two strategies (A1 and A2). Number of waiting patients for each grouping strategy were compared to the reference of all workflows handled separately.

Results

There were 128 RT workflows for 3209 patients during the studied period. The 80/20 Pareto rule resulted in 14/8/21 groups for curative/palliative/disregarding treatment intent. Correspondingly, A1 and A2 resulted in 7-40/≤4-36/7-82 groups depending on r cutoff. Results for the Pareto rule and A2 at r≥85 were comparable to the reference.

Conclusions

The performance of a simulation model over the RT process will depend on the grouping strategy of patient input data. Either the Pareto rule or the grouping of patients by resource use can be expected to better reflect overall departmental effects to various changes than when merging all data into one group. Our proposed approach to identify groups based on similarity in resource use can potentially be used in any setting with variable incoming flows of objects which go through a multi-step process comparable to RT where the aim is to reduce the complexity of associated model structures without compromising with overall performance.
Identification and characterization of a subpopulation of CD133+ cancer stem‐like cells derived from SK-UT-1 cells
Authors: Gao Jiuping , Yang Ting , Wang Xu , Zhang Yi , Wang Jing , Zhang Beilei , Tang Dihong , Liu Yanqiong , Gao Ting , Lin Qiuhui , Tang Jun , Cai Jingting
Published: March 2021

Background

Uterine leiomyosarcoma (ULMS) is a malignant tumor found in the smooth muscle lining the walls of the uterus. Cancer stem cells (CSCs) are responsible for metastasis, drug resistance, and relapse of cancer, resulting in treatment failure. However, little is known about CSCs and their associated-markers in ULMS. We aimed to characterize and identify a subpopulation of CD133+cancer stem-like cells derived from SK-UT-1 cell line.

Methods

SK-UT-1 cells were sphere-forming cultured in vitro. We also sorted the CD133+cells derived from SK-UT-1 cell line by immunomagnetic beads. CD133+subpopulation and apoptotic cells were detected by flow cytometry. Self-renewal and anchorage-independent growth capabilities were examined using sphere and colony formation assays. The tumorigenicity of the fourth-passage spheres and parental SK-UT-1 cells was used by mouse xenograft model in vivo. Cell proliferation ability and sensitivity to doxorubicin (DXR) were assessed by CCK-8 assay. Cell migration and invasion were tested by wound healing assay or Transwell migration and invasion assays. Expressions of CSC-related marker were analyzed by Western blotting.

Results

The fourth-passage spheres were defined as a CD133+cell population, which was accompanied by increase of sphere and colony forming rate, migration and invasion abilities, as well as drug-resistant properties in vitro. Moreover, the fourth-passage spheres showed a stronger tumorigenic potential in vivo. CD133+cell population sorted from SK-UT-1 line showed an increased ability in sphere and colony formation, proliferation, migration, invasion, resistance to apoptosis after treatment with doxorubicin (DXR) compared with CD133−cell population. The expression levels of CSCs-related markers (e.g., CD44, ALDH1,BMI1, and Nanog), were significantly elevated in CD133+cells compared with those in CD133−cells.

Conclusions

Collectively, our findings indicated that CD133 may be a significant marker for cancer stem-like cells, and it may be a potential therapeutic target for human ULMS.
Digitized smart surveillance and micromanagement using information technology for malaria elimination in Mangaluru, India: an analysis of five-year post-digitization data
Authors: Baliga B. Shantharam , Baliga Shrikala , Jain Animesh , Kulal Naveen , Kumar Manu , Koduvattat Naren , Kumar B. G. Prakash , Kumar Arun , Ghosh Susanta K.
Published: March 2021

Background

Malaria control system (MCS), an Information technology (IT)-driven surveillance and monitoring intervention is being adopted for elimination of malaria in Mangaluru city, Karnataka, India since October 2015. This has facilitated ‘smart surveillance’ followed by required field response within a timeline. The system facilitated data collection of individual case, data driven mapping and strategies for malaria elimination programme. This paper aims to present the analysis of post-digitization data of 5 years, discuss the current operational functionalities of MCS and its impact on the malaria incidence.

Methods

IT system developed for robust malaria surveillance and field response is being continued in the sixth year. Protocol for surveillance control was followed as per the national programme guidelines mentioned in an earlier publication. Secondary data from the malaria control system was collated and analysed. Incidence of malaria, active surveillance, malariogenic conditions and its management, malariometric indices, shrinking malaria maps were also analysed.

Results

Smart surveillance and subsequent response for control was sustained and performance improved in five years with participation of all stakeholders. Overall malaria incidence significantly reduced by 83% at the end of 5 years when compared with year of digitization (DY) (p < 0.001). Early reporting of new cases (within 48 h) was near total followed by complete treatment and vector control. Slide positivity rate (SPR) decreased from 10.36 (DY) to 6.5 (PDY 5). Annual parasite incidence (API) decreased from 16.17 (DY) to 2.64 (PDY 5). There was a negative correlation between contact smears and incidence of malaria. Five-year data analyses indicated declining trends in overall malaria incidence and correlation between closures by 14 days. The best impact on reduction in incidence of malaria was recorded in the pre-monsoon months (~ 85%) compared to lower impact in July–August months (~ 40%).

Conclusion

MCS helped to micromanage control activities, such as robust reporting, incidence-centric active surveillance, early and complete treatment, documentation of full treatment of each malaria patient, targeted mosquito control measures in houses surrounding reported cases. The learnings and analytical output from the data helped to modify strategies for control of both disease and the vector, heralding the city into the elimination stage.
Prevalence and molecular characterization of Escherichia coli isolates during radish sprout production in the Republic of Korea
Authors: Rajalingam Nagendran , Yoon Jae-Hyun , Yoon Bohyun , Hung Nguyen Bao , Kim Won-Il , Kim Hyunju , Park Byeong Yong , Kim Se-Ri
Published: March 2021

This study was conducted to investigate the prevalence of coliforms andEscherichia coliacross radish sprout production facilities in the Republic of Korea and to characterize isolatedE. coli. A total of 324 samples were collected from three different radish sprout production units in spring and summer. Overall, the levels of coliforms were significantly higher (> 3.75 log CFU/g) in radish sprouts during summer season than in spring.E. coliwas detected in the pre-harvest (50%) and post-harvest (39%) sprouts and water samples (33%) from farms B and C. Of the 48E. coliisolates, fiveE. coliisolates were positive for theeaeAgene, indicative of EPEC O110, two isolates wereeaeA-positive (EPEC ONT) and one isolate wasipaH-positive (ETEC O71). These threeE. colistrains were identified as novel sequence types by the multilocus sequence-typing assay based on the combination of allelic profiles. In addition, the EPEC O110 isolates obtained from the stream water stored in container of farm C were toxic toCaenorhabditis elegans.It is necessary to implement safety measures during the production of radish sprouts to preventE. colioutbreaks.
Deciphering the effects of kosmotrope and chaotrope salts during aqueous two phase extraction (ATPE) of polyphenolic compounds and glycoalkaloids from the leaves of a nutraceutical plant, Solanum retroflexum, with the aid of UPLC-QTOF-MS
Authors: Mokgehle Tebogo , Madala Ntakadzeni , Gitari Wilson , Tavengwa Nikita
Published: March 2021

Solanum plants (Solanaceae) are renowned source of nutraceuticals and have widely been explored for their phytochemical constituents. This work investigated the effects of kosmotropic and chaotropic salts on the number of phytochemicals extracted from the leaves of a nutraceutical plant, Solanum retroflexum, and analyzed on the ultra-performance liquid chromatography hyphenated to a quadrupole time of flight mass spectrometer (UPLC-QTOF-MS) detector. Here, a total of 20 different compounds were putatively characterized. The majority of the identified compounds were polyphenols and glycoalkaloids. Another compound, caffeoyl malate was identified for the first time in this plant. Glycoalkaloids such as solanelagnin, solamargine, solasonine, β-solanine (I) and β-solanine (II) were found to be extracted by almost all the salts used herein. Kosmotrope salts, overall, were more efficient in extracting polar compounds with 4 more polyphenolic compounds extracted compared to the chaotropes. Chaotropes were generally more selective for the extraction of less polar compounds (glycoalkaloids) with 3 more extracted than the kosmotropes. The chaotrope and the kosmotrope that extracted the most metabolites were NaCl and Na2SO4, respectively, with 12 metabolites extracted for each salt. This work demonstrated that a comprehensive metabolome of S. retroflexum, more than what was previously reported on the same plant, can be achieved by application of kosmotropes and chaotropes as extractants with the aid of the Aqueous Two Phase Extraction approach. The best-performing salts, Na2SO4 or NaCl, could potentially be applied on a commercial scale, to meet the ever-growing demand of the studied metabolites. The Aqueous Two Phase Extraction technique was found to be efficient in simultaneous extraction of multiple metabolites which can be applied in metabolomics.
Methods for exploring the faecal microbiome of premature infants: a review
Authors: Westaway Jacob A. F. , Huerlimann Roger , Miller Catherine M. , Kandasamy Yoga , Norton Robert , Rudd Donna
Published: March 2021

The premature infant gut microbiome plays an important part in infant health and development, and recognition of the implications of microbial dysbiosis in premature infants has prompted significant research into these issues. The approaches to designing investigations into microbial populations are many and varied, each with its own benefits and limitations. The technique used can influence results, contributing to heterogeneity across studies. This review aimed to describe the most common techniques used in researching the preterm infant microbiome, detailing their various limitations. The objective was to provide those entering the field with a broad understanding of available methodologies, so that the likely effects of their use can be factored into literature interpretation and future study design. We found that although many techniques are used for characterising the premature infant microbiome, 16S rRNA short amplicon sequencing is the most common. 16S rRNA short amplicon sequencing has several benefits, including high accuracy, discoverability and high throughput capacity. However, this technique has limitations. Each stage of the protocol offers opportunities for the injection of bias. Bias can contribute to variability between studies using 16S rRNA high throughout sequencing. Thus, we recommend that the interpretation of previous results and future study design be given careful consideration.
Ruptured intra-abdominal testicular seminoma with hemorrhage shock, after inadequate surgical exploration for undescended testis: a case report
Authors: Gonda Hirotake , Saito Takuya , Osawa Takaaki , Kurahashi Shintaro , Matsumura Tatsuki , Fukami Yasuyuki , Komatsu Shunichiro , Kaneko Kenitiro , Hiramatsu Kazuhiro , Kato Takehito , Sano Tsuyoshi
Published: March 2021

Background

Undescended testes are associated with an increased risk of malignancy and infertility, and surgical treatment in childhood is recommended.

Case presentation

A 35-year-old man presented to the emergency department with abdominal pain and vomiting. Despite a history of surgery for a left undescended testis in infancy, his left-sided scrotum appeared underdeveloped. Contrast-enhanced computed tomography showed a pelvic mass, involving a major axis of approximately 15 cm, with high-density ascites suggestive of hemorrhage. A ruptured gastrointestinal stromal tumor was suspected. As he was in hemorrhagic shock, an emergency laparotomy was indicated. The active bleeding mass was controlled through complete resection. A pathological evaluation of the mass revealed a seminoma arising from an undescended testis. His post-operative course was uneventful, and he was discharged on post-operative day 6. Recurrence on the retroperitoneal lymph nodes was detected 1 year postoperatively, and a retroperitoneal lymph node dissection was performed after chemotherapy. He remains well without any apparent signs of recurrence.

Conclusions

Paying close attention to an empty scrotum is advisable, even postoperatively, for undescended testis because of possible subsequent potential malignancy presenting with hemorrhage, as our patient demonstrated.
The potential of herbal extracts to inhibit SARS-CoV-2: a pilot study
Authors: De Pellegrin Michela Luisa , Rohrhofer Anette , Schuster Philipp , Schmidt Barbara , Peterburs Philipp , Gessner André
Published: March 2021

Background

Herbal medicinal products have a long-standing history of use in the therapy of common respiratory infections. We sought to assess the potential of five validated herbal extracts regarding their ability to restrict SARS-CoV-2 replication in vitro: Bronchipret thyme-ivy (BRO TI), Bronchipret thyme-primrose (BRO TP), Imupret (IMU), Sinupret extract (SINx) and Tonsipret (TOP).

Methods

Vero cells were incubated with different concentrations of herbal extracts and infected with SARS-CoV-2 for 48 hours. The inhibition of viral replication was assessed by determination of the viral RNA load in the cell culture supernatant using quantitative polymerase chain reaction (qPCR).

Results

SARS-CoV-2 RNA load was reduced by non-cytotoxic concentrations of BRO-TP (up to approximately 1,000-fold) and, to a lesser extent, IMU and TOP (approximately 10-fold).

Conclusions

Some herbal extracts showed a promising in vitro effectiveness against SARS-CoV-2, suggesting an antiviral potential of herbal medicinal products. The potential of herbal medicines to restrict SARS-CoV-2 and to treat COVID-19 should be investigated further in a clinical setting.
A survey on the current status and future perspective of informed consent management in the MIRACUM consortium of the German Medical Informatics Initiative
Authors: Hampf Christopher , Bialke Martin , Geidel Lars , Vass Albert , Bahls Thomas , Blasini Romina , Blumentritt Arne , Boeker Martin , Bruns Christian , Jandrig Burkhard , Fünfgeld Maximilian , Heinrich Philipp , Leddig Torsten , Michel-Backofen Achim , Pirkl Anna , Rautenberg Michael , Simons Fabian , Stahl Dana , Prokosch Hans-Ulrich , Hoffmann Wolfgang
Published: March 2021

Background

The consent management is an essential component for supporting the implementation of consents and withdrawals and thus, the realisation of patient’s rights. In MIRACUM, one of the four consortia of the Medical Informatics Initiative (MII), ten university hospitals intend to integrate the generic Informed Consent Service® (gICS) in their Data Integration Center (DIC). To provide a tool that supports the local workflows of the MIRACUM sites, the gICS should be improved.

Methods

We used three standardised questionnaires with 46 questions to elicit requirements from the ten sites. Each site answered the questions from the current and the desired future perspective. This made it possible to understand the individual processes at each site and it was possible to identify features and improvements that were generally necessary.

Results

The results of the survey were classified according to their impact on the gICS. Feature requests of new functionalities, improvements of already implemented functionalities and conceptual support for implementing processes were identified. This is the basis for an improved gICS release to support the ten sites’ individual consent management processes.

Conclusions

A release plan for the feature requests and improvements was coordinated with all sites. All sites have confirmed that the implementation of these features and enhancements will support their software-based consent management processes.
Two deaths due to explosion of cylinders of liquid petroleum gas
Authors: Sonwani Nagendra Singh , Ateriya Navneet , Kumar Arvind , Kohli Anil
Published: March 2021

Background

Cylinder blasts can inflict multi-system life-threatening injuries to one or many persons simultaneously if they are nearby. The explosion in high-pressure equipment produces injuries due to its varied effects. Cases have been reported where the blast occurred in balloon gas cylinder, oxyacetylene gas cylinder, oxygen cylinder, coffee machine, and compressor of a split air conditioner (AC). Most of the cases are accidental. The investigation into the blast circumstances is of utmost importance to find out the manner and device involved.

Case presentation

Here, we present a report of two cases where victims suffered blast injuries at the same location due to the explosion of two different capacity liquefied petroleum gas (LPG) domestic cylinder and died on the spot.

Conclusion

The investigation into the blast circumstances is of utmost importance to find out the manner and device involved. Malpractice involving use of cylinder to fill another one might be dangerous for the person involved and present in the vicinity. This practice should be discouraged by lay person.
First results of BDS positioning for LBS applications in the UK
Authors: Xia Yan , Meng Xiaolin , Yang Yusong , Pan Shuguo , Zhao Qing , Gao Wang
Published: March 2021

The last satellite of BeiDou Navigation Satellite System with Global Coverage (BDS-3) constellation was successfully launched on June 23rd, 2020, and the entire system began to provide Positioning, Navigation, and Timing (PNT) services worldwide. We evaluated the performance of location services using BDS with a smartphone that can track the Global Navigation Satellite System (GNSS) satellites in Nottingham, UK. The static and kinematic experiments were conducted in an open meadow and a lakeside route covered by trees, respectively. Experimental results show that BDS has good visibility, and its overall signal carrier-to-noise density ratio (C/N0) is comparable to that of Global Positioning System (GPS). The average C/N0 of BDS-3 satellites with elevation angles above 45° on B1 band is the highest among all systems, reaching 40.0 dB·Hz. The noise level of the BDS pseudorange measurements is within 0.5 m, and it has a good consistency among satellites. In the static experiment, the standard deviations of BDS positioning in the east, north and up directions are 1.09, 1.16, and 3.02 m, respectively, and the R95 value of the horizontal position is 2.88 m. In harsh environments, the number of BDS satellites tracked by the smartphone is susceptible to environmental factors. The bias Root Mean Squares (RMS) in the three directions of the whole kinematic positioning are 6.83, 6.68, 11.67 m, in which the positioning bias RMS values in a semi-open environment are only 2.81, 1.11, 3.29 m. Furthermore, the inclusion of BDS in multiple GNSS systems can significantly improve the positioning precision. This study intends to provide a reference for the further improvements of BDS global PNT services, particularly for Location-Based Services (LBS).