bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?
Authors: Loos Nancy H. C. , Beijnen Jos H. , Schinkel Alfred H.
Published: August 2022

Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its clinical importance, the exact mechanism of ritonavir-mediated CYP3A4 inactivation is still not fully understood. Nonetheless, ritonavir is clearly a potent mechanism-based inactivator, which irreversibly blocks CYP3A4. Here, we discuss four fundamentally different mechanisms proposed for this irreversible inactivation/inhibition, namely the (I) formation of a metabolic-intermediate complex (MIC), tightly coordinating to the heme group; (II) strong ligation of unmodified ritonavir to the heme iron; (III) heme destruction; and (IV) covalent attachment of a reactive ritonavir intermediate to the CYP3A4 apoprotein. Ritonavir further appears to inactivate CYP3A4 and CYP3A5 with similar potency, which is important since ritonavir is applied in patients of all ethnicities. Although it is currently not possible to conclude what the primary mechanism of action in vivo is, it is unlikely that any of the proposed mechanisms are fundamentally wrong. We, therefore, propose that ritonavir markedly inactivates CYP3A through a mixed set of mechanisms. This functional redundancy may well contribute to its overall inhibitory efficacy.
An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche
Authors: Elchaninov Andrey , Vishnyakova Polina , Menyailo Egor , Sukhikh Gennady , Fatkhudinov Timur
Published: August 2022

Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity.
Shared and Non-Shared sIgA-Coated and -Uncoated Bacteria in Intestine of Mother–Infant Pairs
Authors: Ding Mengfan , Chen Haiqin , Yu Renqiang , Ross Reynolds Paul , Stanton Catherine , Zhang Hao , Yang Bo , Chen Wei
Published: August 2022

The infant gut microbiota is critical for promoting and maintaining early-life health. The study aimed to analyze the composition of sIgA-coated and sIgA-uncoated bacterial communities at genus level and lactobacilli and bifidobacterial communities at species level in human breast milk (HBM) and infant and maternal feces. Eleven pregnant women were recruited successfully. HBM; infant feces during colostrum, transition, and mature stages; and maternal feces within the mature stage were collected. sIgA-coated and sIgA-uncoated bacteria were separated with magnetic-activated cell sorting. Then, 16S rRNA sequencing, bifidobacterial groEL gene sequencing, and lactobacilli groEL gene sequencing were performed to analyze the bacterial community. PCoA revealed that the compositions of sIgA-coated and sIgA-uncoated bacteria were different among HBM and infant and maternal feces. Higher relative abundance of sIgA-uncoated Bifidobacterium was found in the three lactation stages in infant feces compared to the corresponding HBM, and a higher relative abundance of sIgA-uncoated Faecalibacterium was found in maternal feces compared to HBM and infant feces. For bifidobacterial community, sIgA-coated and sIgA-uncoated B. longum subsp. infantis and B. pseudocatenulatum was dominant in infant feces and maternal feces, respectively. The relative abundance of sIgA-uncoated B. longum subsp. infantis was significantly higher in infant feces compared to that in maternal feces. For the Lactobacillus community, L. paragasseri and L. mucosae were dominant in infant and maternal feces, respectively. HBM and infant and maternal feces showed distinct diversity and composition of both sIgA-coated and sIgA-uncoated bacteria at genus level. Infant and maternal feces showed similar composition of Bifidobacterium at species level. The same Bifidobacterium species could be detected both in sIgA-coated and -uncoated form. This article provided deeper understanding on the microbiota profile in HBM and infant and maternal feces.
TRIM28 Is a Novel Regulator of CD133 Expression Associated with Cancer Stem Cell Phenotype
Authors: Kim Yan S. , Potashnikova Daria M. , Gisina Alisa M. , Kholodenko Irina V. , Kopylov Arthur T. , Tikhonova Olga V. , Kurbatov Leonid K. , Saidova Aleena A. , Tvorogova Anna V. , Kholodenko Roman V. , Belousov Pavel V. , Vorobjev Ivan A. , Zgoda Victor G. , Yarygin Konstantin N. , Lupatov Alexey Yu.
Published: August 2022

CD133 is an extensively studied marker of the most malignant tumor cell population, designated as cancer stem cells (CSCs). However, the function of this glycoprotein and its involvement in cell regulatory cascades are still poorly understood. Here we show a positive correlation between the level of CD133 plasma membrane expression and the proliferative activity of cells of the Caco-2, HT-29, and HUH7 cancer cell lines. Despite a substantial difference in the proliferative activities of cell populations with different levels of CD133 expression, transcriptomic and proteomic profiling revealed only minor distinctions between them. Nonetheless, a further in silico assessment of the differentially expressed transcripts and proteins revealed 16 proteins that could be involved in the regulation of CD133 expression; these were assigned ranks reflecting the apparent extent of their involvement. Among them, the TRIM28 transcription factor had the highest rank. The prominent role of TRIM28 in CD133 expression modulation was confirmed experimentally in the Caco2 cell line clones: the knockout, though not the knockdown, of the TRIM28 gene downregulated CD133. These results for the first time highlight an important role of the TRIM28 transcription factor in the regulation of CD133-associated cancer cell heterogeneity.
Sex Differences in Coronary Artery Disease and Diabetes Revealed by scRNA-Seq and CITE-Seq of Human CD4+ T Cells
Authors: Saigusa Ryosuke , Vallejo Jenifer , Gulati Rishab , Suthahar Sujit Silas Armstrong , Suryawanshi Vasantika , Alimadadi Ahmad , Makings Jeffrey , Durant Christopher P. , Freuchet Antoine , Roy Payel , Ghosheh Yanal , Pandori William , Pattarabanjird Tanyaporn , Drago Fabrizio , Taylor Angela , McNamara Coleen A. , Shemesh Avishai , Lanier Lewis L. , Hedrick Catherine C. , Ley Klaus
Published: August 2022

Despite the decades-old knowledge that males and people with diabetes mellitus (DM) are at increased risk for coronary artery disease (CAD), the reasons for this association are only partially understood. Among the immune cells involved, recent evidence supports a critical role of T cells as drivers and modifiers of CAD. CD4+ T cells are commonly found in atherosclerotic plaques. We aimed to understand the relationship of CAD with sex and DM by single-cell RNA (scRNA-Seq) and antibody sequencing (CITE-Seq) of CD4+ T cells. Peripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by scRNA-Seq combined with 49 surface markers (CITE-Seq). CAD severity was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD−. Four pairs of groups were matched for clinical and demographic parameters. To test how sex and DM changed cell proportions and gene expression, we compared matched groups of men and women, as well as diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 16 women and 45 men with and without coronary artery disease and with and without DM. We identified 16 clusters in CD4+ T cells. The proportion of cells in CD4+ effector memory cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. This same cluster, CD4T8, was significantly decreased in female participants, along with two other CD4+ T cell clusters. In CD4+ T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature. We conclude that (1) CAD and DM are clearly reflected in PBMC transcriptomes, and (2) significant differences exist between women and men and (3) between subjects with DM and non-DM.
Small Prokaryotic Proteins Interacting with Nucleic Acids
Authors: Węgrzyn Alicja , Węgrzyn Grzegorz
Published: August 2022

Among proteins that interact with DNA or RNA, more or less specifically, there is a special group of relatively small polypeptides which are present in prokaryotic cells and interact with nucleic acids [...]
Synchrotron Infrared Microspectroscopy for Stem Cell Research
Authors: Qian Jiang , Gao Xue , Wang Ya-Di , Li Xue-Ling , Hu Jun , Lü Jun-Hong
Published: August 2022

Stem cells have shown great potential functions for tissue regeneration and repair because of their unlimited self-renewal and differentiation. Stem cells reside in their niches, making them a hotspot for the development and diagnosis of diseases. Complex interactions between niches and stem cells create the balance between differentiation, self-renewal, maturation, and proliferation. However, the multi-facet applications of stem cells have been challenged since the complicated responses of stem cells to biological processes were explored along with the limitations of current systems or methods. Emerging evidence highlights that synchrotron infrared microspectroscopy, known as synchrotron radiation-based Fourier transform infrared microspectroscopy, has been investigated as a potentially attractive technology with its non-invasive and non-biological probes in stem cell research. With their unique vibration bands, the quantitative mapping of the content and distribution of biomolecules can be detected and characterized in cells or tissues. In this review, we focus on the potential applications of synchrotron infrared microspectroscopy for investigating the differentiation and fate determination of stem cells.
How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells
Authors: Aiello Anna , Ligotti Mattia Emanuela , Garnica Maider , Accardi Giulia , Calabrò Anna , Pojero Fanny , Arasanz Hugo , Bocanegra Ana , Blanco Ester , Chocarro Luisa , Echaide Miriam , Fernandez-Rubio Leticia , Ramos Pablo , Piñeiro-Hermida Sergio , Kochan Grazyna , Zareian Nahid , Farzaneh Farzin , Escors David , Caruso Calogero , Candore Giuseppina
Published: August 2022

Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals.
An Application of IoT in a Drone Inspection Service for Environmental Control
Authors: Cabianca Muriel , Clemente Maria Laura , Gatto Gianluca , Impagliazzo Carlo , Leoni Lidia , Masia Martino , Piras Riccardo
Published: August 2022

This paper presents an exploratory activity with a drone inspection service for environmental control. The aim of the service is to provide technical support to decision-makers in environmental risk management. The proposed service uses IoT for the interaction between a mobile application, a Smart City platform, and an Unmanned Aircraft System (UAS). The mobile application allows the users to report risky situations, such as fire ignition, spills of pollutants in water, or illegal dumping; the user has only to specify the class of the event, while the geographical coordinates are automatically taken from device-integrated GPS. The message sent from the mobile application arrives to a Smart City platform, which shows all the received alerts on a 3D satellite map, to support decision-makers in choosing where a drone inspection is required. From the Smart City platform, the message is sent to the drone service operator; a CSV file defining the itinerary of the drone is automatically built and shown through the platform; the drone starts the mission providing a video, which is used by the decision-makers to understand whether the situation calls for immediate action. An experimental activity in an open field was carried out to validate the whole chain, from the alert to the drone mission, enriched by a Smart City platform to enable a decision-maker to better manage the situation.
Prognostic Value of C-Reactive Protein and Albumin in Neurocritically Ill Patients with Acute Stroke
Authors: Jang Ji Hoon , Hong SungMin , Ryu Jeong-Am
Published: August 2022

We evaluated the prognostic value of C-reactive protein (CRP), albumin, CRP clearance (CRPc) and CRP/albumin ratio (CAR) in neurocritically ill patients with acute stroke. This is a retrospective, observational study. We included acute stroke patients who were hospitalized in the neurosurgical ICU from January 2013 to September 2019. The primary outcome was in-hospital mortality. A total of 307 patients were enrolled in the study. Among them, 267 (87.0%) survived until discharge from the hospital. CRP and CAR were significantly higher in non-survivors than in survivors (both p < 0.001). Serum albumin levels were significantly lower in the non-survivors than in the survivors (p < 0.001). In receiver operating characteristic curve analysis for prediction of in-hospital mortality, the area under the curve of CRP (C-statistic: 0.820) and CAR (C-statistic: 0.824) were greater than that of CRPc (C-statistic: 0.650) and albumin (C-statistic: 0.734) (all p < 0.005). However, there was no significant difference in the predictive performance between CRP and CAR (p = 0.287). In this study, CRP and CAR were more important than CRPc and albumin in predicting mortality of neurocritically ill patients with stroke. Early CRP level and CAR determination may help to predict the in-hospital mortality of these patients.
GAAGs, COMP, and YKL-40 as Potential Markers of Cartilage Turnover in Blood of Children with Juvenile Idiopathic Arthritis Treated with Etanercept—Relationship with ADAMTS4, ADAMTS5, and PDGF-BB
Authors: Dąbkowska Klaudia , Wojdas Magdalena , Kuźnik-Trocha Kornelia , Wisowski Grzegorz , Gruenpeter Anna , Komosińska-Vassev Katarzyna , Olczyk Krystyna , Winsz-Szczotka Katarzyna
Published: August 2022

We quantified galactosaminoglycans (GAAGs), oligomeric cartilage matrix protein (COMP), and human cartilage glycoprotein 39 (YKL-40) in blood obtained from juvenile idiopathic arthritis (JIA) before and during 2-year treatment with etanercept (ETA), as potential biomarkers of cartilage extracellular matrix (ECM) dysfunction and indicators of efficacy of biologic therapy. We also evaluated the relationship of the mentioned markers with the factors that regulate their metabolism, disintegrin and thrombospondin motif metalloproteinases 4 (ADAMTS4), ADAMTS5, and platelet-derived growth factor BB (PDGF-BB). Methods: We studied 38 children diagnosed with JIA and 45 healthy children. We quantified GAAGs by assessing the concentration of unsaturated disaccharide units formed by digestion of isolated glycosaminoglycans with chondroitinase ABC, while COMP, YKL-40, and PDGF-BB were quantified using immunoenzymatic methods. Results: Compared to the control group, GAAGs and COMP levels were significantly lower, while YKL-40 levels were higher in the blood of patients with aggressive JIA, qualified for ETA treatment. ETA therapy leading to clinical improvement simultaneously promoted normalization of COMP and YKL-40 levels, but not GAAGs. After 24 months of taking ETA, glycan levels were still significantly lower, relative to controls. GAAGs, COMP, and YKL-40 levels were significantly influenced by ADAMTS4, ADAMTS5, and PDGF-BB levels both before and during ETA treatment. Conclusions: The dynamics of changes in marker concentrations during treatment seem to indicate that measurement of COMP and YKL-40 levels can be used to assess the chondroprotective biological efficacy of therapy. In contrast, changes in GAAGs concentrations reflect systemic extracellular matrix transformations in the course of JIA.
Complete Revascularization and One-Year Survival with Good Neurological Outcome in Patients Resuscitated from an Out-of-Hospital Cardiac Arrest
Authors: Kajana Vilma , Baldi Enrico , Gentile Francesca Romana , Compagnoni Sara , Quilico Federico , Vicini Scajola Luca , Repetto Alessandra , Mandurino-Mirizzi Alessandro , Ferlini Marco , Marinoni Barbara , Ferrario Ormezzano Maurizio , Primi Roberto , Bendotti Sara , Currao Alessia , Savastano Simone
Published: August 2022

Background. The survival benefit of complete versus infarct-related artery (IRA)-only revascularization during the index hospitalization in patients resuscitated from an out-of-hospital cardiac arrest (OHCA) with multivessel disease is unknown. Methods. We considered all the OHCA patients prospectively enrolled in the Lombardia Cardiac Arrest Registry (Lombardia CARe) from 1 January 2015 to 1 May 2021 who underwent coronary angiography (CAG) at the Fondazione IRCCS Policlinico San Matteo (Pavia). Patients’ prehospital, angiographical and survival data were reviewed. Results. Out of 239 patients, 119 had a multivessel coronary disease: 69% received IRA-only revascularization, and 31% received a complete revascularization: 8 during the first procedure and 29 in a staged-procedure after a median time of 5 days [IQR 2.5–10.3]. The complete revascularization group showed significantly higher one-year survival with good neurological outcome than the IRA-only group (83.3% vs. 30.4%, p < 0.001). After correcting for cardiac arrest duration, shockable presenting rhythm, peak of Troponin-I, creatinine on admission and the need for circulatory support, complete revascularization was independently associated with the probability of death and poor neurological outcome [HR 0.3 (95%CI 0.1–0.8), p = 0.02]. Conclusions. This observation study shows that complete myocardial revascularization during the index hospitalization improves one-year survival with good neurological outcome in patients resuscitated from an OHCA with multivessel coronary disease.
Comparison of Clinical Outcomes after Non-ST-Segment and ST-Segment Elevation Myocardial Infarction in Diabetic and Nondiabetic Populations
Authors: Kim Yong Hoon , Her Ae-Young , Rha Seung-Woon , Choi Cheol Ung , Choi Byoung Geol , Kim Ji Bak , Park Soohyung , Kang Dong Oh , Park Ji Young , Park Sang-Ho , Jeong Myung Ho
Published: August 2022

Using a new-generation drug-eluting stent, we compared the 2-year clinical outcomes of patients with diabetes mellitus (DM) and non-DM concomitant with a non-ST-segment elevation myocardial infarction (NSTEMI) and an ST-segment elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention. A total of 11,798 patients with acute myocardial infarction were classified into two groups: DM (NSTEMI, n = 2399; STEMI, n = 2693) and non-DM (NSTEMI, n = 2694; STEMI, n = 4012). The primary clinical outcome was the occurrence of major adverse cardiac events (MACE), defined as all-cause death, recurrent myocardial infarction, or any coronary repeat revascularization. The secondary outcome was the occurrence of definite or probable stent thrombosis. In all the patients, both multivariable and propensity score-adjusted analyses revealed that the incidence rates of MACE (adjusted hazard ratio (aHR), 1.214; p = 0.006 and aHR, 1.298; p = 0.002, respectively), all-cause death, cardiac death (CD), and non-CD rate were significantly higher in the NSTEMI group than in the STEMI group. Additionally, among patients with NSTEMI, there was a higher non-CD rate (aHR, 2.200; p = 0.007 and aHR, 2.484; p = 0.004, respectively) in the DM group and a higher CD rate (aHR, 2.688; p < 0.001 and 2.882; p < 0.001, respectively) in the non-DM group. In this retrospective study, patients with NSTEMI had a significantly higher 2-year mortality rate than those with STEMI did. Furthermore, strategies to reduce the non-CD rate in patients with DM and the CD rate in patients without DM could be beneficial for those with NSTEMI.
The Mortality Risk and Pulmonary Fibrosis Investigated by Time-Resolved Fluorescence Spectroscopy from Plasma in COVID-19 Patients
Authors: Wybranowski Tomasz , Pyskir Jerzy , Bosek Maciej , Napiórkowska Marta , Cyrankiewicz Michał , Ziomkowska Blanka , Pilaczyńska-Cemel Marta , Pyskir Małgorzata , Rogańska Milena , Kruszewski Stefan , Przybylski Grzegorz
Published: August 2022

A method of rapidly pointing out the risk of developing persistent pulmonary fibrosis from a sample of blood is extraordinarily needed for diagnosis, prediction of death, and post-infection prognosis assessment. Collagen scar formation has been found to play an important role in the lung remodeling following SARS-CoV-2 infection. For this reason, the concentration of collagen degradation products in plasma may reflect the process of lung remodeling and determine the extent of fibrosis. According to our previously published results of an in vitro study, an increase in the concentration of type III collagen degradation products in plasma resulted in a decrease in the fluorescence lifetime of plasma at a wavelength of 450 nm. The aim of this study was to use time-resolved fluorescence spectroscopy to assess pulmonary fibrosis, and to find out if the lifetime of plasma fluorescence is shortened in patients with COVID-19. The presented study is thus far the only one to explore the fluorescence lifetime of plasma in patients with COVID-19 and pulmonary fibrosis. The time-resolved spectrometer Life Spec II with the sub-nanosecond pulsed 360 nm EPLED® diode was used in order to measure the fluorescence lifetime of plasma. The survival analysis showed that COVID-19 mortality was associated with a decreased mean fluorescence lifetime of plasma. The AUC of mean fluorescence lifetime in predicting death was 0.853 (95% CI 0.735–0.972, p < 0.001) with a cut-off value of 7 ns, and with 62% sensitivity and 100% specificity. We observed a significant decrease in the mean fluorescence lifetime in COVID-19 non-survivors (p < 0.001), in bacterial pneumonia patients without COVID-19 (p < 0.001), and in patients diagnosed with idiopathic pulmonary fibrosis (p < 0.001), relative to healthy subjects. Furthermore, these results suggest that the development of pulmonary fibrosis may be a real and serious problem in former COVID-19 patients in the future. A reduction in the mean fluorescence lifetime of plasma was observed in many patients 6 months after discharge. On the basis of these data, it can be concluded that a decrease in the mean fluorescence lifetime of plasma at 450 nm may be a risk factor for mortality, and probably also for pulmonary fibrosis in hospitalized COVID-19 patients.
Treatment Effect and Safety of Nanoliposomal Irinotecan with Fluorouracil and Folinic Acid after Gemcitabine-Based Therapy in Patients with Advanced Pancreatic Cancer: A Multicenter, Prospective Observational Study
Authors: Miki Masami , Fujimori Nao , Ueda Keijiro , Lee Lingaku , Murakami Masatoshi , Takamatsu Yu , Shimokawa Yuzo , Niina Yusuke , Oono Takamasa , Hisano Terumasa , Furukawa Masayuki , Ogawa Yoshihiro
Published: August 2022

Although the combination of nanoliposomal irinotecan plus fluorouracil/folinic acid (nal-IRI/FF) exhibited survival benefits in gemcitabine-refractory patients with advanced pancreatic cancer (APC) in the phase III NAPOLI-1 trial, there is limited data on the efficacy and safety of this regimen in real-world settings in Japan. This multicenter, prospective observational study enrolled patients with APC who received nal-IRI/FF after a gemcitabine-based regimen from July 2020 to June 2021. We collected and analyzed clinical data and conducted survival and multivariate analyses. Thirty-one (78%) of the 40 patients had metastases. Nal-IRI/FF was the second-line therapy in 36 patients (90%). The median duration was 3.2 months. The disease control rate was 57%. The median progression-free survival and overall survival (OS) were 4.5 months (95% confidence interval [CI]: 2.8–5.5) and 7.4 months (95% CI: 5.1–10.6), respectively. Common ≥grade 3 toxicities included neutropenia (28%) and fatigue (23%). Fatigue led to treatment discontinuation in 6 out of 10 patients. Multivariate analysis showed that a neutrophil-to-lymphocyte ratio > 4 was a significant risk factor for a short OS (hazard ratio (HR) = 3.08, 95% CI: 1.21–7.85, p = 0.02). In conclusion, nal-IRI/FF is an appropriate treatment option for APC following gemcitabine-containing regimens.
Implementation of a Night Service of Helicopter Transportation to Reduce the Time to Revascularization in STEMI Patients in a Mountainous Region: Impact on Outcomes
Authors: Zilio Filippo , Rigoni Marta , Muraglia Simone , Borghesi Marco , Zucchelli Federico , Todaro Daniel , Dallago Michele , Braito Giuseppe , Damaggio Fabrizio , Nollo Giandomenico , Bonmassari Roberto
Published: August 2022

Background: Treatment delays are the most easily audited index of quality of care in the setting of ST-segment elevation myocardial infarction; among the components of ischemia time, system delay has been demonstrated to be a predictor of outcomes, and in a mountainous region it relies mostly upon helicopter rescue service. Aim: The aim of the study is to analyze the impact of the activation of helicopter rescue service for the nighttime for urgent transportation of patients on the time to revascularization and on the outcomes of STEMI patients. Methods: Data were prospectively collected in a database and retrospectively split into two different cohorts, based on the presentation date in the 18 months before, or after, the first day of implementation of the new organizational model. The patients were also split into two groups based on the place of STEMI diagnosis, either the chief town territory or the rest of the region, and retrospectively evaluated for vital status at 30 days and 2 years after index event. Results: The number of patients included was 751. For patients coming from outside Trento, an improvement in ST-segment resolution was shown (ST-segment elevation reduction >50% in 54.0% of the patients vs. 36.4%, p < 0.01). Moreover, a reduction in diagnosis-to-reperfusion median time has been demonstrated (from 105 to 97 min, p < 0.01), mainly driven by a reduction during the night shift (from 119 to 100 min, p = 0.02). With regard to 30-day and 2-year mortality, no statistically significant differences were achieved. Discussion: The organizational effort has translated into a significant reduction in the treatment delay for patients coming from outside the chief town. However, although a longer diagnosis to reperfusion time has been related to a higher mortality, a significant reduction in mortality was not demonstrated in our study. However, an improvement in ST-segment elevation resolution was shown for patients coming from outside the city of Trento, a result that could have other potential clinical benefits. Conclusions: Implementation of night flight proved to be effective in reducing the time between the diagnosis and the treatment of patients in the setting of STEMI, improving ST-segment elevation resolution, although no impact was shown on short- and long-term mortality.
“To Do or Not to Do, That Is the Question”, Surgery and Pregnancy
Authors: Mastrolia Salvatore Andrea
Published: August 2022

Whenever we associate the terms “pregnancy” and “surgery”, we tend to first think to cesarean sections [...]
Symptomatic Joint Hypermobility Is Associated with Low Back Pain: A National Adolescents Cohort Study
Authors: Hershkovich Oded , Gordon Barak , Derazne Estela , Tzur Dorit , Afek Arnon , Lotan Raphael
Published: August 2022

Background: Low back pain (LBP) is a widespread medical complaint affecting many people worldwide and costing billions. Studies suggest a link between LBP and joint hypermobility. This study aimed to examine the association between symptomatic joint hypermobility (SJH), LBP, and gender. Methods: Data were obtained from a medical database containing 17-year-old candidates’ records before recruitment into mandatory military service. According to the Regulations of Medical Fitness Determination, information on disability codes associated with LBP and SJH was retrieved. Results: According to this national survey, the prevalence of SJH is 0.11% (1355 cases out of 1,220,073 subjects). LBP was identified in 3.7% of the cohort (44,755 subjects). Subjects were further subdivided into LBP without objective findings (LBPWF) (3.5%) and LBP with objective findings (LBPOF) (0.2%). The association between SJH and LBP was examined: the Odds Ratio (OR) was 2.912 (p < 0.0001). The odds rations for LBPWF and LBPOF were further calculated to be 2.914 (p < 0.000) and 2.876 (p < 0.000), respectively. Subjects with SJH were almost three times more prone to LBPWF and LBPOF. Conclusion: SJH is strongly associated with LBP in young adults. Further pathophysiological research is needed.
Unresolved Systemic Inflammation, Long COVID, and the Common Pathomechanisms of Somatic and Psychiatric Comorbidity
Authors: Liang Chih-Sung , Gałecki Piotr , Su Kuan-Pin
Published: August 2022

Monoamine hypothesis is an overestimated hypothesis of major depressive disorder (MDD), and the treatments and biomarkers that target it only show modest effect in randomized controlled trials+ (RCTs) or case–control studies [...]
Dietary Habits Modify the Association of Physical Exercise with Cognitive Impairment in Community-Dwelling Older Adults
Authors: Wei Kai , Yang Junjie , Lin Shaohui , Mei Yi , An Na , Cao Xinyi , Jiang Lijuan , Liu Chi , Li Chunbo
Published: August 2022

Background: Previous studies have confirmed that both healthy diets and physical exercise have preventive effects with respect to cognitive decline with aging. The aim of this study was to investigate whether the associations of physical exercise with cognitive impairment differ in community-dwelling older adults with different dietary habits. Methods: In the 2008/2009 wave of the Chinese Longitudinal Healthy Longevity Survey, 14,966 community-dwelling older adults (≥65 years) were included for analyses. Dietary habits (including daily intake of fruits, vegetables, tea, meat, fish, eggs, food made from beans, salt-preserved vegetables, sugar, garlic, milk products, nut products, mushroom or algae, vitamins and medicinal plants) and physical exercise were assessed. Cognitive impairment was evaluated using the Chinese version of the MMSE in the 2008/2009 and 2011/2012 waves. The effect modifications of physical exercise on cognitive impairment by dietary habits were estimated using logistic regression models. Results: Older adults who practiced physical exercise exhibited a trend of decreased probability of cognitive impairment at baseline and follow-up (OR = 0.92, 95% CI = 0.80–1.06, p = 0.273; OR = 0.83, 95% CI = 0.65–1.05, p = 0.123, respectively) compared with those who did not practice physical exercise. When stratified by dietary habits, physical exercise had a protective effect with respect to prevalent cognitive impairment in older adults who ate fruits (OR = 0.74, 95% CI = 0.58–0.94, p = 0.016), ate food made from beans (OR = 0.76, 95% CI = 0.62–0.93, p = 0.007), did not eat sugar (OR = 0.81, 95% CI = 0.68–0.98, p = 0.028) and ate milk products (OR = 0.75, 95% CI = 0.57–0.97, p = 0.030); in the longitudinal analyses, physical exercise had a protective effect with respect to incident cognitive impairment in older adults who ate fruits (OR = 0.63, 95% CI = 0.41–0.98, p = 0.040) and milk products (OR = 0.57, 95% CI = 0.35–0.94, p = 0.027). Fruits, food made from beans and milk products modified the associations of physical exercise with prevalent cognitive impairment (p values for interaction = 0.008, 0.005 and 0.082, respectively). Conclusions: The associations of physical exercise with cognitive impairment could be modified by certain dietary habits. Physical exercise was not found to be significantly protective with respect to cognitive impairment in older adults unless they had specific dietary habits. Thus, dietary habits should be emphasized when investigating the beneficial effects of physical exercise on cognitive function in community-dwelling older adults.
Novel LRP6 Mutations Causing Non-Syndromic Oligodontia
Authors: Lee Yejin , Chae Wonseon , Kim Youn Jung , Kim Jung-Wook
Published: August 2022

The process of tooth formation is a series of reciprocal interactions between the ectoderm and mesoderm, and it is believed that many genetic factors are involved in this complex process. More than a dozen genes have been identified in non-syndromic tooth agenesis; however, the genetic etiology underlying tooth agenesis is not fully understood yet. In this study, we identified two novel LRP6 mutations in two non-syndromic oligodontia families. Both probands had 16 and 17 missing teeth in their permanent dentition. Mutational analysis identified a de novo frameshift mutation by a 1-bp insertion in exon 9 (NM_002336.2: c.1870dupA, p.(Met624Asnfs*29)) and a splicing donor site mutation in intron 8 (c.1762+2T>C). An in vitro splicing assay confirmed the deletion of exon 8, and the deletion would result in a frameshift. Due to the premature termination codons introduced by the frameshift, both mutant transcripts would be degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency.
A Differential Profile of Biomarkers between Patients with Atrial Fibrillation and Healthy Controls
Authors: Merino-Merino Ana , Saez-Maleta Ruth , Salgado-Aranda Ricardo , AlKassam-Martinez Daniel , Pascual-Tejerina Virginia , Martin-Gonzalez Javier , Garcia-Fernandez Javier , Perez-Rivera Jose-Angel
Published: August 2022

Atrial fibrillation (AF) is explained by anatomical and electrophysiological changes in the atria determined by high pressure, dilatation, infiltration and inflammation in the myocardium. There are some biomarkers implicated in these processes, namely, NT-proBNP, high sensitivity troponin (Hs-Tn), urate, galectin-3, ST2, C reactive protein and fibrinogen. The aim of this study was to assess differences in these biomarkers between patients with AF and healthy controls. We designed a cross-sectional study consecutively including all patients undergoing electrical cardioversion in our hospital for persistent AF and matched healthy controls. We included 115 patients with persistent non-valvular AF and 33 healthy subjects. The biomarkers NT-proBNP, ST2 and Hs-Tn T were significantly related to the presence of AF (1054 ± 833.30 vs. 58.31 ± 59.40, p < 0.001; 35.43 ± 15.89 vs. 27.43 ± 10.95, p < 0.001 and 10.25 ± 6.11 vs. 8.42 ± 6.85, p < 0.001, respectively). NT-proBNP was the best biomarker differentiating AF patients (area under the curve 0.995). The best NT-proBNP cut-off point to differentiate AF was 102 pg/mL; for Hs-Tn T it was 11.5 ng/L and for ST2 it was 37.7 ng/mL. It is possible that these biomarkers intervene at the onset of AF and have no role in AF maintenance.
Predictive Power for Thrombus Detection after Atrial Appendage Closure: Machine Learning vs. Classical Methods
Authors: Antúnez-Muiños Pablo , Vicente-Palacios Víctor , Pérez-Sánchez Pablo , Sampedro-Gómez Jesús , Sánchez-Puente Antonio , Dorado-Díaz Pedro Ignacio , Nombela-Franco Luis , Salinas Pablo , Gutiérrez-García Hipólito , Amat-Santos Ignacio , Peral Vicente , Morcuende Antonio , Asmarats Lluis , Freixa Xavier , Regueiro Ander , Caneiro-Queija Berenice , Estevez-Loureiro Rodrigo , Rodés-Cabau Josep , Sánchez Pedro Luis , Cruz-González Ignacio
Published: August 2022

Device-related thrombus (DRT) after left atrial appendage (LAA) closure is infrequent but correlates with an increased risk of thromboembolism. Therefore, the search for DRT predictors is a topic of interest. In the literature, multivariable methods have been used achieving non-consistent results, and to the best of our knowledge, machine learning techniques have not been used yet for thrombus detection after LAA occlusion. Our aim is to compare both methodologies with respect to predictive power and the search for predictors of DRT. To this end, a multicenter study including 1150 patients who underwent LAA closure was analyzed. Two lines of experiments were performed: with and without resampling. Multivariate and machine learning methodologies were applied to both lines. Predictive power and the extracted predictors for all experiments were gathered. ROC curves of 0.5446 and 0.7974 were obtained for multivariate analysis and machine learning without resampling, respectively. However, the resampling experiment showed no significant difference between them (0.52 vs. 0.53 ROC AUC). A difference between the predictors selected was observed, with the multivariable methodology being more stable. These results question the validity of predictors reported in previous studies and demonstrate their disparity. Furthermore, none of the techniques analyzed is superior to the other for these data.
Resistant and Relapsing Collapsing Glomerulopathy Successfully Treated with Rituximab—A Case Report
Authors: Zagorec Nikola , Klarić Dragan , Klarić Marta , Horvatić Ivica , Šenjug Petar , Horaček Matija , Nikić Jagoda , Galešić Ljubanović Danica , Galešić Krešimir
Published: August 2022

Collapsing glomerulopathy (CG) or collapsing focal segmental glomerulosclerosis (cFSGS) is an aggressive disease with a high tendency of progression to end-stage renal disease due to common resistance to conventional immunosuppressants. Rituximab (RTX), a monoclonal antibody against CD20 B cells, showed some benefit in the treatment of CG. We are reporting about female patients with an idiopathic form of CG presenting with nephrotic syndrome (NS) and renal insufficiency resistant to several immunosuppressive agents such as steroids (ST), calcineurin inhibitors (CNI), and cyclophosphamide (CYC). This multidrug-resistant disease responded to RTX with complete remission. Forty-four months after initial RTX administration, a relapse of CG with severe NS and acute renal insufficiency occurred. Repeated application of RTX led to complete remission again. To the best of our knowledge, we are reporting the first case of the relapsing multidrug-resistant form of CG, which responded to RTX. Current data about the treatment of CG with RTX is lacking and is based on rare case reports and small case series. Thus, our report can contribute to determining the role of RTX in the treatment of CG.
DNA Directed Pro-Dopamine Regulation Coupling Subluxation Repair, H-Wave® and Other Neurobiologically Based Modalities to Address Complexities of Chronic Pain in a Female Diagnosed with Reward Deficiency Syndrome (RDS): Emergence of Induction of “Dopamine Homeostasis” in the Face of the Opioid Crisis
Authors: Bajaj Anish , Blum Kenneth , Bowirrat Abdalla , Gupta Ashim , Baron David , Fugel David , Nicholson Ayo , Fitch Taylor , Downs B. William , Bagchi Debasis , Dennen Catherine A. , Badgaiyan Rajendra D.
Published: August 2022

Addiction is a complex multifactorial condition. Established genetic factors can provide clear guidance in assessing the risk of addiction to substances and behaviors. Chronic stress can accumulate, forming difficult to recognize addiction patterns from both genetic and epigenetic (environmental) factors. Furthermore, psychological/physical/chemical stressors are typically categorized linearly, delaying identification and treatment. The patient in this case report is a Caucasian female, aged 36, who presented with chronic pain and partial disability following a surgically repaired trimalleolar fracture. The patient had a history of unresolved attention deficit disorder and an MRI scan of her brain revealed atrophy and functional asymmetry. In 2018, the patient entered the Bajaj Chiropractic Clinic, where initial treatment focused on re-establishing integrity of the spine and lower extremity biomechanics and graduated into cognitive behavior stabilization assisted by DNA pro-dopamine regulation guided by Genetic Addiction Risk Severity testing. During treatment (2018–2021), progress achieved included: improved cognitive clarity, focus, sleep, anxiety, and emotional stability in addition to pain reduction (75%); elimination of powerful analgesics; and reduced intake of previously unaddressed alcoholism. To help reduce hedonic addictive behaviors and pain, coupling of H-Wave with corrective chiropractic care seems prudent. We emphasize the importance of genetic assessment along with attempts at inducing required dopaminergic homeostasis via precision KB220PAM. It is hypothesized that from preventive care models, a new standard is emerging including self-awareness and accountability for reward deficiency as a function of hypodopaminergia. This case study documents the progression of a patient dealing with the complexities of an injury, pain management, cognitive impairment, anxiety, depression, and the application of universal health principles towards correction versus palliative care.
Temporal and Spatial Attractiveness Characteristics of Wuhan Urban Riverside from the Perspective of Traveling
Authors: Chen Yuting , Jia Bingyao , Wu Jing , Liu Xuejun , Luo Tianyue
Published: August 2022

Improving the attractiveness of urban waterfronts has become an important objective to promote economic development and improve the environmental quality. However, few studies have focused on the inherent characteristics of urban waterfront attractiveness. In this study, mobile phone signaling data and the TOPSIS (Technique for Order Preference by Similarity to an Ideal Solution) were used to construct the attractiveness evaluation system of the riverside in Wuhan. The OLS (ordinary least squares) regression model was used to analyze the relationship between the POI (point of interest) and the attractiveness of river waterfronts. Furthermore, the high-or-low-value aggregation classification of research units was performed according to attractiveness and the POI indicators to reveal the influencing factors of the attractiveness of the Wuhan urban riverside. Results showed the following. (1) The high-value distribution of attractiveness of the river waterfronts in Wuhan presented regional aggregation characteristics, and the attractiveness of economically developed areas was high. (2) Consumer POIs (CPOIs) and outdoor recreation POIs (RPOIs) had a positive effect on the attractiveness of the riverside in Wuhan, while housing POIs (HPOIs), public service POIs (OPOIs), and the high degree of POI mixing had a negative impact on the attractiveness of the urban riverside. (3) The high–high agglomeration spaces were mainly concentrated in the economically developed areas of the city center, which are mainly open spaces where urban cultural activities are held, while the low–low agglomeration spaces were mostly gathered in the suburban areas. The spatial distribution of the high–low agglomeration spaces, which are mainly green open spaces, was relatively fragmented, while the low–high agglomeration spaces, which are mainly freight terminals, linear walks, and residential areas, were near the city center.
Safety of COVID-19 Vaccines: Spotlight on Neurological Complications
Authors: Tondo Giacomo , Virgilio Eleonora , Naldi Andrea , Bianchi Angelo , Comi Cristoforo
Published: August 2022

The COVID-19 pandemic has led to unprecedented demand on the global healthcare system. Remarkably, at the end of 2021, COVID-19 vaccines received approvals for human use in several countries worldwide. Since then, a solid base for response in the fight against the virus has been placed. COVID-19 vaccines have been shown to be safe and effective drugs. Nevertheless, all kinds of vaccines may be associated with the possible appearance of neurological complications, and COVID-19 vaccines are not free from neurological side effects. Neurological complications of COVID-19 vaccination are usually mild, short-duration, and self-limiting. However, severe and unexpected post-vaccination complications are rare but possible events. They include the Guillain-Barré syndrome, facial palsy, other neuropathies, encephalitis, meningitis, myelitis, autoimmune disorders, and cerebrovascular events. The fear of severe or fatal neurological complications fed the “vaccine hesitancy” phenomenon, posing a vital communication challenge between the scientific community and public opinion. This review aims to collect and discuss the frequency, management, and outcome of reported neurological complications of COVID-19 vaccines after eighteen months of the World Health Organization’s approval of COVID-19 vaccination, providing an overview of safety and concerns related to the most potent weapon against the SARS-CoV-2.