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Volume 12
Issue 6
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J. Pers. Med., Volume 12, Issue 6 (June 2022) – 167 articles

Cover Story (view full-size image): Non-obstructive azoospermia (NOA) is a form of male infertility, which is characterized by a complete lack of spermatozoa in the ejaculate due to a severe spermatogenic failure. The most extreme manifestation of NOA leads to a total absence of the germ line known as Sertoli cell-only (SCO) syndrome. Recent advances in the field have shown that idiopathic NOA is a complex disease. Therefore, common genetic variation involved in the control of gene expression during spermatogenesis might have a relevant role in NOA. The PIN1 locus encodes a prolyl isomerase that is essential for the survival of the spermatogonial cell linage and the maintenance of the blood–testis barrier. Cerván-Martín et al. have shown that common non-coding single-nucleotide polymorphisms involved in the gene and isoform expression of PIN1 increase the genetic risk of developing SCO. View this paper
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2 pages, 178 KiB  
Editorial
Personalized Diagnosis and Therapy for Multiple Sclerosis
by Cristina Ramo-Tello
J. Pers. Med. 2022, 12(6), 1017; https://doi.org/10.3390/jpm12061017 - 20 Jun 2022
Viewed by 1564
Abstract
This Special Issue, entitled “Personalized Diagnosis and Therapy for Multiple Sclerosis” encompasses eight publications that we consider relevant, because their reading will help the clinician working regularly with people who suffer from multiple sclerosis (MS) [...] Full article
(This article belongs to the Special Issue Personalized Diagnosis and Therapy for Multiple Sclerosis)
12 pages, 38781 KiB  
Article
HR-pQCT for the Evaluation of Muscle Quality and Intramuscular Fat Infiltration in Ageing Skeletal Muscle
by Simon Kwoon-Ho Chow, Marloes van Mourik, Vivian Wing-Yin Hung, Ning Zhang, Michelle Meng-Chen Li, Ronald Man-Yeung Wong, Kwok-Sui Leung and Wing-Hoi Cheung
J. Pers. Med. 2022, 12(6), 1016; https://doi.org/10.3390/jpm12061016 - 20 Jun 2022
Cited by 2 | Viewed by 2986
Abstract
Myosteatosis is the infiltration of fat in skeletal muscle during the onset of sarcopenia. The quantification of intramuscular adipose tissue (IMAT) can be a feasible imaging modality for the clinical assessment of myosteatosis, important for the early identification of sarcopenia patients and timely [...] Read more.
Myosteatosis is the infiltration of fat in skeletal muscle during the onset of sarcopenia. The quantification of intramuscular adipose tissue (IMAT) can be a feasible imaging modality for the clinical assessment of myosteatosis, important for the early identification of sarcopenia patients and timely intervention decisions. There is currently no standardized method or consensus for such an application. The aim of this study was to develop a method for the detection and analysis of IMAT in clinical HR-pQCT images of the distal tibia to evaluate skeletal muscle during the ageing process, validated with animal and clinical experimentation. A pre-clinical model of ovariectomized (OVX) rats with known intramuscular fat infiltration was used, where gastrocnemii were scanned by micro-computed tomography (micro-CT) at an 8.4 μm isotropic voxel size, and the images were analyzed using our modified IMAT analysis protocol. IMAT, muscle density (MD), and muscle volume (MV) were compared with SHAM controls validated with Oil-red-O (ORO) staining. Furthermore, the segmentation and IMAT evaluation method was applied to 30 human subjects at ages from 18 to 81 (mean = 47.3 ± 19.2). Muscle-related parameters were analyzed with functional outcomes. In the animal model, the micro-CT adipose tissue-related parameter of IMAT% segmented at −600 HU to 100 HU was shown to strongly associate with the ORO-positively stained area (r = 0.898, p = 0.002). For the human subjects, at an adjusted threshold of −600 to −20 HU, moderate positive correlations were found between MV and MD (r = 0.642, p < 0.001), and between MV and IMAT volume (r = 0.618, p < 0.01). Moderate negative correlations were detected between MD and IMAT% (r = −0.640, p < 0.001). Strong and moderate associations were found between age and MD (r = −0.763, p < 0.01), and age and IMAT (r = 0.559, p < 0.01). There was also a strong correlation between IMAT% and chair rise time (r = 0.671, p < 0.01). The proposed HR-pQCT evaluation protocol for intramuscular adipose-tissue produced MD and IMAT results that were associated with age and physical performance measures, and were of good predictive value for the progression of myosteatosis or sarcopenia. The protocol was also validated on animal skeletal muscle samples that showed a good representation of histological lipid content with positive correlations, further supporting the clinical application for the rapid evaluation of muscle quality and objective quantification of skeletal muscle at the peripheral for sarcopenia assessment. Full article
(This article belongs to the Special Issue Personalized Medicine in Orthopaedics)
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<p>Representative images showing representation of the IMAT analysis protocol and the resulting 3D images. (<b>A</b>) In the original image, the ROI was selected using the muscle contours determined by the STA protocol, which is (<b>B</b>) depicted in green. (<b>C</b>) The intended segmentation threshold with an upper threshold of 100 HU did not produce a realistic result and was, therefore, rejected. (<b>D</b>) The upper threshold of −20 HU was defined manually. (<b>E</b>) The STA protocol produces a 3D segmentation, with the bones depicted in grey, the muscles in red, and fat in transparent green. (<b>F</b>) Application of the IMAT segmentation produces a 3D image, as shown with the IMAT depicted in green and the muscle depicted in transparent red.</p> Full article ">Figure 2
<p>(<b>A</b>) IMAT% was significantly higher in OVX rats than in SHAM rats (* <span class="html-italic">p</span> &lt; 0.05). (<b>B</b>) No significance was detected for MD between the two groups.</p> Full article ">Figure 3
<p>Morphological differences and fat infiltration of skeletal muscles in SHAM and OVX rats. (<b>A</b>) The OVX group presented more intramuscular fat tissue than the SHAM group by H&amp;E taken at 20× magnification, where fat tissues are indicated by black arrows. (<b>B</b>) The OVX group showed a higher ORO signal (red area) than the SHAM group. (<b>C</b>) Quantitative analysis revealed that the ORO area of the OVX group was significantly higher (* <span class="html-italic">p</span> &lt; 0.05, Student’s T-test).</p> Full article ">Figure 4
<p>MicroCT fat-related parameter of IMAT% was highly correlated with ORO-positively stained area (r = 0.898, r<sup>2</sup> = 0.806; <span class="html-italic">p</span> &lt; 0.05).</p> Full article ">
9 pages, 1064 KiB  
Review
Morphological Investigation of Mandibular Lingula: A Literature Review
by Kun-Jung Hsu, Hui-Na Lee and Chun-Ming Chen
J. Pers. Med. 2022, 12(6), 1015; https://doi.org/10.3390/jpm12061015 - 20 Jun 2022
Cited by 2 | Viewed by 2651
Abstract
Purpose: The purpose of the study was to review the literature on the shape of the mandibular lingula. Methods: English articles published from 1970 to 2021 in databases (PubMed, Web of Science, and Embase) were selected. Articles meeting the search strategy were evaluated [...] Read more.
Purpose: The purpose of the study was to review the literature on the shape of the mandibular lingula. Methods: English articles published from 1970 to 2021 in databases (PubMed, Web of Science, and Embase) were selected. Articles meeting the search strategy were evaluated based on the eligibility criteria (participants aged 18 years and over). Dry mandibles and cone beam computed tomography (CBCT) images were used as research materials. The shapes of mandibular lingula were classified as triangular, truncated, nodular, and assimilated. Results: Based on the eligibility criteria, 10 articles (six with dry mandibles and four with CBCT images) were selected for full-text reading and detailed examination. In the dry mandible group, triangular, truncated, nodular, and assimilated lingula were observed on 446, 398, 232, and 69 sides, respectively. In the CBCT group, nodular, truncated, triangular, and assimilated lingula were observed on 892, 517, 267, and 88 sides, respectively. Therefore, the most common lingula types in the dry mandible and CBCT groups were different. The assimilated type was the least common in both groups. Conclusion: In the dry mandible group, the most common lingula type was triangular, followed by truncated, nodular, and assimilated types. In the CBCT group, the most common lingula type was nodular, followed by truncated, triangular, and assimilated types. There were no significant differences in lingula types between the left and right sides of the mandible. Full article
(This article belongs to the Special Issue Prevention and Management of Oral Healthcare)
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<p>Four types of lingula. (<b>A</b>) Nodular (<b>B</b>) Truncated (<b>C</b>) Triangular (<b>D</b>) Assimilated.</p> Full article ">Figure 2
<p>Process flow of article selection in the dry mandible group and CBCT group.</p> Full article ">Figure 3
<p>The distribution of lingula types in the dry mandible group and CBCT group.</p> Full article ">
9 pages, 260 KiB  
Article
Surgical Treatment for Empyema Thoracis: Prognostic Role of Preoperative Transthoracic Echocardiography and Serum Calcium
by Pei-Yi Chu, Yu-Cheng Wu, Ya-Ling Lin, Hung Chang, Shih-Chun Lee, Tsai-Wang Huang and Yuan-Ming Tsai
J. Pers. Med. 2022, 12(6), 1014; https://doi.org/10.3390/jpm12061014 - 20 Jun 2022
Cited by 4 | Viewed by 2037
Abstract
Background: Empyema is a major cause of mortality and hospitalization. Symptoms include difficulty breathing and chest pain. Calcium plays an essential role in the physiology of the cardiovascular system. However, there is little evidence on the role of echocardiography and the serum calcium [...] Read more.
Background: Empyema is a major cause of mortality and hospitalization. Symptoms include difficulty breathing and chest pain. Calcium plays an essential role in the physiology of the cardiovascular system. However, there is little evidence on the role of echocardiography and the serum calcium levels of patients undergoing video-assisted thoracoscopic surgery (VATS) for empyema. This study aimed to investigate the risk factors for postoperative mortality in patients with empyema who required surgery. Methods: This single-institution retrospective study compared the outcomes of VATS for thoracic empyema (in terms of survival and mortality) in 122 patients enrolled between July 2015 and June 2019. Results: This study examined patients with thoracic empyema. The majority of the patients were males (100/122, 81.9%). The in-hospital/30-day mortality rate was 10.6% (13 patients). The calcium levels were 7.82 ± 1.17 mg/dL in the survival group and 6.88 ± 1.88 mg/dL in the mortality group (p = 0.032). In the mortality group, the utilization of echocardiography and serum calcium levels independently contributed to the risk prediction more than clinical variables. Patients in our cohort exhibited elevated pulmonary artery systolic pressure (PASP) and hypocalcemia, which were associated with increased postoperative mortality. Conclusion: Elevated PASP and calcium levels at the low end of the normal range demonstrated significant prognostic value in predicting mortality in patients with thoracic empyema who required surgical intervention. Recognizing this potential is critical in order to obtain better outcomes. Full article
(This article belongs to the Special Issue Cardiovascular Disease: Personalized Prevention, Management, and Treatment)
13 pages, 2088 KiB  
Article
Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis
by Yu-Shu Huang, Ting-Hsuan Fang, Belle Kung and Chia-Hsiang Chen
J. Pers. Med. 2022, 12(6), 1013; https://doi.org/10.3390/jpm12061013 - 20 Jun 2022
Cited by 11 | Viewed by 3046
Abstract
Intellectual disability (ID) and autism spectrum disorder (ASD) are complex neurodevelopmental disorders with high heritability. To search for the genetic deficits in two siblings affected with ID and ASD in a family, we first performed a genome-wide copy number variation (CNV) analysis using [...] Read more.
Intellectual disability (ID) and autism spectrum disorder (ASD) are complex neurodevelopmental disorders with high heritability. To search for the genetic deficits in two siblings affected with ID and ASD in a family, we first performed a genome-wide copy number variation (CNV) analysis using chromosomal microarray analysis (CMA). We found a 3.7 Mb microdeletion at 22q13.3 in the younger sister. This de novo microdeletion resulted in the haploinsufficiency of SHANK3 and several nearby genes involved in neurodevelopment disorders. Hence, she was diagnosed with Phelan–McDermid syndrome (PMS, OMIM#606232). We further performed whole-genome sequencing (WGS) analysis in this family. We did not detect pathogenic mutations with significant impacts on the phenotypes of the elder brother. Instead, we identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders: KLHL17, TDO2, TRRAP, EIF3F, ATP10A, DICER1, and CDH15. These variants were transmitted from his unaffected parents, indicating these variants have only moderate clinical effects. We propose that these variants worked together and led to the clinical phenotypes in the elder brother. We also suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Recent Advances in Precision Psychiatry)
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<p>Pedigree of the family with two siblings affected with ID and ASD.</p> Full article ">Figure 2
<p>CMA revealed a 3.7 Mb microdeletion at 22q13.3 (red arrow) in the younger sister in this family.</p> Full article ">Figure 3
<p>Real-time quantitative PCR showed the haploinsufficiency of an amplicon of <span class="html-italic">SHANK3</span> (exon3) in the younger sister (<span class="html-italic">HCG786</span>) but not in her elder brother (<span class="html-italic">HYS271</span>) or her parents (<span class="html-italic">HYS272</span> and <span class="html-italic">HYS273</span>).</p> Full article ">Figure 4
<p>Sanger sequencing verified the authenticity and the origin of the seven inherited missense variants identified in the elder brother. Red arrows indicate the locations of the variants.</p> Full article ">
9 pages, 1841 KiB  
Article
Multifactorial Analysis of Endodontic Microsurgery Using Finite Element Models
by Raphael Richert, Jean-Christophe Farges, Jean-Christophe Maurin, Jérôme Molimard, Philippe Boisse and Maxime Ducret
J. Pers. Med. 2022, 12(6), 1012; https://doi.org/10.3390/jpm12061012 - 20 Jun 2022
Cited by 4 | Viewed by 2026
Abstract
Background: The present study aimed to classify the relative contributions of four biomechanical factors—the root-end filling material, the apical preparation, the root resection length, and the bone height—on the root stresses of the resected premolar. Methods: A design of [...] Read more.
Background: The present study aimed to classify the relative contributions of four biomechanical factors—the root-end filling material, the apical preparation, the root resection length, and the bone height—on the root stresses of the resected premolar. Methods: A design of experiments approach based on a defined subset of factor combinations was conducted to calculate the influence of each factor and their interactions. Sixteen finite element models were created and analyzed using the von Mises stress criterion. The robustness of the design of experiments was evaluated with nine supplementary models. Results: The current study showed that the factors preparation and bone height had a high influence on root stresses. However, it also revealed that nearly half of the biomechanical impact was missed without considering interactions between factors, particularly between resection and preparation. Conclusions: Design of experiments appears to be a valuable strategy to classify the contributions of biomechanical factors related to endodontics. Imagining all possible interactions and their clinical impact is difficult and can require relying on one’s own experience. This study proposed a statistical method to quantify the mechanical risk when planning apicoectomy. A perspective could be to integrate the equation defined herein in future software to support decision-making. Full article
(This article belongs to the Special Issue Recent Advances and Personalized Treatment in Dental Health)
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<p>Representative schema of the resected tooth with A the root end-filling material, B the retro preparation, C the resection level, and D the bone height.</p> Full article ">Figure 2
<p>Von Mises root stresses represented by a color diagram from blue (low values) to red (high values); (<b>a</b>) simulations M1 to M8 are related to finite element (FE) models with a low bone height, and (<b>b</b>) simulations M9 to M16 are related to finite element (FE) models with a low bone height. The area of highest stress is indicated by a white asterisk.</p> Full article ">Figure 3
<p>Pareto chart representing the absolute values of the 10 strongest effects and interactions in descending order as bars and the cumulative total as a line. The difference between 0 and 100% represents the variation between lowest and highest stress.</p> Full article ">
10 pages, 242 KiB  
Article
Ethical and Legal Aspects of Technology-Assisted Care in Neurodegenerative Disease
by Bjoern Schmitz-Luhn, Jennifer Chandler and on behalf of the iCARE-PD Consortium
J. Pers. Med. 2022, 12(6), 1011; https://doi.org/10.3390/jpm12061011 - 20 Jun 2022
Cited by 5 | Viewed by 2328
Abstract
Technological solutions are increasingly seen as a way to respond to the demands of managing complex chronic conditions, especially neurodegenerative diseases such as Parkinson’s Disease. All of these new possibilities provide a variety of chances to improve the lives of affected persons and [...] Read more.
Technological solutions are increasingly seen as a way to respond to the demands of managing complex chronic conditions, especially neurodegenerative diseases such as Parkinson’s Disease. All of these new possibilities provide a variety of chances to improve the lives of affected persons and their families, friends, and caregivers. However, there are also a number of challenges that should be considered in order to safeguard the interests of affected persons. In this article, we discuss the ethical and legal considerations associated with the use of technology-assisted care in the context of neurodegenerative conditions. Full article
(This article belongs to the Special Issue Care Personalization in Parkinson Disease)
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Graphical abstract

Graphical abstract
Full article ">
24 pages, 1466 KiB  
Review
Role of ABCA1 in Cardiovascular Disease
by Jing Wang, Qianqian Xiao, Luyun Wang, Yan Wang, Daowen Wang and Hu Ding
J. Pers. Med. 2022, 12(6), 1010; https://doi.org/10.3390/jpm12061010 - 20 Jun 2022
Cited by 28 | Viewed by 5907
Abstract
Cholesterol homeostasis plays a significant role in cardiovascular disease. Previous studies have indicated that ATP-binding cassette transporter A1 (ABCA1) is one of the most important proteins that maintains cholesterol homeostasis. ABCA1 mediates nascent high-density lipoprotein biogenesis. Upon binding with apolipoprotein A-I, [...] Read more.
Cholesterol homeostasis plays a significant role in cardiovascular disease. Previous studies have indicated that ATP-binding cassette transporter A1 (ABCA1) is one of the most important proteins that maintains cholesterol homeostasis. ABCA1 mediates nascent high-density lipoprotein biogenesis. Upon binding with apolipoprotein A-I, ABCA1 facilitates the efflux of excess intracellular cholesterol and phospholipids and controls the rate-limiting step of reverse cholesterol transport. In addition, ABCA1 interacts with the apolipoprotein receptor and suppresses inflammation through a series of signaling pathways. Thus, ABCA1 may prevent cardiovascular disease by inhibiting inflammation and maintaining lipid homeostasis. Several studies have indicated that post-transcriptional modifications play a critical role in the regulation of ABCA1 transportation and plasma membrane localization, which affects its biological function. Meanwhile, carriers of the loss-of-function ABCA1 gene are often accompanied by decreased expression of ABCA1 and an increased risk of cardiovascular diseases. We summarized the ABCA1 transcription regulation mechanism, mutations, post-translational modifications, and their roles in the development of dyslipidemia, atherosclerosis, ischemia/reperfusion, myocardial infarction, and coronary heart disease. Full article
(This article belongs to the Special Issue Cardiovascular Diseases—From Risk Factors to Diagnosis and Personalized Management)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p><span class="html-italic">ABCA1</span> expression is regulated by transcription factors. (<b>A</b>) PPARγ, oxysterol, and retinoic acid target LXR and RXR, respectively, to activate <span class="html-italic">ABCA1</span> expression. LXR and RXR bind to DR-4 element sequence, which are constituted by direct repeats of TGACCT and separated by four base-pairs. (<b>B</b>) USF and SREBP2 bind to E-box of <span class="html-italic">ABCA1</span>, and CXCL12 promotes TCF21 to interact with <span class="html-italic">ABCA1</span> promoter to inhibit <span class="html-italic">ABCA1</span> expression.</p> Full article ">Figure 2
<p>Plasma membrane location and post-translational modifications of ABCA1. According to the sucrose equilibrium density gradient, the plasma membrane was sub-divided into 10 fractions from low to high, the lipid raft region was fractions 1–5 and the non-lipid raft region was fractions 7–10. ABCA1 is located in the non-lipid raft region of the plasma membrane [<a href="#B86-jpm-12-01010" class="html-bibr">86</a>]. There were two palmitoylation sites in each of the N-terminus and NBD1 regions of ABCA1: C3S, C23S, C1110S, and C1111S. ABCA1 is palmitoylated by palmitoyl transferase DHHC8. Seven N-linked glycosylation sites are located in two ECD regions of ABCA1: N98, N400, N489, N521, N1453, N1504, and N1647. On the ECD1 region of ABCA1, Thr505 is phosphorylated by PKC. Ser1042 and Ser2054, which are phosphorylated by PKA, are located in NBD1 and NBD2 regions of ABCA1, respectively. Five additional phosphorylation sites in NBD1 are phosphorylated by CK2. NBD, nucleotide-binding domain; DHHC, Asp-His-His-Cys; ECD, extracellular domain; PKA, protein kinase A; PKC, protein kinase C; CK2, casein kinase 2.</p> Full article ">Figure 3
<p>The preventive effects of <span class="html-italic">ABCA1</span> involvement in cardiovascular disease. RCT, reverse cholesterol transport; LDL, low-density lipoprotein; NO, nitric oxide.</p> Full article ">
13 pages, 832 KiB  
Commentary
Researching Mitigation of Alcohol Binge Drinking in Polydrug Abuse: KCNK13 and RASGRF2 Gene(s) Risk Polymorphisms Coupled with Genetic Addiction Risk Severity (GARS) Guiding Precision Pro-Dopamine Regulation
by Kenneth Blum, Mark S. Brodie, Subhash C. Pandey, Jean Lud Cadet, Ashim Gupta, Igor Elman, Panayotis K. Thanos, Marjorie C. Gondre-Lewis, David Baron, Shan Kazmi, Abdalla Bowirrat, Marcelo Febo, Rajendra D. Badgaiyan, Eric R. Braverman, Catherine A. Dennen and Mark S. Gold
J. Pers. Med. 2022, 12(6), 1009; https://doi.org/10.3390/jpm12061009 - 20 Jun 2022
Cited by 9 | Viewed by 2976
Abstract
Excessive alcohol intake, e.g., binge drinking, is a serious and mounting public health problem in the United States and throughout the world. Hence the need for novel insights into the underlying neurobiology that may help improve prevention and therapeutic strategies. Therefore, our group [...] Read more.
Excessive alcohol intake, e.g., binge drinking, is a serious and mounting public health problem in the United States and throughout the world. Hence the need for novel insights into the underlying neurobiology that may help improve prevention and therapeutic strategies. Therefore, our group employed a darkness-induced alcohol intake protocol to define the reward deficiency domains of alcohol and other substance use disorders in terms of reward pathways’ reduced dopamine signaling and its restoration via specifically-designed therapeutic compounds. It has been determined that KCNK13 and RASGRF2 genes, respectively, code for potassium two pore domain channel subfamily K member 13 and Ras-specific guanine nucleotide-releasing factor 2, and both genes have important dopamine-related functions pertaining to alcohol binge drinking. We present a hypothesis that identification of KCNK13 and RASGRF2 genes’ risk polymorphism, coupled with genetic addiction risk score (GARS)-guided precision pro-dopamine regulation, will mitigate binge alcohol drinking. Accordingly, we review published reports on the benefits of this unique approach and provide data on favorable outcomes for both binge-drinking animals and drunk drivers, including reductions in alcohol intake and prevention of relapse to drinking behavior. Since driving under the influence of alcohol often leads to incarceration rather than rehabilitation, there is converging evidence to support the utilization of GARS with or without KCNK13 and RASGRF2 risk polymorphism in the legal arena, whereby the argument that “determinism” overrides the “free will” account may be a plausible defense strategy. Obviously, this type of research is tantamount to helping resolve a major problem related to polydrug abuse. Full article
(This article belongs to the Special Issue Personalized Molecular Neurobiology of Brain Mapping of Global Pain and Mental Illness)
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<p>A schematic showing the steady state of VTA neurons (<b>A</b>) and how acute administration of ethanol stimulates VTA neurons by inhibiting KCNK13 (<b>B</b>); this molecule can modulate both VTA neuronal activity and binge drinking. KCNK13 is expressed in dopamine and non-dopamine neurons in the VTA. Kcnk13 gene expression is upregulated by acute alcohol consumption (Reproduced with permission from [<a href="#B26-jpm-12-01009" class="html-bibr">26</a>]).</p> Full article ">Figure 2
<p>Group statistical maps comparing KB22OZ (Febo et al. [<a href="#B80-jpm-12-01009" class="html-bibr">80</a>], with permission).</p> Full article ">
11 pages, 899 KiB  
Systematic Review
The Role of Hemodynamics through the Circle of Willis in the Development of Intracranial Aneurysm: A Systematic Review of Numerical Models
by Yuanyuan Shen, Rob Molenberg, Reinoud P. H. Bokkers, Yanji Wei, Maarten Uyttenboogaart and J. Marc C. van Dijk
J. Pers. Med. 2022, 12(6), 1008; https://doi.org/10.3390/jpm12061008 - 20 Jun 2022
Cited by 9 | Viewed by 5038
Abstract
Background: The role of regional hemodynamics in the intracranial aneurysmal formation, growth, and rupture has been widely discussed based on numerical models over the past decades. Variation of the circle of Willis (CoW), which results in hemodynamic changes, is associated with the aneurysmal [...] Read more.
Background: The role of regional hemodynamics in the intracranial aneurysmal formation, growth, and rupture has been widely discussed based on numerical models over the past decades. Variation of the circle of Willis (CoW), which results in hemodynamic changes, is associated with the aneurysmal formation and rupture. However, such correlation has not been further clarified yet. The aim of this systematic review is to investigate whether simulated hemodynamic indices of the CoW are relevant to the formation, growth, or rupture of intracranial aneurysm. Methods: We conducted a review of MEDLINE, Web of Science, and EMBASE for studies on the correlation between hemodynamics indices of the CoW derived from numerical models and intracranial aneurysm up to December 2020 in compliance with PRISMA guidelines. Results: Three case reports out of 1046 publications met our inclusion and exclusion criteria, reporting 13 aneurysms in six patients. Eleven aneurysms were unruptured, and the state of the other two aneurysms was unknown. Wall shear stress, oscillatory shear index, von-Mises tension, flow velocity, and flow rate were reported as hemodynamic indices. Due to limited cases and significant heterogeneity between study settings, meta-analysis could not be performed. Conclusion: Numerical models can provide comprehensive information on the cerebral blood flow as well as local flow characteristics in the intracranial aneurysm. Based on only three case reports, no firm conclusion can be drawn regarding the correlation between hemodynamic parameters in the CoW derived from numerical models and aneurysmal formation or rupture. Due to the inherent nature of numerical models, more sensitive analysis and rigorous validations are required to determine its measurement error and thus extend their application into clinical practice for personalized management. Prospero registration number: CRD42021125169. Full article
(This article belongs to the Special Issue Cardiovascular Diseases—From Risk Factors to Diagnosis and Personalized Management)
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<p>Schematic diagram of a classic circle of Willis. ACA anterior cerebral artery; MCA middle cerebral artery; PCA posterior cerebral artery; ICA internal carotid artery; BA basilar artery; AComA anterior communicating artery; PComA posterior communicating artery.</p> Full article ">Figure 2
<p>PRISMA Flow Diagram. * <span class="html-italic">List in <a href="#app1-jpm-12-01008" class="html-app">Supplementary S2</a></span>.</p> Full article ">
31 pages, 3515 KiB  
Article
Regulation of Key Immune-Related Genes in the Heart Following Burn Injury
by Jake J. Wen, Keyan Mobli, Geetha L. Radhakrishnan and Ravi S. Radhakrishnan
J. Pers. Med. 2022, 12(6), 1007; https://doi.org/10.3390/jpm12061007 - 20 Jun 2022
Cited by 3 | Viewed by 2772
Abstract
Immune cascade is one of major factors leading to cardiac dysfunction after burn injury. TLRs are a class of pattern-recognition receptors (PRRs) that initiate the innate immune response by sensing conserved molecular patterns for early immune recognition of a pathogen. The Rat Toll-Like [...] Read more.
Immune cascade is one of major factors leading to cardiac dysfunction after burn injury. TLRs are a class of pattern-recognition receptors (PRRs) that initiate the innate immune response by sensing conserved molecular patterns for early immune recognition of a pathogen. The Rat Toll-Like Receptor (TLR) Signaling Pathway RT² Profiler PCR Array profiles the expression of 84 genes central to TLR-mediated signal transduction and innate immunity, and is a validated tool for identifying differentially expressed genes (DEGs). We employed the PCR array to identify burn-induced cardiac TLR-signaling-related DEGs. A total of 38 up-regulated DEGs and 19 down-regulated DEGs were identified. Network analysis determined that all DEGS had 10 clusters, while up-regulated DEGs had 6 clusters and down-regulated DEGs had 5 clusters. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that DEGs were involved in TLR signaling, the RIG-I-Like receptor signaling pathway, the IL-17 signaling pathway, and the NFkB signaling pathway. Function analysis indicated that DEGs were associated with Toll-like receptor 2 binding, Lipopeptide binding, Toll-like receptor binding, and NAD(P)+ nucleosidase activity. The validation of 18 up-regulated DEGs (≥10-fold change) and 6 down-regulated DEGs (≤5-fold change) demonstrated that the PCR array is a trusted method for identifying DEGs. The analysis of validated DEG-derived protein–protein interaction networks will guide our future investigations. In summary, this study not only identified the TLR-signaling-pathway-related DEGs after burn injury, but also confirmed that the burn-induced cardiac cytokine cascade plays an important role in burn-induced heart dysfunction. The results will provide the novel therapeutic targets to protect the heart after burn injury. Full article
(This article belongs to the Section Mechanisms of Diseases)
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<p>Highly intact RNA: RNA was purified from heart tissues using the Qiagen RNeasy Mini Kit. The purified RNA was analyzed using a Beckman 700 system (ratio of 28 S to 18 S rRNA: ≥1.55), NanoDrop 2000, and Agilent 2100 Bioanalyzer (ratio of 28 S to 18 S rRNA: ≥1.7). A high RNA integrity number (RIN) of 9.6 was obtained, indicating highly intact RNA. (<b>A</b>) sham; (<b>B</b>) 24 hpb; (<b>C</b>) real values from Agilent 2100 Bioanalyzer.</p> Full article ">Figure 2
<p>(<b>A</b>) Heat maps of real-time RT 2 Profiler PCR Array showing differential expression of 84 TLR-related genes stimulated by burn injury. (<b>B</b>) The ≥1.5-fold changes represent the genes that are up-regulated, and the ≤−1.5-fold changes represent the genes that are down-regulated by burn injury.</p> Full article ">Figure 3
<p>Expression of TLR-Related Genes in burn injury rats. Sham control or burn injury analyzed through a Rat TLR RT2 Profiler PCR Array (QIAGEN): (<b>A</b>) Heatmap displaying hierarchical clustering of the entire dataset of expressed genes and indicating co-regulated genes across sham control and burn experimental groups: healthy sham control rats—CTRL; burn injury rats—24 hpb. Clustering analysis showed that genes upregulated in burn injury rats belong to apoptosis modulation, IL-1 signaling, TLR signaling, RIG-I-like receptor signaling and IL-17 signaling pathways; (<b>B</b>) The volcano plots identify significant changes in gene expression between groups. The volcano plot displays the statistical significance (<span class="html-italic">p</span> &lt; 0.05) versus fold change on the y and x axes, respectively; (<b>C</b>) Venn diagram and list of TLR-related genes regulated in burn injury rats. The expression levels of genes are presented as fold-regulation values (those greater than 1.5 are indicated, and those less than 1.5 are indicated for burn injury rats compared to those for controls (24 hpb vs. CTRL column). Complete data are provided in <a href="#app1-jpm-12-01007" class="html-app">Table S1a–e</a>.</p> Full article ">Figure 4
<p>(<b>A</b>–<b>C</b>) Protein–protein interaction network of all identified genes for burn injury using String-DB. Genes were identified using our network approach. Colored nodes indicate first shell interactions. Edges represent protein–protein associations. Blue indicates that the information is from curated databases, and pink indicates that it is experimentally determined; green is the gene neighborhood; dark blue represents gene co-occurrence; yellow represents information gathered from text mining; black represents co-expression; and light blue represents protein homology. Proteins with no interactions are not included in the figure for clarity. (<b>A</b>) all DEGs; (<b>B</b>) up-regulated DEGs; and (<b>C</b>) down-regulated DEGs. (<b>A</b>,<b>B</b>) Functional interaction network based on the STRING database and Gene Ontology classification. Different colors represent different clusters, and the details are described in the text.</p> Full article ">Figure 5
<p>(<b>A</b>) Mapping of TLR-signaling pathway in burn injury rats. Each gene in the KEGG TLR-signaling network (KEGG rno04620) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>B</b>) Mapping of IL-17 signaling pathway in burn injury rats. Each gene in the KEGG TLR-signaling network (KEGG rno04657) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>C</b>) Mapping of RIG-I-Like receptor signaling pathway in burn injury rats. Each gene in the KEGG TLR-signaling network (KEGG rno04622) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>D</b>) Mapping of TNF signaling pathway in burn-injury-induced upregulated DEGs in rats. Each gene in the KEGG TNF signaling network (KEGG rno04668) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>E</b>) Mapping of NfkB signaling pathway in burn injury rats. Each gene in the KEGG NFkB signaling network (KEGG rno04064) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue. The ubiquitous expression level is indicated in grey. The gene that is shown in the blank was not measured in the experiment.</p> Full article ">Figure 5 Cont.
<p>(<b>A</b>) Mapping of TLR-signaling pathway in burn injury rats. Each gene in the KEGG TLR-signaling network (KEGG rno04620) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>B</b>) Mapping of IL-17 signaling pathway in burn injury rats. Each gene in the KEGG TLR-signaling network (KEGG rno04657) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>C</b>) Mapping of RIG-I-Like receptor signaling pathway in burn injury rats. Each gene in the KEGG TLR-signaling network (KEGG rno04622) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>D</b>) Mapping of TNF signaling pathway in burn-injury-induced upregulated DEGs in rats. Each gene in the KEGG TNF signaling network (KEGG rno04668) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue; (<b>E</b>) Mapping of NfkB signaling pathway in burn injury rats. Each gene in the KEGG NFkB signaling network (KEGG rno04064) is colored according to its expression level in the burn injury group compared with that of the sham group. Genes that were significantly upregulated are colored red, and those that were significantly downregulated are marked blue. The ubiquitous expression level is indicated in grey. The gene that is shown in the blank was not measured in the experiment.</p> Full article ">Figure 6
<p>Validation of burn-induced regulated genes using qPCR. Triplicate total RNA samples from rat hearts (either sham healthy or 60% TBSA burn for 24 h) were transcribed to cDNA; then, real-time qPCR was run with our own designed primers (<a href="#jpm-12-01007-t001" class="html-table">Table 1</a>); (<b>A</b>) burn-injury-induced up-regulated TLR-related DEGs, and (<b>B</b>) burn-injury-induced down-regulated TLR-related DEGs.</p> Full article ">Figure 7
<p>Burn-injury-induced TLR-related DEP–protein interaction networks. (<b>A</b>) burn-injury-induced up-regulated TLR-related DEP–protein interactions including Casp8 (<b>A.a</b>), Ccl2 (<b>A.b</b>), Cd86 (<b>A.c</b>), Cebpb (<b>A.d</b>), Hmgb1 (<b>A.e</b>), Hspa1a (<b>A.f</b>), Ifna1 (<b>A.g</b>), IL10 (<b>A.h</b>), IL1b (<b>A.i</b>), IL2 (<b>A.j</b>), IL6 (<b>A.k</b>), Kcnh8 (<b>A.l</b>), Lta (<b>A.m</b>), Ly96 (<b>A.n</b>), Ptgs2 (<b>A.o</b>), Tlr2 (<b>A.p</b>), Tlr7 (<b>A.q</b>), and Tradd (<b>A.r</b>) by selecting fold change ≥ 10; (<b>B</b>) burn-injury-induced down-regulated TLR-related DEP–protein interactions including Map4k4 (<b>B.a</b>), Nr2c2 (<b>B.b</b>), Ripk2 (<b>B.c</b>), Rbf138 (<b>B.d</b>), Tbk1 (<b>B.e</b>), and Tollip (<b>B.f</b>) by selecting fold change ≤ 5. The interaction network was created using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database version 10.5. A high confidence cutoff of 0.7 or 0.9 was implemented in this work. In the resulting protein association network, proteins are presented as nodes, which are connected by lines whose thickness represents the confidence level (0.7–0.9).</p> Full article ">
15 pages, 887 KiB  
Protocol
A Double-Blind Randomized Trial to Investigate Mechanisms of Antidepressant-Related Dysfunctional Arousal in Depressed or Anxious Youth at Familial Risk for Bipolar Disorder
by Duncan C. Honeycutt, Melissa P. DelBello, Jeffrey R. Strawn, Laura B. Ramsey, Luis R. Patino, Kyle Hinman, Jeffrey Welge, David J. Miklowitz, Booil Jo, Thomas J. Blom, Kaitlyn M. Bruns, Sarah K. Hamill Skoch, Nicole Starace, Maxwell J. Tallman and Manpreet K. Singh
J. Pers. Med. 2022, 12(6), 1006; https://doi.org/10.3390/jpm12061006 - 20 Jun 2022
Cited by 3 | Viewed by 3481
Abstract
Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth [...] Read more.
Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth with a family history of bipolar disorder (BD) who are at heightened risk for dysfunction in neurobiological systems that regulate emotion and arousal. To further understand this phenomenon, this study will examine (a) baseline risk factors associated with dysfunctional arousal in a sample of youth at high-risk for BD treated with or without an antidepressant, (b) whether antidepressant-related changes in arousal are mediated by changes in prefrontal-limbic circuitry, and (c) whether pharmacogenetic factors influence antidepressant-related changes in arousal. High-risk youth (aged 12–17 years with moderate to severe depressive and/or anxiety symptoms and at least one first-degree relative with bipolar I disorder) will be randomized to receive psychotherapy plus escitalopram or psychotherapy plus placebo. Neuroimaging and behavioral measures of arousal will be collected prior to randomization and at 4 weeks. Samples for pharmacogenetic analysis (serum escitalopram concentration, CYP2C19 metabolizer phenotype, and HTR2A and SLC6A4 genotypes) will be collected at 8 weeks. Youth will be followed for up to 16 weeks to assess change in arousal measures. Full article
(This article belongs to the Section Pharmacogenetics)
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<p>Escitalopram is predominantly metabolized by CYP2C19, and reduced CYP2C19 metabolism has been associated with increased risk of hyperarousal in youth at high risk for bipolar disorder. Youth homozygous for the “short (S)” allele of SLC6A4 exhibit reduced SLC6A4 and greater rates of adverse drug events. Furthermore, 5-HT2A may play a role in escitalopram pharmacodynamics, but its role in the development of hyperarousal or bipolar disorder is less clear. Adapted from Strawn et al. (2021) [<a href="#B80-jpm-12-01006" class="html-bibr">80</a>].</p> Full article ">Figure 2
<p>Conceptual framework for the formal evaluation of neural mechanisms of change as mediating medication effect on the development of hyperarousal. Legend: ↑ = increase; ↓ = decrease; + = hyperconnectivity.</p> Full article ">
17 pages, 1787 KiB  
Article
Intestinal Permeability and Dysbiosis in Female Patients with Recurrent Cystitis: A Pilot Study
by Cristina Graziani, Lucrezia Laterza, Claudia Talocco, Marco Pizzoferrato, Nicoletta Di Simone, Silvia D’Ippolito, Caterina Ricci, Jacopo Gervasoni, Silvia Persichilli, Federica Del Chierico, Valeria Marzano, Stefano Levi Mortera, Aniello Primiano, Andrea Poscia, Francesca Romana Ponziani, Lorenza Putignani, Andrea Urbani, Valentina Petito, Federica Di Vincenzo, Letizia Masi, Loris Riccardo Lopetuso, Giovanni Cammarota, Daniela Romualdi, Antonio Lanzone, Antonio Gasbarrini and Franco Scaldaferriadd Show full author list remove Hide full author list
J. Pers. Med. 2022, 12(6), 1005; https://doi.org/10.3390/jpm12061005 - 20 Jun 2022
Cited by 6 | Viewed by 3634
Abstract
Recurrent cystitis (RC) is a common disease, especially in females. Anatomical, behavioral and genetic predisposing factors are associated with the ascending retrograde route, which often causes bladder infections. RC seems to be mainly caused by agents derived from the intestinal microbiota, and most [...] Read more.
Recurrent cystitis (RC) is a common disease, especially in females. Anatomical, behavioral and genetic predisposing factors are associated with the ascending retrograde route, which often causes bladder infections. RC seems to be mainly caused by agents derived from the intestinal microbiota, and most frequently by Escherichia coli. Intestinal contiguity contributes to the etiopathogenesis of RC and an alteration in intestinal permeability could have a major role in RC. The aim of this pilot study is to assess gut microbiome dysbiosis and intestinal permeability in female patients with RC. Patients with RC (n = 16) were enrolled and compared with healthy female subjects (n = 15) and patients with chronic gastrointestinal (GI) disorders (n = 238). We calculated the Acute Cystitis Symptom Score/Urinary Tract Infection Symptom Assessment (ACSS/UTISA) and Gastrointestinal Symptom Rating Scale (GSRS) scores and evaluated intestinal permeability and the fecal microbiome in the first two cohorts. Patients with RC showed an increased prevalence of gastrointestinal symptoms compared with healthy controls. Of the patients with RC, 88% showed an increased intestinal permeability with reduced biodiversity of gut microbiota compared to healthy controls, and 68% of the RC patients had a final diagnosis of gastrointestinal disease. Similarly, GI patients reported a higher incidence of urinary symptoms with a diagnosis of RC in 20%. Gut barrier impairment seems to play a major role in the pathogenesis of RC. Further studies are necessary to elucidate the role of microbiota and intestinal permeability in urinary tract infections. Full article
(This article belongs to the Special Issue Targeting the Microbiome for Disease Diagnosis and Therapy: New Frontiers for Personalized Medicine)
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<p>Symptoms and quality of life impairment in patients affected by RC (cohort I): ACSS/UTISA scores. (<b>A</b>) ACUTE CYSTITIS SYMPTOM SCORE (ACSS) AND UTI SYMPTOM ASSESSMENT (UTISA); (<b>A</b>) SELECTED ITEMS FROM ACSS/UTISA QUESTIONNAIRE. Patients with recurrent cystitis showed higher scores for the questionnaires compared to controls, both in the area of typical and atypical symptoms (<b>A</b>) Similarly, they scored significantly higher in items evaluating the perceived impact on quality of life. Selected items are reported in (<b>B</b>). All the differences were statistically significant (<span class="html-italic">p</span> &lt; 0.05).</p> Full article ">Figure 2
<p>Gastroenterological complaints in RC patients (cohort I): Gastrointestinal Symptoms Rating Scale (GSRS) score. This questionnaire contains 15 questions related to five areas of interest in the gastroenterological clinic, concerning symptoms such as diarrhea, constipation, abdominal pain, reflux, dyspepsia. Among the enrolled patients, most showed an increased prevalence of all the items in the GSRS questionnaire. (<b>A</b>) Full GSRS score. (<b>B</b>) GSRS SCORE divided per gastrointestinal symptoms area score: reflux, diarrhea, constipation, abdominal pain, indigestion. (<b>C</b>) Intensity of symptoms according at GSRS for each single area: percentage of patients indicating a score of 3 (higher) or 2 or 1 or 0 (lower), respectively. Higher scores are consistent with increased severity of symptoms.</p> Full article ">Figure 3
<p>Intestinal permeability modification in patients with RC (cohort I). (<b>A</b>) Intestinal permeability. Patients affected by recurrent cystitis showed a statistically significant increase in intestinal permeability, measured as L/M ratio (lactulose/mannitol) with an average urinary ratio of lactulose/mannitol equal to 0.050 compared to 0.02 of controls. (<span class="html-italic">p</span> &lt; 0.05). (<b>B</b>) Prevalence of altered L/M ratio. Of patients affected by recurrent cystitis, 88% displayed an altered L/M ratio compared to controls.</p> Full article ">Figure 4
<p>Increased prevalence of alteration at breath testing in RC (cohort I). Prevalence of SIBO (<b>A</b>) and prevalence of oro-cecal transit time alterations (<b>B</b>). The Breath Test showed that patients with recurrent cystitis showed a trend towards an increased prevalence of SIBO and alterations of the oro-cecal transit time, compared to the control population (differences were not statistically significant, <span class="html-italic">p</span> &gt; 0.05).</p> Full article ">Figure 5
<p>Gut microbiota alteration in RC patient (cohort I). (<b>A</b>) Boxplots representing α-diversity indices. The interquartile range is represented by the box and the line in the box is the median. The whiskers indicate the largest and the lowest data points, respectively, while the dots symbolize samples. The analysis of the gut microbiota showed a certain degree of reduction in the observed species and of the CHAO 1 and of Shannon indexes between the two groups. Furthermore, a greater degree of reduction in biodiversity seems more evident in the group of patients (cohort I) versus controls (cohort II). (<b>B</b>) <span class="html-italic">β</span> diversity analysis performed by Bray Curtis distance matrix and plotted by PCoA plot. Patients affected by RC (green, PTS, cohort I) tend to cluster differently than controls (red, ctr, cohort I). PERMANOVA <span class="html-italic">p</span> value = 0.02. (<b>C</b>) Phylum distribution (left side) and species distribution between RC patients (cohort I) and controls (cohort II) (right side). Firmicutes and Verrucomicrobia were the most represented phylum of gut microbiota (left side). In terms of prevalent microbial species, some species seem more abundant than others species. In the controls, particular abundance was found for <span class="html-italic">Acinetobacter</span>, while the most candidate species as potential markers of dysbiosis in the course of recurrent cystitis seem to belong above all to the phylum of <span class="html-italic">Firmicutes</span>, such as <span class="html-italic">Ruminococcus</span>, <span class="html-italic">Blautia</span>, <span class="html-italic">Veillonella</span>, <span class="html-italic">Streptococcus spp.</span> Mann–Whitney U test <span class="html-italic">p</span> values ≤ 0.05 (right side).</p> Full article ">Figure 6
<p>UTIs etiology. Urinary tract infections appear to be mainly caused by agents derived from the intestinal microflora. The main representative was <span class="html-italic">E. coli</span>, but other widely present species included <span class="html-italic">Streptococcus agalactiae</span>, <span class="html-italic">Enterococcus faecalis</span>, and to a lesser extent, <span class="html-italic">Shigella</span> and <span class="html-italic">Proteus mirabilis</span>.</p> Full article ">
13 pages, 1660 KiB  
Article
Psilocybin—Mediated Attenuation of Gamma Band Auditory Steady-State Responses (ASSR) Is Driven by the Intensity of Cognitive and Emotional Domains of Psychedelic Experience
by Vojtěch Viktorin, Inga Griškova-Bulanova, Aleksandras Voicikas, Dominika Dojčánová, Peter Zach, Anna Bravermanová, Veronika Andrashko, Filip Tylš, Jakub Korčák, Michaela Viktorinová, Vlastimil Koudelka, Kateřina Hájková, Martin Kuchař, Jiří Horáček, Martin Brunovský and Tomáš Páleníček
J. Pers. Med. 2022, 12(6), 1004; https://doi.org/10.3390/jpm12061004 - 19 Jun 2022
Cited by 5 | Viewed by 3896
Abstract
Psilocybin is a classical serotoninergic psychedelic that induces cognitive disruptions similar to psychosis. Gamma activity is affected in psychosis and is tightly related to cognitive processing. The 40 Hz auditory steady-state responses (ASSR) are frequently used as indicators to test the ability to [...] Read more.
Psilocybin is a classical serotoninergic psychedelic that induces cognitive disruptions similar to psychosis. Gamma activity is affected in psychosis and is tightly related to cognitive processing. The 40 Hz auditory steady-state responses (ASSR) are frequently used as indicators to test the ability to generate gamma activity. Based on previous literature, we studied the impact of psilocybin on 40 Hz ASSR in healthy volunteers. The study was double blind and placebo controlled with a crossover design. A sample of 20 healthy subjects (10M/10F) received psilocybin orally 0.26 mg/kg or placebo. Participants were measured four times in total, one time before ingestion of psilocybin/placebo and one time after ingestion, during the peak of intoxication. A series of 500 ms click trains were used for stimulation. Psilocybin induced a psychedelic effect and decreased 40 Hz ASSR phase-locking index compared to placebo. The extent of the attenuation was related to Cognition and Affect on the Hallucinogen Rating Scale. The current study shows that psilocybin lowers the synchronization level and the amplitude of 40 Hz auditory steady-state responses, which yields further support for the role of gamma oscillations in cognitive processing and its disturbance. Full article
(This article belongs to the Special Issue Towards Precision Medicine in Psychosis)
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<p>(<b>A</b>) The graph shows comparisons of 11 factors from the Altered states of consciousness scale, including the clustering of factors into three main subscales Oceanic boundlessness, Self-disintegration and Perception in 12 subjects during psilocybin intoxication vs. placebo. (<b>B</b>) The graph shows comparison of 6 factors from the Hallucinogen rating scale in 12 subjects during psilocybin intoxication vs. placebo. (<b>C</b>) Grand averages of the PLI, EA and ERSP curves across fronto-central ROI in pre-placebo, post-placebo, pre-psilocybin, and post-psilocybin conditions. (<b>D</b>) Time-frequency plots of PLI, EA and ERSP. (<b>E</b>) Scatterplots showing significant correlations between PLI difference values and facets of HRS—affect, cognition; scatterplot showing significant correlation between PLI values in the peak of intoxication and HRS facet intensity. Legend: PLI = Phase-locking index; ERSP = Event-related spectral perturbation; EA = Evoked amplitude; Pre = measurement before drug intake; Post = measurement in the peak of intoxication.</p> Full article ">Figure 2
<p>Individual PLI curves in pre-placebo, post-placebo, pre-psilocybin and post-psilocybin conditions. X axis—time in milliseconds, Y axis—PLI values.</p> Full article ">
9 pages, 955 KiB  
Article
IL-10 Induced by mTNF Crosslinking-Mediated Reverse Signaling in a Whole Blood Assay Is Predictive of Response to TNFi Therapy in Rheumatoid Arthritis
by Marco Krasselt, Natalya Gruz, Matthias Pierer, Christoph Baerwald and Ulf Wagner
J. Pers. Med. 2022, 12(6), 1003; https://doi.org/10.3390/jpm12061003 - 19 Jun 2022
Cited by 2 | Viewed by 1842
Abstract
(1) Background: To date, the response of patients with rheumatoid arthritis (RA) to the various biologic DMARD available cannot be predicted due to a lack of reliable biomarkers. Based on our preliminary work on tmTNF reverse signaling, we developed a whole-blood assay measuring [...] Read more.
(1) Background: To date, the response of patients with rheumatoid arthritis (RA) to the various biologic DMARD available cannot be predicted due to a lack of reliable biomarkers. Based on our preliminary work on tmTNF reverse signaling, we developed a whole-blood assay measuring tmTNF crosslinking-induced IL-10 production to predict the response to TNF inhibitor (TNFi) therapy. (2) Methods: This prospective study included patients with active RA. Depending on the clinical judgment of the attending rheumatologist, either therapy with a TNF or JAK inhibitor was initiated. Clinical parameters and blood samples were obtained at baseline and after 8 weeks of therapy. The blood samples were collected using a newly developed whole-blood assay based on the principle of tmTNF reverse signalling. Subsequently, IL-10 was measured via enzyme-linked immunosorbent assay (ELISA) technique. (3) Results: 63 patients with RA were enrolled. In fifteen patients, TNFi therapy was initiated, while eight patients started a JAKi treatment. The cross-sectional analysis of all patients showed a positive correlation between tmTNF crosslinking-induced IL-10 and parameters of disease activity (CRP [r = 0.4091, p = 0.0009], DAS28 [r = 0.3303, p = 0.0082]) at baseline. In the TNFi treatment study, IL-10 was found to be significantly higher in EULAR responders than in non-responders (p = 0.0033). After initiation of JAKi treatment, in contrast, IL-10 induction was not linked to response. Longitudinal analysis of the TNFi-treated patients revealed IL-10 to decrease in responders (p = 0.04), but not in non-responders after 8 weeks of therapy. Of importance, the IL-10 production at baseline correlated inversely with TNFi response determined by ΔDAS28 in patients with TNFi treatment (r = −0.5299, p = 0.0422) while no such link was observed under JAKi therapy (p = 0.22). Receiver operation characteristics (ROC) analysis demonstrated a high performance of tmTNF/crosslinking-induced IL-10 in predicting a TNFi therapy response according to the EULAR criteria (AUC = 0.9286, 95% Confidence interval 0.7825–1.000, p = 0.0055). (4) Conclusions: In this pilot investigation, we demonstrated the feasibility of a whole-blood assay measuring tmTNF-induced IL-10 to predict clinical response to TNF inhibitor treatment. This approach might support rheumatologists in their decision for an individually tailored RA therapy. Full article
(This article belongs to the Section Personalized Therapy and Drug Delivery)
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<p>tmTNF/crosslinking-induced IL-10 at baseline in all patients (<span class="html-italic">n</span> = 63). Shown is the absolute IL-10 production. IL-10 is correlated to both, CRP (<b>A</b>) and DAS28 (<b>B</b>) as markers of disease activity.</p> Full article ">Figure 2
<p>tmTNF crosslinking-induced IL-10 at baseline (<span class="html-italic">n</span> = 15) is higher among responders to TNFi therapy. (<b>A</b>) depicts the absolute IL-10 values while (<b>B</b>) shows the IL-10 production in relation to the human IgG Fc control (x-fold). Responders (light grey) are defined using the EULAR response criteria (any response). Depicted are boxplots and 5th to 95th percentile. (<b>C</b>) compares the mean values of absolute IL-10 levels in all test tubes of the EULAR responders (<span class="html-italic">n</span> = 7) using a one-way ANOVA and Holm-Sidak multiple comparison test. Depicted are the means with standard error of the mean. * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 3
<p>(<b>A</b>,<b>B</b>) Scatter plot shows the correlation between tmTNF crosslinking-induced IL-10 and the change in DAS28 after initiating treatment with either TNFi (<span class="html-italic">n</span> = 15, (<b>A</b>)) or JAKi (<span class="html-italic">n</span> = 8, (<b>B</b>)). Shown is the induced IL-10 production in relation to the human IgG Fc control (x-fold). (<b>C</b>) Receiver operating characteristic (ROC) analysis of the value of tmTNF crosslinking-induced IL-10 in predicting TNFi therapy response (<span class="html-italic">n</span> = 15). The area under the curve (AUC) is shown with standard error (±SE), 95% confidence interval (CI) and <span class="html-italic">p</span> value.</p> Full article ">
12 pages, 1783 KiB  
Article
Translated Mutant DSPP mRNA Expression Level Impacts the Severity of Dentin Defects
by Youn Jung Kim, Yejin Lee, Hong Zhang, Figen Seymen, Mine Koruyucu, Sule Bayrak, Nuray Tuloglu, James P. Simmer, Jan C.-C. Hu and Jung-Wook Kim
J. Pers. Med. 2022, 12(6), 1002; https://doi.org/10.3390/jpm12061002 - 19 Jun 2022
Cited by 8 | Viewed by 2342
Abstract
Hereditary dentin defects are conventionally classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). Mutations in the dentin sialophosphoprotein (DSPP) gene have been identified to cause DGI type II and III and DD type II; [...] Read more.
Hereditary dentin defects are conventionally classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). Mutations in the dentin sialophosphoprotein (DSPP) gene have been identified to cause DGI type II and III and DD type II; therefore, these are not three different conditions, but rather allelic disorders. In this study, we recruited three families with varying clinical phenotypes from DGI-III to DD-II and performed mutational analysis by candidate gene analysis or whole-exome sequencing. Three novel mutations including a silent mutation (NM_014208.3: c.52-2del, c.135+1G>C, and c.135G>A; p.(Gln45=)) were identified, all of which affected pre-mRNA splicing. Comparison of the splicing assay results revealed that the expression level of the DSPP exon 3 deletion transcript correlated with the severity of the dentin defects. This study did not only expand the mutational spectrum of DSPP gene, but also advanced our understanding of the molecular pathogenesis impacting the severity of hereditary dentin defects. Full article
(This article belongs to the Special Issue Precision Medicine in Oral Science and Dentistry)
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<p>Pedigree, clinical photos, and panoramic radiograph of family 1. (<b>A</b>) Pedigree of family 1. Black symbols indicate affected individuals and the proband is indicated by a black arrow. Plus signs above the symbols indicate participating individuals. (<b>B</b>–<b>D</b>) Clinical photos of the proband (III:1) at age 8. Weak deciduous dentition shows severe attrition in most teeth to the level of gingiva. His erupting permanent mandibular anterior teeth exhibit amber−brown discoloration. The first molars (white arrows) show defective enamel formation. (<b>E</b>) Panoramic radiograph of the proband at age 8 shows severe attrition and complete pulp obliteration in all deciduous teeth. Enamel defects in the developing dentition, especially in the maxillary and mandibular canines (red arrows), can be seen radiographically.</p> Full article ">Figure 2
<p>Pedigree, clinical photos, and panoramic radiograph of family 2. (<b>A</b>) Pedigree of family 2. Black-filled symbols indicate affected individuals and the proband is indicated by a black arrow. Plus signs above the symbols indicate participating individuals. (<b>B</b>–<b>F</b>) Clinical photos of the proband (II:2) at age 9. All of his deciduous teeth except the mandibular canines are missing due to severe attrition. Thin enamel (white arrows) can be seen in the maxillary central incisors and severe attrition can be seen in the first molars (black arrows). (<b>G</b>) Panoramic radiograph of the proband at age 9 shows severe attrition in first molars (red arrows). The enamel appears thin and mineralization of the enamel and dentin also appears to be reduced.</p> Full article ">Figure 3
<p>Pedigree, clinical photos, and panoramic radiograph of family 3. (<b>A</b>) Pedigree of family 3. Black symbols indicate affected individuals and the proband is indicated by a black arrow. Plus signs above the symbols indicate participating individuals. (<b>B</b>–<b>D</b>) Clinical photos of the proband (II:1) at age 18. Mild discoloration can be seen in the anterior teeth. Labial surfaces of the maxillary anterior teeth have been restored with resin composite (black arrows). Increased attrition and dentin exposure can be seen in the maxillary and mandibular incisors (white arrows). Posterior teeth are normal without discoloration and attrition. (<b>E</b>) Panoramic radiograph of the proband at age 18 years shows partial pulpal obliterations resembling thistle-tube-shaped pulp chambers (white arrows).</p> Full article ">Figure 4
<p>Agarose gel image of the splicing assay of the wild-type and mutants. Left lane is the DNA ladder. Wild-type and mutant names are shown above the gel image. Wild-type sequence resulted in normal splicing products including exons 2, 3, and 4. Deletion mutation (c.52-2del) resulted in an exon 3 deletion. Mutations c.135+1G&gt;C and c.135G&gt;A resulted in two bands: alternative splicing band using a cryptic 5′ splicing site (a shorter exon 3 with orange color) and an exon 3 deletion band. Band intensity comparison shows that the exon 3 deletion band intensity of the c.135G&gt;A mutation is significantly weaker than the other two mutants (asterisk indicates <span class="html-italic">p</span> &lt; 0.01). Intensity of the wild type band was stronger than the exon 3 deletion band of all the mutants (asterisk indicates <span class="html-italic">p</span> &lt; 0.01). Sequencing chromatograms of the alternative splicing band are shown below. Abnormal, shorter exon 3 sequences are indicated with an orange box above the chromatogram. Cryptic and natural 5′ splicing sites are indicated with black circles. The sequences included in the chromatogram are indicated with black lines above the sequences.</p> Full article ">
30 pages, 2449 KiB  
Article
Co-Designing an Integrated Care Network with People Living with Parkinson’s Disease: A Heterogeneous Social Network of People, Resources and Technologies
by Amélie Gauthier-Beaupré, Emely Poitras, Sylvie Grosjean, Tiago A. Mestre and on behalf of the iCARE-PD Consortium
J. Pers. Med. 2022, 12(6), 1001; https://doi.org/10.3390/jpm12061001 - 19 Jun 2022
Cited by 3 | Viewed by 3407
Abstract
As part of the iCARE-PD project, a multinational and multidisciplinary research endeavour to address complex care in Parkinson’s disease, a Canadian case study focused on gaining a better understanding of people living with Parkinson’s disease (PwP) experiences with health and medical services, particularly [...] Read more.
As part of the iCARE-PD project, a multinational and multidisciplinary research endeavour to address complex care in Parkinson’s disease, a Canadian case study focused on gaining a better understanding of people living with Parkinson’s disease (PwP) experiences with health and medical services, particularly their vision for a sustainable, tailored and integrated care delivery network. The multifaceted nature of the condition means that PwP must continuously adapt and adjust to every aspect of their lives, and progressively rely on support from care partners (CP) and various health care professionals (HCP). To envision the integrated care delivery network from the perspective of PwP, the study consisted of designing scenarios for an integrated care delivery network with patients, their CP and their HCP, as well as identifying key requirements for designing an integrated care delivery network. The results demonstrate that numerous networks interact, representing specific inscriptions, actors and mediators who meet at specific crossing points. This resulted in the creation of a roadmap and toolkit that takes into consideration the unique challenges faced by PwP, and the necessity for an integrated care delivery network that can be personalized and malleable so as to adapt to evolving and changing needs over time. Full article
(This article belongs to the Special Issue Care Personalization in Parkinson Disease)
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<p>Co-design approach for the iCARE-PD project.</p> Full article ">Figure 2
<p>Journey Map for Canada.</p> Full article ">Figure 3
<p>Configuration of the Integrated Care Network in Canada.</p> Full article ">Figure 4
<p>Roadmap and toolkit for the constitution of the iCARE-PD project in Canada.</p> Full article ">
11 pages, 600 KiB  
Article
Venous Segmental Flow Changes after Superficial Venous Intervention Demonstrating by Quantitative Phase-Contrast Magnetic Resonance Analysis: Preliminary Data from a Longitudinal Cohort Study
by Chien-Wei Chen, Yuan-Hsi Tseng, Chih-Chen Kao, Yeh Giin Ngo, Chung-Yuan Lee, Teng-Yao Yang, Yu-Hui Lin and Yao-Kuang Huang
J. Pers. Med. 2022, 12(6), 1000; https://doi.org/10.3390/jpm12061000 - 19 Jun 2022
Viewed by 1950
Abstract
The effects of superficial venous intervention on hemodynamics can be quantified using two-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI). Twelve patients received pre- and postintervention 2D PC-MRI analysis using quantitative hemodynamic parameters. Fifteen healthy volunteers served as controls. The 2D PC-MRI results of [...] Read more.
The effects of superficial venous intervention on hemodynamics can be quantified using two-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI). Twelve patients received pre- and postintervention 2D PC-MRI analysis using quantitative hemodynamic parameters. Fifteen healthy volunteers served as controls. The 2D PC-MRI results of the target limbs (limbs scheduled for intervention for venous reflux) differed from those of the controls in terms of stroke volume (SV), forward flow volume (FFV), absolute stroke volume (ASV), and mean flux (MF) in all venous segments. The velocity time integral (VTI) and mean velocity (MV) of the popliteal vein (PV) segments were similar between the target limbs and controls preoperatively. After intervention, the target limbs exhibited an increase in VTI and MV in the femoral vein (FV) and PV segments. We compared the target and nontreated limbs of the individual patients preoperatively and postoperatively to minimalize individual bias. All QFlow parameter ratios in the FV segment increased after venous intervention (VTI, p = 0.025; MV, p = 0.024). In the PV segment, FFV and ASV increased significantly (p = 0.035 and 0.024, respectively). After interventions, the volume (FFV and ASV) of the PV segment and the efficiency (VTI and MV) of the FV segment significantly increased. Full article
(This article belongs to the Special Issue Chronic Vascular Disease and Personalized Medicine: Unraveling New Horizons)
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<p>Cohorts of the study.</p> Full article ">Figure 2
<p>Typical stasis leg ulcer with venous reflux in the gaiter area (Also seen in <a href="#app1-jpm-12-01000" class="html-app">Video S1</a>). (<b>A</b>) Wet and nonhealing stasis leg ulcer. Black Arrow: unhealed venous ulcer with cellulitis. (<b>B</b>) Preintervention: The gated 3D-TSE-STIR MRA demonstrates the venous anatomy both leg veins. The white arrow indicates the diseased great saphenous vein of the wounded leg. (<b>C</b>) Postintervention: gated 3D-TSE-STIR MRA. The red arrow indicates the diseased great saphenous vein occluded. (<b>D</b>) Stasis leg ulcer healed after truncal ablation. Gated 3D-TSE-STIR MRA for venous systems. Black arrow: healed ulcers.</p> Full article ">
12 pages, 284 KiB  
Review
Biologic Therapies in Pediatric Asthma
by Evanthia P. Perikleous, Paschalis Steiropoulos, Evangelia Nena and Emmanouil Paraskakis
J. Pers. Med. 2022, 12(6), 999; https://doi.org/10.3390/jpm12060999 - 18 Jun 2022
Cited by 15 | Viewed by 3363
Abstract
Undeniably, childhood asthma is a multifactorial and heterogeneous chronic condition widespread in children. Its management, especially of the severe form refractory to standard therapy remains challenging. Over the past decades, the development of biologic agents and their subsequent approval has provided an advanced [...] Read more.
Undeniably, childhood asthma is a multifactorial and heterogeneous chronic condition widespread in children. Its management, especially of the severe form refractory to standard therapy remains challenging. Over the past decades, the development of biologic agents and their subsequent approval has provided an advanced and very promising treatment alternative, eventually directing toward a successful precision medicine approach. The application of currently approved add-on treatments for severe asthma in children, namely omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab have been shown to be effective in terms of asthma control and exacerbation rate. However, to date, information is still lacking regarding its long-term use. As a result, data are frequently extrapolated from adult studies. Thus, the selection of the appropriate biologic agent, the potential predictors of good asthma response, and the long-term outcome in the pediatric population are still to be further investigated. The aim of the present study was to provide an overview of the current status of the latest evidence about all licensed monoclonal antibodies (mAbs) that have emerged and been applied to the field of asthma management. The innovative future targets are also briefly discussed. Full article
(This article belongs to the Special Issue Asthma: From Phenotypes to Personalized Medicine)
12 pages, 3640 KiB  
Article
Three-Dimensional Postoperative Results Prediction for Orthognathic Surgery through Deep Learning-Based Alignment Network
by Seung Hyun Jeong, Min Woo Woo, Dong Sun Shin, Han Gyeol Yeom, Hun Jun Lim, Bong Chul Kim and Jong Pil Yun
J. Pers. Med. 2022, 12(6), 998; https://doi.org/10.3390/jpm12060998 - 18 Jun 2022
Cited by 6 | Viewed by 2790
Abstract
To date, for the diagnosis of dentofacial dysmorphosis, we have relied almost entirely on reference points, planes, and angles. This is time consuming, and it is also greatly influenced by the skill level of the practitioner. To solve this problem, we wanted to [...] Read more.
To date, for the diagnosis of dentofacial dysmorphosis, we have relied almost entirely on reference points, planes, and angles. This is time consuming, and it is also greatly influenced by the skill level of the practitioner. To solve this problem, we wanted to know if deep neural networks could predict postoperative results of orthognathic surgery without relying on reference points, planes, and angles. We use three-dimensional point cloud data of the skull of 269 patients. The proposed method has two main stages for prediction. In step 1, the skull is divided into six parts through the segmentation network. In step 2, three-dimensional transformation parameters are predicted through the alignment network. The ground truth values of transformation parameters are calculated through the iterative closest points (ICP), which align the preoperative part of skull to the corresponding postoperative part of skull. We compare pointnet, pointnet++ and pointconv for the feature extractor of the alignment network. Moreover, we design a new loss function, which considers the distance error of transformed points for a better accuracy. The accuracy, mean intersection over union (mIoU), and dice coefficient (DC) of the first segmentation network, which divides the upper and lower part of skull, are 0.9998, 0.9994, and 0.9998, respectively. For the second segmentation network, which divides the lower part of skull into 5 parts, they were 0.9949, 0.9900, 0.9949, respectively. The mean absolute error of transverse, anterior–posterior, and vertical distance of part 2 (maxilla) are 0.765 mm, 1.455 mm, and 1.392 mm, respectively. For part 3 (mandible), they were 1.069 mm, 1.831 mm, and 1.375 mm, respectively, and for part 4 (chin), they were 1.913 mm, 2.340 mm, and 1.257 mm, respectively. From this study, postoperative results can now be easily predicted by simply entering the point cloud data of computed tomography. Full article
(This article belongs to the Special Issue Recent Advances and Personalized Treatment in Dental Health)
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<p>Two main stages for three-dimensional orthognathic surgery prediction.</p> Full article ">Figure 2
<p>Three-dimensional point alignment network for prediction of postoperative result of orthognathic surgery.</p> Full article ">Figure 3
<p>Box plot for the absolute difference of 6 transformation parameters, and coordinates for (<b>a</b>) part 2, (<b>b</b>) part 3, and (<b>c</b>) part 4. Yellow, green, blue, and red colors of the graph are error of network using pointnet, pointconv, pointnet++, and present method.</p> Full article ">Figure 3 Cont.
<p>Box plot for the absolute difference of 6 transformation parameters, and coordinates for (<b>a</b>) part 2, (<b>b</b>) part 3, and (<b>c</b>) part 4. Yellow, green, blue, and red colors of the graph are error of network using pointnet, pointconv, pointnet++, and present method.</p> Full article ">Figure 4
<p>Pre-operative (<b>left</b>) and post-operative (<b>right</b>) surgery prediction through the alignment network of two randomly selected patients.</p> Full article ">Figure 4 Cont.
<p>Pre-operative (<b>left</b>) and post-operative (<b>right</b>) surgery prediction through the alignment network of two randomly selected patients.</p> Full article ">
7 pages, 1292 KiB  
Case Report
Rapid Personalised Virtual Planning and On-Demand Surgery for Acute Spinal Trauma Using 3D-Printing, Biomodelling and Patient-Specific Implant Manufacture
by Ralph Jasper Mobbs, William C. H. Parr, Christopher Huang and Tajrian Amin
J. Pers. Med. 2022, 12(6), 997; https://doi.org/10.3390/jpm12060997 - 18 Jun 2022
Cited by 7 | Viewed by 2294
Abstract
Three-dimensional printing is a rapidly growing field, with extensive application to orthopaedics and spinal surgery. Three-dimensional-printed (3DP) patient-specific implants (PSIs) offer multiple potential benefits over generic alternatives, with their use increasingly being described in the spinal literature. This report details a unique, emergency [...] Read more.
Three-dimensional printing is a rapidly growing field, with extensive application to orthopaedics and spinal surgery. Three-dimensional-printed (3DP) patient-specific implants (PSIs) offer multiple potential benefits over generic alternatives, with their use increasingly being described in the spinal literature. This report details a unique, emergency case of a traumatic spinal injury in a 31-year-old male, acquired rurally and treated with a 3DP PSI in a tertiary unit. With increasing design automation and process improvements, rapid, on-demand virtual surgical planning (VSP) and 3DP PSIs may present the future of orthopaedics and trauma care, enabling faster, safer, and more cost-effective patient-specific procedures. Full article
(This article belongs to the Section Methodology, Drug and Device Discovery)
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<p>Rapid preoperative design and production. Preoperative imaging received from peripheral hospital demonstrated, via sagittal (<b>A</b>) and axial (<b>B</b>) bone windows, a C7 burst fracture with retropulsion of fragment (red arrows in <b>A</b>,<b>B</b>,<b>D</b>) into the spinal canal with stenosis (<b>A</b>–<b>D</b>). Production of a 3D-printed biomodel (<b>C</b>) and anterior approach patient-specific implant design (<b>E</b>) for use with integral fixation screws (<b>F</b>, blue arrows). The biomodel (<b>C</b>), combined with the 3D-printed implants (see <a href="#jpm-12-00997-f002" class="html-fig">Figure 2</a>) aided determination of the width of vertebral body resected (blue dashed lines); yellow shows nerve root paths, red shows location of vertebral arteries.</p> Full article ">Figure 2
<p>Implantation and postoperative imaging. (<b>A</b>) dynamic biomodel allowed for trialling of different sized implants and aided in determining the extents of C7 vertebral body resection. Surgical decompression prior to implant placement. (<b>B</b>) Immediate press fit of the implant was achieved with integral screw fixation used to maximise initial stability of the construct (<b>C</b>). Virtual surgery planning (VSP) simulated X-rays (<b>D</b>) were compared to intra-operative X-rays (<b>E</b>) to check depth of implantation and screw trajectories. (<b>F</b>) C7 (grey) with pathological (red) C4-6 vertebral relative positioning compared to immediate postoperative positioning (green) of the same vertebrae. Note that the procedure restored height (green [post-op] is higher than red [pre-op]). (<b>G</b>) Green, as in F, is the immediate postoperative vertebrae positioning compared to blue, which is 10 weeks post-op. (<b>H</b>) Ten-week post-op (blue) vertebral positioning compared to pre-op pathological (red) positioning. Ten-week post-op sagittal (<b>I</b>) and coronal (<b>J</b>) CT slices demonstrate: excellent cord decompression, new (fusion) bone growth through the graft window of the device, the stability of the construct (osseointegration with the device), excellent implant positioning.</p> Full article ">Figure 3
<p>Chronology of rapid implementation of personalised spinal trauma surgery. Patient and device manufacture timelines. The patient was injured in a rural location shortly after midday on Saturday and was transported to a local hospital for medical imaging. Primary diagnosis led to contact with a tertiary hospital with a spinal unit and transfer of the computer tomography imaging, which was used for virtual surgical planning, biomodel and patient-specific implant (PSI) design. After a weather delay, the patient was airlifted to the tertiary hospital. Meanwhile, the biomodel and PSI were being manufactured at a ‘near-the-point-of-care’ facility. After manufacture, post-processing and quality checks, the implants were delivered and sterilised by the hospital’s Central Sterile Supply Department. Surgery was scheduled as first on Monday’s list.</p> Full article ">
15 pages, 1693 KiB  
Article
Physiologic Range of Myocardial Mechano-Energetic Efficiency among Healthy Subjects: Impact of Gender and Age
by Francesco Ferrara, Valentina Capone, Filippo Cademartiri, Olga Vriz, Rosangela Cocchia, Brigida Ranieri, Monica Franzese, Rossana Castaldo, Antonello D’Andrea, Rodolfo Citro, Salvatore Chianese, Roberto Annunziata, Flavio Marullo, Mario Siniscalchi, Marianna Conte, Chiara Sepe, Renato Maramaldi, Salvatore Rega, Giuseppe Russo, Massimo Majolo, Eliana Raiola, Andrea Salzano, Ciro Mauro, Bruno Trimarco, Raffaele Izzo and Eduardo Bossoneadd Show full author list remove Hide full author list
J. Pers. Med. 2022, 12(6), 996; https://doi.org/10.3390/jpm12060996 - 18 Jun 2022
Cited by 7 | Viewed by 2164
Abstract
Background: Myocardial mechano-energetic efficiency (MEE) is the capability of the left ventricle (LV) to convert the chemical energy obtained from the cardiac oxidative metabolism into mechanical work. The aim of present study was to establish normal non-invasive MEE and MEEi reference values. Methods: [...] Read more.
Background: Myocardial mechano-energetic efficiency (MEE) is the capability of the left ventricle (LV) to convert the chemical energy obtained from the cardiac oxidative metabolism into mechanical work. The aim of present study was to establish normal non-invasive MEE and MEEi reference values. Methods: In total, 1168 healthy subjects underwent physical examinations, clinical assessment, and standardized transthoracic echocardiographic (TTE) examination. MEE was obtained by TTE as the ratio between stroke volume (SV) and heart rate (HR): MEE = SV/HR [HR expressed in seconds (HR/60)]. Because MEE is highly related to left ventricular mass (LVM), MEE was then divided by LVM with the purpose of obtaining an estimate of energetic expenditure per unit of myocardial mass (i.e., indexed MEE, MEEi, mL/s/g). Results: The mean values of MEE and MEEi in the overall population were 61.09 ± 18.19 mL/s; 0.45 ± 0.14, respectively. In a multivariable analysis, gender, body surface area (BSA), diastolic blood pressure, left atrial volume indexed to BSA, E/e’ and tricuspid annular plane systolic excursion (TAPSE) were the independent variables associated with MEE, while age, gender, BSA and TAPSE were the independent variables associated with MEEi. Conclusions: The knowledge of age- and gender-based MEE and MEEi normal values may improve the global assessment of LV cardiac mechanics and serve as a reference to identify phenotypes at high risk of cardiovascular events. Full article
(This article belongs to the Special Issue Personalized Medicine Interdisciplinary Aspects and Sex Gender-Specific Differences)
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<p>Normal ranges for MEE (<b>A</b>) and MEEi (<b>B</b>) by gender and normal ranges for MEE (<b>C</b>) and MEEi (<b>D</b>) by age.</p> Full article ">Figure 2
<p>Univariate analysis of MEE (<b>A</b>) and MEEi (<b>B</b>) values by age.</p> Full article ">Figure 3
<p>Univariate analysis of MEE (<b>A</b>) and MEEi (<b>B</b>) values.</p> Full article ">
20 pages, 1613 KiB  
Review
Recapping the Features of SARS-CoV-2 and Its Main Variants: Status and Future Paths
by Miguel A. Ortega, Cielo García-Montero, Oscar Fraile-Martinez, Paolo Colet, Ardak Baizhaxynova, Kymbat Mukhtarova, Melchor Alvarez-Mon, Kaznagul Kanatova, Angel Asúnsolo and Antonio Sarría-Santamera
J. Pers. Med. 2022, 12(6), 995; https://doi.org/10.3390/jpm12060995 - 18 Jun 2022
Cited by 9 | Viewed by 3325
Abstract
Over the two years that we have been experiencing the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, our challenges have been the race to develop vaccines and the difficulties in fighting against new variants due to the rapid ability of the virus to [...] Read more.
Over the two years that we have been experiencing the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, our challenges have been the race to develop vaccines and the difficulties in fighting against new variants due to the rapid ability of the virus to evolve. In this sense, different organizations have identified and classified the different variants that have been emerging, distinguishing between variants of concern (VOC), variants of interest (VOI), or variants under monitoring (VUM). The following review aims to describe the latest updates focusing on VOC and already de-escalated variants, as well as to describe the impact these have had on the global situation. Understanding the intrinsic properties of SARS-CoV-2 and its interaction with the immune system and vaccination is essential to make out the underlying mechanisms that have led to the appearance of these variants, helping to determine the next steps for better public management of this pandemic. Full article
(This article belongs to the Special Issue Personalized Medicine and Management of COVID-19)
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<p>A global picture of SARS-CoV-2 structure and viral cycle. As shown, SARS-CoV-2 is mainly composed by the spike (S), nucleocapsid (N), envelope (E), and membrane (M) proteins, and a +ssRNA. SARS-CoV-2 enters into the cell through the binding of the S protein with ACE2, leading to the formation of endosomes or through membrane fusion. Then, the ssRNA is translated, starting with the open reading frame (ORF) 1a and ORF1b regions codifying polyproteins (pp)1a and pp1b. Through proteolytic cleavage, these polyproteins form 16 nonstructural proteins (nsps), which are related to the replication and transcriptional complex (RTC). In this sense, of note is the role of nsp12, also known as RNA-dependent RNA polymerase (RdRp), in the replication and transcription of the ssRNA. Then, the above-mentioned viral S, N, E, and M proteins are translated and packaged in the endomembranous system, from the endoplasmic reticulum (ER) to the Golgi complex, where it is finally assembled, and a set of viral particles are finally released through exocytosis. Last but not least, it should be highlighted that both S and N proteins can easily mutate during the viral replication cycle. As will be later discussed, this property of the SARS-CoV-2 is directly related to the onset and development of novel variants.</p> Full article ">Figure 2
<p>A general picture of the evolution and emergence of SARS-CoV-2 variants. As shown, due to the intrinsic properties of the virus (genetics, recombination, and viral cycle) and selective pressure (host and immune coadaptation, infectivity and transmissibility efficacy, and the actual vaccination context), a set of variants has been developing with enhanced features compared to their parental lineages, including greater transmission, infection rates, or circulation. Of them, currently Delta and Omicron are considered VOCs, where Omicron * represents the dominant variant worldwide. Simultaneously, there may be novel variants appearing, as well as further lineages of previously established variants. To limit the impact and slow the continuous evolution of SARS-CoV-2, virus- and immune-based approaches and, more prominently, prophylactic measures and improved vaccination strategies are needed.</p> Full article ">
13 pages, 2145 KiB  
Article
Serological Response and Relationship with Gender-Sensitive Variables among Healthcare Workers after SARS-CoV-2 Vaccination
by Roberto Cangemi, Manuela Di Franco, Antonio Angeloni, Alessandra Zicari, Vincenzo Cardinale, Marcella Visentini, Guido Antonelli, Anna Napoli, Emanuela Anastasi, Giulio Francesco Romiti, Fabrizio d’Alba, Domenico Alvaro, Antonella Polimeni, Stefania Basili and SAPIENZAVAX Collaborators
J. Pers. Med. 2022, 12(6), 994; https://doi.org/10.3390/jpm12060994 - 18 Jun 2022
Cited by 6 | Viewed by 4174
Abstract
Vaccine-induced immunity is a key strategy in the long-term control of the COVID-19 pandemic. The aim of our study was to explore the relationship between mRNA vaccine-induced antibodies and gender-sensitive variables among healthcare workers. Two thousand-sixty-five volunteers who received the BNT162b2 vaccine were [...] Read more.
Vaccine-induced immunity is a key strategy in the long-term control of the COVID-19 pandemic. The aim of our study was to explore the relationship between mRNA vaccine-induced antibodies and gender-sensitive variables among healthcare workers. Two thousand-sixty-five volunteers who received the BNT162b2 vaccine were enrolled in the study and followed up. Demographic, clinical, and social variables (educational level, marital status, occupation, childcare) were evaluated through a self-administered questionnaire. Anti-Spike (S) IgG were measured at 1 month (T1) and at 5 months (T2) after the second vaccine dose. At T1, median anti-S IgG values were 693 [394–>800] AU/mL (1 AU = 2.6 BAU). Values > 800 AU/mL (2080 BAU/mL) were directly associated with a previous COVID-19 (p < 0.001) infection and inversely with age (p < 0.001), smoking habit (p < 0.001), and autoimmune diseases (p < 0.001). At T2, a significant decreasing in anti-S IgG values was observed (187 [81–262] AU/mL), with a median decrease of 72 [60–82]%. On multivariate data analysis, a reduction of more than 82% was directly associated with male sex (p < 0.021), age (p < 0.001), smoking (p = 0.038), hypertension (p = 0.042), and, inversely, with previous COVID-19 infection (p < 0.001) and being “cohabiting” (p = 0.005). Our findings suggest that demographic, clinical, and social variables play a role in anti-S IgG values decreasing in long-term follow up and should be considered to find personalized vaccine schedules. Full article
(This article belongs to the Special Issue Personalized Medicine Interdisciplinary Aspects and Sex Gender-Specific Differences)
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<p>Anti-Spike IgG concentrations according to sex (Panel A), smoking habit (Panel B), age decades (Panel C), hypertension (Panel D), COPD (Panel E), autoimmune diseases (Panel F) at T1 and T2. Legend: Red boxes: median and IQR concentrations at T1. <span class="html-italic">p</span>-values: statistical differences at T1. Orange boxes: median concentrations at T2. 1 AU = 2.6 BAU.</p> Full article ">Figure 2
<p>Anti-Spike IgG concentrations according to kind of occupation (Panel A), scholarship (Panel B), marital status (Panel C), childcare (Panel D), BMI (Panel E) and previous COVID-19 infection (Panel F) at T1 and at T2. Legend: Red boxes: median and IQR concentrations at T1. <span class="html-italic">p</span>-values: statistical differences at T1. Orange boxes: median concentrations at T2. 1 AU = 2.6 BAU.</p> Full article ">Figure 3
<p>Anti-S IgG at T2 among male and female participants, according to age (Panel A) and marital status (Panel B). ** <span class="html-italic">p</span> &lt; 0.001. Legend: 1 AU/mL = 2.6 BAU/mL.</p> Full article ">Figure 4
<p>Anti-Spike IgG concentrations at T1 and T2 (i.e., after 1 and 5 months from second dose vaccine, respectively). Legend: 1 AU/mL = 2.6 BAU/mL.</p> Full article ">
12 pages, 2323 KiB  
Article
Vav1 Selectively Down-Regulates Akt2 through miR-29b in Certain Breast Tumors with Triple Negative Phenotype
by Silvia Grassilli, Federica Brugnoli, Stefano Cairo, Nicoletta Bianchi, Jean-Gabriel Judde and Valeria Bertagnolo
J. Pers. Med. 2022, 12(6), 993; https://doi.org/10.3390/jpm12060993 - 17 Jun 2022
Cited by 4 | Viewed by 2549
Abstract
Triple negative breast cancer (TNBC) represents the most aggressive breast tumor, showing a high intrinsic variability in terms of both histopathological features and response to therapies. Blocking the Akt signaling pathway is a well-studied approach in the treatment of aggressive breast tumors. The [...] Read more.
Triple negative breast cancer (TNBC) represents the most aggressive breast tumor, showing a high intrinsic variability in terms of both histopathological features and response to therapies. Blocking the Akt signaling pathway is a well-studied approach in the treatment of aggressive breast tumors. The high homology among the Akt isoforms and their distinct, and possibly opposite, oncogenic functions made it difficult to develop effective drugs. Here we investigated the role of Vav1 as a potential down-regulator of individual Akt isozymes. We revealed that the over-expression of Vav1 in triple negative MDA-MB-231 cells reduced only the Akt2 isoform, acting at the post-transcriptional level through the up-modulation of miR-29b. The Vav1/miR-29b dependent decrease in Akt2 was correlated with a reduced lung colonization of circulating MDA-MB-231 cells. In cell lines established from PDX, the Vav1 induced down-modulation of Akt2 is strongly dependent on miR-29b and occurs only in some TNBC tumors. These findings may contribute to better classify breast tumors having the triple negative phenotype, and suggest that the activation of the Vav1/miR-29b axis, precisely regulating the amount of an Akt isozyme crucial for tumor dissemination, could have great potential for driving more accurate therapies to TNBCs, often not eligible or resistant to treatments. Full article
(This article belongs to the Special Issue Personalized Diagnosis and Treatment of Breast Cancer)
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<p>Correlation between Vav1 and Akt isoforms in MDA-MB-231 cells. (<b>A</b>) Representative immunochemical analysis of lysates from MDA-MB-231 cells transfected with siRNAs specific for Vav1 (Vav1 siRNAs) or with a construct expressing Vav1 (Over Vav1). Scramble siRNAs (Ctrl siRNAs) and an empty vector were used as controls. β-Tubulin was blotted as an internal control of loaded proteins. (<b>B</b>) qRT-PCR analysis of mRNA (2<sup>−ΔCt</sup> method) and (<b>C</b>) representative Western blot of Akt1, Akt2 and Akt3 in MDA-MB-231 cells cultured under the above reported experimental conditions. (<b>D</b>) Levels of Akt isoforms as deduced from the chemiluminescence signal normalized with β-Tubulin. Asterisks indicate statistically significant differences with respect to corresponding controls taken as 1. All the data are the means of 3 separate experiments ± SD. * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 2
<p>Correlation between Vav1, miR-29b and Akt2 in MDA-MB-231 cells. (<b>A</b>) qRT-PCR analysis of miR-29b-3p and miR-615-3p in MDA-MB-231 cells in which Vav1 was down-modulated or over-expressed. The values were determined using the 2 <sup>−ΔΔCT</sup> method and the asterisks indicate statistically significant differences compared to respective controls (Ctrl) taken as 1. (<b>B</b>) Representative immunoblot analysis of Akt2 in lysates from MDA-MB-231 cells transfected with miR-29b-3p inhibitor or mimic. In (<b>C</b>), amounts of Akt2 as deduced from the chemiluminescence signals normalized with β-Tubulin. The asterisks indicate significant differences compared to transfection with scramble oligonucleotides (Negative control, NC), taken as 1. All the data represent the mean of three separate experiments ± SD. * <span class="html-italic">p</span>  &lt;  0.05.</p> Full article ">Figure 3
<p>Correlation between Vav1, miR-29b and Akt2 in MDA-MB-231-derived xenografts. (<b>A</b>) Representative immunochemical analysis of MDA-MB-231 cells stably expressing an empty vector or Vav1. (<b>B</b>) Representative immunohistochemical analysis with the anti-Akt2 antibody of xenografts from the above-described MDA-MB-231 cells. (<b>C</b>) Analysis of Akt2 staining in xenografts that reports the Intensity of Positive pixels/Area (Ip/µm<sup>2</sup>). (<b>D</b>) qRT-PCR analysis (2<sup>−ΔCt</sup>) of miR-29b-3p in laser micro-dissected xenografts sections. * <span class="html-italic">p</span> &lt; 0.05 between bars.</p> Full article ">Figure 4
<p>Effects of Vav1 on lung colonization of MDA-MB-231 cells. (<b>A</b>) Dynamic monitoring of invasiveness of MDA-MB-231 cells stably expressing an empty vector or Vav1. Cell Index (CI) values are reported, and error bars indicate SD. (<b>B</b>) Representative HE images of lung sections from mice following intravenous injection of MDA-MB-231 cells transfected with an empty vector or stably expressing Vav1. The arrow indicates a lung secondary tumor, whose immunohistochemical analysis of Vav1 and Akt2 was shown in (<b>C</b>).</p> Full article ">Figure 5
<p>Correlation between miR-29b and Akt2 in cell lines from triple negative PDXs. (<b>A</b>) Amounts of miR-29b and Akt2 in PDX-derived cell lines in which Vav1 was silenced or over-expressed. The values are relative to those of cells transfected with control siRNAs or empty vectors (Ctrl), respectively, taken as 1. * <span class="html-italic">p</span> &lt;0.05. (<b>B</b>) Representative Western blot analysis of PDX-derived cell lines in which miR-29b-3p was down- (Inhibitor) or up-modulated (Mimic). In (<b>C</b>), amounts of Akt2 as deduced from the chemiluminescence signal normalized with β-Tubulin. * <span class="html-italic">p</span>  &lt;  0.05 compared to transfection with scramble oligonucleotides (NC). All the data are the means of 3 separate experiments ± SD.</p> Full article ">
12 pages, 2228 KiB  
Review
Blood Cell Count Inflammatory Markers as Prognostic Indicators of Periodontitis: A Systematic Review and Meta-Analysis
by Oana Almășan, Daniel-Corneliu Leucuța and Mihaela Hedeșiu
J. Pers. Med. 2022, 12(6), 992; https://doi.org/10.3390/jpm12060992 - 17 Jun 2022
Cited by 10 | Viewed by 2858
Abstract
(1) Background: Our study aimed to assess the association between the neutrophil to lymphocyte ratio (NLR), platelet to leukocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), red cell distribution width (RDW), and systemic immune inflammation index (SII) and periodontitis. (2) Methods: We searched [...] Read more.
(1) Background: Our study aimed to assess the association between the neutrophil to lymphocyte ratio (NLR), platelet to leukocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), red cell distribution width (RDW), and systemic immune inflammation index (SII) and periodontitis. (2) Methods: We searched PubMed, Embase, Scopus, Web of Science, and LILACS databases, identifying observational studies. The Newcastle Ottawa scale was used to evaluate the quality of the included studies. The principal summary outcome measure in our random effects meta-analysis was the mean difference (MD). (3) Results: After screening 682 search results, a total of 10 studies including 3164 subjects were selected for quantitative assessment. We found a higher mean NLR, PLR, and LMR in the periodontitis group compared to the control group (0.41 (95% CI 0.12–0.7), p = 0.006; 7.43 (95% CI 0.31–14.54), p = 0.04; 2.05 (95% CI 0.27–3.83), p = 0.024). No differences were observed for RDW. (4) Conclusions: We found an association between NLR, LMR, and PLR and periodontitis, which might be thought of as emerging blood cell count inflammatory biomarkers that could shed light on the link between periodontitis and systemic disbalances, as well as for periodontitis prognosis and grading. Full article
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<p>Flow diagram of the literature search and selection criteria adapted for PRISMA 2020.</p> Full article ">Figure 2
<p>Neutrophile to lymphocyte ratio-mean difference between periodontitis and control subjects.</p> Full article ">Figure 3
<p>Platelet to leucocyte ratio-mean difference between periodontitis and control subjects.</p> Full article ">Figure 4
<p>Lymphocyte to monocyte ratio -mean difference between periodontitis and control subjects.</p> Full article ">Figure 5
<p>Red cell distribution width-mean difference between periodontitis and control subjects.</p> Full article ">
15 pages, 3253 KiB  
Article
TRIM24 Expression as an Independent Biomarker for Prognosis and Tumor Recurrence in HNSCC
by Luise Klapper, Christian Idel, Patrick Kuppler, Tobias Jagomast, Amelie von Bernuth, Karl-Ludwig Bruchhage, Dirk Rades, Anne Offermann, Jutta Kirfel, Sven Perner and Julika Ribbat-Idel
J. Pers. Med. 2022, 12(6), 991; https://doi.org/10.3390/jpm12060991 - 17 Jun 2022
Cited by 7 | Viewed by 2234
Abstract
Background: Head and neck squamous cell carcinomas (HNSCCs) are among the most common cancers in humans worldwide and have a rather poor prognosis. TRIM24 has various intracellular functions and was identified in other cancer entities as a poor prognostic factor for patients. Methods: [...] Read more.
Background: Head and neck squamous cell carcinomas (HNSCCs) are among the most common cancers in humans worldwide and have a rather poor prognosis. TRIM24 has various intracellular functions and was identified in other cancer entities as a poor prognostic factor for patients. Methods: The expression of TRIM24 was evaluated by using immunohistochemistry. We used a large and representative cohort of 341 HNSCC patients. Data derived from immunohistochemistry evaluation was correlated with clinicopathological data from HNSCC patients. Results: The TRIM24 expression in HNSCC primary tumors is negatively correlated with the p16 status of the tumor tissues. Primary tumors of patients who developed a local recurrence were significantly more often positive for TRIM24. Kaplan–Meier analyses and Cox regression showed that patients with TRIM24 expressing tumors have significantly worse overall survival and progression-free survival and that TRIM24 expression is independent of other established risk factors. Conclusions: TRIM24 might be a new prognostic biomarker for the survival prognosis and early detection of local recurrences in HNSCC patients. It could be used for risk stratification of HNSCC patients and to identify those patients who are more prone to develop a local recurrence and therefore could profit from more frequent follow-up examinations. Full article
(This article belongs to the Section Mechanisms of Diseases)
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<p>TRIM24 expression patterns in HNSCC tissue. (<b>a</b>) “Negative” HNSCC—no detectable TRIM24 expression within the tumor cells. (<b>b</b>,<b>c</b>) “Combined expression”—expression of TRIM24 in the tumor nuclei and in the tumor cytoplasm. (<b>d</b>–<b>f</b>) “Nuclear expression”—TRIM24 expression exclusively in the tumor nuclei. (<b>d</b>) Low nuclear expression. (<b>e</b>) Medium nuclear expression. (<b>f</b>) High nuclear expression. (<b>g</b>–<b>i</b>) “Cytoplasmatic expression”—TRIM24 expression exclusively in the cytoplasm. (<b>g</b>) Low cytoplasmatic expression. (<b>h</b>) Medium cytoplasmatic expression. (<b>i</b>) High cytoplasmatic expression.</p> Full article ">Figure 2
<p>TRIM24 expression in the tissue of PTs, LNs, LRs, and DMs and in different HNSCC tumor sites. (<b>a</b>) TRIM24 is expressed more frequently in the tissue of LRs. There are significantly more TRIM24+ LRs than PTs (Chi-square test, <span class="html-italic">p</span> = 0.01). There are no significant differences between PTs and LNs and PTs and DMs (Chi-square test, <span class="html-italic">p</span> &gt; 0.05). (<b>b</b>) Most TRIM24+ tumors could be found in the oral cavity, compared to laryngeal HNSCCs (Chi-square test, <span class="html-italic">p</span> = 0.002) and pharyngeal HNSCCs (Chi-square test, <span class="html-italic">p</span> &lt; 0.001). Laryngeal HNSCCs are significantly more often TRIM24+ than pharyngeal HNSCCs (Chi-square test, <span class="html-italic">p</span> = 0.001). (n.s. = not significant, ** <span class="html-italic">p</span> ≤ 0.01, *** <span class="html-italic">p</span> ≤ 0.001).</p> Full article ">Figure 3
<p>TRIM24 expression in PTs with different N-Stages. (<b>a</b>) HNSCC PTs without any LNs at the time of the first diagnosis were significantly more often TRIM24+ than PTs with LNs (Chi-square test, <span class="html-italic">p</span> = 0.006). (Chi-square test, <span class="html-italic">p</span> &gt; 0.005). (<b>b</b>) We compared all HNSCC PTs by their p16 status and TRIM24 expression. P16− PTs are significantly more often TRIM24+ than p16+ PTs (Chi-square test, <span class="html-italic">p</span> = 0.018). (<b>c</b>) We compared exclusively oropharyngeal HNSCC PTs by their p16 status and TRIM24 expression. P16− PTs were also significantly more often TRIM24+ than p16+ PTs. (n.s. = not significant, * <span class="html-italic">p</span> ≤ 0.05, ** <span class="html-italic">p</span> ≤ 0.01).</p> Full article ">Figure 4
<p>Correlation of TRIM24 expression with the development of a LR and the p16 status in HNSCC. PTs which developed a subsequent LR are significantly more frequent TRIM24+ than PTs without a LR (Chi-square test, <span class="html-italic">p</span> = 0.001). (*** <span class="html-italic">p</span> ≤ 0.001).</p> Full article ">Figure 5
<p>Kaplan–Meier analyses of TRIM24 expressing HNSCC PTs. (<b>a</b>) There is a significant difference in the OS rates over 60 months of patients with TRIM24 negative, low, medium, and high expressing PTs (log–rank test, <span class="html-italic">p</span> = 0.019). (<b>b</b>) We compared all TRIM24 expressing PTs against the TRIM24- tumors. The patients with TRIM24+ PTs show a significantly worse OS over 60 months than patients with TRIM24− PTs (log–rank test, <span class="html-italic">p</span> = 0.002).</p> Full article ">Figure 6
<p>Kaplan–Meier analyses of TRIM24 expressing HNSCC PTs. (<b>a</b>) We could show a significant difference in the PFS rates over 60 months of patients with TRIM24 negative, low, medium, and high expressing PTs (log–rank test, <span class="html-italic">p</span> = 0.002). (<b>b</b>) We compared all TRIM24 expressing PTs against the TRIM24− tumors. The patients with TRIM24+ PTs show a significantly worse PFS over 60 months than patients with TRIM24− PTs (log–rank test, <span class="html-italic">p</span> &lt; 0.001).</p> Full article ">Figure 7
<p>TRIM24 expression in PTs of different T− and UICC-stages. (<b>a</b>) There is no significant difference in the proportion of TRIM24 expressing PTs between low T-Stages (T1/2) and higher T-Stages (T3/T4) (<span class="html-italic">p</span> &gt; 0.05). (<b>b</b>) There is no significant difference in the proportion of TRIM24 expressing PTs between low UICC-Stages (I/II) and higher UICC-Stages (III/IV) (<span class="html-italic">p</span> &gt; 0.05). (n.s. = not significant).</p> Full article ">
16 pages, 2302 KiB  
Article
Prediction of All-Cause Mortality Following Percutaneous Coronary Intervention in Bifurcation Lesions Using Machine Learning Algorithms
by Jacopo Burrello, Guglielmo Gallone, Alessio Burrello, Daniele Jahier Pagliari, Eline H. Ploumen, Mario Iannaccone, Leonardo De Luca, Paolo Zocca, Giuseppe Patti, Enrico Cerrato, Wojciech Wojakowski, Giuseppe Venuti, Ovidio De Filippo, Alessio Mattesini, Nicola Ryan, Gérard Helft, Saverio Muscoli, Jing Kan, Imad Sheiban, Radoslaw Parma, Daniela Trabattoni, Massimo Giammaria, Alessandra Truffa, Francesco Piroli, Yoichi Imori, Bernardo Cortese, Pierluigi Omedè, Federico Conrotto, Shao-Liang Chen, Javier Escaned, Rosaly A. Buiten, Clemens Von Birgelen, Paolo Mulatero, Gaetano Maria De Ferrari, Silvia Monticone and Fabrizio D’Ascenzoadd Show full author list remove Hide full author list
J. Pers. Med. 2022, 12(6), 990; https://doi.org/10.3390/jpm12060990 - 17 Jun 2022
Cited by 3 | Viewed by 2352
Abstract
Stratifying prognosis following coronary bifurcation percutaneous coronary intervention (PCI) is an unmet clinical need that may be fulfilled through the adoption of machine learning (ML) algorithms to refine outcome predictions. We sought to develop an ML-based risk stratification model built on clinical, anatomical, [...] Read more.
Stratifying prognosis following coronary bifurcation percutaneous coronary intervention (PCI) is an unmet clinical need that may be fulfilled through the adoption of machine learning (ML) algorithms to refine outcome predictions. We sought to develop an ML-based risk stratification model built on clinical, anatomical, and procedural features to predict all-cause mortality following contemporary bifurcation PCI. Multiple ML models to predict all-cause mortality were tested on a cohort of 2393 patients (training, n = 1795; internal validation, n = 598) undergoing bifurcation PCI with contemporary stents from the real-world RAIN registry. Twenty-five commonly available patient-/lesion-related features were selected to train ML models. The best model was validated in an external cohort of 1701 patients undergoing bifurcation PCI from the DUTCH PEERS and BIO-RESORT trial cohorts. At ROC curves, the AUC for the prediction of 2-year mortality was 0.79 (0.74–0.83) in the overall population, 0.74 (0.62–0.85) at internal validation and 0.71 (0.62–0.79) at external validation. Performance at risk ranking analysis, k-center cross-validation, and continual learning confirmed the generalizability of the models, also available as an online interface. The RAIN-ML prediction model represents the first tool combining clinical, anatomical, and procedural features to predict all-cause mortality among patients undergoing contemporary bifurcation PCI with reliable performance. Full article
(This article belongs to the Special Issue Cardiovascular Disease Risk Stratification in the Era of Machine Learning and Personalized Medicine)
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<p><b>RAIN-ML model.</b> The RAIN-ML prediction model was built in the discovery cohort (n = 2393). (<b>A</b>) The discovery cohort was randomized in a training and in an internal validation cohort. The model was developed in the training cohort (n = 1795): 5 machine learning models (linear discriminant analysis [LDA], random forest regressor [RF], support vector machine [SVM] with different kernels, and isolation forest) and 3 algorithms for dataset imbalance correction (SMOTE, Synthetic Minority Oversampling Technique, SMOTE &amp; nearest neighbours, and random oversampling) have been evaluated; the best model was an RF with random oversampling algorithm (reported in bold). The model was then tested in the internal and external validation cohorts (n = 598, n = 1701, respectively) and by K-center cross-validation, risk stratification analysis, and continual learning. (<b>B</b>) Radar chart reporting the 8 normalized best predictors associated with patient outcome. (<b>C</b>) Representative classification tree from the RAIN-ML RF model. (<b>D</b>) Confusion matrix, real and predicted diagnosis (Death vs. No event), accuracy, sensitivity, and specificity for the RAIN-ML model at training, internal validation, and external validation. CKD, Chronic Kidney Disease; PCI, Percutaneous Coronary Intervention; EF, Ejection Fraction; ACS, Acute Coronary Syndrome.</p> Full article ">Figure 2
<p><b>Predictive performance.</b> Receiver operating characteristics curve to assess the area under the curve and its 95% confidence interval (lower and upper limits) for the RAIN-ML prediction model at training (n = 1795), internal (n = 598), external validation (n = 1701), and in the mixed cohort (n = 4094). (<b>A</b>) Performance at 30-day follow-up; (<b>B</b>) Performance at 1-year follow-up; (<b>C</b>) Performance at 2-year follow-up; (<b>D</b>) Performance considering all the events at follow-up.</p> Full article ">Figure 3
<p><b>Stratification of all-cause mortality risk according to the RAIN-ML model</b>. Patient distribution and risk stratification analysis in the mixed discovery and external validation cohort (n = 4094). (<b>A</b>–<b>D</b>) Histograms showing the proportion of patients (<span class="html-italic">y</span>-axis, %) stratified according to their outcome (No Event, grey vs. Death, black); on the <span class="html-italic">x</span>-axis are reported the ML coefficients (for the RAIN-ML prediction model). Patients were stratified considering death occurrence at different follow-ups (30 days, 1 year, 2 years, and all events). (<b>E</b>) The table shows confusion matrix reporting risk stratification analysis, sensitivity, and specificity, for the RAIN-ML prediction model * Sensitivity and specificity were derived on a mixed cohort composed of the low- and high-risk groups, after exclusion of patients at intermediate risk.</p> Full article ">Figure 4
<p><b>Continual Learning of RAIN-ML prediction model.</b> Graphs showing diagnostic performance (left y-axes) with a continual learning strategy in the discovery cohort (n = 2393). Squares indicates the number of patients (right y-axes) over the enrolment time (x-axes). (<b>A</b>) Learning simulation for RAIN-ML prediction model at the increase in the enrollment time; 70% of the discovery cohort is used for training (patients enrolled first), 30% for validation (last enrolled patients). Mean and standard deviation are shown after 10 repetitions of the analysis. Accuracy at training: from 86.1% to 79.9%. Accuracy at validation: from 67.9% to 78.7%. (<b>B</b>) Accuracy, sensitivity, and specificity at validation.</p> Full article ">
13 pages, 1847 KiB  
Article
Evaluation of a Diagnostic and Management Algorithm for Adult Caustic Ingestion: New Concept of Severity Stratification and Patient Categorization
by Yu-Jhou Chen, Chen-June Seak, Hao-Tsai Cheng, Chien-Cheng Chen, Tsung-Hsing Chen, Chang-Mu Sung, Chip-Jin Ng, Shih-Ching Kang, Ming-Yao Su and Sen-Yung Hsieh
J. Pers. Med. 2022, 12(6), 989; https://doi.org/10.3390/jpm12060989 - 17 Jun 2022
Cited by 9 | Viewed by 8607
Abstract
Background: Caustic ingestion has gained increasing attention worldwide. However, the insight into whether to use esophagogastroduodenoscopy (EGD) or computed tomography (CT) for first-line investigation remains controversial. This study aimed to evaluate a diagnostic and management algorithm that combines EGD and CT for rapid [...] Read more.
Background: Caustic ingestion has gained increasing attention worldwide. However, the insight into whether to use esophagogastroduodenoscopy (EGD) or computed tomography (CT) for first-line investigation remains controversial. This study aimed to evaluate a diagnostic and management algorithm that combines EGD and CT for rapid triage. Methods: We established an algorithm for our hospital in 2013, aiming to maximize the benefits and minimize the limitations of EGD and CT. Then, we retrospectively analyzed the 163 enrolled patients treated between 2014 and 2019 and categorized them into 4 groups: A = 3 (1.8%): with perforation signs and directly confirmed by CT, B = 10 (6.1%): clinically suspected perforation but not initially proven by CT, C = 91 (55.8%): initial perforation less favored but with EGD grade ≥ 2b or GI/systemic complications, and D = 59 (36.2%): clinically stable with EGD grade ≤ 2a, according to initial signs/symptoms and EGD/CT grading. The morbidity and mortality of each group were analyzed. The predictive values of EGD and CT were examined by logistic regression analyses and receiver operating characteristic (ROC) curves. Results: The outcomes of such algorithm were reported. CT was imperative for patients with toxic signs and suspected perforation. For non-emergent operations, additional EGD was safe and helpful in identifying surgical necessity. For patients with an initially low perforation risk, EGD alone sufficiently determined admission necessity. Among inpatients, EGD provided excellent discrimination for predicting the risk for signs/symptoms’ deterioration. Routine additional CT was only beneficial for those with deteriorating signs/symptoms. Conclusions: According to the analyses, initial signs/symptoms help to choose EGD or CT as the first-line investigative tool in caustic patients. CT is necessary for seriously injured patients, but it cannot replace EGD for moderate/mild injuries. The severity stratification and patient categorization help to simplify complex scenarios, accelerate decision-making, and prevent unnecessary intervention/therapy. External validation in a larger sample size is further indicated for this algorithm. Full article
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<p>Reported flowchart of patient categorization and management for caustic ingestion used in Linkou Chang Gung Memorial Hospital (CGMH). Abbreviations: CT, computed tomography; EGD, esophagogastroduodenoscopy; F/U, follow-up; GI, gastrointestinal; NPO, nulla per os (nothing by mouth); OPD, out-patient department; S/S, signs/symptoms; TPN, total parenteral nutrition.</p> Full article ">Figure 2
<p>Enrollment diagram of the study population. Abbreviations: CGMH, Chang Gung Memorial Hospital; GI, gastrointestinal.</p> Full article ">Figure 3
<p>The most severe grade of each patient group estimated using EGD and CT.</p> Full article ">Figure 4
<p>Overall survival of each patient group.</p> Full article ">Figure 5
<p>Grades of esophagogastroduodenoscopy (EGD) and computed tomography (CT) in differentiating group C2 (requiring operation) and group C3 (not requiring operation). The “most severe EGD/CT grades” refers to the most severe grade among the esophagus, stomach, and duodenum in each patient under EGD (Zargar’s 0, 1, 2a, 2b, 3a, 3b) and CT (grades 1, 2, 3, 4), respectively. The “combination of EGD + CT grades” is calculated by EGD (Zargar’s 0, 0 point; Zargar’s 1, 1 point; Zargar’s 2a, 2 points; Zargar’s 2b, 3 points; Zargar’s 3a, 4 points; Zargar’s 3b, 5 points) plus CT (grade 1, 1 point; grade 2, 2 points; grade 3, 3 points; grade 4, 4 points). Hence, the “combination of EGD + CT grades” ranges from 1 to 9 points. Abbreviations: AUROC, area under the receiver operating characteristic curve; CI, confidence interval; CT, computed tomography; EGD, esophagogastroduodenoscopy.</p> Full article ">
21 pages, 4648 KiB  
Article
CardioNet: Automatic Semantic Segmentation to Calculate the Cardiothoracic Ratio for Cardiomegaly and Other Chest Diseases
by Abbas Jafar, Muhammad Talha Hameed, Nadeem Akram, Umer Waqas, Hyung Seok Kim and Rizwan Ali Naqvi
J. Pers. Med. 2022, 12(6), 988; https://doi.org/10.3390/jpm12060988 - 17 Jun 2022
Cited by 19 | Viewed by 3219
Abstract
Semantic segmentation for diagnosing chest-related diseases like cardiomegaly, emphysema, pleural effusions, and pneumothorax is a critical yet understudied tool for identifying the chest anatomy. A dangerous disease among these is cardiomegaly, in which sudden death is a high risk. An expert medical practitioner [...] Read more.
Semantic segmentation for diagnosing chest-related diseases like cardiomegaly, emphysema, pleural effusions, and pneumothorax is a critical yet understudied tool for identifying the chest anatomy. A dangerous disease among these is cardiomegaly, in which sudden death is a high risk. An expert medical practitioner can diagnose cardiomegaly early using a chest radiograph (CXR). Cardiomegaly is a heart enlargement disease that can be analyzed by calculating the transverse cardiac diameter (TCD) and the cardiothoracic ratio (CTR). However, the manual estimation of CTR and other chest-related diseases requires much time from medical experts. Based on their anatomical semantics, artificial intelligence estimates cardiomegaly and related diseases by segmenting CXRs. Unfortunately, due to poor-quality images and variations in intensity, the automatic segmentation of the lungs and heart with CXRs is challenging. Deep learning-based methods are being used to identify the chest anatomy segmentation, but most of them only consider the lung segmentation, requiring a great deal of training. This work is based on a multiclass concatenation-based automatic semantic segmentation network, CardioNet, that was explicitly designed to perform fine segmentation using fewer parameters than a conventional deep learning scheme. Furthermore, the semantic segmentation of other chest-related diseases is diagnosed using CardioNet. CardioNet is evaluated using the JSRT dataset (Japanese Society of Radiological Technology). The JSRT dataset is publicly available and contains multiclass segmentation of the heart, lungs, and clavicle bones. In addition, our study examined lung segmentation using another publicly available dataset, Montgomery County (MC). The experimental results of the proposed CardioNet model achieved acceptable accuracy and competitive results across all datasets. Full article
(This article belongs to the Special Issue The Challenges and Prospects in Cardiology)
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<p>Chest anatomy segmentation to calculate cardiomegaly: (<b>a</b>) original CXR PA image, (<b>b</b>) segmented image by CardioNet, (<b>c</b>) maximum width of heart and thorax to calculate the CTR.</p> Full article ">Figure 2
<p>Flowchart of the proposed CardioNet methodology.</p> Full article ">Figure 3
<p>The proposed CardioNet architecture for CXR semantic segmentation.</p> Full article ">Figure 4
<p>The CardioNet dense connectivity feature concatenation method.</p> Full article ">Figure 5
<p>CardioNet features boost block concatenation.</p> Full article ">Figure 6
<p>Sample CXR images from the JSRT dataset with corresponding ground truth.</p> Full article ">Figure 7
<p>The proposed data augmentation approach increases the data size; the horizontal flip is represented as H-Flip.</p> Full article ">Figure 8
<p>The training loss curves are on the left, and the training accuracy curves are on the right sides of the figures. The two-fold training is d on the number of epochs: (<b>a</b>) first fold, (<b>b</b>) second fold.</p> Full article ">Figure 9
<p>Examples of chest-related organs by CardioNet: (<b>a</b>) original chest PA X-ray image; (<b>b</b>) image with a ground-truth mask; (<b>c</b>) CardioNet predicted mask.</p> Full article ">Figure 10
<p>Examples of MC chest X-ray images with ground truths.</p> Full article ">Figure 11
<p>Examples of CardioNet lung semantic segmentation for MC data: (<b>a</b>) represents the best and most accurate segmentation (right image) and (<b>b</b>) shows the worst lung segmentation (right image) by proposed CardioNet.</p> Full article ">Figure 12
<p>Example image from the JSRT dataset for calculating CTR using the proposed CardioNet: (<b>a</b>) original image; (<b>b</b>) ground truth image annotated with the cardiothoracic ratio (G-CTR); (<b>c</b>) predicted mask annotated with the cardiothoracic ratio (P-CTR).</p> Full article ">
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