bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell analysis reveals cell communication triggered by macrophages associated with the reduction and exhaustion of CD8+ T cells in COVID-19
Authors: He Lei , Zhang Quan , Zhang Yue , Fan Yixian , Yuan Fahu , Li Songming
Published: July 2021

Background

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand–receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures.

Methods

A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand–receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1β, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured.

Results

Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand–receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis.

Conclusions

Our study showed that macrophages driving ligand–receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1β, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy.

Trial registration: This is a retrospective observational study without a trial registration number.
Reducing fatigue in pediatric rheumatic conditions: a systematic review
Authors: Kant-Smits K. , Van Brussel M. , Nijhof S. , Van der Net J.
Published: July 2021

Background

Although fatigue is a prevalent distressing symptom in children and adolescents with Pediatric Rheumatic Conditions (PRCs), intervention studies designed for reducing fatigue in PRCs are limited.

Aim

To systematically review evidence regarding the efficacy of interventions intended to reduce fatigue in patients with PRCs.

Methods

Comprehensive electronic searches were performed in PubMed/ MEDLINE, Embase, Web of Science and Cinahl. The risk of bias was assessed using the ‘Revised Cochrane risk-of-bias tool for randomized trials’ and ‘Quality Assessment Tool for Before-After Studies With No Control Group’ for respectively studies with and without a control group.

Results

Ten out of 418 studies were included with a total of 240 participants (age range 5–23 years). Interventions included land-based and aquatic-based exercise therapy, prednisolone, vitamin-D and creatine supplementation, psychological therapy and a transition program into an adult rheumatology program. Fatigue was assessed with self-reported questionnaires in all included studies. Land-based exercise therapy was effective in one pre-post intervention study, whereas not effective in two randomized controlled trials. Aquatic-based exercise therapy was found more effective than land-based exercise therapy. Two placebo-controlled studies showed a significant positive effect in reducing subjective fatigue with prednisolone and vitamin-D. Creatine was not found effective. Cognitive therapy was effective in one pre-post intervention study, while one RCT did not show an effect in reducing fatigue. A transition program based on health education showed a small reducing effect, however, it was not clear if this was a significant effect. Six studies showed a high risk of bias, three studies a moderate risk, and one study had a low risk of bias.

Conclusions

Insufficient evidence is provided to substantiate the efficacy of current interventions to reduce fatigue in PRCs. The low number of studies, non-comparable interventions, risk of bias, and inconclusive outcomes of the included studies denote future research should focus on intervention studies aimed at the treatment of fatigue in children and adolescents with PRCs. Identification of possible underlying biological and psychosocial mechanisms as possible treatment targets to reduce complaints of fatigue in children and adolescents with PRCs is warranted.
Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder
Authors: Galvani Giuseppe , Mottolese Nicola , Gennaccaro Laura , Loi Manuela , Medici Giorgio , Tassinari Marianna , Fuchs Claudia , Ciani Elisabetta , Trazzi Stefania
Published: July 2021

Background

CDKL5 deficiency disorder (CDD), a severe neurodevelopmental disorder characterized by early onset epilepsy, intellectual disability, and autistic features, is caused by mutations in theCDKL5gene. Evidence in animal models of CDD showed that absence of CDKL5 negatively affects neuronal survival, as well as neuronal maturation and dendritic outgrowth; however, knowledge of the substrates underlying these alterations is still limited. Neuroinflammatory processes are known to contribute to neuronal dysfunction and death. Recent evidence shows a subclinical chronic inflammatory status in plasma from CDD patients. However, to date, it is unknown whether a similar inflammatory status is present in the brain of CDD patients and, if so, whether this plays a causative or exacerbating role in the pathophysiology of CDD.

Methods

We evaluated microglia activation using AIF-1 immunofluorescence, proinflammatory cytokine expression, and signaling in the brain of a mouse model of CDD, theCdkl5KO mouse, which is characterized by an impaired survival of hippocampal neurons that worsens with age. Hippocampal neuron survival was determined by DCX, NeuN, and cleaved caspase-3 immunostaining inCdkl5KO mice treated with luteolin (10 mg/kg), a natural anti-inflammatory flavonoid. Since hippocampal neurons ofCdkl5KO mice exhibit increased susceptibility to excitotoxic stress, we evaluated neuronal survival inCdkl5KO mice injected with NMDA (60 mg/kg) after a 7-day treatment with luteolin.

Results

We found increased microglial activation in the brain of theCdkl5KO mouse. We found alterations in microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and activation of STAT3 signaling. Remarkably, treatment with luteolin recovers microglia alterations as well as neuronal survival and maturation inCdkl5KO mice, and prevents the increase in NMDA-induced cell death in the hippocampus.

Conclusions

Our results suggest that neuroinflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of luteolin as a treatment option in CDD patients.
A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations
Authors: Canaud Guillaume , Hammill Adrienne M. , Adams Denise , Vikkula Miikka , Keppler-Noreuil Kim M.
Published: July 2021

Background

PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders.

Main body

PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations, and PIK3CA-related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA-related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA-related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA-related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib).

Conclusion

Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.
Diagnosis, treatment and postsurgical complications in a dog with epileptic seizures and a naso-ethmoidal meningoencephalocele
Authors: Mojarradi Abtin , Van Meervenne Sofie , Suarez-Bonnet Alejandro , De Decker Steven
Published: July 2021

Background

Naso-ethmoidal meningoencephalocele is usually a congenital anomaly consisting of a protrusion of cerebral tissue and meninges into the ethmoidal labyrinth. The condition is a rare cause of structural epilepsy in dogs. We report the clinical presentation, surgical intervention, postoperative complications and outcome in a dog with drug resistant epilepsy secondary to a meningoencephalocele.

Case presentation

A 3.3-year-old male neutered Tamaskan Dog was referred for assessment of epileptic seizures secondary to a previously diagnosed left-sided naso-ethmoidal meningoencephalocele. The dog was drug resistant to medical management with phenobarbital, potassium bromide and levetiracetam. Surgical intervention was performed by a transfrontal craniotomy with resection of the meningoencephalocele and closure of the dural defect. Twenty-four hours after surgery the dog demonstrated progressive cervical hyperaesthesia caused by tension pneumocephalus and pneumorrhachis. Replacement of the fascial graft resulted in immediate resolution of the dog’s neurological signs. Within 5 months after surgery the dog progressively developed sneezing and haemorrhagic nasal discharge, caused by sinonasal aspergillosis. Systemic medical management with oral itraconazole (7 mg/kg orally q12h) was well-tolerated and resulted in resolution of the clinical signs. The itraconazole was tapered with no relapsing upper airway signs. The dog’s frequency of epileptic seizures was not affected by surgical resection of the meningoencephalocele. No treatment adjustments of the anti-epileptic medication have been necessary during the follow-up period of 15 months.

Conclusions

Surgical resection of the meningoencephalocele did not affect the seizure frequency of the dog. Further research on prognostic factors associated with surgical treatment of meningoencephaloceles in dogs is necessary. Careful monitoring for postsurgical complications allows prompt initiation of appropriate treatment.
Effect of arterial oxygen partial pressure inflection point on Venoarterial extracorporeal membrane oxygenation for emergency cardiac support
Authors: Zhou Hao , Zhu Yi , Zhang Zhongman , Lv Jinru , Li Wei , Hu Deliang , Chen Xufeng , Mei Yong
Published: July 2021

Background

Temporary circulatory support is a bridge between acute circulatory failure and definitive treatment or recovery. Currently, venoarterial extracorporeal membrane oxygenation (VA-ECMO) is considered to be one of the effective circulatory support methods, although cardiac function monitoring during the treatment still needs further investigation. Inflection point of arterial oxygen partial pressure (IPPaO2) may occur at an early stage in part of patients with a good prognosis after VA-ECMO treatment, and the relationship between time of IPPaO2 (tIPPaO2) and recovery of cardiac function or prognosis remains unclear.

Methods

To investigate this relationship, we retrospectively analyzed the clinical data of 71 patients with different conditions after treatment with VA-ECMO in the emergency center of Jiangsu Province Hospital between May 2015 and July 2020. Spearman’s correlation analysis was used for the correlation between tIPPaO2 and quantitative data, and ROC curve for the predictive effect of tIPPaO2 on the 28-day mortality.

Results

Thirty-five patients were admitted because of refractory cardiogenic shock (26 of 35 survived) and the remaining 36 patients due to cardiac arrest (13 of 36 survived). The overall survival rate was 54.9% (39 of 71 survived). Acute physiology and chronic health evaluation II, ECMO time, tIPPaO2, continuous renal replacement therapy time, mechanical ventilation time, and bleeding complications in the survival group were lower than those in the non-survival group, with length of stay, intensive care unit stay, and platelet levels were being higher. The tIPPaO2 was negatively correlated with ejection fraction, and the shorter tIPPaO2 resulted in a higher 28-day survival probability, higher predictive value for acute myocardial infarction and fulminant myocarditis.

Conclusions

Therefore, tIPPaO2 could be a reliable qualitative indicator of cardiac function in patients treated with VA-ECMO, which can reveal appropriate timing for adjusting VA-ECMO flow or weaning.

Trial registration

ChiCTR1900026105.
Risk factors for overuse injuries in a cohort of elite Swedish track and field athletes
Authors: Lundberg Zachrisson Andreas , Ivarsson Andreas , Desai Pia , Karlsson Jon , Grau Stefan
Published: July 2021

Background

Most injuries in track and field are caused by overuse with conflicting reports concerning the underlying mechanisms. The purpose of this study was to evaluate how biomechanical and clinical factors relate to the risk of overuse injuries, and to investigate whether the relationships between potential risk factors and injury become stronger if injuries are grouped by location.

Methods

The study is a prospective cohort study conducted during a Swedish track and field season over eleven months, from October to August. The cohort consisted of elite male and female track and field athletes competing in either middle- and long-distance running, sprinting, jumping, or throwing events (n = 96). Athletes performed a baseline screening at enrollment consisting of a clinical examination, running, and strength tests. Injury data was collected during the season by medical professionals and divided according to their anatomical location into upper-body, thigh/hip, knee, or foot/shank injuries.

Results

Thirty-four (54.8%) injuries where located at the foot/shank, followed by sixteen injuries at the thigh/hip (25.8%). Only eight knee (12.9%) and four upper-body (6.5%) injuries were registered during the season and therefore not analysed. Effect sizes were calculated for all test variables. Small effect sizes (rpb = .10–.23) were found for eleven risk factors between the overall injured (all injuries combined) and non-injured athletes. By further sub-grouping the injured group into thigh/hip injuries, effect size increased in hip adduction range of motion knee flexion velocity and the muscle flexibility of the iliopsoas. For foot/shank injuries, only the hamstring:quadriceps strength ratios increased for the right side to a small effect size.

Conclusions

Injury grouping appears to increase effect size for certain risk factors. Athletes with a slower knee flexion velocity during stance phase were more likely to become injured (p-value <.03, rpb = .37). An increased cohort size to further sub-divide injuries into specific diagnoses is needed.
The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes
Authors: Beacon Tasnim H. , Delcuve Geneviève P. , López Camila , Nardocci Gino , Kovalchuk Igor , van Wijnen Andre J. , Davie James R.
Published: July 2021

Transcriptionally active chromatin is marked by tri-methylation of histone H3 at lysine 4 (H3K4me3) located after first exons and around transcription start sites. This epigenetic mark is typically restricted to narrow regions at the 5`end of the gene body, though a small subset of genes have a broad H3K4me3 domain which extensively covers the coding region. Although most studies focus on the H3K4me3 mark, the broad H3K4me3 domain is associated with a plethora of histone modifications (e.g., H3 acetylated at K27) and is therein termed broad epigenetic domain. Genes marked with the broad epigenetic domain are involved in cell identity and essential cell functions and have clinical potential as biomarkers for patient stratification. Reducing expression of genes with the broad epigenetic domain may increase the metastatic potential of cancer cells. Enhancers and super-enhancers interact with the broad epigenetic domain marked genes forming a hub of interactions involving nucleosome-depleted regions. Together, the regulatory elements coalesce with transcription factors, chromatin modifying/remodeling enzymes, coactivators, and the Mediator and/or Integrator complex into a transcription factory which may be analogous to a liquid–liquid phase-separated condensate. The broad epigenetic domain has a dynamic chromatin structure which supports frequent transcription bursts. In this review, we present the current knowledge of broad epigenetic domains.
Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo
Authors: Mensch Maria , Dunot Jade , Yishan Sandy M. , Harris Samuel S. , Blistein Aline , Avdiu Alban , Pousinha Paula A. , Giudici Camilla , Busche Marc Aurel , Jedlicka Peter , Willem Michael , Marie Hélène
Published: July 2021

Background

Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo.

Methods

With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology.

Results

We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo.

Conclusions

These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.
A bivalent protein targeting glycans and HR1 domain in spike protein potently inhibited infection of SARS-CoV-2 and other human coronaviruses
Authors: Cai Yanxing , Xu Wei , Tang Jiayi , Cao Najing , Lan Qiaoshuai , Lu Lu , Jiang Shibo
Published: July 2021

Background

Our previous studies have shown that combining the antiviral lectin GRFT and the pan-CoV fusion inhibitory peptide EK1 results in highly potent inhibitory activity against SARS-CoV-2 infection. In this study, we aimed to design and construct a bivalent protein consisting of GRFT and EK1 components and evaluate its inhibitory activity and mechanism of action against infection by SARS-CoV-2 and its mutants, as well as other human coronaviruses (HCoVs).

Methods

The bivalent proteins were expressed in E. coli and purified with Ni-NTA column. HIV backbone-based pseudovirus (PsV) infection and HCoV S-mediated cell–cell fusion assays were performed to test their inhibitory activity. ELISA and Native-PAGE were conducted to illustrate the mechanism of action of these bivalent proteins. Five-day-old newborn mice were intranasally administrated with a selected bivalent protein before or after HCoV-OC43 challenge, and its protective effect was monitored for 14 days.

Results

Among the three bivalent proteins purified, GL25E exhibited the most potent inhibitory activity against infection of SARS-CoV-2 PsVs expressing wild-type and mutated S protein. GL25E was significantly more effective than GRFT and EK1 alone in inhibiting HCoV S-mediated cell–cell fusion, as well as infection by SARS-CoV-2 and other HCoVs, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and HCoV-OC43. GL25E could inhibit authentic SASR-CoV-2, HCoV-OC43 and HCoV-229E infection in vitro and prevent newborn mice from authentic HCoV-OC43 infection in vivo. GL25E could bind to glycans in the S1 subunit and HR1 in the S2 subunit in S protein, showing a mechanism of action similar to that of GRFT and EK1 alone.

Conclusions

Since GL25E showed highly potent and broad-spectrum inhibitory activity against infection of SARS-CoV-2 and its mutants, as well as other HCoVs, it is a promising candidate for further development as a broad-spectrum anti-HCoV therapeutic and prophylactic to treat and prevent COVID-19 and other emerging HCoV diseases.
Technical reliability of shipboard technologies for the application of alternative fuels
Authors: Popp Lukas , Müller Karsten
Published: July 2021

Background

Naval traffic is highly dependent on depleting fossil resources and causes significant greenhouse gas emissions. At the same time, marine transportation is a major backbone of world trade. Thus, alternative fuel concepts are highly needed. Different fuels such as ammonia, methanol, liquefied natural gas and hydrogen have been proposed. For some of them, first prototype vessels have been in operation. However, practical experience is still limited. Most studies so far focus on aspects such as efficiency and economics. However, particularly in marine applications, reliability of propulsion systems is of utmost importance, because failures on essential ship components at sea pose a huge safety risk. If the respective components lose their functionality, repair can be much more challenging due to large distances to dockyards and the complicated transport of spare parts to the ship. Consequently, evaluation of reliability should be a core element of system analysis for new marine fuels.

Results

In this study, reliability was studied for four potential fuels. The analysis involved several steps: estimation of overall failure rates, identification of most vulnerable components and assessment of criticality by including severity of fault events. On the level of overall failure rate, ammonia is shown to be very promising. Extending the view over a pure failure rate-based evaluation shows that other approaches, such as LOHC or methanol, can be competitive in terms of reliability and risk. As different scenarios require different weightings of the different reliability criteria, the conclusion on the best technology can differ. Relevant aspects for this decision can be the availability of technical staff, high-sea or coastal operation, the presence of non-naval personnel onboard and other factors.

Conclusions

The analysis allowed to compare different alternative marine fuel concepts regarding reliability. However, the analysis is not limited to assessment of overall failure rates, but can also help to identify critical elements that deserve attention to avoid fault events. As a last step, severity of the individual failure modes was included. For the example of ammonia, it is shown that the decomposition unit and the fuel cell should be subject to measures for increasing safety and reducing failure rates.
Class- and subject teachers’ self-efficacy and emotional stability and students’ perceptions of the teacher–student relationship, classroom management, and classroom disruptions
Authors: Wettstein Alexander , Ramseier Erich , Scherzinger Marion
Published: July 2021

Background

Teacher self-efficacy and emotional stability are considered crucial resources for coping with classroom demands. We examined how class and subject teachers’ self-efficacy beliefs and emotional stability are related to teachers' and students' perceptions of the teacher–student relationship, classroom management, and classroom disruptions.

Methods

In a sample of eighty-two swiss german 5th and 6th grade classes, 1290 students, their class teacher (N = 82), and a selected subject teacher (N = 82) filled out a questionnaire assessing classroom disruptions, teacher–student relationships, and classroom management. In a first step, we conducted t-tests on whether class teachers and subject teachers differ in their self-efficacy beliefs and emotional stability. In a second step, we explored by correlation analyses the relations between teacher self-efficacy in classroom management and emotional stability and the teachers’ and students’ perceptions of classroom disruptions, teacher–student relationships, and classroom management. In a third step, we examined by stepwise multiple regression analyses to what extent psychological variables predict teacher perceptions after controlling for students’ ratings, representing rather “objective” classroom features.

Results

In class teachers, high self-rated emotional stability and self-efficacy are associated with a more positive appraisal of teacher–student relationships and classroom management skills (compared with student ratings). By contrast, in subject teachers, high self-efficacy beliefs are associated with a more favorable perception of classroom disruptions, teacher–student relationships, and classroom management, from both the teachers' and students' perspectives.

Conclusions

The results of the present study show a distinctive pattern for class teachers and subject teachers. In class teachers, high self-rated emotional stability and self-efficacy are associated with a more positive evaluation (compared to student ratings) of the teacher–student relationship and classroom management skills but not teacher perceptions of student misbehavior. On the contrary, subject teachers' firm self-efficacy beliefs are associated with more favorable perceptions of classroom characteristics, both from the teachers' and students' perspectives.
Combining assumptions and graphical network into gene expression data analysis
Authors: Fofana Demba , George E. O. , Bowman Dale
Published: July 2021

Background

Analyzing gene expression data rigorously requires taking assumptions into consideration but also relies on using information about network relations that exist among genes. Combining these different elements cannot only improve statistical power, but also provide a better framework through which gene expression can be properly analyzed.

Material and methods

We propose a novel statistical model that combines assumptions and gene network information into the analysis. Assumptions are important since every test statistic is valid only when required assumptions hold. So, we propose hybrid p-values and show that, under the null hypothesis of primary interest, these p-values are uniformly distributed. These proposed hybrid p-values take assumptions into consideration. We incorporate gene network information into the analysis because neighboring genes share biological functions. This correlation factor is taken into account via similar prior probabilities for neighboring genes.

Results

With a series of simulations our approach is compared with other approaches. Area Under the ROC Curves (AUCs) are constructed to compare the different methodologies; the AUC based on our methodology is larger than others. For regression analysis, AUC from our proposed method contains AUCs of Spearman test and of Pearson test. In addition, true negative rates (TNRs) also known as specificities are higher with our approach than with the other approaches. For two group comparison analysis, for instance, with a sample size of n=10, specificity corresponding to our proposed methodology is 0.716146 and specificities for t-test and rank sum are 0.689223 and 0.69797, respectively. Our method that combines assumptions and network information into the analysis is shown to be more powerful.

Conclusions

These proposed procedures are introduced as a general class of methods that can incorporate procedure-selection, account for multiple-testing, and incorporate graphical network information into the analysis. We obtain very good performance in simulations, and in real data analysis.
Variable returns to scale DEA—Taguchi approach for ternary additives optimization in expansive soil subgrade enhancement
Authors: Ikeagwuani Chijioke Christopher , Nwonu Donald Chimobi
Published: July 2021

In this study, variable returns to scale (VRS) data envelopment analysis was integrated into the Taguchi approach to optimize ternary additives for expansive soil enhancement. The ternary additives selected were sawdust ash (SDA), quarry dust (QD) and ordinary Portland cement (OPC). The additives were set as the input variables while multiple responses obtained from the experiments performed with the Taguchi orthogonal array were set as the output variables. Each row in the orthogonal array were defined as a decision making unit (DMU) in the optimization process and output-oriented VRS model was used to obtain the efficiency score for each DMU. Next, benevolent formulation was utilized to obtain the multipliers for the inputs and outputs which were subsequently used to determine the cross efficiency scores for each DMU. The cross-efficiency scores were used to construct the cross-efficiency matrix. Thereafter, the mean cross-efficiency score (MCES) was determined for each DMU. Parameter level that maximizes the MCES was chosen as the optimal level for that parameter. Optimum combination of additives was found at A6 B2 C3. Lastly, confirmatory experiments performed by blending the soil with the optimum combination of additives showed the effectiveness of this method in the enhancement of expansive soil properties.
Dietary diversity and food security status among heart failure patients in the north of Iran
Authors: Mahdavi-Roshan Marjan , Vakilpour Azin , Mousavi Seyed Mehdi , Ashouri Asieh
Published: July 2021

Background

Dietary diversity score (DDS) is an indicator for assessing nutritional adequacy. Food security is another important measure in nutrition field which can be associated with several cardiovascular risk factors. Considering the importance of nutrition in heart failure (HF) patients, this study was designed to evaluate the DDS and food security of patients with HF.

Methods

A total of 200 HF patients were enrolled. DDS was evaluated using valid and reliable food frequency questionnaire and was calculated by scoring food intakes as 5 main groups. Household food insecurity access scale was applied to assess food security status. Data were analyzed using descriptive statistics, Chi-square and Kruskal-Wallis tests and multiple logistic regression models.

Results

The mean age of patients was 65 (standard deviation: 12) years and 59% of patients were male. Median of DDS was 1.96 (range: 0.29 to 6.12). Adjusted odds of greater DDS (> = median of 2) was 2.58 times higher for patients without hypertension than for patients with hypertension (95%CI: 1.31–5.08, P = 0.006). Also, odds of greater DDS were more in ex-smokers’ patients when compared to non-smokers (adjusted odds ratio (AOR): 2.70, 95%CI: 1.27–5.75, P = 0.010), patients with supplement use (AOR: 2.42, 95%CI: 1.16–5.05, P = 0.019), patients with lower total cholesterol level (AOR: 1.01, 95%CI: 1.00–1.02, P = 0.051), and patients with higher ejection fraction (AOR: 1.03, 95%CI: 1.00–1.05, with borderline.

P = 0.073). About 57% of patients had experienced degrees of food insecurity as mild (26%), moderate (16%) and severe (15%). On the other hand, women (AOR: 1.90, 95%CI: 0.90–3.71, with borderline P = 0.061) and patients with middle (AOR: 3.48, 95%CI: 1.79–6.76, P < 0.001) or high (AOR: 20.32, 95%CI: 2.56–161.19, P = 0.004) socio-economic status were more likely to be food secure or mild insecure. Also, no relation between DDS and food security was found (r = − 0.08, P = 0.262).

Conclusion

This study found that HF patients had a low DDS and more than half of the patients were food insecure to some extents.
Chromium and cobalt intoxication mimicking mitochondriopathy
Authors: Rattay Tim W. , Kluba Torsten , Schöls Ludger
Published: July 2021

A 53-year old male with a history of progressive visual impairment, hearing loss, peripheral neuropathy, poorly controlled diabetes mellitus, cardiomyopathy, and weight loss was referred to the rare disease center due to the suspicion of mitochondrial cytopathy. In line with mitochondrial dysfunction, lactate in CSF was increased. Genetic testing by whole-exome sequencing and mitochondrial DNA did not reveal a likely cause. The case remained unsolved until he developed pain in his right hip, where he had received total hip arthroplasty 12 years earlier. An orthopedic evaluation revealed substantial shrinkage of the head of the hip prosthesis. Due to metal-on-metal wear, debris chromium and cobalt levels in serum were massively increased and significantly improved with multisystemic impairment after exchanging the defective implant.
Contrast of Digital and Health Literacy Between IT and Health Care Specialists Highlights the Importance of Multidisciplinary Teams for Digital Health—A Pilot Study
Authors: Pfob André , Sidey-Gibbons Chris , Schuessler Maximilian , Lu Sheng-Chieh , Xu Cai , Dubsky Peter , Golatta Michael , Heil Joerg
Published: July 2021

PURPOSE

Despite their promises, digital innovations have scarcely translated to technologies used in routine clinical practice, making the identification of barriers to successful implementation a research priority. Low levels of transdisciplinary skills represent such a barrier but so far, this has not been evaluated and compared between information technology (IT) and health care specialists. In this study, we evaluated the level of digital health literacy among IT and health care specialists.

MATERIALS AND METHODS

An anonymous questionnaire was distributed to staff at a breast cancer unit and an IT department of two German universities in December 2020. The survey questionnaire consisted of the previously validated eHealth Literacy Assessment Toolkit and additional questions with respect to age, profession, and career stage. Mann-Whitney or Wilcoxon rank-sum tests and two-sample chi-square tests were used for the analysis.

RESULTS

The survey was completed by 113 individuals: 70 (61.9%) IT specialists and 43 (38.1%) health care specialists. Health care specialists scored significantly higher on the health-related scales and IT specialists scored significantly higher on the digitally related scales. No single participant identified themselves to have the highest level of literacy on all survey questions (n = 0 of 113; 0%). Only one person (n = 1 of 113; 0.9%) consistently reported a high or the highest level of literacy.

CONCLUSION

Although IT and health care specialists showed great literacy in their respective disciplines, only few individuals combined both digital and health care literacy. Multidisciplinary teams and transdisciplinary curricula are crucial to bridge skill gaps between disciplines and to drive the implementation of digital health initiatives.
Benefits and Harms of Lung Cancer Screening by Chest Computed Tomography: A Systematic Review and Meta-Analysis
Authors: Passiglia Francesco , Cinquini Michela , Bertolaccini Luca , Del Re Marzia , Facchinetti Francesco , Ferrara Roberto , Franchina Tindara , Larici Anna R. , Malapelle Umberto , Menis Jessica , Passaro Antonio , Pilotto Sara , Ramella Sara , Rossi Giulio , Trisolini Rocco , Novello Silvia
Published: July 2021

PURPOSE

This meta-analysis aims to combine and analyze randomized clinical trials comparing computed tomography lung screening (CTLS) versus either no screening (NS) or chest x-ray (CXR) in subjects with cigarette smoking history, to provide a precise and reliable estimation of the benefits and harms associated with CTLS.

MATERIALS AND METHODS

Data from all published randomized trials comparing CTLS versus either NS or CXR in a highly tobacco-exposed population were collected, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for dichotomous outcomes. The certainty of the evidence was assessed using the GRADE approach.

RESULTS

Nine eligible trials (88,497 patients) were included. Pooled analysis showed that CTLS is associated with: a significant reduction of lung cancer–related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80; 95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis (overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to 0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76 to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99; 95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS, 38%; 95% CI, 14 to 63). The analysis of lung cancer–related mortality by sex revealed nonsignificant differences between men and women ( P = .21; I-squared = 33.6%).

CONCLUSION

Despite there still being uncertainty about overdiagnosis estimate, this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects with cigarette smoking history, ultimately supporting the systematic implementation of lung cancer screening worldwide.
Trajectories of Subjective Health: Testing Longitudinal Models for Self-rated Health From Adolescence to Midlife
Authors: Bollen Kenneth A. , Gutin Iliya
Published: July 2021

Self-rated health (SRH) is ubiquitous in population health research. It is one of the few consistent health measures in longitudinal studies. Yet, extant research offers little guidance on its longitudinal trajectory. The literature on SRH suggests several possibilities, including SRH as (1) a more fixed, longer-term view of past, present, and anticipated health; (2) a spontaneous assessment at the time of the survey; (3) a result of lagged effects from prior responses; (4) a function of life course processes; and (5) a combination of the preceding. Different perspectives suggest different longitudinal models, but evidence is lacking about which model best captures SRH trajectory. Using data from the National Longitudinal Study of Adolescent to Adult Health and the National Longitudinal Survey of Youth, we employ structural equation modeling to correct for measurement error and identify the best-fitting, theoretically guided models describing SRH trajectories. Results support a hybrid model that combines the lagged effect of SRH with the enduring perspectives, fitted with a type of autoregressive latent trajectory (ALT) model. This model structure consistently outperforms other commonly used models and underscores the importance of accounting for lagged effects combined with time-invariant effects in longitudinal studies of SRH. Interestingly, comparisons of this latent, time-invariant autoregressive model across gender and racial/ethnic groups suggest that there are differences in starting points but less variability in SRH trajectories from early life into adulthood.
Inducible manipulation of motor–cargo interaction using engineered kinesin motors
Authors: Hummel Jessica J. A. , Hoogenraad Casper C.
Published: July 2021

Molecular motors drive long-range intracellular transport of various vesicles and other cargoes within a cell. Identifying which kinesin motors interact with which type of transport vesicles has been challenging, especially in complex neuronal cells. Here, we present a highly adaptable toolbox of engineered kinesin motors to control and interrogate the selectivity and regulation of cargo transport with acute chemical induction. Selectivity of cargo–motor interaction can be addressed by systematic screening of a library of kinesin tails and neuronal cargoes. Additionally, our toolbox can be used to study kinesin–cargo regulatory mechanisms, and we found that cargo trafficking by KIF16B is regulated by its PX domain. Furthermore, our toolbox enables acute manipulation of polarized trafficking in living neurons by steering transport into axons or dendrites. Engineering kinesin motors provides a powerful tool to map the specificity of interactions between kinesin and cargoes, manipulate polarized transport and investigate cargo–motor interaction modes.
Alanine alters the carbohydrate metabolism of rainbow trout: glucose flux and cell signaling
Authors: Jubouri Mais , Talarico Giancarlo G. M. , Weber Jean-Michel , Mennigen Jan A.
Published: July 2021

In rainbow trout, dietary carbohydrates are poorly metabolized compared with other macronutrients. One prevalent hypothesis suggests that high dietary amino acid levels could contribute to the poor utilization of carbohydrates in trout. In mammals, alanine is considered an important gluconeogenic precursor, but has recently been found to stimulate AMP-activated protein kinase (AMPK) to reduce glucose levels. In trout, the effect of alanine on glucose flux is unknown. The goal of this study was to determine the effects of 4 h exogenous alanine infusion on glucose metabolism in rainbow trout. Glucose flux, and the rate of glucose appearance (Ra) and disposal (Rd) were measured in vivo. Key glycolytic and gluconeogenic enzyme expression and activity, and cell signaling molecules relevant to glucose metabolism were assessed in the liver and muscle. The results show that alanine inhibits glucose Ra (from 13.2±2.5 to 7.3±1.6 μmol kg−1 min−1) and Rd (from 13.2±2.5 to 7.4±1.5 μmol kg−1 min−1) and the slight mismatch between Ra and Rd caused a reduction in glycemia, similar to the effects of insulin in trout. The reduction in glucose Rd can be partially explained by a reduction in glut4b expression in red muscle. In contrast to mammals, trout alanine-dependent glucose-lowering effects did not involve hepatic AMPK activation, suggesting a different mechanistic basis. Interestingly, protein kinase B (AKT) activation increased only in muscle, similar to effects observed in insulin-infused trout. We speculate that alanine-dependent effects were probably mediated through stimulation of insulin secretion, which could indirectly promote alanine oxidation to provide the needed energy.
Application of low-dose CT combined with model-based iterative reconstruction algorithm in oncologic patients during follow-up: dose reduction and image quality
Authors: Ippolito Davide , Maino Cesare , Pecorelli Anna , Salemi Ilaria , Gandola Davide , Riva Luca , Talei Franzesi Cammillo , Sironi Sandro
Published: July 2021

Objectives:

To compare image quality and radiation dose of CT images reconstructed with model-based iterative reconstruction (MBIR) and hybrid-iterative (HIR) algorithm in oncologic patients.

Methods:

125 oncologic patients underwent both contrast-enhanced low- (100 kV), and standard (120 kV) dose CT, were enrolled. Image quality was assessed by using a 4-point Likert scale. CT attenuation values, expressed in Hounsfield unit (HU), were recorded within a regions of interest (ROI) of liver, spleen, paraspinal muscle, aortic lumen, and subcutaneous fat tissue. Image noise, expressed as standard deviation (SD), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were calculated. Radiation dose were analyzed. Paired Student’s t-test was used to compare all continuous variables.

Results:

The overall median score assessed as image quality for CT images with the MBIR algorithm was significantly higher in comparison with HIR [4 (range 3–4) vs 3 (3-4), p = 0.017]. CT attenuation values and SD were significantly higher and lower, respectively, in all anatomic districts in images reconstructed with MBIR in comparison with HIR ones (all p < 0.001). SNR and CNR values were higher in CT images reconstructed with MBIR, reaching a significant difference in all districts (all p < 0.001). Radiation dose were significantly lower in the MBIR group compared with the HIR group (p < 0.001).

Conclusions:

MBIR combined with low-kV setting allows an important dose reduction in whole-body CT imaging, reaching a better image quality both qualitatively and quantitatively.

Advances in knowledge:

MBIR with low-dose approach allows a reduction of dose exposure, maintaining high image quality, especially in patients which deserve a longlasting follow-up.