Editor’s Choice Articles

The discovery of therapeutic miRNAs is one of the most exciting challenges for pharmaceutical companies. Since the first miRNA was discovered in 1993, our knowledge of miRNA biology has grown considerably. Many studies have demonstrated that miRNA expression is dysregulated in many diseases, making them appealing tools for novel therapeutic approaches. This review aims to discuss miRNA biogenesis and function, as well as highlight strategies for delivering miRNA agents, presenting viral, non-viral, and exosomic delivery as therapeutic approaches for different cancer types. We also consider the therapeutic role of microRNA-mediated drug repurposing in cancer therapy. Full article

The advancement of sciences and technologies, economic challenges, increasing expectations, and consumerism result in a radical transformation of health and social care around the globe, characterized by foundational organizational, methodological, and technological paradigm changes. The transformation of the health and social care ecosystems aims at ubiquitously providing personalized, preventive, predictive, participative precision (5P) medicine, considering and understanding the individual’s health status in a comprehensive context from the elementary particle up to society. For designing and implementing such advanced ecosystems, an understanding and correct representation of the structure, function, and relations of their components is inevitable, thereby including the perspectives, principles, and methodologies of all included disciplines. To guarantee consistent and conformant processes and outcomes, the specifications and principles must be based on international standards. A core standard for representing transformed health ecosystems and managing the integration and interoperability of systems, components, specifications, and artifacts is ISO 23903:2021, therefore playing a central role in this publication. Consequently, ISO/TC 215 and CEN/TC 251, both representing the international standardization on health informatics, declared the deployment of ISO 23903:2021 mandatory for all their projects and standards addressing more than one domain. The paper summarizes and concludes the first author’s leading engagement in the evolution of pHealth in Europe and beyond over the last 15 years, discussing the concepts, principles, and standards for designing, implementing, and managing 5P medicine ecosystems. It not only introduces the theoretical foundations of the approach but also exemplifies its deployment in practical projects and solutions regarding interoperability and integration in multi-domain ecosystems. The presented approach enables comprehensive and consistent integration of and interoperability between domains, systems, related actors, specifications, standards, and solutions. That way, it should help overcome the problems and limitations of data-centric approaches, which still dominate projects and products nowadays, and replace them with knowledge-centric, comprehensive, and consistent ones. Full article

With the recent diffusion of access to publicly available large language models (LLMs), common interest in generative artificial-intelligence-based applications for medical purposes has skyrocketed. The increased use of these models by tech-savvy patients for personal health issues calls for a scientific evaluation of whether LLMs provide a satisfactory level of accuracy for treatment decisions. This observational study compares the concordance of treatment recommendations from the popular LLM ChatGPT 3.5 with those of a multidisciplinary tumor board for breast cancer (MTB). The study design builds on previous findings by combining an extended input model with patient profiles reflecting patho- and immunomorphological diversity of primary breast cancer, including primary metastasis and precancerous tumor stages. Overall concordance between the LLM and MTB is reached for half of the patient profiles, including precancerous lesions. In the assessment of invasive breast cancer profiles, the concordance amounts to 58.8%. Nevertheless, as the LLM makes considerably fraudulent decisions at times, we do not identify the current development status of publicly available LLMs to be adequate as a support tool for tumor boards. Gynecological oncologists should familiarize themselves with the capabilities of LLMs in order to understand and utilize their potential while keeping in mind potential risks and limitations. Full article

Airway management is usually an uncomplicated and safe intervention; however, when problems arise with the primary airway technique, the clinical situation can rapidly deteriorate, resulting in significant patient harm. Videolaryngoscopy has been shown to improve patient outcomes when compared with direct laryngoscopy, including improved first-pass success at tracheal intubation, reduced difficult laryngeal views, reduced oxygen desaturation, reduced airway trauma, and improved recognition of oesophageal intubation. The shared view that videolaryngoscopy affords may also facilitate superior teaching, training, and multidisciplinary team performance. As such, its recommended role in airway management has evolved from occasional use as a rescue device (when direct laryngoscopy fails) to a first-intention technique that should be incorporated into routine clinical practice, and this is reflected in recently updated guidelines from a number of international airway societies. However, currently, overall videolaryngoscopy usage is not commensurate with its now widespread availability. A number of factors exist that may be preventing its full adoption, including perceived financial costs, inadequacy of education and training, challenges in achieving deliverable decontamination processes, concerns over sustainability, fears over “de-skilling” at direct laryngoscopy, and perceived limitations of videolaryngoscopes. This article reviews the most up-to-date evidence supporting videolaryngoscopy, explores its current scope of utilisation (including specialist techniques), the potential barriers preventing its full adoption, and areas for future advancement and research. Full article

Since its introduction in the early 2000s, robotic surgery has represented a significative innovation within a minimally invasive surgery approach. A variety of robotic platforms have been made available throughout the years, and the outcomes related to those platforms have been described in the literature for many types of surgeries. Medtronic’s Hugo^TM RAS system is one of the newest robotic generations launched, but because of its recent placing on the field, comprehensive clinical data are still lacking. The aim of the present state of the art is to address the current literature concerning the use of the Hugo^TM RAS robot in order to report its feasibility, safety and clinical applications in different surgical branches. Two reviewers independently conducted a search on the “PubMed” electronic database, using the keywords “Hugo” and “Hugo RAS”. After the initial screening of 35 results, a total of 15 articles concerning the Hugo RAS system were selected for the review, including both oncological and benign surgery. Patients’ demographic and baseline data were compared including, when available, docking system times, complications and oncological outcomes in the fields of urologic, gynecologic and general surgery. With reference to urological procedures, a total of 156 robot-assisted radical prostatectomies, 10 robot-assisted partial nephrectomies, and 5 robot-assisted adrenalectomies were performed, involving a total of 171 patients. The surgical branch in which the Hugo system found its major application was urology, which was followed by gynecology and general surgery. The Hugo RAS system by Medtronic represents an innovative and safe surgical platform, with excellent perspective for the future and different clinical applications in many surgical branches. More studies are needed to validate the safety and results from this new robotic platform. Full article

Artificial Intelligence (AI) has emerged as a transformative technology with immense potential in the field of medicine. By leveraging machine learning and deep learning, AI can assist in diagnosis, treatment selection, and patient monitoring, enabling more accurate and efficient healthcare delivery. The widespread implementation of AI in healthcare has the role to revolutionize patients’ outcomes and transform the way healthcare is practiced, leading to improved accessibility, affordability, and quality of care. This article explores the diverse applications and reviews the current state of AI adoption in healthcare. It concludes by emphasizing the need for collaboration between physicians and technology experts to harness the full potential of AI. Full article

Triple-negative breast cancer (TNBC) poses a significant challenge in terms of prognosis and disease recurrence. The limited treatment options and the development of resistance to chemotherapy make it particularly difficult to manage these patients. However, recent research has been shifting its focus towards biomarker-based approaches for TNBC, with a particular emphasis on the tumor immune landscape. Immune biomarkers in TNBC are now a subject of great interest due to the presence of tumor-infiltrating lymphocytes (TILs) in these tumors. This characteristic often coincides with the presence of PD-L1 expression on both neoplastic cells and immune cells within the tumor microenvironment. Furthermore, a subset of TNBC harbor mismatch repair deficient (dMMR) TNBC, which is frequently accompanied by microsatellite instability (MSI). All of these immune biomarkers hold actionable potential for guiding patient selection in immunotherapy. To fully capitalize on these opportunities, the identification of additional or complementary biomarkers and the implementation of highly customized testing strategies are of paramount importance in TNBC. In this regard, this article aims to provide an overview of the current state of the art in immune-related biomarkers for TNBC. Specifically, it focuses on the various testing methodologies available and sheds light on the immediate future perspectives for patient selection. By delving into the advancements made in understanding the immune landscape of TNBC, this study aims to contribute to the growing body of knowledge in the field. The ultimate goal is to pave the way for the development of more personalized testing strategies, ultimately improving outcomes for TNBC patients. Full article

Background: Acute heart failure (AHF) is a major cause of hospitalization and mortality worldwide. Early and accurate diagnosis, as well as effective risk stratification, are essential for optimizing clinical management and improving patient outcomes. In this context, biomarkers have gained increasing interest in recent years as they can provide important diagnostic and prognostic information in patients with AHF. Aim and Methods: The primary objective of the present study was to compare the levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), and C-reactive protein (CRP) between patients diagnosed with acute heart failure (AHF) and those without AHF and sepsis. Furthermore, the study aimed to assess the diagnostic and prognostic value of the use of a multimarker approach in AHF patients. To achieve these objectives, a total of 145 patients with AHF and 127 patients without AHF and sepsis, serving as the control group, were consecutively enrolled in the study. Results: Levels of MR-proADM (median: 2.07; (25th–75th percentiles: 1.40–3.02) vs. 1.11 (0.83–1.71) nmol/L, p < 0.0001), and NT-proBNP (5319 (1691–11,874) vs. 271 (89–931.5) pg/mL, p < 0.0001) were significantly higher in patients with AHF compared to controls, whereas CRP levels did not show significant differences. The mortality rate in the AHF group during in-hospital stay was 12%, and the rate of new re-admission for AHF within 30 days after discharge was 10%. During in-hospital follow-up, Cox regression analyses showed that levels of NT-proBNP > 10,132 pg/mL (hazard ratio (HR) 2.97; 95% confidence interval (CI): 1.13–7.82; p = 0.0284) and levels of MR-proADM > 2.8 nmol/L (HR: 8.57; CI: 2.42–30.28; p = 0.0009) predicted mortality. The combined use of MR-proADM and NT-proBNP provided significant additive predictive value for mortality and new re-admission for AHF at 30 days after discharge. A logistic regression analysis showed that the presence of NT-proBNP pg/mL > 12,973 pg mL and/or MR-proADM > 4.2 nmol/L predicted hospital re-admission within 30 days (OR: 3.23; CI: 1.05–9.91; p = 0.041). Conclusion: The combined assay of MR-proADM and NT-proBNP could be helpful in accurately identifying AHF and in defining prognosis and re-admission for AHF. The complementary use of these biomarkers can provide a useful clinical evaluation of AHF while also orienting clinicians to the pathophysiology underlying heart damage and assisting them in tailoring therapy. Full article

Fitting cochlear implant (CI) users can be challenging. Anatomy-based fitting (ABF) maps may have the potential to lead to better objective and subjective outcomes than conventional clinically based fitting (CBF) methods. ABF maps were created via information derived from exact electrode contact positions, which were determined via post-operative high-resolution flat panel volume computer tomography and clinical fitting software. The outcome measures were speech understanding in quiet and noise and self-perceived sound quality with the CBF map and with the ABF map. Participants were 10 experienced bilateral CI users. The ABF map provided better speech understanding in quiet and noisy environments compared to the CBF map. Additionally, two approaches of reducing the frequency-to-place mismatch revealed that participants are more likely to accept the ABF map if their electrode array is inserted deep enough to stimulate the apical region of their cochlea. This suggests an Angular Insertion Depth of the most apical contact of around 720°–620°. Participants had better speech understanding in quiet and noise with the ABF map. The maps’ self-perceived sound quality was similar. ABF mapping may be an effective tool for compensating the frequency-to-place mismatch in experienced bilateral CI users. Full article

Introduction: Pancreas transplantation is currently the only treatment that can re-establish normal endocrine pancreatic function. Despite all efforts, pancreas allograft survival and rejection remain major clinical problems. The purpose of this study was to identify features that could signal patients at risk of pancreas allograft rejection. Methods: We collected 74 features from 79 patients who underwent simultaneous pancreas–kidney transplantation (SPK) and used two widely-applicable classification methods, the Naive Bayesian Classifier and Support Vector Machine, to build predictive models. We used the area under the receiver operating characteristic curve and classification accuracy to evaluate the predictive performance via leave-one-out cross-validation. Results: Rejection events were identified in 13 SPK patients (17.8%). In feature selection approach, it was possible to identify 10 features, namely: previous treatment for diabetes mellitus with long-term Insulin (U/I/day), type of dialysis (peritoneal dialysis, hemodialysis, or pre-emptive), de novo DSA, vPRA_Pre-Transplant (%), donor blood glucose, pancreas donor risk index (pDRI), recipient height, dialysis time (days), warm ischemia (minutes), recipient of intensive care (days). The results showed that the Naive Bayes and Support Vector Machine classifiers prediction performed very well, with an AUROC and classification accuracy of 0.97 and 0.87, respectively, in the first model and 0.96 and 0.94 in the second model. Conclusion: Our results indicated that it is feasible to develop successful classifiers for the prediction of graft rejection. The Naive Bayesian generated nomogram can be used for rejection probability prediction, thus supporting clinical decision making. Full article

There is an increasing need for inexpensive and rapid screening tests in point-of-care clinical oncology settings. Herein, we develop a swab “dip” test in saliva obtained from consenting patients participating in a lung-cancer-screening programme being undertaken in North West England. In a pilot study, a total of 211 saliva samples (n = 170 benign, 41 designated cancer-positive) were randomly taken during the course of this prospective lung-cancer-screening programme. The samples (sterile Copan blue rayon swabs dipped in saliva) were analysed using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy. An exploratory analysis using principal component analysis (PCA,) with or without linear discriminant analysis (LDA), was then undertaken. Three pairwise comparisons were undertaken including: (1) benign vs. cancer following swab analysis; (2) benign vs. cancer following swab analysis with the subtraction of dry swab spectra; and (3) benign vs. cancer following swab analysis with the subtraction of wet swab spectra. Consistent and remarkably similar patterns of clustering for the benign control vs. cancer categories, irrespective of whether the swab plus saliva sample was analysed or whether there was a subtraction of wet or dry swab spectra, was observed. In each case, MANOVA demonstrated that this segregation of categories is highly significant. A k-NN (using three nearest neighbours) machine-learning algorithm also showed that the specificity (90%) and sensitivity (75%) are consistent for each pairwise comparison. In detailed analyses, the swab as a substrate did not alter the level of spectral discrimination between benign control vs. cancer saliva samples. These results demonstrate a novel swab “dip” test using saliva as a biofluid that is highly applicable to be rolled out into a larger lung-cancer-screening programme. Full article

The rapid advancement of digital technologies and recent global pandemic-like scenarios have pressed our society to reform and adapt health and social care toward personalizing the home care setting. This transformation assists in avoiding treatment in crowded secondary health care facilities and improves the experience and impact on both healthcare professionals and service users alike. The interoperability challenge through standards-based roadmaps is the lynchpin toward enabling the efficient interconnection between health and social care services. Hence, facilitating safe and trustworthy data workflow from one healthcare system to another is a crucial aspect of the communication process. In this paper, we showcase a methodology as to how we can extract, transform and load data in a semi-automated process using a common semantic standardized data model (CSSDM) to generate a personalized healthcare knowledge graph (KG). CSSDM is based on a formal ontology of ISO 13940:2015 ContSys for conceptual grounding and FHIR-based specification to accommodate structural attributes to generate KG. The goal of CSSDM is to offer an alternative pathway to discuss interoperability by supporting a unique collaboration between a company creating a health information system and a cloud-enabled health service. The resulting pathway of communication provides access to multiple stakeholders for sharing high-quality data and information. Full article

Breast cancer is the most common and most commonly diagnosed non-skin cancer in women. There are several risk factors related to habits and heredity, and screening is essential to reduce the incidence of mortality. Thanks to screening and increased awareness among women, most breast cancers are diagnosed at an early stage, increasing the chances of cure and survival. Regular screening is essential. Mammography is currently the gold standard for breast cancer diagnosis. In mammography, we can encounter problems with the sensitivity of the instrument; in fact, in the case of a high density of glands, the ability to detect small masses is reduced. In fact, in some cases, the lesion may not be particularly evident, it may be hidden, and it is possible to incur false negatives as partial details that may escape the radiologist’s eye. The problem is, therefore, substantial, and it makes sense to look for techniques that can increase the quality of diagnosis. In recent years, innovative techniques based on artificial intelligence have been used in this regard, which are able to see where the human eye cannot reach. In this paper, we can see the application of radiomics in mammography. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and is related to fatal and non-fatal liver, metabolic, and cardiovascular complications. Its non-invasive diagnosis and effective treatment remain an unmet clinical need. NAFLD is a heterogeneous disease that is most commonly present in the context of metabolic syndrome and obesity, but not uncommonly, may also be present without metabolic abnormalities and in subjects with normal body mass index. Therefore, a more specific pathophysiology-based subcategorization of fatty liver disease (FLD) is needed to better understand, diagnose, and treat patients with FLD. A precision medicine approach for FLD is expected to improve patient care, decrease long-term disease outcomes, and develop better-targeted, more effective treatments. We present herein a precision medicine approach for FLD based on our recently proposed subcategorization, which includes the metabolic-associated FLD (MAFLD) (i.e., obesity-associated FLD (OAFLD), sarcopenia-associated FLD (SAFLD, and lipodystrophy-associated FLD (LAFLD)), genetics-associated FLD (GAFLD), FLD of multiple/unknown causes (XAFLD), and combined causes of FLD (CAFLD) as well as advanced stage fibrotic FLD (FAFLD) and end-stage FLD (ESFLD) subcategories. These and other related advances, as a whole, are expected to enable not only improved patient care, quality of life, and long-term disease outcomes, but also a considerable reduction in healthcare system costs associated with FLD, along with more options for better-targeted, more effective treatments in the near future. Full article

(1) Background: Percutaneous left ventricle assist devices (pLVADs) demonstrated an improvement in mid-term clinical outcomes in selected patients with severely depressed left ventricular ejection fraction (LVEF) undergoing percutaneous coronary interventions. However, the prognostic impact of in-hospital LVEF recovery is unclear. Accordingly, the present sub-analysis aims to evaluate the impact of LVEF recovery in both cardiogenic shock (CS) and high-risk percutaneous coronary intervention (HR PCI) supported with pLVADs in the IMP-IT registry. (2) Methods: A total of 279 patients (116 patients in CS and 163 patients in HR PCI) treated with Impella 2.5 or CP in the IMP-IT registry were included in this analysis, after excluding those who died while in the hospital or with missing data on LVEF recovery. The primary study objective was a composite of all-cause death, rehospitalisation for heart failure, left ventricle assist device (LVAD) implantation, or heart transplantation (HT), overall referred to as the major adverse cardiac events (MACE) at 1 year. The study aimed to evaluate the impact of in-hospital LVEF recovery on the primary study objective in patients treated with Impella for HR PCI and CS, respectively. (3) Results: The mean in-hospital change in LVEF was 10 ± 1% (p < 0.001) in the CS cohort and 3 ± 7% (p < 0.001) in the HR PCI group, achieved by 44% and 40% of patients, respectively. In the CS group, patients with less than 10% in-hospital LVEF recovery experienced higher rates of MACE at 1 year of follow-up (FU) (51% vs. 21%, HR 3.8, CI 1.7–8.4, p < 0.01). After multivariate analysis, LVEF recovery was the main independent protective factor for MACE at FU (HR 0.23, CI 0.08–0.64, p = 0.02). In the HR PCI group, LVEF recovery (>3%) was not associated with lower MACE at multivariable analysis (HR 0.73, CI 0.31–1.72, p = 0.17). Conversely, the completeness of revascularisation was found to be a protective factor for MACE (HR 0.11, CI 0.02–0.62, p = 0.02) (4) Conclusions: Significant LVEF recovery was associated with improved outcomes in CS patients treated with PCI during mechanical circulatory support with Impella, whereas complete revascularisation showed a significant clinical relevance in HR PCI. Full article

Background: Hemostasis of the femoral arterial access site by manual compression or a vascular closure device is critical to the safe completion of any endovascular procedure. Previous investigations evaluated the hemostatic efficacy at the radial access site of some chitosan-based hemostatic pads. This study aims to assess the efficacy and safety of a new chitosan-based hemostatic dressing, namely Axiostat^®, in aiding manual compression closure of the femoral arterial access site in patients undergoing endovascular treatments. Furthermore, the outcomes were compared with evidence on manual compression alone and vascular closure devices. Methods: This investigation is a two-center retrospective analysis of 120 consecutive patients who had undergone, from July 2022 to February 2023, manual compression closure of the femoral arterial access site aided by the Axiostat^® hemostatic dressing. Endovascular procedures performed with introducer sheaths ranging from 4 Fr to 8 Fr were evaluated. Results: Primary technical success was achieved in 110 (91.7%) patients, with adequate hemostasis obtained in all cases of prolonged manual compression requirements. The mean time-to-hemostasis and time-to-ambulation were 8.9 (±3.9) and 462 (±199) minutes, respectively. Clinical success was achieved in 113 (94.2%) patients, with bleeding-related complications noted in 7 (5.8%) patients. Conclusions: Manual compression aided by the Axiostat^® hemostatic dressing is effective and safe in achieving hemostasis of the femoral arterial access site in patients undergoing endovascular treatment with a 4–8 Fr introducer sheath. Full article

Background: The aim of this study was to analyze the relationship between extent, severity (stage), and rate of progression (grade) of periodontitis with systemic diseases as well as smoking using a large database. Methods: Patients’ records identified in the BigMouth Dental Data Repository with a periodontal diagnosis based on the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions were evaluated. Patients were further categorized based on extent, severity, and rate of progression. Data were extracted from patients’ electronic health records including demographic characteristics, dental procedural codes, and self-reported medical conditions, as well as the number of missing teeth. Results: A total of 2069 complete records were ultimately included in the analysis. Males were more likely to have generalized periodontitis and stage III or IV periodontitis. Older individuals were more likely diagnosed with grade B and stage III or IV periodontitis. Individuals with generalized disease, grade C, and stage IV demonstrated a significantly higher number of missing teeth. Higher numbers of tooth loss reported during supportive periodontal treatment were noted in generalized disease and stage IV periodontitis. Multiple sclerosis and smoking were significantly associated with grade C periodontitis. Conclusions: Within the limitations of this retrospective study that utilized the BigMouth dental data repository, smokers were significantly associated with rapid progression of periodontitis (grade C). Gender, age, number of missing teeth, and number of tooth loss during supportive periodontal treatment were associated with disease characteristics. Full article

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. The association between lung and gut microbiomes in the pathogenesis of COPD has been recently uncovered. The goal of this study was to discuss the role of the lung and gut microbiomes in COPD pathophysiology. A systematic search of the PubMed database for relevant articles submitted up to June 2022 was performed. We examined the association between the lung and gut microbiome dysbiosis, reflected in bronchoalveolar lavage (BAL), lung tissue, sputum, and feces samples, and the pathogenesis and progression of COPD. It is evident that the lung and gut microbiomes affect each other and both play a vital role in the pathogenesis of COPD. However, more research needs to be carried out to find the exact associations between microbiome diversity and COPD pathophysiology and exacerbation genesis. Another field that research should focus on is the impact of treatment interventions targeting the human microbiome in preventing COPD genesis and progression. Full article

Raman spectroscopy recently proved a tremendous capacity to identify disease-specific markers in various (bio)samples being a non-invasive, rapid, and reliable method for cancer detection. In this study, we first aimed to record vibrational spectra of salivary exosomes isolated from oral and oropharyngeal squamous cell carcinoma patients and healthy controls using surface enhancement Raman spectroscopy (SERS). Then, we assessed this method’s capacity to discriminate between malignant and non-malignant samples by means of principal component–linear discriminant analysis (PC-LDA) and we used area under the receiver operating characteristics with illustration as the area under the curve to measure the power of salivary exosomes SERS spectra analysis to identify cancer presence. The vibrational spectra were collected on a solid plasmonic substrate developed in our group, synthesized using tangential flow filtered and concentrated silver nanoparticles, capable of generating very reproducible spectra for a whole range of bioanalytes. SERS examination identified interesting variations in the vibrational bands assigned to thiocyanate, proteins, and nucleic acids between the saliva of cancer and control groups. Chemometric analysis indicated discrimination sensitivity between the two groups up to 79.3%. The sensitivity is influenced by the spectral interval used for the multivariate analysis, being lower (75.9%) when the full-range spectra were used. Full article

In patients undergoing percutaneous coronary intervention, the second-generation drug-eluting stents (DES) are considered the gold standard of care for revascularization. By reducing neointimal hyperplasia, drug-eluting coronary stents decrease the need for repeat revascularizations compared with conventional coronary stents without an antiproliferative drug coating. It is important to note that early-generation DESs were associated with an increased risk of very late stent thrombosis, most likely due to delayed endothelialization or a delayed hypersensitivity reaction to the polymer. Studies have shown a lower risk of very late stent thrombosis with developing second-generation DESs with biocompatible and biodegradable polymers or without polymers altogether. In addition, research has indicated that thinner struts are associated with a reduced risk of intrastent restenosis and angiographic and clinical results. A DES with ultrathin struts (strut thickness of 70 µm) is more flexible, facilitates better tracking, and is more crossable than a conventional second-generation DES. The question is whether ultrathin eluting drug stents suit all kinds of lesions. Several authors have reported that improved coverage with less thrombus protrusion reduced the risk of distal embolization in patients with ST-elevation myocardial infarction (STEMI). Others have described that an ultrathin stent might recoil due to low radial strength. This could lead to residual stenosis and repeated revascularization of the artery. In CTO patients, the ultrathin stent failed to prove non-inferiority regarding in-segment late lumen loss and showed statistically higher rates of restenosis. Ultrathin-strut DESs with biodegradable polymers have limitations when treating calcified (or ostial) lesions and CTOs. However, they also possess certain advantages regarding deliverability (tight stenosis, tortuous lesions, high angulation, etc.), ease of use in bifurcation lesions, better endothelialization and vascular healing, and reducing stent thrombosis risk. In light of this, ultrathin-strut stents present a promising alternative to existing DESs of the second and third generation. The aims of the study are to compare ultrathin eluting stents with second- and third-generation conventional stents regarding procedural performance and outcomes based on different lesion types and specific populations. Full article

Successful outcomes of in vitro fertilization (IVF) rely on both the formation of a chromosomally normal embryo and its implantation in a receptive endometrium. Pre-implantation genetic testing for aneuploidy (PGT-A) has been widely accepted as a tool to assess the viability of an embryo. In 2011, the endometrial receptivity array (ERA) was first published as a tool to determine when the endometrium is most receptive to an embryo, commonly referred to as the “window of implantation” (WOI). The ERA uses molecular arrays to assess proliferation and differentiation in the endometrium and screens for inflammatory markers. Unlike PGT-A, there has been dissent within the field concerning the efficacy of the ERA. Many studies that contest the success of the ERA found that it did not improve pregnancy outcomes in patients with an already-good prognosis. Alternatively, studies that utilized the ERA in patients with repeated implantation failure (RIF) and transfer of known euploid embryos demonstrated improved outcomes. This review aims to describe the ERA as a novel technique, review the various settings that the ERA may be used in, such as natural frozen embryo transfer (nFET) and hormone replacement therapy frozen embryo transfer (HRT-FET), and provide a summary of the recent clinical data for embryo transfers in patients with RIF utilizing the ERA. Full article

Critically ill patients are at risk of skin wounds, which reduce their quality of life, complicate their pharmacological regimens, and prolong their hospital stays in intensive care units (ICUs), while also increasing overall mortality and morbidity rates. Cold atmospheric plasma (CAP) has been proposed as a viable option for many biological and medical applications, given its capacity to reduce wound bacterial contamination and promote wound healing. The aim of this narrative review is to describe how CAP works and its operating mechanisms, as well as reporting its possible applications in critical care settings. The success of CAP in the treatment of wounds, in particular, bedsores or pressure sores, presents an innovative path in the prevention of nosocomial infections and an opportunity of reducing the negative implications of these diseases for the NHS. This narrative review of the literature was conducted following the ‘Scale for the Assessment of Narrative Review Articles’ (SANRA) methodology. Previous literature highlights three biological effects of plasma: inactivation of a wide range of microorganisms, including those that are multi-drug-resistant; increased cell proliferation and angiogenesis with a shorter period of plasma treatment; and apoptosis stimulation with a longer and more intensive treatment. CAP is effective in many areas of the medical field, with no significant adverse effects on healthy cells. However, its use can produce potentially serious side effects and should, therefore, be used under expert supervision and in appropriate doses. Full article

Parathyroid Hormone (PTH) plays a crucial role in the maintenance of calcium homeostasis directly acting on bone and kidneys and indirectly on the intestine. However, a large family of PTH-related peptides exists that exerts other physiological effects on different tissues and organs, such as the Central Nervous System (CNS). In humans, PTH-related peptides are Parathyroid Hormone (PTH), PTH-like hormones (PTHrP and PTHLH), and tuberoinfundibular peptide of 39 (TIP39 or PTH2). With different affinities, these ligands can bind parathyroid receptor type 1 (PTH1R) and type 2 (PTH2R), which are part of the type II G-protein-coupled-receptors (GPCRs) family. The PTH/PTHrP/PTH1R system has been found to be expressed in many areas of the brain (hippocampus, amygdala, hypothalamus, caudate nucleus, corpus callosum, subthalamic nucleus, thalamus, substantia nigra, cerebellum), and literature data suggest the system exercises a protective action against neuroinflammation and neurodegeneration, with positive effects on memory and hyperalgesia. TIP39 is a small peptide belonging to the PTH-related family with a high affinity for PTH2R in the CNS. The TIP39/PTH2R system has been proposed to mediate many regulatory and functional roles in the brain and to modulate auditory, nociceptive, and sexual maturation functions. This review aims to summarize the knowledge of PTH-related peptides distribution and functions in the CNS and to highlight the gaps that still need to be filled. Full article

Repetitive Transcranial Magnetic Stimulation (rTMS) has been approved by the FDA as an effective intervention for Treatment-Resistant Depression (TRD). However, there is little evidence about maintenance protocol necessity. The aim of this systematic review is to identify, characterize, and evaluate the current maintenance TMS protocols for MDD and TRD patients who have received acute treatment. A literature search was conducted following the PRISMA guidelines of 2015 on PubMed, Scopus, and Web of Science databases for publications up to March 2022. Fourteen articles were included. High protocol heterogeneity was observed. Most studies highlighted significant efficacy of maintenance protocols in decreasing relapse risk, suggesting that administering two or fewer stimulations per month is ineffective in sustaining an antidepressant effect or in reducing the risk of relapse in responder patients. The risk of relapse was most pronounced after five months from the acute treatment. Maintenance TMS appears to be a resourceful strategy to maintain acute antidepressant treatment effects, significantly reducing relapse risk. The ease of administering and the ability to monitor treatment adherence should be considered when evaluating the future use of maintenance TMS protocols. Further studies are needed to clarify the clinical relevance of overlapping acute TMS effects with maintenance protocols and to evaluate their long-term effectiveness. Full article

Brain-derived neurotrophic factor (BDNF) has a crucial function in the central nervous system and in sensory structures including olfactory and auditory systems. Many studies have highlighted the protective effects of BDNF in the brain, showing how it can promote neuronal growth and survival and modulate synaptic plasticity. On the other hand, conflicting data about BDNF expression and functions in the cochlear and in olfactory structures have been reported. Several clinical and experimental research studies showed alterations in BDNF levels in neurodegenerative diseases affecting the central and peripheral nervous system, suggesting that BDNF can be a promising biomarker in most neurodegenerative conditions, including Alzheimer’s disease, shearing loss, or olfactory impairment. Here, we summarize current research concerning BDNF functions in brain and in sensory domains (olfaction and hearing), focusing on the effects of the BDNF/TrkB signalling pathway activation in both physiological and pathological conditions. Finally, we review significant studies highlighting the possibility to target BDNF as a biomarker in early diagnosis of sensory and cognitive neurodegeneration, opening new opportunities to develop effective therapeutic strategies aimed to counteract neurodegeneration. Full article

Introduction: Ozone is a naturally occurring unstable compound with three oxygen atoms that generally transforms into an oxygen molecule, releasing one oxygen atom. This feature has been exploited in dentistry for numerous applications, including for periodontal diseases and peri-implantitis. Methods: This review was performed in relation to the PRISMA flow chart and was annotated in the PROSPERO register. PICO questions were used as research questions. The risk of bias in the non-randomized clinical trials was appraised using the ROBINS-I tool. Results: An electronic search found a total of 1073 records, in particular, 842 from MEDLINE/PubMed, 13 from Bio Med Central, 160 from Scopus, 1 from the Cochrane library databases, and 57 from the PROSPERO register. A total of 17 studies were included in the present systematic review. Information regarding the characteristics of the periodontal clinical and radiographic parameters for gaseous ozone, ozonate water, ozonate oil, and ozone gel, including clinical attachment loss (CAL) probing depth (PPD), bleeding on probing (BoP), plaque index (PI), gingival index (GI), and marginal bone levels (MBL), were obtained. Conclusions: The studies included in this systematic review show different results regarding the ozone in periodontal treatment in association with or without SRP. Full article

Background: The distal radial artery has emerged as an alternative vascular-access site to conventional transfemoral and transradial approaches. The main advantage over the conventional transradial route is the reduced risk of radial artery occlusion, especially in those patients who, for various clinical reasons, have to undergo repeated endovascular procedures. This study aims to assess the efficacy and safety of distal radial access for transcatheter arterial chemoembolization of the liver. Methods: This investigation is a single-center retrospective analysis of 42 consecutive patients who had undergone, from January 2018 to December 2022, transcatheter arterial chemoembolization of the liver with distal radial access for intermediate-stage hepatocellular carcinoma. Outcome data were compared with a retrospectively constituted control group of 40 patients undergoing drug-eluting beads-transcatheter arterial chemoembolization with femoral access. Results: Technical success was achieved in all cases, with a 2.4% conversion rate for distal radial access. A superselective chemoembolization was performed in 35 (83.3%) cases of distal radial access. No episode of radial artery spasm or radial artery occlusion occurred. No significant differences in efficacy and safety were observed between the distal radial access group and the femoral access group. Conclusions: Distal radial access is effective, safe, and comparable to femoral access in patients undergoing transcatheter arterial chemoembolization of the liver. Full article

The aim of this study was to compare three sensorimotor training forms in patients with chronic low back pain to determine their effects on the reduction of pain-related impairment and changes in posturography. Over two weeks, during the multimodal pain therapy (MMPT) period, six sessions of sensorimotor physiotherapy or training in the Galileo^® or Posturomed^® (n = 25 per group) were performed. A significant reduction in pain-related impairment after the intervention phase was shown across all groups (time effect: p < 0.001; η_p² = 0.415). There was no change in postural stability (time effect: p = 0.666; η_p² = 0.003), but there was a significant improvement in the peripheral vestibular system (time effect: p = 0.014; η_p² = 0.081). An interaction effect was calculated for the forefoot-hindfoot ratio (p = 0.014; η_p² = 0.111). Only the Posturomed^® group showed an improvement in anterior-posterior weight distribution (heel load: 47% vs. 49%). These findings suggest that these forms of sensorimotor training in the context of MMPT are suitable for reducing pain-related impairment. Posturography demonstrated stimulation of a subsystem, but no improvement in postural stability. Full article

In response to the rising incidence of indolent, low-risk prostate cancer (PCa) due to increased prostate-specific antigen (PSA) screening in the 1990s, active surveillance (AS) emerged as a treatment modality to combat overtreatment by delaying or avoiding unnecessary definitive treatment and its associated morbidity. AS consists of regular monitoring of PSA levels, digital rectal exams, medical imaging, and prostate biopsies, so that definitive treatment is only offered when deemed necessary. This paper provides a narrative review of the evolution of AS since its inception and an overview of its current landscape and challenges. Although AS was initially only performed in a study setting, numerous studies have provided evidence for the safety and efficacy of AS which has led guidelines to recommend it as a treatment option for patients with low-risk PCa. For intermediate-risk disease, AS appears to be a viable option for those with favourable clinical characteristics. Over the years, the inclusion criteria, follow-up schedule and triggers for definitive treatment have evolved based on the results of various large AS cohorts. Given the burdensome nature of repeat biopsies, risk-based dynamic monitoring may further reduce overtreatment by avoiding repeat biopsies in selected patients. Full article

Background: Oxidative stress is a major signature of spinal cord injury (SCI). The altered levels of various oxidative stress markers have been demonstrated in acute and chronic SCI. However, the variation of these markers in patients with chronic SCI depending on the time since the initial injury has not been explored yet. Objective: Our aim was to measure plasma levels of malondialdehyde (MDA), a marker of lipid peroxidation in patients with SCI stratified in different periods of suffering the injury (0–5 years, 5–10 years, and more than 10 years). Patients and methods: This cross-sectional study enrolled patients with SCI (N = 105) from different periods of the lesion and healthy control (HC) subjects (N = 38): short period (SCI SP, N = 31, time of evolution less than 5 years); early chronic (SCI ECP, N = 32, time of evolution 5–15 years); and late chronic (SCI LCP, N = 42, time of evolution more than 15 years). The plasma levels of MDA were measured using a commercially available colorimetric assay. Results: Patients with SCI had significantly higher plasma levels of MDA than HC subjects. Receiver operating characteristic (ROC) curve analysis for plasma MDA levels in patients with SCI demonstrated areas under the curve (AUC) of 1 (HC vs. SCI-SP); 0.998 (HC vs. SCI-ECP); and 0.964 (HC vs. SCI-LCP). Additionally, three ROC curves were used to compare the different concentrations of MDA between the subgroups of patients with SCI, and the resulting AUCs were: 0.896 (SCI-SP vs. SCI-ECP); 0.840 (SCI-ECP vs. SCI-LCP); and 0.979 (SCI-SP vs. SCI-LCP). Conclusion: Plasma concentration of MDA can be considered as an oxidative stress biomarker to assess the prognosis of SCI in chronic stages. Full article

Epilepsy is a common condition worldwide, with approximately 50 million people suffering from it. A single seizure does not mean epilepsy; almost 10% of the population can have a seizure during their lifetime. In particular, there are many other central nervous system disorders other than epilepsy in which seizures occur, either transiently or as a comorbid condition. The impact of seizures and epilepsy is, therefore, widespread and easily underestimated. It is estimated that about 70% of patients with epilepsy could be seizure-free if correctly diagnosed and treated. However, for patients with epilepsy, quality of life is influenced not only by seizure control but also by antiepileptic drug-adverse reactions, access to education, mood, employment, and transportation. Full article

Thread carpal tunnel release (TCTR) has been reported to be safe and effective for the treatment of carpal tunnel syndrome. The aim of this study is to evaluate the modified TCTR for safety, efficacy, and postoperative recovery. Seventy-six extremities in 67 patients undergoing TCTR were analyzed pre- and postoperatively using clinical parameters and patient-reported outcome measures. Twenty-nine men and 38 women with a mean age of 59.9 ± 18.9 years underwent TCTR. The mean postoperative time to resume activities of daily living was 5.5 ± 5.5 days, analgesia was completed after 3.7 ± 4.6 days, and return to work was achieved after a mean of 32.6 ± 15.6 days for blue-collar workers and 4.6 ± 4.3 days for white-collar workers. The Boston Carpal Tunnel Questionnaire (BCTQ) and Disability of Arm, Shoulder, and Hand (DASH) scores were comparable with previous studies. Overall, two persistent compressions and one recurrence required open reoperation (3.9%). All three had been operated in the initial phase, and none required reoperation after an additional safety step was introduced. No other complications occurred. TCTR surgery appears to be a safe and reliable technique with almost no wound and scarring and a potentially faster recovery time than open techniques. Although our technical modifications may reduce the risk of incomplete release, TCTR requires both ultrasound and surgical skills and has a considerable learning curve. Full article

In the last 20 years, growing interest in chronic rhinosinusitis (CRS) has become evident in medical literature; nevertheless, it is still difficult to identify the real prevalence of the disease. Epidemiological studies are few and focused on heterogeneous populations and diagnostic methods. Recent research has contributed to identifying CRS as a disease characterized by heterogeneous clinical scenarios, high impact on quality of life, and elevated social costs. Patient stratification with phenotypes and identification of the pathobiological mechanism at the origin of the disease (endotype) and its comorbidities are pivotal in the diagnostic process, and they should be addressed in order to properly tailor treatment. A multidisciplinary approach, shared diagnostic and therapeutic data, and follow-up processes are therefore necessary. Oncological multidisciplinary boards offer models to imitate in accordance with the principles of precision medicine: tracing a diagnostic pathway with the purpose of identifying the patient’s immunological profile, monitoring therapeutical processes, abstaining from having only a single specialist involved in treatment, and placing the patient at the center of the therapeutic plan. Awareness and participation from the patient’s perspective are fundamental steps to optimize the clinical course, improve quality of life, and reduce the socioeconomic burden. Full article

Patient self-inflicted lung injury (P-SILI) is a life-threatening condition arising from excessive respiratory effort and work of breathing in patients with lung injury. The pathophysiology of P-SILI involves factors related to the underlying lung pathology and vigorous respiratory effort. P-SILI might develop both during spontaneous breathing and mechanical ventilation with preserved spontaneous respiratory activity. In spontaneously breathing patients, clinical signs of increased work of breathing and scales developed for early detection of potentially harmful effort might help clinicians prevent unnecessary intubation, while, on the contrary, identifying patients who would benefit from early intubation. In mechanically ventilated patients, several simple non-invasive methods for assessing the inspiratory effort exerted by the respiratory muscles were correlated with respiratory muscle pressure. In patients with signs of injurious respiratory effort, therapy aimed to minimize this problem has been demonstrated to prevent aggravation of lung injury and, therefore, improve the outcome of such patients. In this narrative review, we accumulated the current information on pathophysiology and early detection of vigorous respiratory effort. In addition, we proposed a simple algorithm for prevention and treatment of P-SILI that is easily applicable in clinical practice. Full article

The recent integration of open-source data with machine learning models, especially in the medical field, has opened new doors to studying disease progression and/or regression. However, the ability to use medical data for machine learning approaches is limited by the specificity of data for a particular medical condition. In this context, the most recent technologies, like generative adversarial networks (GANs), are being looked upon as a potential way to generate high-quality synthetic data that preserve the clinical variability of a condition. However, despite some success, GAN model usage remains largely minimal when depicting the heterogeneity of a disease such as prostate cancer. Previous studies from our group members have focused on automating the quantitative multi-parametric magnetic resonance imaging (mpMRI) using habitat risk scoring (HRS) maps on the prostate cancer patients in the BLaStM trial. In the current study, we aimed to use the images from the BLaStM trial and other sources to train the GAN models, generate synthetic images, and validate their quality. In this context, we used T2-weighted prostate MRI images as training data for Single Natural Image GANs (SinGANs) to make a generative model. A deep learning semantic segmentation pipeline trained the model to segment the prostate boundary on 2D MRI slices. Synthetic images with a high-level segmentation boundary of the prostate were filtered and used in the quality control assessment by participating scientists with varying degrees of experience (more than ten years, one year, or no experience) to work with MRI images. Results showed that the most experienced participating group correctly identified conventional vs. synthetic images with 67% accuracy, the group with one year of experience correctly identified the images with 58% accuracy, and the group with no prior experience reached 50% accuracy. Nearly half (47%) of the synthetic images were mistakenly evaluated as conventional. Interestingly, in a blinded quality assessment, a board-certified radiologist did not significantly differentiate between conventional and synthetic images in the context of the mean quality of synthetic and conventional images. Furthermore, to validate the usability of the generated synthetic images from prostate cancer MRIs, we subjected these to anomaly detection along with the original images. Importantly, the success rate of anomaly detection for quality control-approved synthetic data in phase one corresponded to that of the conventional images. In sum, this study shows promise that high-quality synthetic images from MRIs can be generated using GANs. Such an AI model may contribute significantly to various clinical applications which involve supervised machine-learning approaches. Full article

Background: Bladder cancer (BCa) is a heterogeneous disease with a variable prognosis and natural history. Cardiovascular disease (CVD), although completely different, has several similarities and possible interactions with cancer. The association between them is still unknown, but common risk factors between the two suggest a shared biology. Materials and Methods: This was a retrospective study that included patients who underwent transurethral resection of bladder tumor at two high-volume institutions. Depending on the presence of a previous history of CVD or not, patients were divided into two groups. Results: A total of 2050 patients were included, and 1638 (81.3%) were diagnosed with bladder cancer. Regarding comorbidities, the most common were hypertension (59.9%), cardiovascular disease (23.4%) and diabetes (22.4%). At univariate analysis, independent risk factors for bladder cancer were age and male sex, while protective factors were cessation of smoking and presence of CVD. All these results, except for ex-smoker status, were confirmed at the multivariate analysis. Another analysis was performed for patients with high-risk bladder cancer and, in this case, the role of CVD was not statistically significant. Conclusions: Our study pointed out a positive association between CVD and BCa incidence; CVD was an independent protective factor for BCa. This effect was not confirmed for high-risk tumors. Several biological and genomics mechanisms clearly contribute to the onset of both diseases, suggesting a possible shared disease pathway and highlighting the complex interplay of cancer and CVD. CVD treatment can involve different drugs with a possible effect on cancer incidence, but, to date, findings are still inconclusive. Full article

Several risk factors for osteoporotic fractures have been identified but reports of the association of lipid parameters with the occurrence of osteoporotic fractures have been limited. We aimed to examine whether serum total cholesterol (TC) variability is associated with osteoporotic fractures. The study included 3,00,326 subjects who had undergone three or more health examinations between 2003 and 2008. The primary endpoint was the incidence of osteoporotic fractures, including vertebral, hip, distal radius, and humerus fractures. TC variability was evaluated based on the following three parameters: coefficient of variation (CV), standard deviation (SD), and variability independent of the mean (VIM). A total of 29,044 osteoporotic fracture events (9.67%) were identified during a median of 11.6 years of follow-up. The risk of osteoporotic fractures in the highest quartile was significantly higher compared with the lowest quartile according to the three indices of TC variability with adjusted hazard ratios (HR) and 95% confidence intervals (CI) as follows: CV (HR 1.11, 95% CI [1.08–1.15]), SD (HR 1.07, 95% CI [1.04–1.11]) and VIM (HR 1.07, 95% CI [1.04–1.11]). The Kaplan–Meier curves showed a significantly positive relationship between the higher quartile of TC variability and overall osteoporotic fractures. The association remained significant in subgroup analyses of vertebral and hip fractures, regardless of the indices of TC variability. Our study showed that visit-to-visit TC variability was found to be associated with osteoporotic fracture risk. Maintaining TC levels stable may help attenuate the osteoporotic fracture risk in the future. Full article

Background: A significant amount of evidence suggests that Opioid-Free Anaesthesia (OFA) may provide better outcomes for patients undergoing surgery, sparing patients who are particularly vulnerable to adverse side effects of opioids. However, to what extent personalizing OFA is feasible and beneficial has not been adequately described. Methods: We conducted a narrative literature review aiming to provide a comprehensive understanding of nociception and pain and its context within the field of OFA. Physiological (including monitoring), pharmacological, procedural (type of surgery), genetical and phenotypical (including patients’ conditions) were considered. Results: We did not find any monitoring robustly associated with improved outcomes. However, we found evidence supporting particular OFA indications, such as bariatric and cancer surgery. We found that vulnerable patients may benefit more from OFA, with an interesting field of research in patients suffering from vascular disease. We found a variety of techniques and medications making it impossible to consider OFA as a single technique. Our findings suggest that a vast field of research remains unexplored. In particular, a deeper understanding of nociception with an interest in its genetic and acquired contributors would be an excellent starting point paving the way for personalised OFA. Conclusion: Recent developments in OFA may present a more holistic approach, challenging the use of opioids. Understanding better nociception, given the variety of OFA techniques, may help to maximize their potential in different contexts and potential indications. Full article

For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4, influenced AUC. The maximum concentration was affected by age and SLC22A1, but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2, and SLC22A4. The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3. The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3. Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1, SLC2A2, SLC22A2, or SLC47A1. Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization. Full article

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010–2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice. Full article

Recent developments in image analysis have enabled an individual’s brain network to be evaluated and brain age to be predicted from gray matter images. Our study aimed to investigate the effects of age and sex on single-subject gray matter networks using a large sample of healthy participants. We recruited 812 healthy individuals (59.3 ± 14.0 years, 407 females, and 405 males) who underwent three-dimensional T1-weighted magnetic resonance imaging. Similarity-based gray matter networks were constructed, and the following network properties were calculated: normalized clustering, normalized path length, and small-world coefficients. The predicted brain age was computed using a support-vector regression model. We evaluated the network alterations related to age and sex. Additionally, we examined the correlations between the network properties and predicted brain age and compared them with the correlations between the network properties and chronological age. The brain network retained efficient small-world properties regardless of age; however, reduced small-world properties were observed with advancing age. Although women exhibited higher network properties than men and similar age-related network declines as men in the subjects aged < 70 years, faster age-related network declines were observed in women, leading to no differences in sex among the participants aged ≥ 70 years. Brain age correlated well with network properties compared to chronological age in participants aged ≥ 70 years. Although the brain network retained small-world properties, it moved towards randomized networks with aging. Faster age-related network disruptions in women were observed than in men among the elderly. Our findings provide new insights into network alterations underlying aging. Full article

The number of people suffering from diabetes in Taiwan has continued to rise in recent years. According to the statistics of the International Diabetes Federation, about 537 million people worldwide (10.5% of the global population) suffer from diabetes, and it is estimated that 643 million people will develop the condition (11.3% of the total population) by 2030. If this trend continues, the number will jump to 783 million (12.2%) by 2045. At present, the number of people with diabetes in Taiwan has reached 2.18 million, with an average of one in ten people suffering from the disease. In addition, according to the Bureau of National Health Insurance in Taiwan, the prevalence rate of diabetes among adults in Taiwan has reached 5% and is increasing each year. Diabetes can cause acute and chronic complications that can be fatal. Meanwhile, chronic complications can result in a variety of disabilities or organ decline. If holistic treatments and preventions are not provided to diabetic patients, it will lead to the consumption of more medical resources and a rapid decline in the quality of life of society as a whole. In this study, based on the outpatient examination data of a Taipei Municipal medical center, 15,000 women aged between 20 and 80 were selected as the subjects. These women were patients who had gone to the medical center during 2018–2020 and 2021–2022 with or without the diagnosis of diabetes. This study investigated eight different characteristics of the subjects, including the number of pregnancies, plasma glucose level, diastolic blood pressure, sebum thickness, insulin level, body mass index, diabetes pedigree function, and age. After sorting out the complete data of the patients, this study used Microsoft Machine Learning Studio to train the models of various kinds of neural networks, and the prediction results were used to compare the predictive ability of the various parameters for diabetes. Finally, this study found that after comparing the models using two-class logistic regression as well as the two-class neural network, two-class decision jungle, or two-class boosted decision tree for prediction, the best model was the two-class boosted decision tree, as its area under the curve could reach a score of 0.991, which was better than other models. Full article

Huntington’s disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is symptomatic and addresses the hyperkinetic disorders (chorea, dystonia, myoclonus, tics, etc.) and the behavioural and cognitive disturbances (depression, anxiety, psychosis, etc.) associated with the disease. HD is still a complex condition in need of innovative and efficient treatment. The long-term goal of pharmacogenetic studies is to use genotype data to predict the effective treatment response to a specific drug and, in turn, prevent potential undesirable effects of its administration. Chorea, depression, and psychotic symptoms have a substantial impact on HD patients’ quality of life and could be better controlled with the help of pharmacogenetic knowledge. We aimed to carry out a review of the available publications and evidence related to the pharmacogenetics of HD, with the objective of compiling all information that may be useful in optimizing drug administration. The impact of pharmacogenetic information on the response to antidepressants and antipsychotics is well documented in psychiatric patients, but this approach has not been investigated in HD patients. Future research should address several issues to ensure that pharmacogenetic clinical use is appropriately supported, feasible, and applicable. Full article

The correlation between the menstrual cycle and glucose control in type 1 diabetes has been the focus of several studies since the 1920s, but a few critical aspects made it particularly challenging to reach conclusive evidence. The aim of this systematic review is to reveal more solid information about the impact of the menstrual cycle on glycaemic outcomes and insulin sensitivity in type 1 diabetes and highlight the less researched areas. The literature was searched by two authors independently using PubMed/MEDLINE, Embase and Scopus (last search on 2 November 2022). The retrieved data did not allow us to perform a meta-analysis. We included 14 studies published between 1990 and 2022, with sample sizes from 4 to 124 patients. We found a wide heterogeneity in the definition of the menstrual cycle phases, glucose metrics, techniques for determining insulin sensitivity, hormonal assessment and other interfering factors considered, with an overall high risk of bias. There is no conclusive evidence, and published data do not allow us to achieve quantitative results. In a subset of patients, a possible worsening of insulin sensitivity and hyperglycaemia in the luteal phase could be observed. From the clinical standpoint, a cautious strategy based on patient-specific patterns can be considered until new, solid evidence is obtained. Full article

Background: Cardiovascular diseases (CVDs) are a leading cause of death worldwide. Deep learning methods have been widely used in the field of medical image analysis and have shown promising results in the diagnosis of CVDs. Methods: Experiments were performed on 12-lead electrocardiogram (ECG) databases collected by Chapman University and Shaoxing People’s Hospital. The ECG signal of each lead was converted into a scalogram image and an ECG grayscale image and used to fine-tune the pretrained ResNet-50 model of each lead. The ResNet-50 model was used as a base learner for the stacking ensemble method. Logistic regression, support vector machine, random forest, and XGBoost were used as a meta learner by combining the predictions of the base learner. The study introduced a method called multi-modal stacking ensemble, which involves training a meta learner through a stacking ensemble that combines predictions from two modalities: scalogram images and ECG grayscale images. Results: The multi-modal stacking ensemble with a combination of ResNet-50 and logistic regression achieved an AUC of 0.995, an accuracy of 93.97%, a sensitivity of 0.940, a precision of 0.937, and an F1-score of 0.936, which are higher than those of LSTM, BiLSTM, individual base learners, simple averaging ensemble, and single-modal stacking ensemble methods. Conclusion: The proposed multi-modal stacking ensemble approach showed effectiveness for diagnosing CVDs. Full article

Background: Programmed death-ligand 1 (PD-L1) checkpoint inhibitors represent a mainstay of therapy in head and neck squamous cell cancer (HNSCC). However, little is known about the influence of combined therapy on PD-L1 expression. The study aims to gather evidence on this topic. Methods: A systematic search was carried out in electronic databases Pubmed-MEDLINE and Embase to retrieve studies on the comparison of PD-L1 expression before and after conventional therapy. Data were extracted and a quantitative analysis with pooled odds ratios (ORs) was performed when applicable. Results: Of 5688 items, 15 were finally included. Only a minority of studies assessed PD-L1 with the recommended combined positive score (CPS). The results are highly heterogeneous, with some studies reporting an increase in PD-L1 expression and others reporting a decrease. Three studies allowed for quantitative analysis and showed a pooled OR of 0.49 (CI 0.27–0.90). Conclusions: From the present evidence, a clear conclusion towards an increase or decrease in PD-L1 expression after combined therapy cannot be drawn, but even with few studies available, a trend towards an increase in expression in tumor cells at a cutoff of 1% can be noted in patients undergoing platinum-based therapy. Future studies will provide more robust data on the effect of combined therapy on PD-L1 expression. Full article

Background: CT perfusion (CTP) is used in patients with anterior circulation acute ischemic stroke (AIS) for predicting the final infarct volume (FIV). Tandem occlusion (TO), involving both intracranial large vessels and the ipsilateral cervical internal carotid artery could generate hemodynamic changes altering perfusion parameters. Our aim is to evaluate the accuracy of CTP in the prediction of the FIV in TOs. Methods: consecutive patients with AIS due to middle cerebral artery occlusion, referred to a tertiary stroke center between March 2019 and January 2021, with an automated CTP and successful recanalization (mTICI = 2b − 3) after endovascular treatment were retrospectively included in the tandem group (TG) or in the control group (CG). Patients with parenchymal hematoma type 2, according to ECASS II classification of hemorrhagic transformations, were excluded in a secondary analysis. Demographic, clinical, radiological, time intervals, safety, and outcome measures were collected. Results: among 319 patients analyzed, a comparison between the TG (N = 22) and CG (n = 37) revealed similar cerebral blood flow (CBF) > 30% (29.50 ± 32.33 vs. 15.76 ± 20.93 p = 0.18) and FIV (54.67 ± 65.73 vs. 55.14 ± 64.64 p = 0.875). Predicted ischemic core (PIC) and FIV correlated in both TG (tau = 0.761, p < 0.001) and CG (tau = 0.315, p = 0.029). The Bland–Altmann plot showed agreement between PIC and FIV for both groups, mainly in the secondary analysis. Conclusion: automated CTP could represent a good predictor of FIV in patients with AIS due to TO. Full article

Periodontitis and rheumatoid arthritis (RA) are inflammatory diseases that share many similarities. We aimed to investigate the associations of periodontitis and oral hygiene status and behaviors with RA in a nationwide general population cohort. Participants from the National Health Screening cohort database of Korea who underwent oral health screening by dentists between 2003 and 2004 were included. The occurrence of RA was analyzed according to the presence of periodontitis, oral health examination findings, and behaviors. Overall, 2,239,586 participants were included. During a median of 16.7 years, RA occurred in 27,029 (1.2%) participants. The risk for incident RA was higher when participants had periodontitis (hazard ratio (HR) 1.2, 95% confidence interval (CI), 1.08−1.24) and an increased number of missing teeth (HR 1.5, 95% CI, 1.38−1.69). In contrast, better oral hygiene behaviors, such as a higher frequency of daily tooth brushing (HR 0.76, 95% CI 0.73–0.79, p for trend <0.001) and a recent history of dental scaling (HR 0.96, 95% CI 0.94–0.99), were associated with a lower occurrence of RA. Periodontitis and increased missing teeth were associated with an increased risk of RA. Maintaining good oral hygiene through frequent tooth brushing and regular dental scaling may reduce the risk of RA occurrence. Full article

A biomarker is a molecule that can be measured in a biological sample in an objective, systematic, and precise way, whose levels indicate whether a process is normal or pathological. Knowing the most important biomarkers and their characteristics is the key to precision medicine in intensive and perioperative care. Biomarkers can be used to diagnose, in assessment of disease severity, to stratify risk, to predict and guide clinical decisions, and to guide treatments and response to them. In this review, we will analyze what characteristics a biomarker should have and how to ensure its usefulness, and we will review the biomarkers that in our opinion can make their knowledge more useful to the reader in their clinical practice, with a future perspective. These biomarkers, in our opinion, are lactate, C-Reactive Protein, Troponins T and I, Brain Natriuretic Peptides, Procalcitonin, MR-ProAdrenomedullin and BioAdrenomedullin, Neutrophil/lymphocyte ratio and lymphopenia, Proenkephalin, NefroCheck, Neutrophil gelatinase-associated lipocalin (NGAL), Interleukin 6, Urokinase-type soluble plasminogen activator receptor (suPAR), Presepsin, Pancreatic Stone Protein (PSP), and Dipeptidyl peptidase 3 (DPP3). Finally, we propose an approach to the perioperative evaluation of high-risk patients and critically ill patients in the Intensive Care Unit (ICU) based on biomarkers. Full article

We aimed to demonstrate the effective application of keystone perforator island flap (KPIF) in scalp and forehead reconstruction by demonstrating the authors’ experience with modified KPIF reconstruction for small- to moderate-sized scalp and forehead defects. Twelve patients who underwent modified KPIF reconstruction of the scalp and forehead from September 2020 to July 2022 were enrolled in this study. In addition, we retrospectively reviewed and evaluated the patient’s medical records and clinical photographs. All defects (size range, 2 cm × 2 cm to 3 cm × 7 cm) were successfully covered using four modified KPIF techniques (hemi-KPIF, Sydney Melanoma Unit Modification KPIF, omega variation closure KPIF, and modified type II KPIF) with ancillary procedures (additional skin grafts and local flaps). All flaps (size range, 3.5 cm × 4 cm to 7 cm × 16 cm) fully survived, and only one patient developed marginal maceration that healed with conservative management. Furthermore, through the final scar evaluation with the patient satisfaction survey and Harris 4-stage scale, all patients were satisfied with their favorable outcomes at the average final follow-up period of 7.66 ± 2.14 months. The study showed that the KPIF technique with appropriate modifications is an excellent reconstructive modality for covering scalp and forehead defects. Full article