Journal of Clinical Medicine

Review

32 pages, 17043 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Digital Therapeutics for Improving Effectiveness of Pharmaceutical Drugs and Biological Products: Preclinical and Clinical Studies Supporting Development of Drug + Digital Combination Therapies for Chronic Diseases

by Zack Biskupiak, Victor Vinh Ha, Aarushi Rohaj and Grzegorz Bulaj

J. Clin. Med. 2024, 13(2), 403; https://doi.org/10.3390/jcm13020403 - 11 Jan 2024

Cited by 4 | Viewed by 7260

Abstract

Limitations of pharmaceutical drugs and biologics for chronic diseases (e.g., medication non-adherence, adverse effects, toxicity, or inadequate efficacy) can be mitigated by mobile medical apps, known as digital therapeutics (DTx). Authorization of adjunct DTx by the US Food and Drug Administration and draft [...] Read more.

Limitations of pharmaceutical drugs and biologics for chronic diseases (e.g., medication non-adherence, adverse effects, toxicity, or inadequate efficacy) can be mitigated by mobile medical apps, known as digital therapeutics (DTx). Authorization of adjunct DTx by the US Food and Drug Administration and draft guidelines on “prescription drug use-related software” illustrate opportunities to create drug + digital combination therapies, ultimately leading towards drug–device combination products (DTx has a status of medical devices). Digital interventions (mobile, web-based, virtual reality, and video game applications) demonstrate clinically meaningful benefits for people living with Alzheimer’s disease, dementia, rheumatoid arthritis, cancer, chronic pain, epilepsy, depression, and anxiety. In the respective animal disease models, preclinical studies on environmental enrichment and other non-pharmacological modalities (physical activity, social interactions, learning, and music) as surrogates for DTx “active ingredients” also show improved outcomes. In this narrative review, we discuss how drug + digital combination therapies can impact translational research, drug discovery and development, generic drug repurposing, and gene therapies. Market-driven incentives to create drug–device combination products are illustrated by Humira^® (adalimumab) facing a “patent-cliff” competition with cheaper and more effective biosimilars seamlessly integrated with DTx. In conclusion, pharma and biotech companies, patients, and healthcare professionals will benefit from accelerating integration of digital interventions with pharmacotherapies. Full article

(This article belongs to the Special Issue The Convergence of Human and Artificial Intelligence on Clinical Care - Part II)

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14 pages, 3211 KiB

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CMR Mapping: The 4th-Era Revolution in Cardiac Imaging

by Nazario Carrabba, Mattia Alexis Amico, Andrea Igoren Guaricci, Maria Cristina Carella, Viviana Maestrini, Sara Monosilio, Patrizia Pedrotti, Fabrizio Ricci, Lorenzo Monti, Stefano Figliozzi, Camilla Torlasco, Andrea Barison, Andrea Baggiano, Alessandra Scatteia, Gianluca Pontone and Santo Dellegrottaglie

J. Clin. Med. 2024, 13(2), 337; https://doi.org/10.3390/jcm13020337 - 7 Jan 2024

Cited by 5 | Viewed by 2008

Abstract

Cardiac magnetic resonance (CMR) imaging has witnessed substantial progress with the advent of parametric mapping techniques, most notably T1 and T2 mapping. These advanced techniques provide valuable insights into a wide range of cardiac conditions, including ischemic heart disease, cardiomyopathies, inflammatory cardiomyopathies, heart [...] Read more.

Cardiac magnetic resonance (CMR) imaging has witnessed substantial progress with the advent of parametric mapping techniques, most notably T1 and T2 mapping. These advanced techniques provide valuable insights into a wide range of cardiac conditions, including ischemic heart disease, cardiomyopathies, inflammatory cardiomyopathies, heart valve disease, and athlete’s heart. Mapping could be the first sign of myocardial injury and oftentimes precedes symptoms, changes in ejection fraction, and irreversible myocardial remodeling. The ability of parametric mapping to offer a quantitative assessment of myocardial tissue properties addresses the limitations of conventional CMR methods, which often rely on qualitative or semiquantitative data. However, challenges persist, especially in terms of standardization and reference value establishment, hindering the wider clinical adoption of parametric mapping. Future developments should prioritize the standardization of techniques to enhance their clinical applicability, ultimately optimizing patient care pathways and outcomes. In this review, we endeavor to provide insights into the potential contributions of CMR mapping techniques in enhancing the diagnostic processes across a range of cardiac conditions. Full article

(This article belongs to the Special Issue Trends and Prospects in Cardiac MRI)

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27 pages, 509 KiB

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Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives

by Katharine A. Seton, José A. Espejo-Oltra, Karen Giménez-Orenga, Rik Haagmans, Donia J. Ramadan and Jesper Mehlsen

J. Clin. Med. 2024, 13(2), 325; https://doi.org/10.3390/jcm13020325 - 6 Jan 2024

Cited by 2 | Viewed by 16494

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multi-faceted illness. Heterogenous onset and clinical presentation with additional comorbidities make it difficult to diagnose, characterize, and successfully treat. Current treatment guidelines focus on symptom management, but with no clear target or causative [...] Read more.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multi-faceted illness. Heterogenous onset and clinical presentation with additional comorbidities make it difficult to diagnose, characterize, and successfully treat. Current treatment guidelines focus on symptom management, but with no clear target or causative mechanism, remission rates are low, and fewer than 5% of patients return to their pre-morbid activity levels. Therefore, there is an urgent need to undertake robust clinical trials to identify effective treatments. This review synthesizes insights from clinical trials exploring pharmacological interventions and dietary supplements targeting immunological, metabolic, gastrointestinal, neurological, and neuroendocrine dysfunction in ME/CFS patients which require further exploration. Additionally, the trialling of alternative interventions in ME/CFS based on reported efficacy in the treatment of illnesses with overlapping symptomology is also discussed. Finally, we provide important considerations and make recommendations, focusing on outcome measures, to ensure the execution of future high-quality clinical trials to establish clinical efficacy of evidence-based interventions that are needed for adoption in clinical practice. Full article

(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Epidemiology, Treatment and Prognosis)

13 pages, 393 KiB

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Investigating the Association of Assisted Reproduction Techniques and Adverse Perinatal Outcomes

by Anastasios Potiris, Paraskevas Perros, Eirini Drakaki, Despoina Mavrogianni, Nikolaos Machairiotis, Antonios Sfakianakis, Theodoros Karampitsakos, Dionysios Vrachnis, Nikolaos Antonakopoulos, Periklis Panagopoulos, Peter Drakakis and Sofoklis Stavros

J. Clin. Med. 2024, 13(2), 328; https://doi.org/10.3390/jcm13020328 - 6 Jan 2024

Cited by 6 | Viewed by 1730

Abstract

Background: Infertility affects about 80 million individuals worldwide and 10–15% of couples at reproductive age will seek medical assistance. There is increasing evidence that pregnancies after Assisted Reproduction Techniques (ART) are associated with pre-term birth, low birthweight, congenital defects, and increased mortality rates. [...] Read more.

Background: Infertility affects about 80 million individuals worldwide and 10–15% of couples at reproductive age will seek medical assistance. There is increasing evidence that pregnancies after Assisted Reproduction Techniques (ART) are associated with pre-term birth, low birthweight, congenital defects, and increased mortality rates. The aim of this review is to assess all the published literature and provide an updated review on the effect of assisted conception and perinatal and neonatal outcomes. Methods: Comprehensive research on Pubmed/Medline, Scopus, and Google scholar electronic databases was conducted from July 2023 up to September 2023, using the terms assisted reproductive techniques, ART, in vitro fertilization, IVF, intracytoplasmic sperm injection, ICSI, preterm birth, PTB, low birth weight, LBW, chromosomal defects, congenital defects, and hypospadias. In total, 87 full text articles were retrieved and after a careful evaluation, 31 studies were selected for data extraction. Results: Our review demonstrated a higher risk of congenital and chromosomal defects, and a higher incidence of male genital tract defects and heart defects in ART pregnancies. Regarding pre-term birth, our results were contradictory. Conclusions: Although assisted reproduction techniques are associated with increased risks, they are safe regarding perinatal outcomes and couples should not be discouraged from utilizing them. Our results aim to alert clinicians to these specific outcomes and offer more personalized care and counseling to infertile couples and their children. Full article

(This article belongs to the Special Issue Gynecologic and Obstetric Pathologies: From Birth to Menopause)

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23 pages, 1269 KiB

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Relationship between Biochemical Pathways and Non-Coding RNAs Involved in the Progression of Diabetic Retinopathy

by Małgorzata Mrowicka, Jerzy Mrowicki and Ireneusz Majsterek

J. Clin. Med. 2024, 13(1), 292; https://doi.org/10.3390/jcm13010292 - 4 Jan 2024

Cited by 3 | Viewed by 1809

Abstract

Diabetic retinopathy (DR) is a progressive blinding disease, which affects the vision and quality of life of patients, and it severely impacts the society. This complication, caused by abnormal glucose metabolism, leads to structural, functional, molecular, and biochemical abnormalities in the retina. Oxidative [...] Read more.

Diabetic retinopathy (DR) is a progressive blinding disease, which affects the vision and quality of life of patients, and it severely impacts the society. This complication, caused by abnormal glucose metabolism, leads to structural, functional, molecular, and biochemical abnormalities in the retina. Oxidative stress and inflammation also play pivotal roles in the pathogenic process of DR, leading to mitochondrial damage and a decrease in mitochondrial function. DR causes retinal degeneration in glial and neural cells, while the disappearance of pericytes in retinal blood vessels leads to alterations in vascular regulation and stability. Clinical changes include dilatation and blood flow changes in response to the decrease in retinal perfusion in retinal blood vessels, leading to vascular leakage, neovascularization, and neurodegeneration. The loss of vascular cells in the retina results in capillary occlusion and ischemia. Thus, DR is a highly complex disease with various biological factors, which contribute to its pathogenesis. The interplay between biochemical pathways and non-coding RNAs (ncRNAs) is essential for understanding the development and progression of DR. Abnormal expression of ncRNAs has been confirmed to promote the development of DR, suggesting that ncRNAs such as miRNAs, lncRNAs, and circRNAs have potential as diagnostic biomarkers and theranostic targets in DR. This review provides an overview of the interactions between abnormal biochemical pathways and dysregulated expression of ncRNAs under the influence of hyperglycemic environment in DR. Full article

(This article belongs to the Special Issue Diabetic Retinopathy: Current Concepts and Future Directions)

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20 pages, 1260 KiB

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Risk Stratification and Management of Intermediate-Risk Acute Pulmonary Embolism

by Nichole Brunton, Robert McBane, Ana I. Casanegra, Damon E. Houghton, Dinu V. Balanescu, Sumera Ahmad, Sean Caples, Arashk Motiei and Stanislav Henkin

J. Clin. Med. 2024, 13(1), 257; https://doi.org/10.3390/jcm13010257 - 2 Jan 2024

Cited by 5 | Viewed by 12335

Abstract

Pulmonary embolism (PE) is the third most common cause of cardiovascular death and necessitates prompt, accurate risk assessment at initial diagnosis to guide treatment and reduce associated mortality. Intermediate-risk PE, defined as the presence of right ventricular (RV) dysfunction in the absence of [...] Read more.

Pulmonary embolism (PE) is the third most common cause of cardiovascular death and necessitates prompt, accurate risk assessment at initial diagnosis to guide treatment and reduce associated mortality. Intermediate-risk PE, defined as the presence of right ventricular (RV) dysfunction in the absence of hemodynamic compromise, carries a significant risk for adverse clinical outcomes and represents a unique diagnostic challenge. While small clinical trials have evaluated advanced treatment strategies beyond standard anticoagulation, such as thrombolytic or endovascular therapy, there remains continued debate on the optimal care for this patient population. Here, we review the most recent risk stratification models, highlighting differences between prediction scores and their limitations, and discuss the utility of serologic biomarkers and imaging modalities to detect right ventricular dysfunction. Additionally, we examine current treatment recommendations including anticoagulation strategies, use of thrombolytics at full and reduced doses, and utilization of invasive treatment options. Current knowledge gaps and ongoing studies are highlighted. Full article

(This article belongs to the Special Issue Pulmonary Embolism and Its Complications: Causes, Diagnosis and Treatment)

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13 pages, 1317 KiB

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Face the Future—Artificial Intelligence in Oral and Maxillofacial Surgery

by Maximilian F. Miragall, Samuel Knoedler, Martin Kauke-Navarro, Rakan Saadoun, Alex Grabenhorst, Florian D. Grill, Lucas M. Ritschl, Andreas M. Fichter, Ali-Farid Safi and Leonard Knoedler

J. Clin. Med. 2023, 12(21), 6843; https://doi.org/10.3390/jcm12216843 - 30 Oct 2023

Cited by 10 | Viewed by 4202

Abstract

Artificial intelligence (AI) has emerged as a versatile health-technology tool revolutionizing medical services through the implementation of predictive, preventative, individualized, and participatory approaches. AI encompasses different computational concepts such as machine learning, deep learning techniques, and neural networks. AI also presents a broad [...] Read more.

Artificial intelligence (AI) has emerged as a versatile health-technology tool revolutionizing medical services through the implementation of predictive, preventative, individualized, and participatory approaches. AI encompasses different computational concepts such as machine learning, deep learning techniques, and neural networks. AI also presents a broad platform for improving preoperative planning, intraoperative workflow, and postoperative patient outcomes in the field of oral and maxillofacial surgery (OMFS). The purpose of this review is to present a comprehensive summary of the existing scientific knowledge. The authors thoroughly reviewed English-language PubMed/MEDLINE and Embase papers from their establishment to 1 December 2022. The search terms were (1) “OMFS” OR “oral and maxillofacial” OR “oral and maxillofacial surgery” OR “oral surgery” AND (2) “AI” OR “artificial intelligence”. The search format was tailored to each database’s syntax. To find pertinent material, each retrieved article and systematic review’s reference list was thoroughly examined. According to the literature, AI is already being used in certain areas of OMFS, such as radiographic image quality improvement, diagnosis of cysts and tumors, and localization of cephalometric landmarks. Through additional research, it may be possible to provide practitioners in numerous disciplines with additional assistance to enhance preoperative planning, intraoperative screening, and postoperative monitoring. Overall, AI carries promising potential to advance the field of OMFS and generate novel solution possibilities for persisting clinical challenges. Herein, this review provides a comprehensive summary of AI in OMFS and sheds light on future research efforts. Further, the advanced analysis of complex medical imaging data can support surgeons in preoperative assessments, virtual surgical simulations, and individualized treatment strategies. AI also assists surgeons during intraoperative decision-making by offering immediate feedback and guidance to enhance surgical accuracy and reduce complication rates, for instance by predicting the risk of bleeding. Full article

(This article belongs to the Special Issue Clinical Advances in Oral Maxillofacial Surgery)

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34 pages, 649 KiB

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Advances in Therapies to Treat Neonatal Hypoxic-Ischemic Encephalopathy

by Amaresh K. Ranjan and Anil Gulati

J. Clin. Med. 2023, 12(20), 6653; https://doi.org/10.3390/jcm12206653 - 20 Oct 2023

Cited by 14 | Viewed by 5849

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) is a condition that results in brain damage in newborns due to insufficient blood and oxygen supply during or after birth. HIE is a major cause of neurological disability and mortality in newborns, with over one million neonatal deaths [...] Read more.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a condition that results in brain damage in newborns due to insufficient blood and oxygen supply during or after birth. HIE is a major cause of neurological disability and mortality in newborns, with over one million neonatal deaths occurring annually worldwide. The severity of brain injury and the outcome of HIE depend on several factors, including the cause of oxygen deprivation, brain maturity, regional blood flow, and maternal health conditions. HIE is classified into mild, moderate, and severe categories based on the extent of brain damage and resulting neurological issues. The pathophysiology of HIE involves different phases, including the primary phase, latent phase, secondary phase, and tertiary phase. The primary and secondary phases are characterized by episodes of energy and cell metabolism failures, increased cytotoxicity and apoptosis, and activated microglia and inflammation in the brain. A tertiary phase occurs if the brain injury persists, characterized by reduced neural plasticity and neuronal loss. Understanding the cellular and molecular aspects of the different phases of HIE is crucial for developing new interventions and therapeutics. This review aims to discuss the pathophysiology of HIE, therapeutic hypothermia (TH), the only approved therapy for HIE, ongoing developments of adjuvants for TH, and potential future drugs for HIE. Full article

(This article belongs to the Special Issue Clinical Aspects of Cerebral Ischemia)

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18 pages, 2047 KiB

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Heart Failure in Patients with Chronic Kidney Disease

by Andrew Xanthopoulos, Adamantia Papamichail, Alexandros Briasoulis, Konstantinos Loritis, Angeliki Bourazana, Dimitrios E. Magouliotis, Pantelis Sarafidis, Ioannis Stefanidis, John Skoularigis and Filippos Triposkiadis

J. Clin. Med. 2023, 12(18), 6105; https://doi.org/10.3390/jcm12186105 - 21 Sep 2023

Cited by 8 | Viewed by 2907

Abstract

The function of the kidney is tightly linked to the function of the heart. Dysfunction/disease of the kidney may initiate, accentuate, or precipitate of the cardiac dysfunction/disease and vice versa, contributing to a negative spiral. Further, the reciprocal association between the heart and [...] Read more.

The function of the kidney is tightly linked to the function of the heart. Dysfunction/disease of the kidney may initiate, accentuate, or precipitate of the cardiac dysfunction/disease and vice versa, contributing to a negative spiral. Further, the reciprocal association between the heart and the kidney may occur on top of other entities, usually diabetes, hypertension, and atherosclerosis, simultaneously affecting the two organs. Chronic kidney disease (CKD) can influence cardiac function through altered hemodynamics and salt and water retention, leading to venous congestion and therefore, not surprisingly, to heart failure (HF). Management of HF in CKD is challenging due to several factors, including complex interplays between these two conditions, the effect of kidney dysfunction on the metabolism of HF medications, the effect of HF medications on kidney function, and the high risk for anemia and hyperkalemia. As a result, in most HF trials, patients with severe renal impairment (i.e., eGFR 30 mL/min/1.73 m² or less) are excluded. The present review discusses the epidemiology, pathophysiology, and current medical management in patients with HF developing in the context of CKD. Full article

(This article belongs to the Special Issue Review Special Issue Series: Recent Advances in Cardiovascular Medicine)

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14 pages, 299 KiB

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Advances in Targeted Therapy for the Treatment of Cervical Cancer

by Dean E. Watkins, Daniel J. Craig, Shahnaz D. Vellani, Ahmad Hegazi, Kaylee J. Fredrickson, Adam Walter, Laura Stanbery and John Nemunaitis

J. Clin. Med. 2023, 12(18), 5992; https://doi.org/10.3390/jcm12185992 - 15 Sep 2023

Cited by 9 | Viewed by 2613

Abstract

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, [...] Read more.

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care—such as bevacizumab and the immune CPIs—and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells. Full article

(This article belongs to the Section Oncology)

24 pages, 2329 KiB

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Hypertensive Heart Disease: A Narrative Review Series—Part 2: Macrostructural and Functional Abnormalities

by Valeriya Nemtsova, Thilo Burkard and Annina S. Vischer

J. Clin. Med. 2023, 12(17), 5723; https://doi.org/10.3390/jcm12175723 - 1 Sep 2023

Cited by 7 | Viewed by 4299

Abstract

Hypertensive heart disease (HHD) remains a major global public health concern despite the implementation of new approaches for the management of hypertensive patients. The pathological changes occurring during HHD are complex and involve the development of structural and functional cardiac abnormalities. HHD describes [...] Read more.

Hypertensive heart disease (HHD) remains a major global public health concern despite the implementation of new approaches for the management of hypertensive patients. The pathological changes occurring during HHD are complex and involve the development of structural and functional cardiac abnormalities. HHD describes a broad spectrum ranging from uncontrolled hypertension and asymptomatic left ventricular hypertrophy (LVH), either a concentric or an eccentric pattern, to the final development of clinical heart failure. Pressure-overload-induced LVH is recognised as the most important predictor of heart failure and sudden death and is associated with an increased risk of cardiac arrhythmias. Cardiac arrhythmias are considered to be one of the most important comorbidities affecting hypertensive patients. This is the second part of a three-part set of review articles. Here, we focus on the macrostructural and functional abnormalities associated with chronic high pressure, their involvement in HHD pathophysiology, and their role in the progression and prognosis of HHD. Full article

(This article belongs to the Section Cardiology)

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21 pages, 1705 KiB

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Effectiveness and Safety of Xen Gel Stent in Glaucoma Surgery: A Systematic Review of the Literature

by Carlo Enrico Traverso, Roberto G. Carassa, Antonio Maria Fea, Michele Figus, Carlo Astarita, Benedetta Piergentili, Vanessa Vera and Stefano Gandolfi

J. Clin. Med. 2023, 12(16), 5339; https://doi.org/10.3390/jcm12165339 - 16 Aug 2023

Cited by 8 | Viewed by 2191

Abstract

Although topical medical therapy and selective-laser-trabeculoplasty represent the treatments of choice to reduce intraocular pressure, many patients do not achieve adequate glaucoma control; therefore, they require further options and eventually surgery. Trabeculectomy is still considered the gold standard, but the surgical management of [...] Read more.

Although topical medical therapy and selective-laser-trabeculoplasty represent the treatments of choice to reduce intraocular pressure, many patients do not achieve adequate glaucoma control; therefore, they require further options and eventually surgery. Trabeculectomy is still considered the gold standard, but the surgical management of glaucoma has undergone continuous advances in recent years, XEN-gel-stent has been introduced as a safer and less traumatic means of lowering intraocular pressure (IOP) in patients with open-angle glaucoma (OAG). This study aimed to review the effectiveness and safety of clinical data on XEN-stent in OAG patients with a Synthesis-Without-Meta-analysis (SWiM) methodology. A total of 339 studies were identified following a literature search adhering to PRISMA guidelines and, after evaluation, 96 studies are discussed. XEN63 and XEN45 device data were collected both short and long term. In addition, this document has evaluated different aspects related to the XEN implant, including: its role compared to trabeculectomy; the impact of mitomycin-C dose on clinical outcomes; postoperative management of the device; and the identification of potential factors that might predict its clinical outcomes. Finally, current challenges and future perspectives of XEN stent, such as its use in fragile or high myopia patients, were discussed. Full article

(This article belongs to the Special Issue Advances in Glaucoma Surgery)

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16 pages, 3320 KiB

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Infective Endocarditis among Pediatric Patients with Prosthetic Valves and Cardiac Devices: A Review and Update of Recent Emerging Diagnostic and Management Strategies

by Mohamed Dardari, Eliza Cinteza, Corina Maria Vasile, Paul Padovani and Radu Vatasescu

J. Clin. Med. 2023, 12(15), 4941; https://doi.org/10.3390/jcm12154941 - 27 Jul 2023

Cited by 4 | Viewed by 1963

Abstract

Infective endocarditis (IE) is a disease of the endocardium, which leads to the appearance of vegetation on the valves, cardiac structures, or, potentially, vascular endothelium of the heart. The risk of IE can be increased more than 140 times by congenital heart disease [...] Read more.

Infective endocarditis (IE) is a disease of the endocardium, which leads to the appearance of vegetation on the valves, cardiac structures, or, potentially, vascular endothelium of the heart. The risk of IE can be increased more than 140 times by congenital heart disease (50–59% of all IE), particularly if cyanotic. An increase in mortality may result from IE in patients with a complex cardiac pathology or patients with an implanted prosthetic material, most frequently conduits in a pulmonary position. Cardiac implantable electronic devices (CIED) infective endocarditis is a life-threatening complication representing 10% of all cases of endocarditis. Common signs of presentation are often fever and chills; redness and swelling at the pocket of the pacemaker, including the erosion and exteriorization of the device; and life-threatening sepsis. The use of intracardiac echocardiography for the diagnosis of IE is an innovative method. This may be needed, especially in older children undergoing complex cardiac surgery, when transthoracic echocardiography (TTE) and transesophageal echocardiography (TOE) failed to provide a reliable diagnosis. The 2018 European Heart Rhythm Association (EHRA) experts’ consensus statement on transvenous lead extraction recommends complete device removal and antimicrobial therapy for any device-related infection, including CIED-IE. The most detected microorganism was Staphylococcus Aureus. In addition, cardiac surgery and interventional cardiology associated with the placement of prostheses or conduits may increase the risk of IE up to 1.6% for Melody valve implantation. Our manuscript presents a comprehensive review of infective endocarditis associated with cardiac devices and prostheses in the pediatric population, including recent advances in diagnosis and management. Full article

(This article belongs to the Special Issue Clinical Challenges in Endocarditis)

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13 pages, 307 KiB

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The Eight Unanswered and Answered Questions about the Use of Vasopressors in Septic Shock

by Olfa Hamzaoui, Antoine Goury and Jean-Louis Teboul

J. Clin. Med. 2023, 12(14), 4589; https://doi.org/10.3390/jcm12144589 - 10 Jul 2023

Cited by 5 | Viewed by 6650

Abstract

Septic shock is mainly characterized—in addition to hypovolemia—by vasoplegia as a consequence of a release of inflammatory mediators. Systemic vasodilatation due to depressed vascular tone results in arterial hypotension, which induces or worsens organ hypoperfusion. Accordingly, vasopressor therapy is mandatory to correct hypotension [...] Read more.

Septic shock is mainly characterized—in addition to hypovolemia—by vasoplegia as a consequence of a release of inflammatory mediators. Systemic vasodilatation due to depressed vascular tone results in arterial hypotension, which induces or worsens organ hypoperfusion. Accordingly, vasopressor therapy is mandatory to correct hypotension and to reverse organ perfusion due to hypotension. Currently, two vasopressors are recommended to be used, norepinephrine and vasopressin. Norepinephrine, an α₁-agonist agent, is the first-line vasopressor. Vasopressin is suggested to be added to norepinephrine in cases of inadequate mean arterial pressure instead of escalating the doses of norepinephrine. However, some questions about the bedside use of these vasopressors remain. Some of these questions have been well answered, some of them not clearly addressed, and some others not yet answered. Regarding norepinephrine, we firstly reviewed the arguments in favor of the choice of norepinephrine as a first-line vasopressor. Secondly, we detailed the arguments found in the recent literature in favor of an early introduction of norepinephrine. Thirdly, we reviewed the literature referring to the issue of titrating the doses of norepinephrine using an individualized resuscitation target, and finally, we addressed the issue of escalation of doses in case of refractory shock, a remaining unanswered question. For vasopressin, we reviewed the rationale for adding vasopressin to norepinephrine. Then, we discussed the optimal time for vasopressin administration. Subsequently, we addressed the issue of the optimal vasopressin dose, and finally we discussed the best strategy to wean these two vasopressors when combined. Full article

(This article belongs to the Section Intensive Care)

29 pages, 1711 KiB

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Clinical Potential of Mesenchymal Stem Cell-Derived Exosomes in Bone Regeneration

by Bárbara Torrecillas-Baena, Victoria Pulido-Escribano, Gabriel Dorado, María Ángeles Gálvez-Moreno, Marta Camacho-Cardenosa and Antonio Casado-Díaz

J. Clin. Med. 2023, 12(13), 4385; https://doi.org/10.3390/jcm12134385 - 29 Jun 2023

Cited by 11 | Viewed by 3583

Abstract

Bone metabolism is regulated by osteoblasts, osteoclasts, osteocytes, and stem cells. Pathologies such as osteoporosis, osteoarthritis, osteonecrosis, and traumatic fractures require effective treatments that favor bone formation and regeneration. Among these, cell therapy based on mesenchymal stem cells (MSC) has been proposed. MSC [...] Read more.

Bone metabolism is regulated by osteoblasts, osteoclasts, osteocytes, and stem cells. Pathologies such as osteoporosis, osteoarthritis, osteonecrosis, and traumatic fractures require effective treatments that favor bone formation and regeneration. Among these, cell therapy based on mesenchymal stem cells (MSC) has been proposed. MSC are osteoprogenitors, but their regenerative activity depends in part on their paracrine properties. These are mainly mediated by extracellular vesicle (EV) secretion. EV modulates regenerative processes such as inflammation, angiogenesis, cell proliferation, migration, and differentiation. Thus, MSC-EV are currently an important tool for the development of cell-free therapies in regenerative medicine. This review describes the current knowledge of the effects of MSC-EV in the different phases of bone regeneration. MSC-EV has been used by intravenous injection, directly or in combination with different types of biomaterials, in preclinical models of bone diseases. They have shown great clinical potential in regenerative medicine applied to bone. These findings should be confirmed through standardization of protocols, a better understanding of the mechanisms of action, and appropriate clinical trials. All that will allow the translation of such cell-free therapy to human clinic applications. Full article

(This article belongs to the Special Issue Clinical Application of Stem Cells in Regeneration Medicine)

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12 pages, 293 KiB

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Marginal Ulcers after Roux-en-Y Gastric Bypass: Etiology, Diagnosis, and Management

by Marita Salame, Noura Jawhar, Amanda Belluzzi, Mohammad Al-Kordi, Andrew C. Storm, Barham K. Abu Dayyeh and Omar M. Ghanem

J. Clin. Med. 2023, 12(13), 4336; https://doi.org/10.3390/jcm12134336 - 28 Jun 2023

Cited by 17 | Viewed by 8102

Abstract

Marginal ulcer (MU) is a potential complication following Roux-en-Y gastric bypass (RYGB), with a mean prevalence of 4.6%. Early identification and prompt intervention are crucial to mitigating further complications. The pathophysiology of MU is complex and involves multiple factors, including smoking, Helicobacter pylori [...] Read more.

Marginal ulcer (MU) is a potential complication following Roux-en-Y gastric bypass (RYGB), with a mean prevalence of 4.6%. Early identification and prompt intervention are crucial to mitigating further complications. The pathophysiology of MU is complex and involves multiple factors, including smoking, Helicobacter pylori infection, non-steroidal anti-inflammatory drug (NSAID) use, and larger pouch size. Patients with MU may experience acute or chronic abdominal pain. Rarely, they may present with a complication from the ulceration, such as bleeding, perforation, or strictures. Following diagnosis by endoscopy, management of MU typically involves modification of risk factors and medical therapy focused on proton pump inhibitors. In case of complicated ulcers, surgical intervention is often required for the repair of the perforation or resection of the stricture. For recurrent or recalcitrant ulcers, endoscopic coverage of the ulcer bed, resection of the anastomosis, and abdominal or thoracoscopic truncal vagotomy may be considered. This review aims at providing an overview of the etiology, diagnosis, and management of MU after RYGB. Full article

(This article belongs to the Special Issue Complications in Bariatric Surgery (Aftermath and Comorbidities))

15 pages, 314 KiB

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Bronchopulmonary Dysplasia: Pathogenesis and Pathophysiology

by Nilesh Dankhara, Ira Holla, Sumana Ramarao and Renjithkumar Kalikkot Thekkeveedu

J. Clin. Med. 2023, 12(13), 4207; https://doi.org/10.3390/jcm12134207 - 22 Jun 2023

Cited by 19 | Viewed by 6466

Abstract

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is the most common respiratory morbidity in preterm infants. “Old” or “classic” BPD, as per the original description, is less common now. “New BPD”, which presents with distinct clinical and pathological features, is more [...] Read more.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is the most common respiratory morbidity in preterm infants. “Old” or “classic” BPD, as per the original description, is less common now. “New BPD”, which presents with distinct clinical and pathological features, is more frequently observed in the current era of advanced neonatal care, where extremely premature infants are surviving because of medical advancements. The pathogenesis of BPD is complex and multifactorial and involves both genetic and environmental factors. This review provides an overview of the pathology of BPD and discusses the influence of several prenatal and postnatal factors on its pathogenesis, such as maternal factors, genetic susceptibility, ventilator-associated lung injury, oxygen toxicity, sepsis, patent ductus arteriosus (PDA), and nutritional deficiencies. This in-depth review draws on existing literature to explore these factors and their potential contribution to the development of BPD. Full article

(This article belongs to the Special Issue Challenges in Bronchopulmonary Dysplasia)

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15 pages, 327 KiB

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Computer-Aided Detection for Pancreatic Cancer Diagnosis: Radiological Challenges and Future Directions

by Mark Ramaekers, Christiaan G. A. Viviers, Boris V. Janssen, Terese A. E. Hellström, Lotte Ewals, Kasper van der Wulp, Joost Nederend, Igor Jacobs, Jon R. Pluyter, Dimitrios Mavroeidis, Fons van der Sommen, Marc G. Besselink and Misha D. P. Luyer

J. Clin. Med. 2023, 12(13), 4209; https://doi.org/10.3390/jcm12134209 - 22 Jun 2023

Cited by 8 | Viewed by 1894

Abstract

Radiological imaging plays a crucial role in the detection and treatment of pancreatic ductal adenocarcinoma (PDAC). However, there are several challenges associated with the use of these techniques in daily clinical practice. Determination of the presence or absence of cancer using radiological imaging [...] Read more.

Radiological imaging plays a crucial role in the detection and treatment of pancreatic ductal adenocarcinoma (PDAC). However, there are several challenges associated with the use of these techniques in daily clinical practice. Determination of the presence or absence of cancer using radiological imaging is difficult and requires specific expertise, especially after neoadjuvant therapy. Early detection and characterization of tumors would potentially increase the number of patients who are eligible for curative treatment. Over the last decades, artificial intelligence (AI)-based computer-aided detection (CAD) has rapidly evolved as a means for improving the radiological detection of cancer and the assessment of the extent of disease. Although the results of AI applications seem promising, widespread adoption in clinical practice has not taken place. This narrative review provides an overview of current radiological CAD systems in pancreatic cancer, highlights challenges that are pertinent to clinical practice, and discusses potential solutions for these challenges. Full article

(This article belongs to the Special Issue Clinical Application of Artificial Intelligence in Cancer Research, Diagnosis and Therapy)

14 pages, 1116 KiB

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The Biology of Chronic Pain and Its Implications for Pain Neuroscience Education: State of the Art

by Kory Zimney, Wouter Van Bogaert and Adriaan Louw

J. Clin. Med. 2023, 12(13), 4199; https://doi.org/10.3390/jcm12134199 - 21 Jun 2023

Cited by 10 | Viewed by 6784

Abstract

Pain is an individualized experience for the person suffering from chronic pain. Significant strides have been made in the last few decades in understanding various biological changes that coincide with chronic pain. This state-of-the-art overview looks at the current evidence related to the [...] Read more.

Pain is an individualized experience for the person suffering from chronic pain. Significant strides have been made in the last few decades in understanding various biological changes that coincide with chronic pain. This state-of-the-art overview looks at the current evidence related to the biology of chronic pain and the implications these findings have on the delivery of pain neuroscience education (PNE). The paper summarizes the various (epi)genetic, neural, endocrine, and immune factors discovered and explored in the scientific literature concerning chronic pain. Each of these biological factors has various implications for the content and delivery of PNE. We discuss the future directions these biological factors have for the clinical implementation of PNE by linking the importance of behavior change, optimizing the learning environment, and using an individualized multimodal treatment approach with PNE. In addition, future directions for research of PNE based on these biological factors are provided with importance placed on individualized patient-centered care and how PNE can be used with traditional modes of care and growing trends with other care methods. PNE was originally and continues to be rooted in understanding chronic pain biology and how that understanding can improve patient care and outcomes. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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21 pages, 2207 KiB

Open AccessEditor’s ChoiceReview

Personalized Respiratory Support in ARDS: A Physiology-to-Bedside Review

by Salvatore Lucio Cutuli, Domenico Luca Grieco, Teresa Michi, Melania Cesarano, Tommaso Rosà, Gabriele Pintaudi, Luca Salvatore Menga, Ersilia Ruggiero, Valentina Giammatteo, Giuseppe Bello, Gennaro De Pascale and Massimo Antonelli

J. Clin. Med. 2023, 12(13), 4176; https://doi.org/10.3390/jcm12134176 - 21 Jun 2023

Cited by 10 | Viewed by 3936

Abstract

Acute respiratory distress syndrome (ARDS) is a leading cause of disability and mortality worldwide, and while no specific etiologic interventions have been shown to improve outcomes, noninvasive and invasive respiratory support strategies are life-saving interventions that allow time for lung recovery. However, the [...] Read more.

Acute respiratory distress syndrome (ARDS) is a leading cause of disability and mortality worldwide, and while no specific etiologic interventions have been shown to improve outcomes, noninvasive and invasive respiratory support strategies are life-saving interventions that allow time for lung recovery. However, the inappropriate management of these strategies, which neglects the unique features of respiratory, lung, and chest wall mechanics may result in disease progression, such as patient self-inflicted lung injury during spontaneous breathing or by ventilator-induced lung injury during invasive mechanical ventilation. ARDS characteristics are highly heterogeneous; therefore, a physiology-based approach is strongly advocated to titrate the delivery and management of respiratory support strategies to match patient characteristics and needs to limit ARDS progression. Several tools have been implemented in clinical practice to aid the clinician in identifying the ARDS sub-phenotypes based on physiological peculiarities (inspiratory effort, respiratory mechanics, and recruitability), thus allowing for the appropriate application of personalized supportive care. In this narrative review, we provide an overview of noninvasive and invasive respiratory support strategies, as well as discuss how identifying ARDS sub-phenotypes in daily practice can help clinicians to deliver personalized respiratory support and potentially improve patient outcomes. Full article

(This article belongs to the Special Issue New Insights into Acute Respiratory Distress Syndrome)

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13 pages, 457 KiB

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A Comprehensive Summary of the Current Understanding of the Relationship between Severe Obesity, Metabolic Syndrome, and Inflammatory Status

by Razvan-Marius Ion, Melania Sibianu, Adina Hutanu, Felicia Gabriela Beresescu, Daniela Tatiana Sala, Mocian Flavius, Ancuta Rosca, Calin Constantin, Alexandra Scurtu, Renata Moriczi, Mircea Gabriel Muresan, Popescu Gabriel, Raluca Niculescu and Radu Mircea Neagoe

J. Clin. Med. 2023, 12(11), 3818; https://doi.org/10.3390/jcm12113818 - 2 Jun 2023

Cited by 9 | Viewed by 2538

Abstract

At present, obesity, as a part of metabolic syndrome, represents the leading factor for disability, and is correlated with higher inflammation status, morbidity, and mortality. The purpose of our study is to add new insights to the present body of knowledge regarding the [...] Read more.

At present, obesity, as a part of metabolic syndrome, represents the leading factor for disability, and is correlated with higher inflammation status, morbidity, and mortality. The purpose of our study is to add new insights to the present body of knowledge regarding the correlations between chronic systemic inflammation and severe obesity, which cannot be treated without considering other metabolic syndrome conditions. Biomarkers of high-level chronic inflammation are recognized as important predictors of pro-inflammatory disease. Besides the well-known pro-inflammatory cytokines, such as WBCs (white blood cells), IL-1 (interleukin-1), IL-6 (interleukin-6), TNF-alpha (tumor necrosis factor-alpha), and hsCRP (high-sensitivity C-reactive protein), as well as anti-inflammatory markers, such as adiponectin and systemic inflammation, can be determined by a variety of blood tests as a largely available and inexpensive inflammatory biomarker tool. A few parameters, such as the neutrophil-to-lymphocyte ratio; the level of cholesterol 25-hydroxylase, which is part of the macrophage-enriched metabolic network in adipose tissue; or levels of glutamine, an immune–metabolic regulator in white adipose tissue, are markers that link obesity to inflammation. Through this narrative review, we try to emphasize the influence of the weight-loss process in reducing obesity-related pro-inflammatory status and associated comorbidities. All data from the presented studies report positive results following weight-loss procedures while improving overall health, an effect that lasts over time, as far as the existing research data show. Full article

(This article belongs to the Section Endocrinology & Metabolism)

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13 pages, 675 KiB

Open AccessEditor’s ChoiceReview

A Comprehensive Guide to Artificial Intelligence in Endoscopic Ultrasound

by Kareem Khalaf, Maria Terrin, Manol Jovani, Tommy Rizkala, Marco Spadaccini, Katarzyna M. Pawlak, Matteo Colombo, Marta Andreozzi, Alessandro Fugazza, Antonio Facciorusso, Fabio Grizzi, Cesare Hassan, Alessandro Repici and Silvia Carrara

J. Clin. Med. 2023, 12(11), 3757; https://doi.org/10.3390/jcm12113757 - 30 May 2023

Cited by 7 | Viewed by 2961

Abstract

Background: Endoscopic Ultrasound (EUS) is widely used for the diagnosis of bilio-pancreatic and gastrointestinal (GI) tract diseases, for the evaluation of subepithelial lesions, and for sampling of lymph nodes and solid masses located next to the GI tract. The role of Artificial Intelligence [...] Read more.

Background: Endoscopic Ultrasound (EUS) is widely used for the diagnosis of bilio-pancreatic and gastrointestinal (GI) tract diseases, for the evaluation of subepithelial lesions, and for sampling of lymph nodes and solid masses located next to the GI tract. The role of Artificial Intelligence in healthcare in growing. This review aimed to provide an overview of the current state of AI in EUS from imaging to pathological diagnosis and training. Methods: AI algorithms can assist in lesion detection and characterization in EUS by analyzing EUS images and identifying suspicious areas that may require further clinical evaluation or biopsy sampling. Deep learning techniques, such as convolutional neural networks (CNNs), have shown great potential for tumor identification and subepithelial lesion (SEL) evaluation by extracting important features from EUS images and using them to classify or segment the images. Results: AI models with new features can increase the accuracy of diagnoses, provide faster diagnoses, identify subtle differences in disease presentation that may be missed by human eyes, and provide more information and insights into disease pathology. Conclusions: The integration of AI in EUS images and biopsies has the potential to improve the diagnostic accuracy, leading to better patient outcomes and to a reduction in repeated procedures in case of non-diagnostic biopsies. Full article

(This article belongs to the Special Issue Global Updates and Advances in GI Endoscopy in Luminal and Non-luminal GI Conditions)

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29 pages, 628 KiB

Open AccessEditor’s ChoiceReview

Mitral and Tricuspid Valve Disease in Athletes

by Andrea Segreti, Mihail Celeski, Luigi Maria Monticelli, Alfonso Perillo, Simone Pasquale Crispino, Giuseppe Di Gioia, Valeria Cammalleri, Chiara Fossati, Simona Mega, Rocco Papalia, Fabio Pigozzi, Gian Paolo Ussia and Francesco Grigioni

J. Clin. Med. 2023, 12(10), 3562; https://doi.org/10.3390/jcm12103562 - 19 May 2023

Cited by 4 | Viewed by 2151

Abstract

Observing mitral or tricuspid valve disease in an athlete raises many considerations for the clinician. Initially, the etiology must be clarified, with causes differing depending on whether the athlete is young or a master. Notably, vigorous training in competitive athletes leads to a [...] Read more.

Observing mitral or tricuspid valve disease in an athlete raises many considerations for the clinician. Initially, the etiology must be clarified, with causes differing depending on whether the athlete is young or a master. Notably, vigorous training in competitive athletes leads to a constellation of structural and functional adaptations involving cardiac chambers and atrioventricular valve systems. In addition, a proper evaluation of the athlete with valve disease is necessary to evaluate the eligibility for competitive sports and identify those requiring more follow-up. Indeed, some valve pathologies are associated with an increased risk of severe arrhythmias and potentially sudden cardiac death. Traditional and advanced imaging modalities help clarify clinical doubts, allowing essential information about the athlete’s physiology and differentiating between primary valve diseases from those secondary to training-related cardiac adaptations. Remarkably, another application of multimodality imaging is evaluating athletes with valve diseases during exercise to reproduce the sport setting and better characterize the etiology and valve defect mechanism. This review aims to analyze the possible causes of atrioventricular valve diseases in athletes, focusing primarily on imaging applications in diagnosis and risk stratification. Full article

(This article belongs to the Section Cardiovascular Medicine)

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12 pages, 262 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis

by Benjamin L. Gordon and Robert Battat

J. Clin. Med. 2023, 12(10), 3378; https://doi.org/10.3390/jcm12103378 - 10 May 2023

Cited by 5 | Viewed by 2814

Abstract

Therapeutic drug monitoring (TDM) is a useful strategy in ulcerative colitis (UC). Nearly a quarter of UC patients will experience acute severe UC (ASUC) in their lifetime, including 30% who will fail first-line corticosteroid therapy. Steroid-refractory ASUC patients require salvage therapy with infliximab, [...] Read more.

Therapeutic drug monitoring (TDM) is a useful strategy in ulcerative colitis (UC). Nearly a quarter of UC patients will experience acute severe UC (ASUC) in their lifetime, including 30% who will fail first-line corticosteroid therapy. Steroid-refractory ASUC patients require salvage therapy with infliximab, cyclosporine, or colectomy. Fewer data are available for the use of TDM of infliximab in ASUC. The pharmacokinetics of ASUC make TDM in this population more complex. High inflammatory burden is associated with increased infliximab clearance, which is associated with lower infliximab drug concentrations. Observational data support the association between increased serum infliximab concentrations, lower clearance, and favorable clinical and endoscopic outcomes, as well as decreased rates of colectomy. Data regarding the benefit of accelerated or intensified dosing strategies of infliximab—as well as target drug concentration thresholds—in ASUC patients remain more equivocal, though limited by their observational nature. Studies are underway to further evaluate optimal dosing and TDM targets in this population. This review examines the evidence for TDM in patients with ASUC, with a focus on infliximab. Full article

(This article belongs to the Special Issue New Frontiers in Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases)

45 pages, 5392 KiB

Open AccessEditor’s ChoiceReview

The AGE-RAGE Axis and the Pathophysiology of Multimorbidity in COPD

by Niki L. Reynaert, Lowie E. G. W. Vanfleteren and Timothy N. Perkins

J. Clin. Med. 2023, 12(10), 3366; https://doi.org/10.3390/jcm12103366 - 9 May 2023

Cited by 9 | Viewed by 4151

Abstract

Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden [...] Read more.

Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review. Full article

(This article belongs to the Special Issue Clinical Advances in Chronic Obstructive Pulmonary Disease and Its Complications)

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22 pages, 951 KiB

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Diagnosis and Management of Malnutrition in Patients with Heart Failure

by Alberto Esteban-Fernández, Rocío Villar-Taibo, Mirian Alejo, David Arroyo, Juan Luis Bonilla Palomas, Montserrat Cachero, Clara Joaquin, Manuel Méndez Bailón, José Ángel Pérez-Rivera, Juan Carlos Romero-Vigara and Gema Somoza

J. Clin. Med. 2023, 12(9), 3320; https://doi.org/10.3390/jcm12093320 - 6 May 2023

Cited by 10 | Viewed by 7867

Abstract

Heart failure is a disease with an increasingly greater prevalence due to the aging population, the development of new drugs, and the organization of healthcare processes. Malnutrition has been identified as a poor prognostic factor in these patients, very often linked to frailty [...] Read more.

Heart failure is a disease with an increasingly greater prevalence due to the aging population, the development of new drugs, and the organization of healthcare processes. Malnutrition has been identified as a poor prognostic factor in these patients, very often linked to frailty or to other comorbidities, meaning that early diagnosis and treatment are essential. This paper reviews some important aspects of the pathophysiology, detection, and management of malnutrition in patients with heart failure. Full article

(This article belongs to the Section Cardiovascular Medicine)

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20 pages, 2071 KiB

Open AccessEditor’s ChoiceReview

Sarcoidosis-Related Uveitis: A Review

by Stéphane Giorgiutti, Robin Jacquot, Thomas El Jammal, Arthur Bert, Yvan Jamilloux, Laurent Kodjikian and Pascal Sève

J. Clin. Med. 2023, 12(9), 3194; https://doi.org/10.3390/jcm12093194 - 29 Apr 2023

Cited by 11 | Viewed by 3133

Abstract

Sarcoidosis is an inflammatory disease that involves the eyes in 10–55% of cases, sometimes without systemic involvement. All eye structures can be affected, but uveitis is the most common ocular manifestation and causes vision loss. The typical ophthalmological appearance of these uveitis is [...] Read more.

Sarcoidosis is an inflammatory disease that involves the eyes in 10–55% of cases, sometimes without systemic involvement. All eye structures can be affected, but uveitis is the most common ocular manifestation and causes vision loss. The typical ophthalmological appearance of these uveitis is granulomatous (in cases with anterior involvement), which are usually bilateral and with synechiae. Posterior involvement includes vitritis, vasculitis and choroidal lesions. Tuberculosis is a classic differential diagnosis to be wary of, especially in people who have spent time in endemic areas. The diagnosis is based on histology with the presence of non-caseating epithelioid granulomas. However, due to the technical difficulty and yield of biopsies, the diagnosis of ocular sarcoidosis is often based on clinico-radiological features. The international criteria for the diagnosis of ocular sarcoidosis have recently been revised. Corticosteroids remain the first-line treatment for sarcoidosis, but up to 30% of patients require high doses, justifying the use of corticosteroid-sparing treatments. In these cases, immunosuppressive treatments such as methotrexate may be introduced. More recent biotherapies such as anti-TNF are also very effective (as they are in other non-infectious uveitis etiologies). Full article

(This article belongs to the Section Immunology)

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15 pages, 1760 KiB

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Neuro–Immuno–Psychological Aspects of Chronic Urticaria

by Katarzyna Tomaszewska, Aleksandra Słodka, Bartłomiej Tarkowski and Anna Zalewska-Janowska

J. Clin. Med. 2023, 12(9), 3134; https://doi.org/10.3390/jcm12093134 - 26 Apr 2023

Cited by 11 | Viewed by 5671

Abstract

Urticaria is a condition characterized by the development of itchy wheals (hives), angioedema, or both. The pathophysiology of chronic spontaneous urticaria (CSU) is still poorly understood. It is suggested that there is no dominant and independent mechanism of CSU; however, there are different [...] Read more.

Urticaria is a condition characterized by the development of itchy wheals (hives), angioedema, or both. The pathophysiology of chronic spontaneous urticaria (CSU) is still poorly understood. It is suggested that there is no dominant and independent mechanism of CSU; however, there are different immunological and non-immunological abnormalities that act simultaneously or/and follow each other resulting in clinical symptoms. The latest hypothesis points out that mast cells (MCs) to be activated via autoantibodies in autoallergic or autoimmune mechanism mediators released from degranulated MCs are responsible for the vasoactive and neurospecific effect in CSU. According to many clinical observations, it is suggested that psychological stress can be both a triggering factor in the onset of CSU and a modulating one in the course of the disease and therapy effectiveness. Of importance, the mechanistic background of the psychological stress response in the skin has not yet been fully elucidated. However, of note, a variety of inflammatory mediators, neuropeptides, and neurotransmitters facilitate this phenomenon. This review presents recent findings on the neuro–immuno–psychological aspects of CSU, highlighting an emerging role of neuro–immune interactions. It also points out the usefulness of psychological tools employment for the baseline diagnosis of perceived stress level and the presence of its symptoms. Furthermore, it proposes the implementation of non-invasive interventions to reduce psychological stress and anxiety. A bio–psycho–social approach including psychological support and patient education seems to be as important as traditional pharmacotherapy for CSU. It facilitates the effective control of active disease and a prolonged remission time in this disease. Full article

(This article belongs to the Special Issue Urticaria: Clinical Updates on the Cause, Diagnosis, and Treatment)

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12 pages, 310 KiB

Open AccessEditor’s ChoiceReview

Challenges of Treating ADHD with Comorbid Substance Use Disorder: Considerations for the Clinician

by Margherita Barbuti, Marco Maiello, Vincenza Spera, Alessandro Pallucchini, Giulio E. Brancati, Angelo G. I. Maremmani, Giulio Perugi and Icro Maremmani

J. Clin. Med. 2023, 12(9), 3096; https://doi.org/10.3390/jcm12093096 - 24 Apr 2023

Cited by 9 | Viewed by 5375

Abstract

Adults with attention deficit/hyperactivity disorder (ADHD) often present psychiatric comorbidities and, in particular, substance use disorder (SUD). ADHD-SUD comorbidity is characterized by greater severity of both disorders, earlier age of onset, higher likelihood of polydrug-abuse and suicidal behaviors, more hospitalizations, and lower treatment [...] Read more.

Adults with attention deficit/hyperactivity disorder (ADHD) often present psychiatric comorbidities and, in particular, substance use disorder (SUD). ADHD-SUD comorbidity is characterized by greater severity of both disorders, earlier age of onset, higher likelihood of polydrug-abuse and suicidal behaviors, more hospitalizations, and lower treatment adherence. At the present stage, research focused on the pharmacological management of ADHD with comorbid SUD in both adolescents and adults is still lacking. Furthermore, while the short-term effects of stimulants are well studied, less is known about the chronic effects of these drugs on dopamine signaling. Current available evidence is consistent in reporting that high doses of stimulant medications in ADHD-SUD subjects have a mild to moderate efficacy on ADHD symptoms. Some data suggest that pharmacological treatment with stimulants may be beneficial for both ADHD symptoms and comorbid cocaine or amphetamine use. However, in the long run, stimulant medications may have a potential risk for misuse. For the absence of potential misuse, atomoxetine is often recommended for ADHD with comorbid cocaine or amphetamine use disorder. However, its efficacy in reducing addictive behavior is not demonstrated. In subjects with other subtypes of SUD, both atomoxetine and stimulant drugs seem to have scarce impact on addictive behavior, despite the improvement in ADHD symptomatology. In this population, ADHD treatment should be combined with SUD-specific strategies. Full article

(This article belongs to the Section Mental Health)

17 pages, 565 KiB

Open AccessEditor’s ChoiceReview

The Role of Peroxisome Proliferator-Activated Receptors in Polycystic Ovary Syndrome

by Iason Psilopatis, Kleio Vrettou, Eleni Nousiopoulou, Kostas Palamaris and Stamatios Theocharis

J. Clin. Med. 2023, 12(8), 2912; https://doi.org/10.3390/jcm12082912 - 17 Apr 2023

Cited by 6 | Viewed by 1755

Abstract

Polycystic ovary syndrome (PCOS) constitutes the most common endocrine disorder in women of reproductive age. Patients usually suffer from severe menstrual irregularities, skin conditions, and insulin resistance-associated health conditions. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor proteins that regulate gene expression. In order [...] Read more.

Polycystic ovary syndrome (PCOS) constitutes the most common endocrine disorder in women of reproductive age. Patients usually suffer from severe menstrual irregularities, skin conditions, and insulin resistance-associated health conditions. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor proteins that regulate gene expression. In order to investigate the role of PPARs in the pathophysiology of PCOS, we conducted a literature review using the MEDLINE and LIVIVO databases and were able to identify 74 relevant studies published between 2003 and 2023. Different study groups reached contradictory conclusions in terms of PPAR expression in PCOS. Interestingly, numerous natural agents were found to represent a novel, potent anti-PCOS treatment alternatives. In conclusion, PPARs seem to play a significant role in PCOS. Full article

(This article belongs to the Special Issue Polycystic Ovary Syndrome: Clinical Diagnosis and Management)

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26 pages, 2366 KiB

Open AccessEditor’s ChoiceReview

New Insights into Pathophysiology and New Risk Factors for ACS

by Matteo Nardin, Monica Verdoia, Nicola Laera, Davide Cao and Giuseppe De Luca

J. Clin. Med. 2023, 12(8), 2883; https://doi.org/10.3390/jcm12082883 - 14 Apr 2023

Cited by 5 | Viewed by 3298

Abstract

Cardiovascular disease still represents the main cause of mortality worldwide. Despite huge improvements, atherosclerosis persists as the principal pathological condition, both in stable and acute presentation. Specifically, acute coronary syndromes have received substantial research and clinical attention in recent years, contributing to improve [...] Read more.

Cardiovascular disease still represents the main cause of mortality worldwide. Despite huge improvements, atherosclerosis persists as the principal pathological condition, both in stable and acute presentation. Specifically, acute coronary syndromes have received substantial research and clinical attention in recent years, contributing to improve overall patients’ outcome. The identification of different evolution patterns of the atherosclerotic plaque and coronary artery disease has suggested the potential need of different treatment approaches, according to the mechanisms and molecular elements involved. In addition to traditional risk factors, the finer portrayal of other metabolic and lipid-related mediators has led to higher and deep knowledge of atherosclerosis, providing potential new targets for clinical management of the patients. Finally, the impressive advances in genetics and non-coding RNAs have opened a wide field of research both on pathophysiology and the therapeutic side that are extensively under investigation. Full article

(This article belongs to the Section Cardiovascular Medicine)

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19 pages, 5545 KiB

Open AccessEditor’s ChoiceReview

Osteoid Osteoma, a Diagnostic Problem: A Series of Atypical and Mimicking Presentations and Review of the Recent Literature

by Justyna Napora, Szymon Wałejko and Tomasz Mazurek

J. Clin. Med. 2023, 12(7), 2721; https://doi.org/10.3390/jcm12072721 - 5 Apr 2023

Cited by 10 | Viewed by 5006

Abstract

Osteoid osteoma (OO) is a common benign bone tumour, usually affecting young people. Typically, it is localised to the diaphyses or metaphyses of long bones. The classical manifestation includes distinctive night pain, almost always present, responding well to non-steroidal anti-inflammatory drugs, sometimes accompanied [...] Read more.

Osteoid osteoma (OO) is a common benign bone tumour, usually affecting young people. Typically, it is localised to the diaphyses or metaphyses of long bones. The classical manifestation includes distinctive night pain, almost always present, responding well to non-steroidal anti-inflammatory drugs, sometimes accompanied by complaints due to physical activity, and a typical picture on additional tests. A characteristic of osteoid osteoma is the presence of a nidus, usually visible on imaging tests. The nidus generally presents as a single, round lytic lesion up to 1 cm in diameter, surrounded by an area of reactive ossification. However, OO is a multifaceted neoplasm, and its diagnosis can cause numerous difficulties. OO can mimic multiple diseases and vice versa, which often leads to a prolonged diagnostic and therapeutic path and associated complications. There are few literature reviews about the differentiation and diagnostic difficulties of osteoid osteoma. Very effective therapies for this tumour are known, such as ablation and resection. Enhanced detection of osteoid osteoma could result in faster diagnosis and less suffering for the patient, avoidance of complications, and reduced costs of incorrect and prolonged treatment. Full article

(This article belongs to the Section Orthopedics)

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13 pages, 665 KiB

Open AccessEditor’s ChoiceReview

Overview of Atopic Dermatitis in Different Ethnic Groups

by Andrea Chiricozzi, Martina Maurelli, Laura Calabrese, Ketty Peris and Giampiero Girolomoni

J. Clin. Med. 2023, 12(7), 2701; https://doi.org/10.3390/jcm12072701 - 4 Apr 2023

Cited by 18 | Viewed by 4090

Abstract

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a high prevalence worldwide, including countries from Asia, Africa, and Latin America, and in different ethnic groups. In recent years, more attention has been placed on the heterogeneity of AD associated with [...] Read more.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a high prevalence worldwide, including countries from Asia, Africa, and Latin America, and in different ethnic groups. In recent years, more attention has been placed on the heterogeneity of AD associated with multiple factors, including a patient’s ethnic background, resulting in an increasing body of clinical, genetic, epidemiologic, and immune-phenotypic evidence that delineates differences in AD among racial groups. Filaggrin (FLG) mutations, the strongest genetic risk factor for the development of AD, are detected in up to 50% of European and 27% of Asian AD patients, but very rarely in Africans. Th2 hyperactivation is a common attribute of all ethnic groups, though the Asian endotype of AD is also characterized by an increased Th17-mediated signal, whereas African Americans show a strong Th2/Th22 signature and an absence of Th1/Th17 skewing. In addition, the ethnic heterogeneity of AD may hold important therapeutic implications as a patient’s genetic predisposition may affect treatment response and, thereby, a tailored strategy that better targets the dominant immunologic pathways in each ethnic subgroup may be envisaged. Nevertheless, white patients with AD represent the largest ethnicity enrolled and tested in clinical trials and the most treated in a real-world setting, limiting investigations about safety and efficacy across different ethnicities. The purpose of this review is to describe the heterogeneity in the pathophysiology of AD across ethnicities and its potential therapeutic implications. Full article

(This article belongs to the Section Dermatology)

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11 pages, 1048 KiB

Open AccessEditor’s ChoiceReview

Desmoplakin Cardiomyopathy: Comprehensive Review of an Increasingly Recognized Entity

by Mariana Brandão, Riccardo Bariani, Ilaria Rigato and Barbara Bauce

J. Clin. Med. 2023, 12(7), 2660; https://doi.org/10.3390/jcm12072660 - 3 Apr 2023

Cited by 10 | Viewed by 3921

Abstract

Desmoplakin (DSP) is a desmosomal protein that plays an essential role for cell-to-cell adhesion within the cardiomyocytes. The first association between DSP genetic variants and the presence of a myocardial disease referred to patients with Carvajal syndrome. Since then, several reports have linked [...] Read more.

Desmoplakin (DSP) is a desmosomal protein that plays an essential role for cell-to-cell adhesion within the cardiomyocytes. The first association between DSP genetic variants and the presence of a myocardial disease referred to patients with Carvajal syndrome. Since then, several reports have linked the DSP gene to familial forms of arrhythmogenic (ACM) and dilated cardiomyopathies. Left-dominant ACM is the most common phenotype in individuals carrying DSP variants. More recently, a new entity—“Desmoplakin cardiomyopathy”—was described as a distinct form of cardiomyopathy characterized by frequent left ventricular involvement with extensive fibrosis, high arrhythmic risk, and episodes of acute myocardial injury. The purpose of this review was to summarize the available evidence on DSP cardiomyopathy and to identify existing gaps in knowledge that need clarification from upcoming research. Full article

(This article belongs to the Section Cardiovascular Medicine)

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15 pages, 295 KiB

Open AccessEditor’s ChoiceReview

Home High-Flow Therapy in Patients with Chronic Respiratory Diseases: Physiological Rationale and Clinical Results

by Maria Laura Vega Pittao, Gioacchino Schifino, Lara Pisani and Stefano Nava

J. Clin. Med. 2023, 12(7), 2663; https://doi.org/10.3390/jcm12072663 - 3 Apr 2023

Cited by 6 | Viewed by 3372

Abstract

High-flow therapy (HFT) is the administration of gas flows above 15 L/min. It is a non-invasive respiratory support that delivers heated (up to 38 °C), humidified (100% Relative Humidity, RH; 44 mg H₂O/L Absolute Humidity, AH), oxygen-enriched air when necessary, through [...] Read more.

High-flow therapy (HFT) is the administration of gas flows above 15 L/min. It is a non-invasive respiratory support that delivers heated (up to 38 °C), humidified (100% Relative Humidity, RH; 44 mg H₂O/L Absolute Humidity, AH), oxygen-enriched air when necessary, through a nasal cannula or a tracheostomy interface. Over the last few years, the use of HFT in critically ill hypoxemic adults has increased. Although the clinical benefit of home high-flow therapy (HHFT) remains unclear, some research findings would support the use of HHFT in chronic respiratory diseases. The aim of this review is to describe the HFT physiological principles and summarize the published clinical findings. Finally, we will discuss the differences between hospital and home implementation, as well as the various devices available for HHFT application. Full article

(This article belongs to the Special Issue Non-invasive Respiratory Support: How to Get It Right in Clinical Medicine—Volume I)

12 pages, 4616 KiB

Open AccessEditor’s ChoiceReview

Arrhythmic Manifestations of Cardiac Amyloidosis: Challenges in Risk Stratification and Clinical Management

by Natallia Laptseva, Valentina A. Rossi, Isabella Sudano, Rahel Schwotzer, Frank Ruschitzka, Andreas J. Flammer and Firat Duru

J. Clin. Med. 2023, 12(7), 2581; https://doi.org/10.3390/jcm12072581 - 29 Mar 2023

Cited by 10 | Viewed by 2762

Abstract

Amyloidosis is a systemic disease characterized by extracellular deposits of insoluble amyloid in various tissues and organs. Cardiac amyloidosis is a frequent feature of the disease, causing a progressive, restrictive type of cardiomyopathy, and is associated with adverse clinical outcomes and increased mortality. [...] Read more.

Amyloidosis is a systemic disease characterized by extracellular deposits of insoluble amyloid in various tissues and organs. Cardiac amyloidosis is a frequent feature of the disease, causing a progressive, restrictive type of cardiomyopathy, and is associated with adverse clinical outcomes and increased mortality. The typical clinical presentation in patients with cardiac amyloidosis is heart failure (HF) with preserved ejection fraction. Most patients present with typical symptoms and signs of HF, such as exertional dyspnea, pretibial edema, pleural effusions and angina pectoris due to microcirculatory dysfunction. However, patients may also frequently encounter various arrhythmias, such as atrioventricular nodal block, atrial fibrillation and ventricular tachyarrhythmias. The management of arrhythmias in cardiac amyloidosis patients with drugs and devices is often a clinical challenge. Moreover, predictors of life-threatening arrhythmic events are not well defined. This review intends to give a deepened insight into the arrhythmic features of cardiac amyloidosis by discussing the pathogenesis of these arrhythmias, addressing the challenges in risk stratification and strategies for management in these patients. Full article

(This article belongs to the Special Issue Cardiomyopathies: State of the Art Knowledge)

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15 pages, 1733 KiB

Open AccessEditor’s ChoiceReview

Management of Statin Intolerant Patients in the Era of Novel Lipid Lowering Therapies: A Critical Approach in Clinical Practice

by Giosiana Bosco, Francesco Di Giacomo Barbagallo, Salvatore Spampinato, Lorena Lanzafame, Antonino Di Pino, Salvatore Piro, Francesco Purrello and Roberto Scicali

J. Clin. Med. 2023, 12(6), 2444; https://doi.org/10.3390/jcm12062444 - 22 Mar 2023

Cited by 11 | Viewed by 4510

Abstract

Statins are the cornerstone of lipid-lowering therapies effective for cardiovascular risk reduction. Although they are generally well tolerated, statin intolerance (SI) is frequent in clinical practice, and it is usually related to the onset of muscle symptoms, which are defined under the acronym [...] Read more.

Statins are the cornerstone of lipid-lowering therapies effective for cardiovascular risk reduction. Although they are generally well tolerated, statin intolerance (SI) is frequent in clinical practice, and it is usually related to the onset of muscle symptoms, which are defined under the acronym SAMS (Statin-Associated Muscle Side Effects). These side effects are responsible for statin treatment discontinuation that results in increased cardiovascular risk. The National Lipid Association (NLA) has recently provided an updated definition of statin intolerance, and a distinction between complete and partial statin intolerance has been reported. The evaluation of symptom severity and the presence of muscle damage biomarker alterations make it essential to adopt a patient-centered approach aimed at obtaining a personalized therapeutic strategy. Firstly, it could be useful to administer a different statin, reduce the dosage or adopt an alternate dosage regimen. However, some patients are unable to tolerate any statin at every dosage, or despite taking statins at the maximum tolerated dose, they fail to achieve the recommended LDL-C target, and thus it is necessary to introduce a non-statin hypolipidemic treatment. Ezetimibe, proprotein-convertase subtilisin/kexin type 9 (PCSK9) inhibitors such as monoclonal antibodies (alirocumab and evolocumab) or RNA messenger silencing (inclisiran), bempedoic acid or nutraceuticals are non-statin lipid-lowering therapies that could be used as an alternative or in addition to statins to achieve an early and sustained LDL-C reduction in clinical practice. In this review, we evaluated SI management focusing on non-statin lipid lowering therapies and their implications in lipid lowering approaches in clinical practice. Full article

(This article belongs to the Special Issue Dyslipidemia and Cardiovascular Disease)

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21 pages, 1656 KiB

Open AccessEditor’s ChoiceReview

Vascular Endothelial Growth Factor Ligands and Receptors in Breast Cancer

by Klaudia Katarzyna Brogowska, Monika Zajkowska and Barbara Mroczko

J. Clin. Med. 2023, 12(6), 2412; https://doi.org/10.3390/jcm12062412 - 21 Mar 2023

Cited by 12 | Viewed by 2668

Abstract

Breast cancer (BC) is the most common malignancy responsible for the largest number of deaths in women worldwide. The risk of developing BC is predisposed by many factors such as age, presence of genetic mutations or body weight. The diagnosis is mostly made [...] Read more.

Breast cancer (BC) is the most common malignancy responsible for the largest number of deaths in women worldwide. The risk of developing BC is predisposed by many factors such as age, presence of genetic mutations or body weight. The diagnosis is mostly made relatively late, which is why patients are exposed to radical surgical treatments, long-term chemotherapy and lower survival rates. There are no sufficiently sensitive and specific screening tests; therefore, researchers are still looking for new diagnostic biomarkers that would indicate the appearance of neoplastic changes in the initial stage of neoplasm. The VEGF family of proteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, EG-VEGF, PlGF) and their receptors are significant factors in the pathogenesis of BC. They play a significant role in the process of angiogenesis and lymphangiogenesis in both physiological and pathological conditions. The usefulness of these proteins as potential diagnostic biomarkers has been initially proven. Moreover, the blockage of VEGF-related pathways seems to be a valid therapeutic target. Recent studies have tried to describe novel strategies, including targeting pericytes, use of miRNAs and extracellular tumor-associated vesicles, immunotherapeutic drugs and nanotechnology. This indicates their possible contribution to the formation of breast cancer and their usefulness as potential biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Breast Cancer: Pathology, Diagnosis and Treatment)

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12 pages, 1265 KiB

Open AccessEditor’s ChoiceReview

Participant Recruitment Issues in Child and Adolescent Psychiatry Clinical Trials with a Focus on Prevention Programs: A Meta-Analytic Review of the Literature

by Deniz Kilicel, Franco De Crescenzo, Giuseppe Pontrelli and Marco Armando

J. Clin. Med. 2023, 12(6), 2307; https://doi.org/10.3390/jcm12062307 - 16 Mar 2023

Cited by 2 | Viewed by 1913

Abstract

Introduction: There is a strong need to conduct rigorous and robust trials for children and adolescents in mental health settings. One of the main barriers to meeting this requirement is the poor recruitment rate. Effective recruitment strategies are crucial for the success [...] Read more.

Introduction: There is a strong need to conduct rigorous and robust trials for children and adolescents in mental health settings. One of the main barriers to meeting this requirement is the poor recruitment rate. Effective recruitment strategies are crucial for the success of a clinical trial, and therefore, we reviewed recruitment strategies in clinical trials on children and adolescents in mental health with a focus on prevention programs. Methods: We reviewed the literature by searching PubMed/Medline, the Cochrane Library database, and Web of Science through December 2022 as well as the reference lists of relevant articles. We included only studies describing recruitment strategies for pediatric clinical trials in mental health settings and extracted data on recruitment and completion rates. Results: The search yielded 13 studies that enrolled a total of 14,452 participants. Overall, studies mainly used social networks or clinical settings to recruit participants. Half of the studies used only one recruitment method. Using multiple recruitment methods (56.6%, 95%CI: 24.5–86.0) resulted in higher recruitment. The use of monetary incentives (47.0%, 95%CI: 24.6–70.0) enhanced the recruitment rate but not significantly (32.6%, 95%CI: 15.7–52.1). All types of recruitment methods showed high completion rates (82.9%, 95%CI: 61.7–97.5) even though prevention programs showed the smallest recruitment rate (76.1%, 95%CI: 50.9–94.4). Conclusions: Pediatric mental health clinical trials face many difficulties in recruitment. We found that these trials could benefit from faster and more efficient recruitment of participants when more than one method is implemented. Social networks can be helpful where ethically possible. We hope the description of these strategies will help foster innovation in recruitment for pediatric studies in mental health. Full article

(This article belongs to the Section Mental Health)

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13 pages, 323 KiB

Open AccessEditor’s ChoiceReview

Transoral Robotic Surgery for Head and Neck Cancer: Advances and Residual Knowledge Gaps

by Mariam H. Mella, Emilien Chabrillac, Agnès Dupret-Bories, Mathilde Mirallie and Sébastien Vergez

J. Clin. Med. 2023, 12(6), 2303; https://doi.org/10.3390/jcm12062303 - 16 Mar 2023

Cited by 6 | Viewed by 3110

Abstract

Minimally invasive surgery is a growing field in surgical oncology. After acquiring its first Food and Drug Administration approval in 2009 for T1–T2 malignancies of the oral cavity, oropharynx, and larynx, transoral robotic surgery (TORS) has gained popularity thanks to its wristed instruments [...] Read more.

Minimally invasive surgery is a growing field in surgical oncology. After acquiring its first Food and Drug Administration approval in 2009 for T1–T2 malignancies of the oral cavity, oropharynx, and larynx, transoral robotic surgery (TORS) has gained popularity thanks to its wristed instruments and magnified three-dimensional view, enhancing surgical comfort in remote-access areas. Its indications are expanding in the treatment of head and neck cancer, i.e., resection of tumors of the larynx, hypopharynx, or parapharyngeal space. However, this expansion must remain cautious and based on high-level evidence, in order to guarantee safety and oncological outcomes which are comparable to conventional approaches. This narrative review assesses the current role of TORS in head and neck cancer from an evidence-based perspective, and then identifies what knowledge gaps remain to be addressed. Full article

(This article belongs to the Special Issue Diagnosis, Treatment and Management in Head and Neck Squamous Cell Carcinoma)

15 pages, 593 KiB

Open AccessEditor’s ChoiceReview

Antiplatelet Strategies for Older Patients with Acute Coronary Syndromes: Finding Directions in a Low-Evidence Field

by Stefano De Servi, Antonio Landi, Stefano Savonitto, Nuccia Morici, Leonardo De Luca, Claudio Montalto, Gabriele Crimi, Roberta De Rosa and Giuseppe De Luca

J. Clin. Med. 2023, 12(5), 2082; https://doi.org/10.3390/jcm12052082 - 6 Mar 2023

Cited by 6 | Viewed by 2803

Abstract

Patients ≥ 75 years of age account for about one third of hospitalizations for acute coronary syndromes (ACS). Since the latest European Society of Cardiology guidelines recommend that older ACS patients use the same diagnostic and interventional strategies used by the younger ones, [...] Read more.

Patients ≥ 75 years of age account for about one third of hospitalizations for acute coronary syndromes (ACS). Since the latest European Society of Cardiology guidelines recommend that older ACS patients use the same diagnostic and interventional strategies used by the younger ones, most elderly patients are currently treated invasively. Therefore, an appropriate dual antiplatelet therapy (DAPT) is indicated as part of the secondary prevention strategy to be implemented in such patients. The choice of the composition and duration of DAPT should be tailored on an individual basis, after careful assessment of the thrombotic and bleeding risk of each patient. Advanced age is a main risk factor for bleeding. Recent data show that in patients of high bleeding risk short DAPT (1 to 3 months) is associated with decreased bleeding complications and similar thrombotic events, as compared to standard 12-month DAPT. Clopidogrel seems the preferable P2Y12 inhibitor, due to a better safety profile than ticagrelor. When the bleeding risk is associated with a high thrombotic risk (a circumstance present in about two thirds of older ACS patients) it is important to tailor the treatment by taking into account the fact that the thrombotic risk is high during the first months after the index event and then wanes gradually over time, whereas the bleeding risk remains constant. Under these circumstances, a de-escalation strategy seems reasonable, starting with DAPT that includes aspirin and low-dose prasugrel (a more potent and reliable P2Y12 inhibitor than clopidogrel) then switching after 2–3 months to DAPT with aspirin and clopidogrel for up to 12 months. Full article

(This article belongs to the Section Cardiovascular Medicine)

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13 pages, 1407 KiB

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Biochemical Mechanisms beyond Glycosphingolipid Accumulation in Fabry Disease: Might They Provide Additional Therapeutic Treatments?

by Giovanni Bertoldi, Ilaria Caputo, Giulia Driussi, Lucia Federica Stefanelli, Valentina Di Vico, Gianni Carraro, Federico Nalesso and Lorenzo A. Calò

J. Clin. Med. 2023, 12(5), 2063; https://doi.org/10.3390/jcm12052063 - 6 Mar 2023

Cited by 9 | Viewed by 3065

Abstract

Fabry disease is a rare X-linked disease characterized by deficient expression and activity of alpha-galactosidase A (α-GalA) with consequent lysosomal accumulation of glycosphingolipid in various organs. Currently, enzyme replacement therapy is the cornerstone of the treatment of all Fabry patients, although in the [...] Read more.

Fabry disease is a rare X-linked disease characterized by deficient expression and activity of alpha-galactosidase A (α-GalA) with consequent lysosomal accumulation of glycosphingolipid in various organs. Currently, enzyme replacement therapy is the cornerstone of the treatment of all Fabry patients, although in the long-term it fails to completely halt the disease’s progression. This suggests on one hand that the adverse outcomes cannot be justified only by the lysosomal accumulation of glycosphingolipids and on the other that additional therapies targeted at specific secondary mechanisms might contribute to halt the progression of cardiac, cerebrovascular, and renal disease that occur in Fabry patients. Several studies reported how secondary biochemical processes beyond Gb3 and lyso-Gb3 accumulation—such as oxidative stress, compromised energy metabolism, altered membrane lipid, disturbed cellular trafficking, and impaired autophagy—might exacerbate Fabry disease adverse outcomes. This review aims to summarize the current knowledge of these pathogenetic intracellular mechanisms in Fabry disease, which might suggest novel additional strategies for its treatment. Full article

(This article belongs to the Section Nephrology & Urology)

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11 pages, 784 KiB

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What Should Be the Focus of Treatment When Insomnia Disorder Is Comorbid with Depression or Anxiety Disorder?

by Charles M. Morin, Suzanne M. Bertisch, Rafael Pelayo, Nathaniel F. Watson, John W. Winkelman, Phyllis C. Zee and Andrew D. Krystal

J. Clin. Med. 2023, 12(5), 1975; https://doi.org/10.3390/jcm12051975 - 2 Mar 2023

Cited by 7 | Viewed by 8149

Abstract

Insomnia is a significant, highly prevalent, persistent public health problem but often remains undiagnosed and untreated. Current treatment practices are not always evidence-based. When insomnia is comorbid with anxiety or depression, treatment often targets that comorbid condition with the expectation that improvement of [...] Read more.

Insomnia is a significant, highly prevalent, persistent public health problem but often remains undiagnosed and untreated. Current treatment practices are not always evidence-based. When insomnia is comorbid with anxiety or depression, treatment often targets that comorbid condition with the expectation that improvement of the mental health condition will generalize to sleep symptoms. An expert panel of seven members conducted a clinical appraisal of the literature regarding the treatment of insomnia when comorbid anxiety or depression are also present. The clinical appraisal consisted of the review, presentation, and assessment of current published evidence as it relates to the panel’s predetermined clinical focus statement, “Whenever chronic insomnia is associated with another condition, such as anxiety or depression, that psychiatric condition should be the only focus of treatment as the insomnia is most likely a symptom of the condition”. The results from an electronic national survey of US-based practicing physicians, psychiatrists, and sleep (N = 508) revealed that >40% of physicians agree “at least somewhat” that treatment of comorbid insomnia should focus solely on the psychiatric condition. Whereas 100% of the expert panel disagreed with the statement. Thus, an important gap exists between current clinical practices and evidence-based guidelines and more awareness is needed so that insomnia is treated distinctly from comorbid anxiety and depression. Full article

(This article belongs to the Special Issue Insomnia Treatments: New Perspectives)

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26 pages, 2515 KiB

Open AccessEditor’s ChoiceReview

Exercise across the Lung Cancer Care Continuum: An Overview of Systematic Reviews

by Lara Edbrooke, Amy Bowman, Catherine L. Granger, Nicola Burgess, Shaza Abo, Bronwen Connolly and Linda Denehy

J. Clin. Med. 2023, 12(5), 1871; https://doi.org/10.3390/jcm12051871 - 27 Feb 2023

Cited by 7 | Viewed by 3016

Abstract

Background: Growing evidence supports exercise for people with lung cancer. This overview aimed to summarise exercise intervention efficacy and safety across the care continuum. Methods: Eight databases (including Cochrane and Medline) were searched (inception—February 2022) for systematic reviews of RCTs/quasi-RCTs. Eligibility: population—adults with [...] Read more.

Background: Growing evidence supports exercise for people with lung cancer. This overview aimed to summarise exercise intervention efficacy and safety across the care continuum. Methods: Eight databases (including Cochrane and Medline) were searched (inception—February 2022) for systematic reviews of RCTs/quasi-RCTs. Eligibility: population—adults with lung cancer; intervention: exercise (e.g., aerobic, resistance) +/− non-exercise (e.g., nutrition); comparator: usual care/non-exercise; primary outcomes: exercise capacity, physical function, health-related quality of life (HRQoL) and post-operative complications. Duplicate, independent title/abstract and full-text screening, data extraction and quality ratings (AMSTAR-2) were completed. Results: Thirty systematic reviews involving between 157 and 2109 participants (n = 6440 total) were included. Most reviews (n = 28) involved surgical participants. Twenty-five reviews performed meta-analyses. The review quality was commonly rated critically low (n = 22) or low (n = 7). Reviews commonly included combinations of aerobic, resistance and/or respiratory exercise interventions. Pre-operative meta-analyses demonstrated that exercise reduces post-operative complications (n = 4/7) and improves exercise capacity (n = 6/6), whilst HRQoL findings were non-significant (n = 3/3). Post-operative meta-analyses reported significant improvements in exercise capacity (n = 2/3) and muscle strength (n = 1/1) and non-significant HRQoL changes (n = 8/10). Interventions delivered to mixed surgical and non-surgical populations improved exercise capacity (n = 3/4), muscle strength (n = 2/2) and HRQoL (n = 3). Meta-analyses of interventions in non-surgical populations demonstrated inconsistent findings. Adverse event rates were low, however, few reviews reported on safety. Conclusions: A large body of evidence supports lung cancer exercise interventions to reduce complications and improve exercise capacity in pre- and post-operative populations. Additional higher-quality research is needed, particularly in the non-surgical population, including subgroup analyses of exercise type and setting. Full article

(This article belongs to the Special Issue Advances in Pulmonary Rehabilitation)

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12 pages, 570 KiB

Open AccessEditor’s ChoiceReview

Long-Term Use of Insomnia Medications: An Appraisal of the Current Clinical and Scientific Evidence

by Phyllis C. Zee, Suzanne M. Bertisch, Charles M. Morin, Rafael Pelayo, Nathaniel F. Watson, John W. Winkelman and Andrew D. Krystal

J. Clin. Med. 2023, 12(4), 1629; https://doi.org/10.3390/jcm12041629 - 17 Feb 2023

Cited by 7 | Viewed by 7362

Abstract

While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the [...] Read more.

While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the evidence supporting the focus statement, “No insomnia medication should be used on a daily basis for durations longer than 3 weeks at a time”. The panelists’ assessment was also compared to findings from a national survey of practicing physicians, psychiatrists, and sleep specialists. Survey respondents revealed a wide range of opinions regarding the appropriateness of using the US Food and Drug Administration (FDA)-approved medications for the treatment of insomnia lasting more than 3 weeks. After discussion of the literature, the panel unanimously agreed that some classes of insomnia medications, such as non-benzodiazepines hypnotics, have been shown to be effective and safe for long-term use in the appropriate clinical setting. For eszopiclone, doxepin, ramelteon and the newer class of dual orexin receptor antagonists, the FDA label does not specify that their use should be of a limited duration. Thus, an evaluation of evidence supporting the long-term safety and efficacy of newer non-benzodiazepine hypnotics is timely and should be considered in practice recommendations for the duration of pharmacologic treatment of chronic insomnia. Full article

(This article belongs to the Special Issue Insomnia Treatments: New Perspectives)

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16 pages, 691 KiB

Open AccessEditor’s ChoiceReview

Clinical Impacts of Interventions for Physical Activity and Sedentary Behavior on Patients with Chronic Obstructive Pulmonary Disease

by Hiroki Tashiro and Koichiro Takahashi

J. Clin. Med. 2023, 12(4), 1631; https://doi.org/10.3390/jcm12041631 - 17 Feb 2023

Cited by 8 | Viewed by 3328

Abstract

Recently, physical activity has increasingly become the focus in patients with chronic obstructive airway disease (COPD) because it is a strong predictor of COPD-related mortality. In addition, sedentary behavior, which is included as a category of physical inactivity including such behaviors as sitting [...] Read more.

Recently, physical activity has increasingly become the focus in patients with chronic obstructive airway disease (COPD) because it is a strong predictor of COPD-related mortality. In addition, sedentary behavior, which is included as a category of physical inactivity including such behaviors as sitting or lying down, has an independent clinical impact on COPD patients. The present review examines clinical data related to physical activity, focusing on the definition, associated factors, beneficial effects, and biological mechanisms in patients with COPD and with respect to human health regardless of COPD. The data related to how sedentary behavior is associated with human health and COPD outcomes are also examined. Lastly, possible interventions to improve physical activity or sedentary behavior, such as bronchodilators and pulmonary rehabilitation with behavior modification, to ameliorate the pathophysiology of COPD patients are described. A better understanding of the clinical impact of physical activity or sedentary behavior may lead to the planning of a future intervention study to establish high-level evidence. Full article

(This article belongs to the Special Issue Effects of Physical Activity on Chronic Disease)

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12 pages, 296 KiB

Open AccessEditor’s ChoiceReview

Advancing Precision Medicine for the Diagnosis and Treatment of Acute Respiratory Distress Syndrome

by Alicia N. Rizzo, Neil R. Aggarwal, B. Taylor Thompson and Eric P. Schmidt

J. Clin. Med. 2023, 12(4), 1563; https://doi.org/10.3390/jcm12041563 - 16 Feb 2023

Cited by 10 | Viewed by 2811

Abstract

Acute respiratory distress syndrome (ARDS) is a common and life-threatening cause of respiratory failure. Despite decades of research, there are no effective pharmacologic therapies to treat this disease process and mortality remains high. The shortcomings of prior translational research efforts have been increasingly [...] Read more.

Acute respiratory distress syndrome (ARDS) is a common and life-threatening cause of respiratory failure. Despite decades of research, there are no effective pharmacologic therapies to treat this disease process and mortality remains high. The shortcomings of prior translational research efforts have been increasingly attributed to the heterogeneity of this complex syndrome, which has led to an increased focus on elucidating the mechanisms underlying the interpersonal heterogeneity of ARDS. This shift in focus aims to move the field towards personalized medicine by defining subgroups of ARDS patients with distinct biology, termed endotypes, to quickly identify patients that are most likely to benefit from mechanism targeted treatments. In this review, we first provide a historical perspective and review the key clinical trials that have advanced ARDS treatment. We then review the key challenges that exist with regards to the identification of treatable traits and the implementation of personalized medicine approaches in ARDS. Lastly, we discuss potential strategies and recommendations for future research that we believe will aid in both understanding the molecular pathogenesis of ARDS and the development of personalized treatment approaches. Full article

(This article belongs to the Special Issue New Insights into Acute Respiratory Distress Syndrome)

13 pages, 721 KiB

Open AccessEditor’s ChoiceReview

Multimodality Imaging in Arrhythmogenic Left Ventricular Cardiomyopathy

by Emanuele Monda, Marta Rubino, Giuseppe Palmiero, Federica Verrillo, Michele Lioncino, Gaetano Diana, Annapaola Cirillo, Adelaide Fusco, Francesca Dongiglio, Martina Caiazza, Ippolita Altobelli, Alfredo Mauriello, Natale Guarnaccia, Alessandra Scatteia, Arturo Cesaro, Giuseppe Pacileo, Berardo Sarubbi, Giulia Frisso, Barbara Bauce, Antonello D’Andrea, Santo Dellegrottaglie, Maria Giovanna Russo, Paolo Calabrò and Giuseppe Limongelli Show full author list Hide full author list

J. Clin. Med. 2023, 12(4), 1568; https://doi.org/10.3390/jcm12041568 - 16 Feb 2023

Cited by 6 | Viewed by 2769

Abstract

The term arrhythmogenic cardiomyopathy (ACM) describes a large spectrum of myocardial diseases characterized by progressive fibrotic or fibrofatty replacement, which gives the substrate for the occurrence of ventricular tachyarrhythmias and the development of ventricular dysfunction. This condition may exclusively affect the left ventricle, [...] Read more.

The term arrhythmogenic cardiomyopathy (ACM) describes a large spectrum of myocardial diseases characterized by progressive fibrotic or fibrofatty replacement, which gives the substrate for the occurrence of ventricular tachyarrhythmias and the development of ventricular dysfunction. This condition may exclusively affect the left ventricle, leading to the introduction of the term arrhythmogenic left ventricular cardiomyopathy (ALVC). The clinical features of ALVC are progressive fibrotic replacement with the absence or mild dilation of the LV and the occurrence of ventricular arrhythmias within the left ventricle. In 2019, the diagnostic criteria for the diagnosis of ALVC, based on family history and clinical, electrocardiographic, and imaging features, have been proposed. However, since the significant clinical and imaging overlap with other cardiac diseases, genetic testing with the demonstration of a pathogenic variant in an ACM-related gene is required for diagnostic confirmation. In ALVC, the multimodality imaging approach comprises different imaging techniques, such as echocardiography, cardiac magnetic resonance, and cardiac nuclear imaging. It provides essential information for the diagnosis, differential diagnosis, sudden cardiac death risk stratification, and management purposes. This review aims to elucidate the current role of the different multimodality imaging techniques in patients with ALVC. Full article

(This article belongs to the Section Cardiology)

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16 pages, 1745 KiB

Open AccessEditor’s ChoiceReview

Current and Emerging Therapies for Atherosclerotic Cardiovascular Disease Risk Reduction in Hypertriglyceridemia

by Reed Mszar, Sarah Bart, Alexander Sakers, Daniel Soffer and Dean G. Karalis

J. Clin. Med. 2023, 12(4), 1382; https://doi.org/10.3390/jcm12041382 - 9 Feb 2023

Cited by 4 | Viewed by 4117

Abstract

Hypertriglyceridemia (HTG) is a prevalent medical condition in patients with cardiometabolic risk factors and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), if left undiagnosed and undertreated. Current guidelines identify HTG as a risk-enhancing factor and, as a result, recommend [...] Read more.

Hypertriglyceridemia (HTG) is a prevalent medical condition in patients with cardiometabolic risk factors and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), if left undiagnosed and undertreated. Current guidelines identify HTG as a risk-enhancing factor and, as a result, recommend clinical evaluation and lifestyle-based interventions to address potential secondary causes of elevated triglyceride (TG) levels. For individuals with mild to moderate HTG at risk of ASCVD, statin therapy alone or in combination with other lipid-lowering medications known to decrease ASCVD risk are guideline-endorsed. In addition to lifestyle modifications, patients with severe HTG at risk of acute pancreatitis may benefit from fibrates, mixed formulation omega-3 fatty acids, and niacin; however, evidence does not support their use for ASCVD risk reduction in the contemporary statin era. Novel therapeutics including those that target apoC-III and ANGPTL3 have shown to be safe, well-tolerated, and effective for lowering TG levels. Given the growing burden of cardiometabolic disease and risk factors, public health and health policy strategies are urgently needed to enhance access to effective pharmacotherapies, affordable and nutritious food options, and timely health care services. Full article

(This article belongs to the Special Issue New Advances in Dyslipidemia)

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14 pages, 1376 KiB

Open AccessEditor’s ChoiceReview

An Overview of Systematic Reviews and Meta-Analyses on the Effect of Medication Interventions Targeting Polypharmacy for Frail Older Adults

by Aparna Verma, Sanjib Saha, Johan Jarl, Ellen Conlon, Bernadette McGuinness and Dominic Trépel

J. Clin. Med. 2023, 12(4), 1379; https://doi.org/10.3390/jcm12041379 - 9 Feb 2023

Cited by 8 | Viewed by 2349

Abstract

Frailty refers to the lack of resilience and a reduction in a person’s ability to recover following a health problem, and it is increasingly becoming a challenging aspect of ageing populations. Many older adults are exposed to polypharmacy; i.e., they continue to be [...] Read more.

Frailty refers to the lack of resilience and a reduction in a person’s ability to recover following a health problem, and it is increasingly becoming a challenging aspect of ageing populations. Many older adults are exposed to polypharmacy; i.e., they continue to be on medications without timely re-evaluation. Medication reviews have proven successful in managing polypharmacy in the general population, but there is uncertainty regarding their effect among frail older adults. This overview of published systematic reviews assesses the impact of medication reviews on polypharmacy in frail older adults. Embase was searched from its inception to January 2021 and 28 systematic reviews were identified, out of which 10 were included in the overview. Medication reviews were the most common intervention in 8 out of 10 systematic reviews. The frailty score was reported as an outcome in one systematic review that found no evidence for fundamental pharmacological effects on frailty. Six systematic reviews reported a statistically significant reduction in the number of inappropriately prescribed medications. Four systematic reviews reported on hospital admissions, with two of them reporting a decrease in hospitalisations. The quality assessment was moderate in six and critically low in four of the systematic reviews. We conclude that medication reviews help in reducing the use of inappropriate medications in frail older adults, but that there is insufficient evidence in terms of frailty score and hospital admissions. Full article

(This article belongs to the Section Epidemiology & Public Health)

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