bluuebunny/crossref_metadata_2025 huggingface dataset:
What makes knowledge translation work in practice? Lessons from a demand-driven and locally led project in Cameroon, Jordan and Nigeria
Authors: Borst Robert A. J. , Wehrens Rik , Nsangou Moustapha , Arikpo Dachi , Esu Ekpereonne , Al Metleq Ali , Hobden Olivia , Meremikwu Martin , Ongolo-Zogo Pierre , Bal Roland , Kok Maarten Olivier
Published: December 2023

Background

Over the years, the knowledge translation (KT) field has moved from promoting linearized models to embracing the importance of interaction and learning. Likewise, there is now increased attention on the transfer of KT approaches to new environments. Some scholars, however, have warned that ideas about transferability still hinge on linear thinking and doing. In the current study, we therefore sought to use a more reflexive approach to KT and to study how actors align KT approaches with their local environments.

Methods

Our (auto) ethnographic study took place in a wider KT project. This project intended to combine three components: (1) co-organizing demand-driven, locally led and embedded KT cycles in Cameroon, Jordan, and Nigeria, (2) building upon established KT methods and (3) equipping and empowering local teams. We conducted 63 semi-structured interviews with key KT actors, observed 472 h of KT practices, and collected a paper trail of documents. At the same time, we also compiled project exchanges, such as project documents, plans, protocols, field notes, meeting notes and an archive of (email) correspondence between project members. We analysed all data abductively.

Results

We show that there were numerous moments where the design of our project indeed enabled us to align with local practices and needs. Yet this often did not suffice, and the project design sometimes conflicted with other logics and values. By analysing these tensions, we want to show that doing KT work which acts upon different values and knowledges and is sensitive towards the different effects that it produces demands both structuring projects in a specific way and requires significant alignment work of KT actors in practice.

Conclusions

We show that practising KT more reflexively relies on two important conditions. First, KT projects have to be structured with sufficient discretionary space. Second, even though the structure of a project is important, there will be continuous need for alignment work. It is important to facilitate such alignment work and to further support it. In the discussion of this paper, we therefore articulate three design principles and three sensitivities. These elements can be used to make future KT projects more reflexive and sensitive to (social) complexity.
Non-invasive biomarkers for early diagnosis of pancreatic cancer risk: metabolite genomewide association study based on the KCPS-II cohort
Authors: Han Youngmin , Jung Keum Ji , Kim Unchong , Jeon Chan Il , Lee Kwangbae , Jee Sun Ha
Published: December 2023

Background

Pancreatic cancer is a lethal disease with a high mortality rate. The difficulty of early diagnosis is one of its primary causes. Therefore, we aimed to discover non-invasive biomarkers that facilitate the early diagnosis of pancreatic cancer risk.

Methods

The study subjects were randomly selected from the Korean Cancer Prevention Study-II and matched by age, sex, and blood collection point [pancreatic cancer incidence (n = 128) vs. control (n = 256)]. The baseline serum samples were analyzed by non-targeted metabolomics, and XGBoost was used to select significant metabolites related to pancreatic cancer incidence. Genomewide association study for the selected metabolites discovered valuable single nucleotide polymorphisms (SNPs). Moderation and mediation analysis were conducted to explore the variables related to pancreatic cancer risk.

Results

Eleven discriminant metabolites were selected by applying a cut-off of 4.0 in XGBoost. Five SNP presented significance in metabolite-GWAS (p ≤ 5 × 10–6) and logistic regression analysis. Among them, the pair metabolite of rs2370981, rs55870181, and rs72805402 displayed a different network pattern with clinical/biochemical indicators on comparison with allelic carrier and non-carrier. In addition, we demonstrated the indirect effect of rs59519100 on pancreatic cancer risk mediated by γ-glutamyl tyrosine, which affects the smoking status. The predictive ability for pancreatic cancer on the model using five SNPs and four pair metabolites with the conventional risk factors was the highest (AUC: 0.738 [0.661–0.815]).

Conclusions

Signatures involving metabolites and SNPs discovered in the present research may be closely associated with the pathogenesis of pancreatic cancer and for use as predictive biomarkers allowing early pancreatic cancer diagnosis and therapy.
Cucurbitacin E reduces IL-1β-induced inflammation and cartilage degeneration by inhibiting the PI3K/Akt pathway in osteoarthritic chondrocytes
Authors: Wang Lin , Xu Hui , Li Xin , Chen Hongwei , Zhang Haigang , Zhu Xunpeng , Lin Zhijie , Guo Shilei , Bao Zhibo , Rui Haicheng , He Wei , Zhang Hui
Published: December 2023

Background

Osteoarthritis is a degenerative joint disease. Cartilage degeneration is the earliest and most important pathological change in osteoarthritis, and persistent inflammation is one of the driving factors of cartilage degeneration. Cucurbitacin E, an isolated compound in the Cucurbitacin family, has been shown to have anti-inflammatory effects, but its role and mechanism in osteoarthritic chondrocytes are unclear.

Methods

For in vitro experiments, human chondrocytes were stimulated with IL-1β, and the expression of inflammatory genes was measured by Western blotting and qPCR. The expression of extracellular matrix proteins was evaluated by immunofluorescence staining, Western blotting and saffron staining. Differences in gene expression between cartilage from osteoarthritis patients and normal cartilage were analysed by bioinformatics methods, and the relationship between Cucurbitacin E and its target was analysed by a cellular thermal shift assay, molecular docking analysis and molecular dynamics simulation. For in vivo experiments, knee osteoarthritis was induced by DMM in C57BL/6 mouse knee joints, and the effect of Cucurbitacin E on knee joint degeneration was evaluated.

Results

The in vitro experiments confirmed that Cucurbitacin E effectively inhibited the production of the inflammatory cytokine interleukin-1β(IL-1β) and cyclooxygenase-2 (COX-2) by IL-1β-stimulated chondrocytes and alleviates extracellular matrix degradation. The in vivo experiments demonstrated that Cucurbitacin E had a protective effect on the knee cartilage of C57BL/6 mice with medial meniscal instability in the osteoarthritis model. Mechanistically, bioinformatic analysis of the GSE114007 and GSE117999 datasets showed that the PI3K/AKT pathway was highly activated in osteoarthritis. Immunohistochemical analysis of PI3K/Akt signalling pathway proteins in pathological slices of human cartilage showed that the level of p-PI3K in patients with osteoarthritis was higher than that in the normal group. PI3K/Akt were upregulated in IL-1β-stimulated chondrocytes, and Cucurbitacin E intervention reversed this phenomenon. The cellular thermal shift assay, molecular docking analysis and molecular dynamics experiment showed that Cucurbitacin E had a strong binding affinity for the inhibitory target PI3K. SC79 activated Akt phosphorylation and reversed the effect of Cucurbitacin E on IL-1β-induced chondrocyte degeneration, demonstrating that Cucurbitacin E inhibits IL-1β-induced chondrocyte inflammation and degeneration by inhibiting the PI3K/AKT pathway.

Conclusion

Cucurbitacin E inhibits the activation of the PI3K/AKT pathway, thereby alleviating the progression of OA. In summary, we believe that Cucurbitacin E is a potential drug for the treatment of OA.
HIV transmission and associated factors under the scale-up of HIV antiretroviral therapy: a population-based longitudinal molecular network study
Authors: Chen Yi , Cao Zhiqiang , Li Jianjun , Chen Jin , Zhu Qiuying , Liang Shujia , Lan Guanghua , Xing Hui , Liao Lingjie , Feng Yi , Shao Yiming , Ruan Yuhua , Chen Huanhuan
Published: December 2023

Objectives

To evaluate the prevention efficacy of scaling up HIV/AIDS antiretroviral therapy (ART) on HIV transmission at the population level and determine associated factors of HIV secondary transmission.

Methods

We used HIV longitudinal molecular networks to assess the genetic linkage between baseline and newly diagnosed cases. A generalized estimating equation was applied to determine the associations between demographic, clinical characteristics and HIV transmission.

Results

Patients on ART had a 32% lower risk of HIV transmission than those not on ART. A 36% reduction in risk was also seen if ART-patients maintained their HIV viral load lower than 50 copies/mL. A 71% lower risk occurred when patients sustained ART for at least 3 years and kept HIV viral load less than 50 copies/mL. Patients who discontinued ART had a similar HIV transmission risk as those not on ART. Patients who were older, male, non-Han, not single, retired, infected via a heterosexual route of transmission and those who possessed higher CD4 counts had a higher risk of HIV transmission. HIV-1 subtype of CRF01_AE was less transmissible than other subtypes.

Conclusions

The efficacy of ART in a real-world setting was supported by this longitudinal molecular network study. Promoting adherence to ART is crucial to reduce HIV transmission.
Interactions between DC-SIGN and the envelope protein from Dengue and Zika viruses: a structural perspective based on molecular dynamics and MM/GBSA analyses
Authors: Menechino Bruno Stein Barbosa , Kato Rodrigo Bentes , Franz Helena Cristina Ferreira , da Silva Pedro Eduardo Almeida , Corat Marcus , de Lima Neto Daniel Ferreira
Published: December 2023

Zika virus (ZIKV) and dengue virus (DENV) share a lot of similarities being both phylogenetically closely related, share the same insect vector passage for reaching the host, affinity for the same carbohydrate receptor domains (CRDs), indicating feasible competition between them on the natural field. Here, we prospected interactions of both envelope proteins with a DC-SIGN, a transmembrane c-type lectine receptor with the most implicated CRD with the Flavivirus infection presents on dendritic cells involved in viruses replication processes into the host, and among rares CRD receptors susceptible to interacting with a broad of subtypes of DENV. Protein–protein docking procedures produced structures for molecular dynamics experiments, suggesting the most energetically favorable complex. The difference found in the deltaG results prompted the experimentation with molecular dynamics. To investigate further specific residues involved with such interactions we produced a decomposition analysis using molecular dynamics of the docked proteins evaluated afterward with the Generalized Born Surface Area method. Solvent-accessible surface area (SASA) analysis for both showed very similar but with a slight reduction for ZIKV_E, which agreed with residues SASA analysis highlighting regions more exposed in the ZIVK protein than in DENV. Despite residues PHE313 is reponsible for most of the interactions with the envelope of these arboviruses, ZIKV interacted with this residue in DC-SIGN with lower energies and using more interactions with not expexted residues GLU241 and ARG386. Taken together these results suggest better competitive interaction of ZIKV with the DC-SIGN receptor, particularly in the CRD portion.
Vertical changes in the hard tissues after space closure by miniscrew sliding mechanics: a three-dimensional modality analysis
Authors: Su Hong , Zhuang Zimeng , Han Bing , Xu Tianmin , Chen Gui
Published: December 2023

Objectives

This study aimed to investigate vertical changes in the maxillary central incisor and the maxillary first molar, along with alterations in the mandibular plane angle during space closure using miniscrew sliding mechanics.

Methods

Twenty adult patients treated at Peking University Hospital of Stomatology between 2008 and 2013 were included. Digital dental models and craniofacial cone-beam computed tomography (CBCT) scans were obtained at the start of treatment (T0) and immediately after space closure (T1). Stable miniscrews were used for superimposing maxillary digital dental models (T0 and T1), and vertical changes in the maxillary first molar and the maxillary central incisor were measured. Three-dimensional changes in the mandibular plane were assessed through CBCT superimposition.

Results

The maxillary central incisor exhibited an average extrusion of 2.56 ± 0.18 mm, while the maxillary first molar showed an average intrusion of 1.25 ± 1.11 mm with a distal movement of 0.97 ± 0.99 mm. Additionally, the mandibular plane angle decreased by an average of 0.83 ± 1.65°. All three indices exhibited statistically significant differences.

Conclusion

During space closure using the miniscrew sliding technique, significant changes occurred in both the sagittal and vertical dimensions of the upper dentition. This included extrusion of the maxillary central incisors, intrusion of the maxillary first molars, and a slight counterclockwise rotation of the mandibular plane.
Facial profile evaluation and prediction of skeletal class II patients during camouflage extraction treatment: a pilot study
Authors: Guo Runzhi , Tian Yuan , Li Xiaobei , Li Weiran , He Danqing , Sun Yannan
Published: December 2023

Background

The evaluation of the facial profile of skeletal Class II patients with camouflage treatment is of great importance for patients and orthodontists. The aim of this study is to explore the key factors in evaluating the facial profile esthetics and to predict the posttreatment facial profile esthetics of skeletal Class II extraction patients.

Methods

124 skeletal Class II extraction patients were included. The pretreatment and posttreatment cephalograms were analyzed by a trained expert orthodontist. The facial profile esthetics of pretreatment and posttreatment lateral photographs were evaluated by 10 expert orthodontists using the visual analog scale (VAS). The correlation between subjective facial profile esthetics and objective cephalometric measurements was assessed. Three machine-learning methods were used to predict posttreatment facial profile esthetics.

Results

The distances from lower and upper lip to the E plane and U1-APo showed the stronger correlation with profile esthetics. The changes in lower lip to the E plane and U1-APo during extraction exhibited the stronger correlation with changes in VAS score (r = − 0.551 and r = − 0.469). The random forest prediction model had the lowest mean absolute error and root mean square error, demonstrating a better prediction accuracy and fitting effect. In this model, pretreatment upper lip to E plane, pretreatment Pog-NB and the change of U1-GAll were the most important variables in predicting the posttreatment score of facial profile esthetics.

Conclusions

The maxillary incisor protrusion and lower lip protrusion are key objective indicators for evaluating and predicting facial profile esthetics of skeletal Class II extraction patients. An artificial intelligence prediction model could be a new method for predicting the posttreatment esthetics of facial profiles.
A highly penetrant ACTA2 mutation of thoracic aortic disease
Authors: Bobba Christopher M. , Azarrafiy Ryan , Spratt John R. , Hendrickson Jill , Martin Tomas D. , Arnaoutakis George J. , Jeng Eric I. , Beaver Thomas M.
Published: December 2023

Background

The role of ACTA2 mutations in Familial Aortic Disease has been increasingly recognized. We describe a highly penetrant variant (R118Q) in a family with aortic disease.

Case report

A patient presented to us for elective repair of an ascending aortic aneurysm with a family history of his mother expiring after aortic dissection. Genetic testing revealed he was a heterozygous carrier of the ACTA2 missense mutation R118Q. Subsequently, all living family members were tested for this variant and a full medical history was obtained to compile a family tree for the variant and penetrance of an aortic event (defined as lifetime occurrence of aortic surgery / dissection). In total 9 family members were identified and underwent genetic testing with 7/9 showing presence of the ACTA2 R118Q mutation or an aortic event. All patients over the age of 50 (n = 4) had an aortic event. Those events occurred at ages 54, 55, 60, and 62 (mean event at 57.8 ± 3.9 years). Three family members with the variant under the age of 40 have not had an aortic event and most are undergoing regular aortic surveillance via CT scan.

Conclusions

Existing studies of known ACTA2 mutations describe a 76% aortic event rate by 85 years old. The R118Q missense mutation is a less common ACTA2 variant, estimated to be found in about 5% of patients with known mutations. Prior studies have predicted the R118Q mutation to have a slightly decreased risk of aortic events compared to other ACTA2 mutations. In this family, however, we demonstrate 100% penetrance of aortic disease above age 50. In today’s era of excellent outcomes in elective aortic surgery, our team aggressively offers elective repair. We advocate for strict aortic surveillance for patients with this variant and would consider elective aortic replacement at 4.5 cm, or at an even smaller diameter in patients with a strong family history of dissection who are identified with this mutation.
Prediction of asthma using a four-locus gene model including IL13, IL4, FCER1B, and ADRB2 in children of Kazak nationality
Authors: Bai Shasha , Lu Jun , Hua Li , Liu Quanhua , Chen Mengxue , Gu Yutong , Zhang Jianhua , Ma Dongjun , Bao Yixiao
Published: December 2023

Background

To study whether the four locus gene model consisting of ADRB2 rs1042713, IL4 rs2243250, FCER1B rs569108 and L13 rs20541 can predict asthma of the Kazak children in Xinjiang, China.

Methods

Four single nucleotide polymorphisms about the 4 genes were genotyped in asthma group and control group of Han children and Kazak children respectively. The frequencies of different genotypes and alleles were compared between the asthma group and the control group in the two nationalities. Different risk genotypes for asthma were evaluated in the two nationalities.

Results

The differences about frequencies of genotypes in ADRB2 rs1042713 and IL4 rs2243250 and IL13 rs20541 between asthma group and control group were statistically significant in Han children, as were the frequencies of alleles in the 3 single nucleotide polymorphisms, but there were no statistical differences in FCER1B rs569108(P > 0.05). For the Kazak children, no differences were existed among all the genotypes and alleles in asthma group and control group. For the Han children, more children were asthma high risk genotype in the asthma group than those in the control group and no difference was found in the Kazak children.

Conclusions

The four locus gene model consisting of ADRB2 rs1042713, IL4 rs2243250, FCER1B rs569108 and L13 rs20541 can predict asthma of Han children but not for the Kazak children in Xinjiang, which illustrating that the difference of asthma prevalence between different races is closely related to the genetic background.
Haplotype-resolved assemblies and variant benchmark of a Chinese Quartet
Authors: Jia Peng , Dong Lianhua , Yang Xiaofei , Wang Bo , Bush Stephen J. , Wang Tingjie , Lin Jiadong , Wang Songbo , Zhao Xixi , Xu Tun , Che Yizhuo , Dang Ningxin , Ren Luyao , Zhang Yujing , Wang Xia , Liang Fan , Wang Yang , Ruan Jue , Xia Han , Zheng Yuanting , Shi Leming , Lv Yi , Wang Jing , Ye Kai
Published: December 2023

Background

Recent state-of-the-art sequencing technologies enable the investigation of challenging regions in the human genome and expand the scope of variant benchmarking datasets. Herein, we sequence a Chinese Quartet, comprising two monozygotic twin daughters and their biological parents, using four short and long sequencing platforms (Illumina, BGI, PacBio, and Oxford Nanopore Technology).

Results

The long reads from the monozygotic twin daughters are phased into paternal and maternal haplotypes using the parent–child genetic map and for each haplotype. We also use long reads to generate haplotype-resolved whole-genome assemblies with completeness and continuity exceeding that of GRCh38. Using this Quartet, we comprehensively catalogue the human variant landscape, generating a dataset of 3,962,453 SNVs, 886,648 indels (< 50 bp), 9726 large deletions (≥ 50 bp), 15,600 large insertions (≥ 50 bp), 40 inversions, 31 complex structural variants, and 68 de novo mutations which are shared between the monozygotic twin daughters. Variants underrepresented in previous benchmarks owing to their complexity—including those located at long repeat regions, complex structural variants, and de novo mutations—are systematically examined in this study.

Conclusions

In summary, this study provides high-quality haplotype-resolved assemblies and a comprehensive set of benchmarking resources for two Chinese monozygotic twin samples which, relative to existing benchmarks, offers expanded genomic coverage and insight into complex variant categories.
Optic nerve sheath diameter measurement for the paediatric patient with an acute deterioration in consciousness
Authors: Ali Ahmed , McCreary David J.
Published: December 2023

Ocular Point of Care Ultrasound (PoCUS) is emerging as a valuable utility within emergency medicine. Optic nerve sheath diameter (ONSD) has been demonstrated to correlate closely with intracranial pressure (ICP) and an elevated measurement can detect raised ICP readily, where fundoscopy may not, owing to both technical challenges and insufficient clinical skills. A previously fit and well 10-year-old girl presented to the paediatric emergency department with worsening headache, fever and lethargy. On examination, her left pupil was large, and not reactive to light. Initially, her GCS was 15 but suddenly dropped to 8/15. Her blood tests showed raised inflammatory markers. A CT head was reported as possible pansinusitis and MRI of her brain was initially reported as showing evidence of meningeal irritation only. Due to her drop in GCS PoCUS of optic nerve sheath was conducted which showed evidence of increased ICP with increased optic nerve sheath diameter of 6.8mm. This led to a reassessment of the MRI imaging by the neurosurgical team who felt there was evidence of subdural empyema. The patient was transferred to the tertiary neurosurgical centre, where an emergency evacuation of subdural empyema was carried out. Staphylococcus aureus and Streptococcus pyogenes were grown from pus samples. Early detection of raised ICP is of paramount importance in terms of being able to instigate neuroprotective measures and prevent adverse neurological outcomes. PoCUS is a readily available, non-irradiating, easily repeatable, well-tolerated and readily teachable ultrasound modality and a useful tool which should be employed in paediatric and adult emergency departments.
A multi-scale digital twin for adiposity-driven insulin resistance in humans: diet and drug effects
Authors: Herrgårdh Tilda , Simonsson Christian , Ekstedt Mattias , Lundberg Peter , Stenkula Karin G. , Nyman Elin , Gennemark Peter , Cedersund Gunnar
Published: December 2023

Background

The increased prevalence of insulin resistance is one of the major health risks in society today. Insulin resistance involves both short-term dynamics, such as altered meal responses, and long-term dynamics, such as the development of type 2 diabetes. Insulin resistance also occurs on different physiological levels, ranging from disease phenotypes to organ-organ communication and intracellular signaling. To better understand the progression of insulin resistance, an analysis method is needed that can combine different timescales and physiological levels. One such method is digital twins, consisting of combined mechanistic mathematical models. We have previously developed a model for short-term glucose homeostasis and intracellular insulin signaling, and there exist long-term weight regulation models. Herein, we combine these models into a first interconnected digital twin for the progression of insulin resistance in humans.

Methods

The model is based on ordinary differential equations representing biochemical and physiological processes, in which unknown parameters were fitted to data using a MATLAB toolbox.

Results

The interconnected twin correctly predicts independent data from a weight increase study, both for weight-changes, fasting plasma insulin and glucose levels, and intracellular insulin signaling. Similarly, the model can predict independent weight-change data in a weight loss study with the weight loss drug topiramate. The model can also predict non-measured variables.

Conclusions

The model presented herein constitutes the basis for a new digital twin technology, which in the future could be used to aid medical pedagogy and increase motivation and compliance and thus aid in the prevention and treatment of insulin resistance.
Coronavirus disease 2019 (COVID-19)-associated brain abscesses caused by Pseudomonas aeruginosa and Aspergillus fumigatus: two case and a review of the literature
Authors: Yassin Zeynab , Farid Armita , Ahmadi Sayedali , Emamikhah Maziar , Motamedi Omid , Jafari Mohammadamin , Goodarzi Azadeh
Published: December 2023

Background

Bacterial and fungal superinfections are commonly reported in patients with coronavirus disease 2019.

Case presentation

We report the first case of brain and intramedullary abscesses caused by Pseudomonas aeruginosa and a rare case of brain abscesses caused by Aspergillus fumigatus in two post-coronavirus disease 2019 patients. The first patient—34-year-old Iranian woman—presented with weakness of the left upper limb, headaches, and lower limb paresthesia. She had a history of undiagnosed diabetes and had received corticosteroid therapy. The second patient—45-year-old Iranian man—presented with right-sided weakness and had a history of intensive care unit admission. Both patients passed away despite appropriate medical therapy.

Conclusion

The immune dysregulation induced by coronavirus disease 2019 and its’ treatments can predispose patients, especially immunosuppressed ones, to bacterial and fungal infections with unusual and opportunistic pathogens in the central nervous system. Pseudomonas aeruginosa and Aspergillus fumigatus should be considered as potential causes of brain infection in any coronavirus disease 2019 patient presenting with neurological symptoms and evidence of brain abscess in imaging, regardless of sinonasal involvement. These patients should get started on appropriate antimicrobial therapy as soon as possible, as any delay in diagnosis or treatment can be associated with adverse outcomes.
Adhatoda vasica and Tinospora cordifolia extracts ameliorate clinical and molecular markers in mild COVID-19 patients: a randomized open-label three-armed study
Authors: Verma Mukta , Rawat Neha , Rani Ritu , Singh Manju , Choudhary Aditi , Abbasi Sarfaraz , Kumar Manish , Kumar Sachin , Tanwar Ankur , Misir Bishnu Raman , Khanna Sangeeta , Agrawal Anurag , Faruq Mohammed , Rai Shalini , Tripathi Richa , Kumar Anil , Pujani Mukta , Bhojani Meera , Pandey Anil Kumar , Nesari Tanuja , Prasher Bhavana
Published: December 2023

Background

SARS-CoV-2 infections caused mild-to-moderate illness. However, a sizable portion of infected people experience a rapid progression of hyper-inflammatory and hypoxic respiratory illness that necessitates an effective and safer remedy to combat COVID-19.

Methods

A total of 150 COVID-19-positive patients with no to mild symptoms, between the age groups 19–65 years were enrolled in this randomized, open-labeled three-armed clinical trial. Among them, 136 patients completed the study with RT-PCR negative reports. The patients received herbal drugs orally (Group A (Adhatoda vasica; AV; 500 mg; n = 50); Group B (Tinospora cordifolia; TC; 500 mg; n = 43), and Group C (AV + TC; 250 mg each; n = 43)) for 14 days. Clinical symptoms, vital parameters, and viral clearance were taken as primary outcomes, and biochemical, hematological parameters, cytokines, and biomarkers were evaluated at three time points as secondary outcomes.

Results

We found that the mean viral clearance time was 13.92 days (95% confidence interval [CI] 12.85–14.99) in Group A, 13.44 days (95% confidence interval [CI] 12.14–14.74) in Group B, and 11.86 days (95% confidence interval [CI] 10.62–13.11) days in Group C. Over a period of 14 days, the mean temperature in Groups A, and B significantly decreased linearly. In Group A, during the trial period, eosinophils, and PT/INR increased significantly, while monocytes, SGOT, globulin, serum ferritin, and HIF-1α, a marker of hypoxia reduced significantly. On the other hand, in Group B hsCRP decreased at mid-treatment. Eosinophil levels increased in Group C during the treatment, while MCP-3 levels were significantly reduced.

Conclusions

All the patients of the three-armed interventions recovered from COVID-19 and none of them reported any adverse effects from the drugs. Group C patients (AV + TC) resulted in a quicker viral clearance as compared to the other two groups. We provide the first clinical report of AV herbal extract acting as a modifier of HIF-1α in COVID-19 patients along with a reduction in levels of ferritin, VEGF, and PT/INR as the markers of hypoxia, inflammation, and thrombosis highlighting the potential use in progression stages, whereas the TC group showed immunomodulatory effects.

Trial registration Clinical Trials Database -India (ICMR-NIMS), CTRI/2020/09/028043. Registered 24th September 2020, https://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=47443&EncHid=&modid=&compid=%27,%2747443det%27

Graphical Abstract
A Concise on the Effect of Calcium Oxide on the Properties of Alkali-Activated Materials: A Manual for Civil Engineers
Authors: Rashad Alaa M.
Published: December 2023

As known, calcium oxide (CaO) is an alkaline material, which can be used widely to increase the clay-containing soils load carrying capacity, to produce aerated concrete and calcium aluminate cement. In the last few years, introducing CaO into alkali-activated materials (AAMs) became a hot topic and attained more attention than other times. Generally, CaO can be incorporated into AAMs as an additive/a part of the main precursor and a sole activator without/with an auxiliary activator. Incorporating CaO into the matrices may improve some properties and worsen others. This mainly depends on the ratio of CaO, curing conditions, activator type and activator concentration, precursor type and testing age. This review collected, summarized and analyzed the available studies focused on the effect of CaO on the fresh (reaction kinetic, workability, setting time) and hardened (mechanical strength, durability and length change) properties of AAMs. In addition, some recommendations for future works were included. The results showed that the inclusion of CaO in AAMs decreased workability and setting time. In spite of there are contradictory results about the effect of CaO on the compressive strength of AAMs, most of them reported higher compressive strength, especially at the early ages. The incorporation of CaO up to 5% in the matrix is more effective than the incorporation of higher ratios. The inclusion of CaO in the matrix decreased water absorption, decreased total porosity, increased wetting/drying as well as acid attack resistivity. The CaO (5–10%) can be used as a sole activator for precursors. Auxiliary activators such as Al2(SO4)3, Na2CO3, Na2SiO3, Na2SO4, CaSO4, NaOH, Ca(NO3)2, NaNO3, Mg(NO3)2, Mg(HCOO)2, Ca(HCOO)2, SO3, gypsum and MgO can be used to enhance the compressive strength of CaO-activated materials, especially at the early ages.
Study on the structural stability of the blistering of the Vajrasana pagoda in Miaozhan Temple, Kunming, Yunnan, China
Authors: Li Bo , Zhang Yao , Bao Xun , Wang Yu , Zhang Ying , Cui Deshan , Guo Hong
Published: December 2023

The Vajrasana pagoda is the only stone overturned-bowl pagoda among the 12 existing Vajrasana pagodas built during the Ming Dynasty in the Guandu District, Kunming City, Yunnan Province, China. The location of the Vajrasana pagoda is in an earthquake-active zone with high rainfall. The small towers on the upper side were damaged by an earthquake in 1696 AD. All the stone statues representing religious figures have blistered and may peel further due to external factors, such as sunshine and rainfall. To assess the structural stability of the blistering, we employed 3D laser scanning to record the building’s geometry over time. Subsequently, X-ray diffraction, thin section identification, and uniaxial compressive strength tests were conducted on the pagoda stone to reveal physical–mechanical properties. Finally, a finite element model was constructed to analyze stress and displacement in various scenarios. The results revealed: (1) Blistering on the pagoda stone is secure under self-gravity and heavy rainfall. (2) In an earthquake, the upper blistering near the junction of two sides may break. (3) A 3D color deviation model of blistering over 8 months showed peeling and bursting within the finite element simulation's predicted range. This research offers a fresh approach to stone tower preservation, shifting from reactive measures to proactive prevention and prediction. These methods and concepts hold relevance for stone towers in similar high-rainfall and earthquake-prone regions.
Added value of regional 18F-FDG PET/MRI-assisted whole-body 18F-FDG PET/CT in malignant ascites with unknown primary origin
Authors: Fu Yiru , Ruan Weiwei , Sun Xun , Hu Fan , Lan Xiaoli , Liu Fang
Published: December 2023

Background

Comparing to PET/CT, integrative PET/MRI imaging provides superior soft tissue resolution. This study aims to evaluate the added value of regional delayed 18F-FDG PET/MRI-assisted whole-body 18F-FDG PET/CT in diagnosing malignant ascites patients.

Results

The final diagnosis included 22 patients with ovarian cancer (n = 11), peritoneal cancer (n = 3), colon cancer (n = 2), liver cancer (n = 2), pancreatic cancer (n = 2), gastric cancer (n = 1), and fallopian tube cancer (n = 1). The diagnosis of the primary tumor using whole-body PET/CT was correct in 11 cases. Regional PET/MRI-assisted whole-body PET/CT diagnosis was correct in 18 cases, including 6 more cases of ovarian cancer and 1 more case of fallopian tube cancer. Among 4 cases that were not diagnosed correctly, 1 case had the primary tumor outside of the PET/MRI scan area, 2 cases were peritoneal cancer, and 1 case was colon cancer. The diagnostic accuracy of regional PET/MRI-assisted whole-body PET/CT was higher than PET/CT alone (81.8% vs. 50.0%, κ 2 = 5.14, p = 0.023). The primary tumor conspicuity score of PET/MRI was higher than PET/CT (3.67 ± 0.66 vs. 2.76 ± 0.94, P < 0.01). In the same scan area, more metastases were detected in PET/MRI than in PET/CT (156 vs. 86 in total, and 7.43 ± 5.17 vs. 4.10 ± 1.92 per patient, t = 3.89, P < 0.01). Lesion-to-background ratio in PET/MRI was higher than that in PET/CT (10.76 ± 5.16 vs. 6.56 ± 3.45, t = 13.02, P < 0.01).

Conclusion

Comparing to whole-body PET/CT alone, additional delayed regional PET/MRI with high soft tissue resolution is helpful in diagnosing the location of the primary tumor and identifying more metastases in patients with malignant ascites. Yet larger sample size in multicenter and prospective clinical researches is still needed.
The genomes of Scedosporium between environmental challenges and opportunism
Authors: Venice Francesco , Spina Federica , Davolos Domenico , Ghignone Stefano , Varese Giovanna Cristina
Published: December 2023

Emerging fungal pathogens are a global challenge for humankind. Many efforts have been made to understand the mechanisms underlying pathogenicity in bacteria, and OMICs techniques are largely responsible for those advancements. By contrast, our limited understanding of opportunism and antifungal resistance is preventing us from identifying, limiting and interpreting the emergence of fungal pathogens. The genus Scedosporium (Microascaceae) includes fungi with high tolerance to environmental pollution, whilst some species can be considered major human pathogens, such as Scedosporium apiospermum and Scedosporium boydii. However, unlike other fungal pathogens, little is known about the genome evolution of these organisms. We sequenced two novel genomes of Scedosporium aurantiacum and Scedosporium minutisporum isolated from extreme, strongly anthropized environments. We compared all the available Scedosporium and Microascaceae genomes, that we systematically annotated and characterized ex novo in most cases. The genomes in this family were integrated in a Phylum-level comparison to infer the presence of putative, shared genomic traits in filamentous ascomycetes with pathogenic potential. The analysis included the genomes of 100 environmental and clinical fungi, revealing poor evolutionary convergence of putative pathogenicity traits. By contrast, several features in Microascaceae and Scedosporium were detected that might have a dual role in responding to environmental challenges and allowing colonization of the human body, including chitin, melanin and other cell wall related genes, proteases, glutaredoxins and magnesium transporters. We found these gene families to be impacted by expansions, orthologous transposon insertions, and point mutations. With RNA-seq, we demonstrated that most of these anciently impacted genomic features responded to the stress imposed by an antifungal compound (voriconazole) in the two environmental strains S. aurantiacum MUT6114 and S. minutisporum MUT6113. Therefore, the present genomics and transcriptomics investigation stands on the edge between stress resistance and pathogenic potential, to elucidate whether fungi were pre-adapted to infect humans. We highlight the strengths and limitations of genomics applied to opportunistic human pathogens, the multifactoriality of pathogenicity and resistance to drugs, and suggest a scenario where pressures other than anthropic contributed to forge filamentous human pathogens.
‘Smart’ BLE wearables for digital contact tracing in care homes during the COVID-19 pandemic—a process evaluation of the CONTACT feasibility study
Authors: Thompson Carl A. , Daffu-O’Reilly Amrit , Willis Thomas , Gordon Adam , Noakes Catherine , Khaliq Kishwer , Farrin Amanda , Kemp Andrew , Hall Tom , Bojke Chris , Spilsbury Karen
Published: December 2023

Background

Rapid and mass transmission of the SARS-CoV-2 virus amongst vulnerable people led to devastating effects from COVID-19 in care homes. The CONTACT intervention introduced Bluetooth Low Energy ‘smart’ wearable devices (BLE wearables) as a basis for automated contact tracing in, and feedback on infection risks and patterns to, care homes to try and improve infection prevention and control (IPC). We planned a cluster randomised controlled trial (RCT) of CONTACT. To be feasible, homes had to adopt CONTACT’s technology and new ways of working. This paper reports on the process evaluation conducted alongside CONTACT’s feasibility study and explains why it lacked the feasibility and acceptability for a definitive RCT.

Methods

This mixed method process evaluation used Normalisation Process Theory (NPT) qualitative (interviews, field notes, study case report forms and documents, and observation) and quantitative (survey instruments, counts of activity) data to plan, implement, and analyse the mechanisms, effects, and contextual factors that shaped the feasibility and acceptability of the CONTACT intervention.

Results

Thirteen themes within four core NPT constructs explained CONTACT’s lack of feasibility. Coherence: the home’s varied in the scale and extent of commitment and understanding of the technology and study procedures. Leadership credibility was important but compromised by competing priorities. Management and direct care staff saw CONTACT differently. Work to promote (cognitive participation) and enact (collective action) CONTACT was burdensome and failed to be prioritised over competing COVID-19-related demands on time and scarce human and cognitive resources. Ultimately, staff appraisal of the value of CONTACT-generated information and study procedures (reflexivity) was that any utility for IPC was insufficient to outweigh the perceived burden and complexity involved.

Conclusions

Despite implementation failure, dismissing BLE wearables’ potential for contact tracing is premature. In non-pandemic conditions, with more time, better co-design and integration of theory-driven implementation strategies tailored to care homes’ unique contexts, researchers could enhance normalisation in readiness for future pandemic challenges.

Trial registration

ISRCTN registration: 11,204,126 registered 17/02/2021.
Structure, function and drug discovery of GPCR signaling
Authors: Cheng Lin , Xia Fan , Li Ziyan , Shen Chenglong , Yang Zhiqian , Hou Hanlin , Sun Suyue , Feng Yuying , Yong Xihao , Tian Xiaowen , Qin Hongxi , Yan Wei , Shao Zhenhua
Published: December 2023

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.
Morphological Classification of Pituitary Tumors With Suprasellar Extension
Authors: Sarkar Sauradeep , Corrales C. Eduardo , Laws Edward R. , Smith Timothy R.
Published: December 2023

BACKGROUND AND OBJECTIVES:

The objective of this study was to study the association among various morphological parameters and surgical outcomes in pituitary macroadenomas with suprasellar extension.

METHODS:

MRI studies of 160 patients undergoing endoscopic transsphenoidal resection of pituitary macroadenomas with suprasellar extension were reviewed. In the coronal plane, tumors were classified into Type 1 (dome-shaped, no constriction at the level of diaphragma sellae) and Type 2 (dumbbell-shaped, with constriction at the level of diaphragma sellae). Based on the dome-to-neck ratio (D/Nr), Type 2 tumors were further classified as Type 2A (wide neck; D/Nr >1 and <1.3) and Type 2B (narrow neck; D/Nr ≥1.3). Surgical outcomes and complications were analyzed using a logistic regression model. Overall extent of resection (EOR) and presence of residual sellar-suprasellar tumor was separately assessed in all patients with available postoperative MRI (n = 149).

RESULTS:

There were 108 Type 1 tumors and 26 patients each in the Type 2A and Type 2B subgroups. Tumor subtype was significantly associated with tumor size (P < .001), intraoperative cerebrospinal fluid leak (P < .001), EOR (P < .001), postoperative suprasellar residual tumor (P < .001), and postoperative complications, including diabetes insipidus (P = .005) and visual worsening (P = .003). On multivariate analysis, after adjusting for confounders, Type 2B tumors were negatively associated with EOR (odds ratio [OR] 0.22; 95% CI 0.07-0.68; P = .008) and associated with the presence of postoperative suprasellar residual tumor (OR 18.08; 95% CI 5.20-62.89; P < .001), intraoperative cerebrospinal fluid leak (OR 5.33; 95% CI 1.89-14.99; P = .002), and postoperative diabetes insipidus (OR 4.89; 95% CI 1.67-14.35; P < .001).

CONCLUSION:

Preoperative tumor classification based on D/Nr is clinically and surgically relevant, and Type 2B macroadenomas are significantly associated with lower rates of gross total resection and higher rates of postoperative complications after endoscopic transsphenoidal resection.
Challenging Cortical Explorations in Difficult-to-Localize Seizures: The Rationale and Usefulness of Perisylvian Paralimbic Explorations With Orthogonal Stereoelectroencephalography Depth Electrodes
Authors: Aung Thandar , Mallela Arka , Ho Jonathan , Tang Lilly W. , Abou-Al-Shaar Hussam , Gonzalez Martinez Jorge
Published: December 2023

BACKGROUND AND OBJECTIVE:

Stereoelectroencephalography (SEEG) is an invasive monitoring method designed to define and localize the epileptogenic zone (EZ) and explore the putative network responsible for the electroclinical seizures using anatomo-functional-electroclinical correlations. When indicated by semiology in selected patients, exploration of both limbic and paralimbic (PL) regions is indispensable. However, the PL cortex is located in deep and highly vascularized areas in proximity to the anterior Sylvian fissure and middle cerebral artery branches. Thus, those explorations are considered surgically challenging because of the multilobar location and fear of hemorrhagic events. Here, we discuss and illustrate the rationale and SEEG methodology approach in usefulness of exploring the PL regions using standard orthogonal SEEG depth electrode trajectories with the Talariach reference system.

METHODS:

We retrospectively studied PL exploration from a cohort of 71 consecutive SEEG procedures from Nov 2019 to Nov 2022 and identified 31 patients who underwent PL trajectories.

RESULTS:

In 31 patients, there were 32 SEEG trajectories, and no major complications were observed. PL electrodes were consistently implanted in the C10/D10 coordinates of the Talariach reference coordinates. The most common confirmed EZ in our cohort was mesio-temporal (45%), followed by temporo-perisylvian regions (16%), ventromedial frontal (13%), and mesio-lateral temporal regions (13%). The PL contacts were involved in the EZ in 10 patients (32%). Of 31 patients, 25 underwent resective surgery, and 19 obtained Engel 1 outcome with a mean follow-up of 25 months (range 12-41 months) after surgery.

CONCLUSION:

The orthogonal perisylvian PL trajectories are feasible and useful in sampling multiple PL regions with single-electrode trajectories. In patients with perisylvian seizures, sampling PL structures may contribute to an improved understanding of seizure propagation and the optimal anatomic demarcation of the EZs in this surgically challenging region.