bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer
Authors: Mitra Ghosh Taraswi , White Jason , Davis Joshua , Mazumder Suman , Kansom Teeratas , Skarupa Elena , Barnett Grafton S. , Piazza Gary A. , Bird R. Curtis , Mitra Amit K. , Yates Clayton , Cummings Brian S. , Arnold Robert D.
Published: December 2021

Repetitive, low-dose (metronomic; METRO) drug administration of some anticancer agents can overcome drug resistance and increase drug efficacy in many cancers, but the mechanisms are not understood fully. Previously, we showed that METRO dosing of topotecan (TOPO) is more effective than conventional (CONV) dosing in aggressive human prostate cancer (PCa) cell lines and in mouse tumor xenograft models. To gain mechanistic insights into METRO-TOPO activity, in this study we determined the effect of METRO- and CONV-TOPO treatment in a panel of human PCa cell lines representing castration-sensitive/resistant, androgen receptor (+/−), and those of different ethnicity on cell growth and gene expression. Differentially expressed genes (DEGs) were identified for METRO-TOPO therapy and compared to a PCa patient cohort and The Cancer Genome Atlas (TCGA) database. The top five DEGs were SERPINB5, CDKN1A, TNF, FOS, and ANGPT1. Ingenuity Pathway Analysis predicted several upstream regulators and identified top molecular networks associated with METRO dosing, including tumor suppression, anti-proliferation, angiogenesis, invasion, metastasis, and inflammation. Further, the top DEGs were associated with increase survival of PCa patients (TCGA database), as well as ethnic differences in gene expression patterns in patients and cell lines representing African Americans (AA) and European Americans (EA). Thus, we have identified candidate pharmacogenomic biomarkers and novel pathways associated with METRO-TOPO therapy that will serve as a foundation for further investigation and validation of METRO-TOPO as a novel treatment option for prostate cancers.
Ursodeoxycholic Acid Treatment Restores Gut Microbiota and Alleviates Liver Inflammation in Non-Alcoholic Steatohepatitic Mouse Model
Authors: Li Hu , Wang Qingling , Chen Peizhan , Zhou Chenghua , Zhang Xinxin , Chen Li
Published: December 2021

Gut microbiota dysbiosis plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD), and no approved drugs are available for NAFLD treatment. In this study, we aimed to explore the dynamic changes of gut microbiota at the different stages of NAFLD and determine whether ursodeoxycholic acid (UDCA) could improve liver histopathological features of non-alcoholic steatohepatitis (NASH) mice induced by a high-fat high-cholesterol (HFHC) diet and its impact on gut microbiota. 6-week-old male C57BL/6 mice were fed with a HFHC or normal diet for 12, 18, and 24 weeks, respectively, to simulate the different stages of NAFLD. 16s ribosomal RNA genes from mice fecal samples at the different time points were sequenced to evaluate the dynamic changes of the gut microbiota. Then, C57BL/6 mice were fed with a HFHC diet for 24 weeks to establish the NASH model. Different doses of UDCA were administered intragastrically for additional 4 weeks. Normal diet–fed mice were taken as control. Serum samples, liver, and intestine tissues were harvested for biochemical tests and histopathological examinations. 16s ribosomal RNA genes from mice fecal samples were sequenced to assess the structural changes of gut microbiota. HFHC diet–fed mice developed simple steatosis, steatohepatitis, and fibrosis at 12, 18, and 24 weeks, respectively. The profile of gut microbiota dynamically changed with the different stages of NAFLD. NASH mice had significantly higher abundance of Fecalibaculum, Coriobacteriaceae_UCG-002, and Enterorhabdus, and lower abundance of norank_f_Muribaculaceae, Bacteroides, and Alistipes, which were partially restored by UDCA treatment. UDCA treatment significantly attenuated hepatic inflammation of NASH mice as indicated by the sum of ballooning and lobular inflammation of the NALFD activity score (3.2 ± 0.8 vs 1.8 ± 0.8, p = 0.029), and partially restored gut microbiota dysbiosis, and increased the expression of Claudin-1 and ZO-1 in the intestine, but did not activate the suppressed Farnesoid X receptor signal pathway. Conclusions: The gut microbiota dynamically changes with the different stages of NAFLD. UDCA treatment (120 mg/kg) could partially restore gut microbiota, repair gut barrier integrity, and attenuate hepatic inflammation in the NASH mouse model.
Localization of Hidden Attractors in Chua’s System With Absolute Nonlinearity and Its FPGA Implementation
Authors: Wu Xianming , Wang Huihai , He Shaobo
Published: December 2021

Investigation of the classical self-excited and hidden attractors in the modified Chua’s circuit is a hot and interesting topic. In this article, a novel Chua’s circuit system with an absolute item is investigated. According to the mathematical model, dynamic characteristics are analyzed, including symmetry, equilibrium stability analysis, Hopf bifurcation analysis, Lyapunov exponents, bifurcation diagram, and the basin of attraction. The hidden attractors are located theoretically. Then, the coexistence of the hidden limit cycle and self-excited chaotic attractors are observed numerically and experimentally. The numerical simulation results are consistent with the FPGA implementation results. It shows that the hidden attractor can be localized in the digital circuit.
How Do Upper Echelons Perceive Porter’s Five Forces? Evidence From Strategic Entrepreneurship in China
Authors: Shi Chengqi , Agbaku Comfort Afi , Zhang Fan
Published: December 2021

Porter’s five forces model is an authoritative management tool used in analyzing the profitability and attractiveness of industries through an outside-in viewpoint. In the past decade, dramatic and rapid changes have prompted some criticism of the model. The comparison between new and old economy analysis makes the fundamentals of the model seem weak. Moreover, the past decade has shown that strategy and entrepreneurship in China are not completely dependent on the model. This study first aims to verify the sustainability of the five forces model and analyze its integration into China’s entrepreneurial economy. By conducting in-depth interviews among the upper echelons from various industries, it was found that along with the competitive factors emphasized by the model, Chinese entrepreneurs attend to cooperative factors such as Guanxi, the Chinese term for relationship, and the possibilities of technology integration with the five forces. They also tend to enlarge the strategic view to consider factors such as how the market evaluates the forces. To verify these findings, the authors carried out a large-scale survey with a modified questionnaire analyzing the data collected using exploratory factor analysis with SPSS 22. The outcome shows that Porter’s model is still valid to some extent. Companies are still working in a network of buyers, suppliers, substitutes, new entrants, and competitors. However, reinventions are necessary to include the new factors of Guanxi, technology (e-commerce and logistics), and marketing and branding, which have changed the structure of the industry. These factors arise from the cooperative nature of Chinese culture and may have equal or even larger significance compared with their competitive counterparts in today’s business world.
The Association Between Toddlers’ Temperament and Well-Being in Norwegian Early Childhood Education and Care, and the Moderating Effect of Center-Based Daycare Process Quality
Authors: van Trijp Catharina P. J. , Lekhal Ratib , Drugli May Britt , Rydland Veslemøy , van Gils Suzanne , Vermeer Harriet J. , Buøen Elisabet Solheim
Published: December 2021

Children who experience well-being are engaging more confidently and positively with their caregiver(s) and peers, which helps them to profit more from available learning opportunities and support current and later life outcomes. The goodness-of-fit theory suggests that children’s well-being might be a result of the interplay between their temperament and the environment. However, there is a lack of studies that examined the association between children’s temperament and well-being in early childhood education and care (ECEC), and whether this association is affected by ECEC process quality. Using a multilevel random coefficient approach, this study examines the association between toddlers’ (N = 1,561) temperament (shyness, emotionality, sociability, and activity) and well-being in Norwegian ECEC and investigates whether process quality moderates this association. Results reveal an association between temperament and well-being. Staff-child conflict moderates the association between shyness and well-being, and between activity and well-being. Moreover, high emotional behavioral support moderates the association between activity and well-being. Extra attention should be paid by the staff to these children’s needs.
Investigating Medical Student's Preferences for Internet-Based Healthcare Services: A Best-Worst Scaling Survey
Authors: Xu Richard Huan , Zhou Ling-ming , Wong Eliza Lai-yi , Wang Dong
Published: December 2021

Objective: This study aimed to investigate the importance of providing Internet-based healthcare services based on the preference of a sample of medical students in China.

Methods: An online best-worst scaling (BWS) survey with Case 1 design was conducted. Balanced independent block design generated 12 choice task profiles for each participant to answer. Descriptive analysis was used to describe the respondents' characteristics; Multinomial and mixed logit regression methods were used to investigate the importance of Internet-based services based on respondents' preferences.

Results: A total of 1,296 students completed the online survey and rated “Clinical Service,” “Decision Aids,” and “Public health” as the three most important services that should be provided through an Internet-based healthcare system. Providing “Medical Education” via the Internet was chosen as the least important service by the respondents. Subgroup analysis indicated that students studying clinical medicine and non-clinical medicine considered providing “Medical Education” and “Public Health,” respectively, as more important services than others.

Conclusions: This BWS study demonstrated that providing “Clinical Service,” “Decision Aids,” and “Public Health” through the Internet are the three most important services based on medical students' preferences in China. Further research is needed to investigate how to improve medical students' skills in using internet-based healthcare services in medical education programs.
Determinants of Urinary Incontinence and Subtypes Among the Elderly in Nursing Homes
Authors: Tai Hongyan , Liu Shunying , Wang Haiqin , Tan Hongzhuan
Published: December 2021

Urinary incontinence (UI) is a common problem among older adults. This study investigated the prevalence of UI in nursing home residents aged ≥75 years in China and examined potential risk factors associated with UI and its subtypes. Data were collected during face-to-face interviews using a general questionnaire, the International Consultation Incontinence Questionnaire Short-Form, and the Barthel Index. A total of 551 participants aged ≥75 years residing in Changsha city were enrolled from June to December 2018. The UI prevalence rate among nursing home residents aged ≥75 years was 24.3%. The most frequent subtype was mixed (M) UI (38.1%), followed by urge (U) UI (35.1%), stress (S) UI (11.9%), and other types (14.9%). In terms of severity, 57.5% had moderate UI, while 35.1% had mild and 7.5% had severe UI. Constipation, immobility, wheelchair use, cardiovascular disease (CVD), and pelvic or spinal surgery were significant risk factors for UI. Participants with a history of surgery had higher risks of SUI (odds ratio [OR] = 4.87, 95% confidence interval [CI]: 1.55–15.30) and UUI (OR = 1.97, 95% CI: 1.05–3.71), those who were immobile or used a wheelchair had higher rates of MUI (OR = 11.07, 95% CI: 4.19–29.28; OR = 3.36, 95% CI: 1.16–9.78) and other UI types (OR = 7.89, 95% CI: 1.99–31.30; OR = 14.90, 95% CI: 4.88–45.50), those with CVD had a higher rate of UUI (OR = 2.25, 95% CI: 1.17–4.34), and those with diabetes had a higher risk of UUI (OR = 2.250, 95% CI: 1.14–4.44). Use of oral antithrombotic agents increased UUI risk (OR = 4.98, 95% CI: 2.10–11.85) whereas sedative hypnotic drug use was associated with a higher risk of MUI (OR = 3.62, 95% CI: 1.25–10.45). Each UI subtype has distinct risk factors, and elderly residents of nursing homes with a history of CVD and pelvic or spinal surgery who experience constipation should be closely monitored. Reducing time spent in bed and engaging in active rehabilitation including walking and muscle strengthening may aid in UI prevention and treatment.
Moderate and Deep Hypothermic Circulatory Arrest Have Comparable Effects on Severe Systemic Inflammatory Response Syndrome After Total Aortic Arch Replacement in Patients With Type A Aortic Dissection
Authors: Du Yingjie , Fang Zhongrong , Sun Yanhua , Zhang Congya , Lei Guiyu , Chen Yimeng , Yang Lijing , Yang Xiying , Li Jun , Wang Guyan
Published: December 2021

Background: The objective of this study was to compare the incidence of severe systemic inflammatory response syndrome (sSIRS) after total aortic arch replacement between patients who underwent moderate hypothermic circulatory arrest (MHCA) and those who underwent deep hypothermic circulatory arrest (DHCA).

Methods: At Fuwai Hospital, 600 patients who underwent total aortic arch replacement with MHCA or DHCA from January 2013 to December 2016 were consecutively enrolled and divided into DHCA (14.1–20.0°C) and MHCA (20.1–28.0°C) groups. Preliminary statistical analysis revealed that some baseline indicators differed between the two groups; therefore, propensity score matching (PSM) was used to balance the covariates. Post-operative sSIRS as the primary outcome was compared between the groups both before and after PSM.

Results: A total of 275 (45.8%) patients underwent MHCA, and 325 (54.2%) patients underwent DHCA. After PSM analysis, a total of 191 matched pairs were obtained. The overall incidence of sSIRS was 27.3%. There was no significant difference in post-operative sSIRS between the MHCA group and the DHCA group in either the overall cohort or the PSM cohort (no-PSM: P = 0.188; PSM: P = 0.416); however, post-operative sSIRS was increased by ~4% in the DHCA group compared with the MHCA group in both the no-PSM and PSM cohorts (no-PSM: 29.5 vs. 24.7%; PSM: 29.3 vs. 25.1%). Both before and after PSM, the rates of gastrointestinal hemorrhage and pulmonary infection and post-operative length of stay were significantly increased in the DHCA group compared with the MHCA group (P < 0.05), and the remaining secondary outcomes were not significantly different between the groups.

Conclusions: MHCA and DHCA are associated with comparable incidences of sSIRS in patients following total aortic arch replacement for type A aortic dissection. However, the MHCA group had a shorter cardiopulmonary bypass time, a shorter post-operative length of stay and lower pulmonary infection and gastrointestinal hemorrhage rates than the DHCA group. We cautiously recommend the use of MHCA for most total arch replacements in patients with type A aortic dissection.
Pathology and Advanced Imaging—Characterization of a Congenital Cardiac Defect and Complex Hemodynamics in a Pig: A Case Report
Authors: Malbon Alexandra J. , Weisskopf Miriam , Glaus Lukas , Neuber Sebastian , Emmert Maximilian Y. , Stoeck Christian T. , Cesarovic Nikola
Published: December 2021

Domestic pigs are widely used in cardiovascular research as the porcine circulatory system bears a remarkable resemblance to that of humans. In order to reduce variability, only clinically healthy animals enter the study as their health status is assessed in entry examination. Like humans, pigs can also suffer from congenital heart disease, such as an atrial septal defect (ASD), which often remains undetected. Due to the malformation of the endocardial cushion during organ development, mitral valve defects (e.g., mitral clefts) are sometimes associated with ASDs, further contributing to hemodynamic instability. In this work, we report an incidental finding of a hemodynamically highly relevant ASD in the presence of incompetent mitral and tricuspid valves, in an asymptomatic, otherwise healthy juvenile pig. In-depth characterization of the cardiac blood flow by four-dimensional (4D) flow magnetic resonance imaging (MRI) revealed a prominent diastolic left-to-right and discrete systolic right-to-left shunt, resulting in a pulmonary-to-systemic flow ratio of 1.8. Severe mitral (15 mL/stroke) and tricuspid (22 mL/stroke) regurgitation further reduced cardiac output. Pathological examination confirmed the presence of an ostium primum ASD and found a serous cyst of lymphatic origin that was filled with clear fluid partially occluding the ASD. A large mitral cleft was identified as the most likely cause of severe regurgitation, and histology showed mild to moderate endocardiosis in the coaptation area of both atrio-ventricular valves. In summary, although not common, congenital heart defects could play a role as a cause of experimental variability or even intra-experimental mortality when working with apparently heathy, juvenile pigs.
GA Optimization of Variable Angle Tow Composites in Buckling and Free Vibration Analysis through Layerwise Theory
Authors: Fallahi Nasim
Published: December 2021

In the current research, variable angle tow composites are used to improve the buckling and free vibration behavior of a structure. A one-dimensional (1D) Carrera Unified Formulation (CUF) is employed to determine the buckling loads and natural frequencies in Variable Angle Tow (VAT) square plates by taking advantage of the layerwise theory (LW). Subsequently, the Genetic Algorithm (GA) optimization method is applied to maximize the first critical buckling load and first natural frequency using the definition of linear fiber orientation angles. To show the power of the genetic algorithm for the VAT structure, a surrogate model using Response Surface (RS) method was used to demonstrate the convergence of the GA approach. The results showed the cost reduction for optimized VAT performance through GA optimization in combination with the 1D CUF procedure. Additionally, a Latin hypercube sampling (LHS) method with RS was used for buckling analysis. The capability of LHS sampling confirmed that it could be employed for the next stages of research along with GA.
Applicability of Near Infrared Reflectance Spectroscopy to Predict Amylose Contents of Single-Grain Maize
Authors: Dong Qing , Xu Qianqian , Wu Jiandong , Cheng Beijiu , Jiang Haiyang
Published: December 2021

Near infrared reflectance spectroscopy (NIRS) and reference data were used to determine the amylose contents of single maize seeds to enable rapid, effective selection of individual seeds with desired traits. To predict the amylose contents of a single seed, a total of 1069 (865 as calibration set, 204 as validation set) single seeds representing 120 maize varieties were analyzed using chemical methods and performed calibration and external validation of the 150 single seeds set in parallel. Compared to various spectral pretreatments, the regression of partial least squares (PLS) with mathematical treatment of Harmonization showed the final optimization. The single-seed amylose contents showed the root mean square error of calibration (RMSEC) of 2.899, coefficient of determination for calibration (R2) of 0.902, and root mean square error of validation (RMSEV) of 2.948. In external validations, the coefficient of determination in cross-validation (r2), root mean square error of the prediction (RMSEP) and ratio of the standard deviation to SEP (RPD) were 0.892, 2.975 and 3.086 in the range of 20–30%, respectively. Therefore, NIRS will be helpful to breeders for determining the amylose contents of single-grain maize.
The Case for Grazing Dairy Cows
Authors: Wilkinson J. Michael , Chamberlain A. Thomas , Rivero M. Jordana
Published: December 2021

The case for grazing dairy cows at pasture is reviewed in six categories: (i) optimal land use for food production; (ii) soil carbon sequestration; (iii) carbon footprint; (iv) animal health and welfare; (v) effects on human health of milk produced from grazed pasture; and (vi) consumer demand for milk from grazed cows. Land best-suited to grazing is uncultivatable peaty soil receiving relatively low levels of fertilisation. With soil carbon sequestration, carbon footprint is lower for grazing than for other systems of milk production. Some indices of animal health and welfare (e.g., lameness, status of hock integument) are influenced positively by extent of grazing. Benefits to human health may accrue from higher levels of essential amino acids, carotenoids, omega-3 fatty acids and conjugated linoleic acid in milk from cows given pasture compared to diets based on silage and concentrates. Milk producers, processors and supermarkets are responding to consumer demand for milk and milk products from cows given access to pasture during the grazing season. The major constraint to milk production from grazing is energy intake. Research opportunities to address this constraint include application of remote sensing and artificial intelligence to grazing management.
Understanding Antimicrobial Resistance from the Perspective of Public Policy: A Multinational Knowledge, Attitude, and Perception Survey to Determine Global Awareness
Authors: Naing SoeYu , van Wijk Max , Vila Jordi , Ballesté-Delpierre Clara
Published: December 2021

Minimizing the effect of antimicrobial resistance (AMR) requires an adequate policy response that relies on good governance and coordination. This study aims to have a better comprehension of how AMR is understood and perceived by policy-makers and stakeholders in a multinational context. A digital survey was designed to capture the knowledge, attitudes, and perceptions (KAP) towards AMR, and it was distributed to politicians, policy advisors, and stakeholders. A total of 351 individuals from 15 different countries participated, 80% from high-income countries (HICs) and 20% from low- and middle-income countries (LMICs). The Netherlands, Spain, and Myanmar were the top 3 represented countries. Participants had sufficient knowledge regarding AMR and reported the importance of political willingness to tackle AMR. Overall, LMIC participants demonstrated better knowledge of AMR but showed poor perception and attitude towards antimicrobial use compared to HIC participants. In addition, level of education and field of expertise were significantly associated with knowledge, perception, and practices regardless of demographic characteristics. Inter-regional differences in KAP regarding AMR exist among politicians, policy advisors, and relevant stakeholders. This study captures multinational policy-maker and stakeholder mapping that can be used to propose further policy implementation on various governance levels.
Adherence to National Antimicrobial Guidelines in Hospitalized Geriatric Patients with Community-Acquired Pneumonia: A Prospective Observational study in a Malaysian Hospital
Authors: Shakeel Sadia , Muneswarao Jaya , Abdul Aziz Azrina , Yeong Le Heng , Abd. Halim Fatin Syazwanni , Rehman Anees Ur , Hussain Rabia
Published: December 2021

The evaluation of disease progression and onsite therapeutic care choices for community-acquired pneumonia (CAP) patients is vital for their well-being and the optimum utilization of healthcare resources. The current study was conducted to assess physicians’ adherence to clinical practice standards and antibiotic prescribing behavior for the treatment of CAP in older people. A prospective study that included 121 consecutive patients admitted for CAP was conducted at Kulim Hospital, Kedah, from March 2020 to August 2020. Medical records including demographic data, comorbidity, physical examination, laboratory or radiologic findings, and drugs used for the treatment of CAP were accessed from bed head tickets (BHT). The mean age for patients was 73.5 ± 6.2 years, 73 (60.3%) and 48 (39.6%) were males and females, respectively. Amoxicillin/clavulanate (19.8%) was the most prescribed antibiotic for non-severe pneumonia followed by ampicillin sodium/sulbactam sodium (6.6%), while in patients with severe CAP beta-lactam + beta lactamase inhibitors (BLIs) with a combination of macrolide were the most common antibiotics prescribed either in patients with (21.4%) or without co-morbidities (8.2%). The average length of stay in the hospital with severe pneumonia was 6–7 days for 23.9% of patients and < 5 days for 21.4% of patients. The duration of intravenous antibiotics in patients with severe pneumonia was 6–7 days for 32.2% of patients. The present findings revealed the adherence of antibiotic prescribing practices to the Malaysian National Antimicrobial Guideline 2019 for CAP therapy among geriatric patients and adherence to the CAP criteria for hospital admissions.
Pharmacological Properties, Volatile Organic Compounds, and Genome Sequences of Bacterial Endophytes from the Mangrove Plant Rhizophora apiculata Blume
Authors: Dat Ton That Huu , Oanh Phung Thi Thuy , Cuong Le Canh Viet , Anh Le Tuan , Minh Le Thi Hong , Ha Hoang , Lam Le Tung , Cuong Pham Viet , Anh Hoang Le Tuan
Published: December 2021

Mangrove plant endophytic bacteria are prolific sources of bioactive secondary metabolites. In the present study, twenty-three endophytic bacteria were isolated from the fresh roots of the mangrove plant Rhizophora apiculata. The identification of isolates by 16S rRNA gene sequences revealed that the isolated endophytic bacteria belonged to nine genera, including Streptomyces, Bacillus, Pseudovibrio, Microbacterium, Brevibacterium, Microbulbifer, Micrococcus, Rossellomorea, and Paracoccus. The ethyl acetate extracts of the endophytic bacteria’s pharmacological properties were evaluated in vitro, including antimicrobial, antioxidant, α-amylase and α-glucosidase inhibitory, xanthine oxidase inhibitory, and cytotoxic activities. Gas chromatography–mass spectrometry (GC-MS) analyses of three high bioactive strains Bacillus sp. RAR_GA_16, Rossellomorea vietnamensis RAR_WA_32, and Bacillus sp. RAR_M1_44 identified major volatile organic compounds (VOCs) in their ethyl acetate extracts. Genome analyses identified biosynthesis gene clusters (BGCs) of secondary metabolites of the bacterial endophytes. The obtained results reveal that the endophytic bacteria from R. apiculata may be a potential source of pharmacological secondary metabolites, and further investigations of the high bioactive strains—such as fermentation and isolation of pure bioactive compounds, and heterologous expression of novel BGCs in appropriate expression hosts—may allow exploring and exploiting the promising bioactive compounds for future drug development.
Presumed Urinary Tract Infection in Patients Admitted with COVID-19: Are We Treating Too Much?
Authors: Van Laethem Johan , Wuyts Stephanie C. M. , Pierreux Jan , Seyler Lucie , Verschelden Gil , Depondt Thibault , Meuwissen Annelies , Lacor Patrick , Piérard Denis , Allard Sabine D.
Published: December 2021

Despite the low rates of bacterial co-/superinfections in COVID-19 patients, antimicrobial drug use has been liberal since the start of the COVID-19 pandemic. Due to the low specificity of markers of bacterial co-/superinfection in the COVID-19 setting, overdiagnosis and antimicrobial overprescription have become widespread. A quantitative and qualitative evaluation of urinary tract infection (UTI) diagnoses and antimicrobial drug prescriptions for UTI diagnoses was performed in patients admitted to the COVID-19 ward of a university hospital between 17 March and 2 November 2020. A team of infectious disease specialists performed an appropriateness evaluation for every diagnosis of UTI and every antimicrobial drug prescription covering a UTI. A driver analysis was performed to identify factors increasing the odds of UTI (over)diagnosis. A total of 622 patients were included. UTI was present in 13% of included admissions, and in 12%, antimicrobials were initiated for a UTI diagnosis (0.71 daily defined doses (DDDs)/admission; 22% were scored as ‘appropriate’). An evaluation of UTI diagnoses by ID specialists revealed that of the 79 UTI diagnoses, 61% were classified as probable overdiagnosis related to the COVID-19 hospitalization. The following factors were associated with UTI overdiagnosis: physicians who are unfamiliar working in an internal medicine ward, urinary incontinence, mechanical ventilation and female sex. Antimicrobial stewardship teams should focus on diagnostic stewardship of UTIs, as UTI overdiagnosis seems to be highly prevalent in admitted COVID-19 patients.
Prediction of Protein Sites and Physicochemical Properties Related to Functional Specificity
Authors: Pazos Florencio
Published: December 2021

Specificity Determining Positions (SDPs) are protein sites responsible for functional specificity within a family of homologous proteins. These positions are extracted from a family’s multiple sequence alignment and complement the fully conserved positions as predictors of functional sites. SDP analysis is now routinely used for locating these specificity-related sites in families of proteins of biomedical or biotechnological interest with the aim of mutating them to switch specificities or design new ones. There are many different approaches for detecting these positions in multiple sequence alignments. Nevertheless, existing methods report the potential SDP positions but they do not provide any clue on the physicochemical basis behind the functional specificity, which has to be inferred a-posteriori by manually inspecting these positions in the alignment. In this work, a new methodology is presented that, concomitantly with the detection of the SDPs, automatically provides information on the amino-acid physicochemical properties more related to the change in specificity. This new method is applied to two different multiple sequence alignments of homologous of the well-studied RasH protein representing different cases of functional specificity and the results discussed in detail.
The Functional Role of IgA in the IgM/IgA-Enriched Immunoglobulin Preparation Trimodulin
Authors: Bohländer Fabian , Weißmüller Sabrina , Riehl Dennis , Gutscher Marcus , Schüttrumpf Jörg , Faust Stefanie
Published: December 2021

In comparison to human immunoglobulin (Ig) G, antibodies of IgA class are not well investigated. In line with this, the functional role of the IgA component in IgM/IgA-enriched immunoglobulin preparations is also largely unknown. In recent years, powerful anti-pathogenic and immunomodulatory properties of human serum IgA especially on neutrophil function were unraveled. Therefore, the aim of our work is to investigate functional aspects of the trimodulin IgA component, a new plasma-derived polyvalent immunoglobulin preparation containing ~56% IgG, ~23% IgM and ~21% IgA. The functional role of IgA was investigated by analyzing the interaction of IgA with FcαRI, comparing trimodulin with standard intravenous IgG (IVIG) preparation and investigating Fc receptor (FcR)-dependent functions by excluding IgM-mediated effects. Trimodulin demonstrated potent immunomodulatory, as well as anti-pathogenic effects in our neutrophil model (neutrophil-like HL-60 cells). The IgA component of trimodulin was shown to induce a strong FcαRI-dependent inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) signaling, counteract lipopolysaccharide-induced inflammation and mediate phagocytosis of Staphylococcus aureus. The fine-tuned balance between immunomodulatory and anti-pathogenic effects of trimodulin were shown to be dose-dependent. Summarized, our data demonstrate the functional role of IgA in trimodulin, highlighting the importance of this immunoglobulin class in immunoglobulin therapy.
Hyperspectral Imaging for the Evaluation of Microcirculatory Tissue Oxygenation and Perfusion Quality in Haemorrhagic Shock: A Porcine Study
Authors: Dietrich Maximilian , Özdemir Berkin , Gruneberg Daniel , Petersen Clara , Studier-Fischer Alexander , von der Forst Maik , Schmitt Felix C. F. , Fiedler Mascha O. , Nickel Felix , Müller-Stich Beat Peter , Brenner Thorsten , Weigand Markus A. , Uhle Florian , Schmidt Karsten
Published: December 2021

Background: The ultimate goal of haemodynamic therapy is to improve microcirculatory tissue and organ perfusion. Hyperspectral imaging (HSI) has the potential to enable noninvasive microcirculatory monitoring at bedside. Methods: HSI (Tivita® Tissue System) measurements of tissue oxygenation, haemoglobin, and water content in the skin (ear) and kidney were evaluated in a double-hit porcine model of major abdominal surgery and haemorrhagic shock. Animals of the control group (n = 7) did not receive any resuscitation regime. The interventional groups were treated exclusively with either crystalloid (n = 8) or continuous norepinephrine infusion (n = 7). Results: Haemorrhagic shock led to a drop in tissue oxygenation parameters in all groups. These correlated with established indirect markers of tissue oxygenation. Fluid therapy restored tissue oxygenation parameters. Skin and kidney measurements correlated well. High dose norepinephrine therapy deteriorated tissue oxygenation. Tissue water content increased both in the skin and the kidney in response to fluid therapy. Conclusions: HSI detected dynamic changes in tissue oxygenation and perfusion quality during shock and was able to indicate resuscitation effectivity. The observed correlation between HSI skin and kidney measurements may offer an estimation of organ oxygenation impairment from skin monitoring. HSI microcirculatory monitoring could open up new opportunities for the guidance of haemodynamic management.
Angiotensin-Converting Enzyme 2 Protein Is Overexpressed in a Wide Range of Human Tumour Types: A Systematic Tissue Microarray Study on >15,000 Tumours
Authors: Meiners Jan , Jansen Kristina , Gorbokon Natalia , Büscheck Franziska , Luebke Andreas M. , Kluth Martina , Hube-Magg Claudia , Höflmayer Doris , Weidemann Sören , Fraune Christoph , Möller Katharina , Bernreuther Christian , Lebok Patrick , Menz Anne , Jacobsen Frank , Clauditz Till , Sauter Guido , Uhlig Ria , Wilczak Waldemar , Izbicki Jakob , Perez Daniel , Minner Sarah , Burandt Eike , Krech Till , Marx Andreas , Simon Ronald , Steurer Stefan
Published: December 2021

Angiotensin-converting enzyme 2 (ACE2) is a regulator in the renin-angiotensin system. ACE2 expression was analysed immunohistochemically in 15,306 samples from 119 tumour types and in 608 samples of 76 normal tissue types. In normal tissue, ACE2 was most abundant in testis and corpus luteum, kidney, small intestine and capillaries of selected organs. At least an occasional weak ACE2 positivity of tumour cells was seen in 83 of 119 (70%) tumour types. ACE2 tumour cell positivity was particularly frequent in papillary (94%) and clear cell (86%) renal cell carcinoma, colorectal adenocarcinoma (81%), mucinous ovarian cancer (61%), cholangiocarcinoma (58%), hepatocellular carcinoma (56%), and in adenocarcinomas of the stomach (47%), pancreas (42%), and the lung (35%). ACE2-positive capillaries were found in 409/12,644 (3%) of analysable tumours, most frequently in tumours with endocrine/neuroendocrine activity. Presence of ACE2-positive capillaries was linked to low stage in papillary thyroid cancer and low grade in neuroendocrine neoplasms. In conclusion, ACE2 expression can occur both in tumour cells and tumour-associated capillaries in a broad variety of different tumour types at highly variable frequencies.
Assessing Treatment Success or Failure as an Outcome in Randomised Clinical Trials of COPD Exacerbations. A Meta-Epidemiological Study
Authors: Mathioudakis Alexander G. , Ananth Sachin , Bradbury Thomas , Csoma Balazs , Sivapalan Pradeesh , Stovold Elizabeth , Fernandez-Romero Gustavo , Lazar Zsofia , Criner Gerard J. , Jenkins Christine , Papi Alberto , Jensen Jens-Ulrik , Vestbo Jørgen ,   on behalf of the DECODE-NET
Published: December 2021

A recently published ERS core outcome set recommends that all trials of COPD exacerbation management should assess the treatment success (or “cure” of the exacerbation), defined as a dichotomous measure of the overall outcome of an exacerbation. This methodological systematic review describes and compares the instruments that were used to assess treatment success or failure in 54 such RCTs, published between 2006–2020. Twenty-three RCTs used composite measures consisting of several undesirable outcomes of an exacerbation, together defining an overall unfavourable outcome, to define treatment failure. Thirty-four RCTs used descriptive instruments that used qualitative or semi-quantitative descriptions to define cure, marked improvement, improvement of the exacerbation, or treatment failure. Treatment success and failure rates among patients receiving guidelines-directed treatments at different settings and timepoints are described and could be used to inform power calculations in future trials. Descriptive instruments appeared more sensitive to treatment effects compared to composite instruments. Further methodological studies are needed to optimise the evaluation of treatment success/failure. In the meantime, based on the findings of this systematic review, the ERS core outcome set recommends that cure should be defined as sufficient improvement of the signs and symptoms of the exacerbation such that no additional systemic treatments are required.
A Three-Dimensional Finite Element Analysis of Displacement and Stress Distributions of Unilateral and Bilateral Cleft Lips by Using Developed Pre-Surgical Treatment Architecture
Authors: Karah bash Ali A. H. , Ercelebi Ergun
Published: December 2021

Cleft lips and cleft palates are the most common birth defects in newborns. Pre-surgical correction of unilateral and bilateral cleft lips and palates has been the subject of interest of many previous works. This condition has necessitated the evolution of many surgical and non-surgical techniques to mitigate the problem of this deformity in children. In this study, we proposed a new architecture that can be used instead of the conventional pre-surgical treatment. The proposed architecture has mechanical and electronic parts. This architecture was adopted to apply external stress to the cleft bones and cleft edges using an airbag that is located in the mechanical part. The amount of air in the airbag can be controlled by an available control unit in the electronic part. The effect of external stress on the cleft bones and the cleft edges was analyzed by using the finite element analysis (FEA) method. The FEA study aimed to analyze the displacement, amount of tensile and compressive forces, and Von Mises stress distributions on the cleft bones, cleft edges, nasal septum, and superior alveolar part of the maxillary jaw of unilateral and bilateral cleft models during pre-surgical treatment with the novel architecture. The results show that displacement and stress affected the clefts of both models. Displacement had a significant effect of gradually bringing the clefts closer to each other and returning them to the posterior. The analysis also investigated the effects of stress on the cleft bone and cleft edge. It was found from the results that the stresses helped to bring the incisions closer to the most appropriate position for plastic surgeons. The results prove that the positive and negative X-displacements move in the opposite direction, which means that the cleft edges gradually converge toward each other. Moreover, the negative Z-displacement affected the movement of cleft bones and cleft edges from outside to inside and gradually returned them to a suitable position. The findings show that the proposed architecture can be contributed to the pre-surgical treatment of the unilateral and bilateral clefts as an alternative to the traditional method.
Spine Fractures in Children and Adolescents—Frequency, Causes, Diagnostics, Therapy and Outcome—A STROBE-Compliant Retrospective Study at a Level 1 Trauma Centre in Central Europe
Authors: Payr Stephan , Schuller Andrea , Dangl Theresia , Chocholka Britta , Binder Harald , Tiefenboeck Thomas M.
Published: December 2021

The aim of this study was to present the frequencies and characteristics of paediatric spine fractures, focusing on injury mechanisms, diagnostics, management, and outcomes. This retrospective, epidemiological study evaluated all patients aged 0 to 18 years with spine fractures that were treated at a level 1 trauma centre between January 2002 and December 2019. The study population included 144 patients (mean age 14.5 ± 3.7 years; 40.3% female and 59.7% male), with a total of 269 fractures. Common injury mechanisms included fall from height injuries (45.8%), with an increasing prevalence of sport incidents (29.9%) and a decreasing prevalence of road incidents (20.8%). The most common localisation was the thoracic spine (43.1%), followed by the lumbar spine (38.2%), and the cervical spine (11.8%). Initially, 5.6% of patients had neurological deficits, which remained postoperatively in 4.2% of patients. Most (75.0%) of the patients were treated conservatively, although 25.0% were treated surgically. A small proportion, 3.5%, of patients presented postoperative complications. The present study emphasises the rarity of spinal fractures in children and adolescents and shows that cervical spine fractures are more frequent in older children, occurring with a higher rate in sport incidents. Over the last few years, a decrease in road incidents and an increase in sport incidents in paediatric spine fractures has been observed.
Pediatric COVID-19: Low Incidence, but Possible Fatality—A Case Report and a Review of the Literature
Authors: Mărginean Cristina Oana , Meliț Lorena Elena , Simu Iunius , Puiac Claudiu , Szederjesi Janos , Săsăran Maria Oana
Published: December 2021

Background: Pediatric COVID-19 is a current health burden mostly due to the lack of knowledge in terms of symptoms, clinical course and management. COVID-19-associated coagulopathy is one of the most recently described complications among adults, along with acquired thrombophilia resulting in an increased risk for venous, arterial and microvascular thrombosis. Case presentation: We report the case of a 4-year-old male child, admitted to our clinic for generalized seizures being intubated and mechanically ventilated before admission, with a personal history of ureterovesical junction obstruction, mild hydronephrosis, and an episode of generalized seizures. The laboratory tests revealed anemia, an increased number of monocytes, and a mildly increased C-reactive protein. A real-time polymerase chain reaction (RT-PCR) of the oropharyngeal swab was performed and it tested positive for SARS-CoV-2 in the child and both of his parents. The thoracic CT showed consolidation in the lower lobe of the left lung associated with an opacity in the right apex, suggesting possible atelectasis. We initiated antibiotic, antiviral, corticosteroids, as well as anticoagulants and antipyretics, continuing the chronic anticonvulsant therapy. The patient’s condition deteriorated progressively, and, after 72 h of hospitalization, he developed desaturation and bradycardia. The laboratory parameters on the third day showed leucopenia, neutropenia, increased creatine kinase, a high ferritin level, hypoalbuminemia, a prolonged prothrombin time and an increased international normalized ration. The patient died on the fourth day of admission. Conclusion: In spite of its low incidence and frequent benign clinical course, COVID-19 complications such as coagulopathy might represent a leading cause of death, even in pediatric patients.
Effectiveness and Coverage of Treatment for Severe Acute Malnutrition Delivered by Community Health Workers in the Guidimakha Region, Mauritania
Authors: Charle-Cuéllar Pilar , Lopez-Ejeda Noemí , Toukou Souleymane Hassane , Yacouba Diagana , Diagana Moussa , Dougnon Abdias Ogobara , Vargas Antonio , Briend André
Published: December 2021

Geographical and economic access barriers to health facilities (HF) have been identified as some of the most important causes of the low coverage of severe acute malnutrition (SAM) treatment. The objective of this study is to assess the effectiveness and coverage of SAM treatment delivered by community health workers (CHWs) in the Guidimakha region in Mauritania, compared to the HF based approach. This study was a nonrandomized controlled trial, including two rural areas. The control group received outpatient treatment for uncomplicated SAM from HF, whilst the intervention group received outpatient treatment for uncomplicated SAM from HF or CHWs. A total of 869 children aged 6–59 months with SAM without medical complications were included in the study. The proportion of cured children was 82.3% in the control group, and 76.4% in the intervention group, we found no significant difference between the groups. Coverage in the intervention zone increased from 53.6% to 71.7%. In contrast, coverage remained at approximately 44% in the control zone from baseline to end-line. This study is the first to demonstrate in Mauritania that the decentralization model of CHWs treating SAM improves acute malnutrition treatment coverage and complies with the international quality standards for community treatment of acute malnutrition. The non-randomized study design may limit the quality of the evidence, but these results could be used by political decision-makers as a first step in revising the protocol for acute malnutrition management.
Reducing the Weight of Spinal Pain in Children and Adolescents
Authors: Palsson Thorvaldur S. , Andreucci Alessandro , Straszek Christian Lund , Rathleff Michael Skovdal , Hoegh Morten
Published: December 2021

Spinal pain in adults is a significant burden, from an individual and societal perspective. According to epidemiologic data, spinal pain is commonly found in children and adolescents, where evidence emerging over the past decade has demonstrated that spinal pain in adults can, in many cases, be traced back to childhood or adolescence. Nevertheless, very little focus has been on how to best manage spinal pain in younger age groups. The purpose of this article is to put the focus on spinal pain in children and adolescents and highlight how and where these problems emerge and how they are commonly dealt with. We will draw on findings from the relevant literature from adults to highlight potential common pathways that can be used in the management of spinal pain in children and adolescents. The overall focus is on how healthcare professionals can best support children and adolescents and their caregivers in making sense of spinal pain (when present) and support them in the self-management of the condition.