Editor’s Choice Articles

Our understanding of the immunopathological features of type 1 diabetes (T1D) has greatly improved over the past two decades and has shed light on disease heterogeneity dictated by multiple immune, metabolic, and clinical parameters. This may explain the limited effects of immunotherapies tested so far to durably revert or prevent T1D, for which life-long insulin replacement remains the only therapeutic option. In the era of omics and precision medicine, offering personalized treatment could contribute to turning this tide. Here, we discuss how to structure the selection of the right patient at the right time for the right treatment. This individualized therapeutic approach involves enrolling patients at a defined disease stage depending on the target and mode of action of the selected drug, and better stratifying patients based on their T1D endotype, reflecting intrinsic disease aggressiveness and immune context. To this end, biomarker screening will be critical, not only to help stratify patients and disease stage, but also to select the best predicted responders ahead of treatment and at early time points during clinical trials. This strategy could contribute to increase therapeutic efficacy, notably through the selection of drugs with complementary effects, and to further develop precision multi-hit medicine. Full article

Healthcare systems worldwide generate vast amounts of data from many different sources. Although of high complexity for a human being, it is essential to determine the patterns and minor variations in the genomic, radiological, laboratory, or clinical data that reliably differentiate phenotypes or allow high predictive accuracy in health-related tasks. Convolutional neural networks (CNN) are increasingly applied to image data for various tasks. Its use for non-imaging data becomes feasible through different modern machine learning techniques, converting non-imaging data into images before inputting them into the CNN model. Considering also that healthcare providers do not solely use one data modality for their decisions, this approach opens the door for multi-input/mixed data models which use a combination of patient information, such as genomic, radiological, and clinical data, to train a hybrid deep learning model. Thus, this reflects the main characteristic of artificial intelligence: simulating natural human behavior. The present review focuses on key advances in machine and deep learning, allowing for multi-perspective pattern recognition across the entire information set of patients in spine surgery. This is the first review of artificial intelligence focusing on hybrid models for deep learning applications in spine surgery, to the best of our knowledge. This is especially interesting as future tools are unlikely to use solely one data modality. The techniques discussed could become important in establishing a new approach to decision-making in spine surgery based on three fundamental pillars: (1) patient-specific, (2) artificial intelligence-driven, (3) integrating multimodal data. The findings reveal promising research that already took place to develop multi-input mixed-data hybrid decision-supporting models. Their implementation in spine surgery may hence be only a matter of time. Full article

Rheumatoid arthritis (RA) is a chronic inflammatory disease, affecting mostly women with a female/male ratio of 3:1. It is characterized by symmetrical polyarthritis, leading to progressive joint damage. Sex differences have been reported in terms of disease course and characteristics, influencing patients reported outcome measures (PROMs) and pain perception, ultimately leading to male–female disparities in treatment response. Notwithstanding, sex and gender discrepancies are still under-reported in clinical trials. Therefore, there is a consistent need for a precise reference of sex and gender issues in RA studies to improve treat-to-target achievement. This narrative review explores the above-mentioned aspects of RA disease, discussing the latest core principles of RA recommendations, from safety issues to early arthritis concept and management, treat-to-target and difficult-to-treat notions, up to the most recent debate on vaccination. Our final purpose is to evaluate how sex and gender can impact current management guidelines and how this issue can be integrated for effective disease control. Full article

Advancements in the development of computer-aided decision (CAD) systems for clinical routines provide unquestionable benefits in connecting human medical expertise with machine intelligence, to achieve better quality healthcare. Considering the large number of incidences and mortality numbers associated with lung cancer, there is a need for the most accurate clinical procedures; thus, the possibility of using artificial intelligence (AI) tools for decision support is becoming a closer reality. At any stage of the lung cancer clinical pathway, specific obstacles are identified and “motivate” the application of innovative AI solutions. This work provides a comprehensive review of the most recent research dedicated toward the development of CAD tools using computed tomography images for lung cancer-related tasks. We discuss the major challenges and provide critical perspectives on future directions. Although we focus on lung cancer in this review, we also provide a more clear definition of the path used to integrate AI in healthcare, emphasizing fundamental research points that are crucial for overcoming current barriers. Full article

Various forms of cognitive behavioral therapy for insomnia (CBT-i) have been developed to improve its scalability and accessibility for insomnia management in young people, but the efficacy of digitally-delivered cognitive behavioral therapy for insomnia (dCBT-i) remains uncertain. This study systematically reviewed and evaluated the effectiveness of dCBT-i among young individuals with insomnia. We conducted comprehensive searches using four electronic databases (PubMed, Cochrane Library, PsycINFO, and Embase; until October 2021) and examined eligible records. The search strategy comprised the following three main concepts: (1) participants were adolescents or active college students; (2) dCBT-I was employed; (3) standardized tools were used for outcome measurement. Four randomized controlled trials qualified for meta-analysis. A significant improvement in self-reported sleep quality with a medium-to-large effect size after treatment (Hedges’s g = −0.58~−0.80) was noted. However, a limited effect was detected regarding objective sleep quality improvement (total sleep time and sleep efficiency measured using actigraphy). These preliminary findings from the meta-analysis suggest that dCBT-i is a moderately effective treatment in managing insomnia in younger age groups, and CBT-i delivered through the web or a mobile application is an acceptable approach for promoting sleep health in young people. Full article

Background: Mandibular advancement devices for obstructive sleep apnea treatment are becoming increasingly popular among patients who do not prefer CPAP devices or surgery. Our study aims to evaluate the literature regarding potential dental and skeletal side effects caused by mandibular advancement appliances used for adult OSA treatment. Methods: Electronic databases were searched for published and unpublished literature along with the reference lists of the eligible studies. Randomized clinical trials and non-randomized trials assessing dental and skeletal changes by comparing cephalometric radiographs were selected. Study selection, data extraction, and risk of bias assessment were performed individually and in duplicate. Fourteen articles were finally selected (two randomized clinical trials and 12 non-randomized trials). Results: The results suggest that mandibular advancement devices used for OSA treatment increase the lower incisor proclination by 1.54 ± 0.16°, decrease overjet by 0.89 ± 0.04 mm and overbite by 0.68 ± 0.04 mm, rotate the mandible downward and forward, and increase the SNA angle by to 0.06 ± 0.03°. The meta-analysis revealed high statistical heterogeneity. Conclusions: The MADs affect the lower incisor proclination, overjet, overbite, the rotation of the mandible and the SNA angle. More randomized clinical trials providing high-quality evidence are needed to support those findings. Full article

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder without a known cure. Current standard-of-care treatments focus on addressing core symptoms directly but have provided limited benefits. In many cases, individuals with ASD have abnormalities in multiple organs, including the brain, immune and gastrointestinal system, and multiple physiological systems including redox and metabolic systems. Additionally, multiple aspects of the environment can adversely affect children with ASD including the sensory environment, psychosocial stress, dietary limitations and exposures to allergens and toxicants. Although it is not clear whether these medical abnormalities and environmental factors are related to the etiology of ASD, there is evidence that many of these factors can modulate ASD symptoms, making them a potential treatment target for improving core and associated ASD-related symptoms and improving functional limitation. Additionally, addressing underlying biological disturbances that drive pathophysiology has the potential to be disease modifying. This article describes a systematic approach using clinical history and biomarkers to personalize medical treatment for children with ASD. This approach is medically comprehensive, making it attractive for a multidisciplinary approach. By concentrating on treatable conditions in ASD, it is possible to improve functional ability and quality of life, thus providing optimal outcomes. Full article

The available data suggest differences in the course of type 2 diabetes mellitus (T2DM) between men and women, influenced by the distinguishing features of the sex. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a relatively new class of antidiabetic drugs that act by mimicking the function of endogenous glucagon-like peptide 1. They constitute valuable agents for the management of T2DM as, in addition to exerting a strong hypoglycemic action, they present cardiorenal protective properties, promote weight loss, and have a good safety profile, particularly with respect to the risk of hypoglycemia. Due to the precedent of studies having identified sexual dimorphic elements regarding the action of other antidiabetic agents, ongoing research has attempted to examine whether this is also the case for GLP-1 RAs. Until now, sex differences have been observed in the impact of GLP1-RAs on glycemic control, weight reduction, and frequency of adverse events. On the contrary, the question of whether these drugs differentially affect the two sexes with respect to cardiovascular risk and incidence of major adverse cardiovascular events remains under investigation. Knowledge of the potential sex-specific effects of these medications is extremely useful for the implementation of individualized therapeutic plans in the treatment of T2DM. This narrative review aims to present the available data regarding the sex-specific action of GLP-1 RAs as well as to discuss the potential pathophysiologic mechanisms explaining these dissimilarities. Full article

In recent years, with the advancement of next-generation sequencing (NGS) technology, gene panel tests have been approved in the field of cancer diseases, and approaches to prescribe optimal molecular target drugs to patients are being developed. In the field of rare diseases, whole-genome and whole-exome analysis has been used to identify the causative genes of undiagnosed diseases and to diagnose patients’ diseases, and further progress in personalized medicine is expected. In order to promote personalized medicine in the future, we investigated the current status and progress of personalized medicine in disease areas other than cancer and rare diseases, where personalized medicine is most advanced. We selected rheumatoid arthritis and psoriasis as the inflammatory disease, in addition to Alzheimer’s disease. These diseases have high unmet needs for personalized medicine from the viewpoints of disease mechanisms, diagnostic biomarkers, therapeutic drugs with diagnostic markers and treatment satisfaction. In rheumatoid arthritis and psoriasis, there are many therapeutic options; however, diagnostic methods have not been developed to select the best treatment for each patient. In addition, there are few effective therapeutic agents in Alzheimer’s disease, although clinical trials of many candidate drugs have been conducted. In rheumatoid arthritis and psoriasis, further elucidation of the disease mechanism is desired to enable the selection of appropriate therapeutic agents according to the patient profile. In the case of Alzheimer’s disease, progress in preventive medicine is desired through the establishment of an early diagnosis method as well as the research and development of innovative therapeutic agents. To this end, we hope for further research and development of diagnostic markers and new drugs through progress in comprehensive data analysis such as comprehensive genomic and transcriptomic information. Furthermore, new types of markers such as miRNAs and the gut microbiome are desired to be utilized in clinical diagnostics. Full article

The use of pharmacogenomic (PGx) tests is increasing, but there are not standard approaches to counseling patients on their implications or results. To inform approaches for patient counseling, we conducted a scoping review of published literature on patient experiences with PGx testing and performed a thematic analysis of qualitative and quantitative reports. A structured scoping review was conducted using Joanna Briggs Institute guidance. The search identified 37 articles (involving n = 6252 participants) published between 2010 and 2021 from a diverse range of populations and using a variety of study methodologies. Thematic analysis identified five themes (reasons for testing/perceived benefit, understanding of results, psychological response, impact of testing on patient/provider relationship, concerns about testing/perceived harm) and 22 subthemes. These results provide valuable context and potential areas of focus during patient counseling on PGx. Many of the knowledge gaps, misunderstandings, and concerns that participants identified could be mitigated by pre- and post-test counseling. More research is needed on patients’ PGx literacy needs, along with the development of a standardized, open-source patient education curriculum and the development of validated PGx literacy assessment tools. Full article

Mantle cell lymphoma (MCL) is a rare mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor outcomes. Virtually all patients will eventually experience refractory or relapsed (R/R) disease, with a virulent course of resistance and serial relapses, making treatment challenging. The available therapies for R/R MCL are not curative with conventional therapy, their goal being to palliate and prolong survival. A variety of agents approved for R/R MCL, including Bruton’s tyrosine kinase inhibitors (BTKi), changed the treatment landscape of R/R MCL. In the pre-BTKi era, the median progression-free survival (PFS) in R/R disease was 4–9 months. With the introduction of ibrutinib, the median PFS improved to 13–14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTKi inevitably develops in a subset of patients. Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen receptor (CAR) T cells, have shown promising results after BTKi failure. The preferred combination and sequencing of therapies beyond BTKi remain unestablished and are currently being investigated. In this review, we describe the current evidence for the available treatment of R/R MCL after progression on BTKi. Full article

Globally, chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality, having a significant socioeconomic effect. Several molecular mechanisms have been related to COPD including chronic inflammation, telomere shortening, and epigenetic modifications. Nowadays, there is an increasing need for novel therapeutic approaches for the management of COPD. These treatment strategies should be based on finding the source of acute exacerbation of COPD episodes and estimating the patient’s own risk. The use of biomarkers and the measurement of their levels in conjunction with COPD exacerbation risk and disease prognosis is considered an encouraging approach. Many types of COPD biomarkers have been identified which include blood protein biomarkers, cellular biomarkers, and protease enzymes. They have been isolated from different sources including peripheral blood, sputum, bronchoalveolar fluid, exhaled air, and genetic material. However, there is still not an exclusive biomarker that is used for the evaluation of COPD but rather a combination of them, and this is attributed to disease complexity. In this review, we summarize the clinical significance of COPD-related biomarkers, their association with disease outcomes, and COPD patients’ management. Finally, we depict the various samples that are used for identifying and measuring these biomarkers. Full article

Dental health is often neglected among the elderly because of the numerous comorbidities in this population, such as cardiovascular diseases. However, dental health influences general health and quality of life by impacting both the general health and the psychological state of the individual. The present review highlights the main dental comorbidities in the elderly population, their impact on the quality of life, the barriers towards access to dental care in the elderly and methods to improve their dental health. Information related to dental care and its importance must be provided both to older individuals and their caregivers in order to detect dental pathology and treat it adequately. Ensuring dental health involves the whole society of elders, caregivers, dental care providers, the public sector, health policymakers, and the private sector. Full article

Comprehensive research conducted over the past decades has shown that there is a definite connection between periodontal and systemic conditions, leading to the development and consolidation of the “periodontal medicine” concept. The 2018 classification of periodontal conditions uses this concept as a key element of the precise diagnosis of and individualized therapeutical protocols for periodontitis patients. The topic of this review is the pathogenic connections that exist between periodontal disease and metabolic/digestive tract conditions. It is important to remember that the oral cavity is a key element of the digestive tract and that any conditions affecting its integrity and function (such as periodontitis or oral cancer) can have a significant impact on the metabolic and gastrointestinal status of a patient. Thus, significant diseases with links to metabolic or digestive disruptions were chosen for inclusion in the review, such as diabetes mellitus, hepatic conditions and gastric cancers. Periodontal pathogenic mechanisms share several significant elements with these conditions, including mutual pro-inflammatory mediators, bacterial elements and genetic predisposition. Consequently, periodontal screening should be recommended for affected patients, and conversely, periodontitis patients should be considered for careful monitoring of their metabolic and digestive status. Full article

Asthma is generally characterized by variable symptoms such as dyspnea and wheezing and variable airflow obstruction. This review focuses on a subset of patients suffering from asthma with persistent airflow limitation that is not fully reversible (asthma with fixed airflow obstruction, FAO). The pathophysiology, the risk factors and the clinical outcomes associated with FAO are presented, as well as the distinct clinical entity of severe asthma and its inflammatory subtypes (T2 and non-T2). The current strategies for the treatment of these endotypes and treatment of the distinct Asthma/COPD overlap (ACO) phenotype are described. Management and medical interventions in FAO and/or ACO patients demand a holistic approach, which is not yet clearly established in guidelines worldwide. Finally, a treatment algorithm that includes FAO/ACO management based on pharmacological and non-pharmacological treatment, guideline-based management for specific co-morbidities, and modification of the risk factors is proposed. Full article

During the past decade, a stem cell-based hypothesis has emerged (among many others) to explain the pathogenesis of endometriosis. The initial hypothesis proposed that endometriosis arose from a single or a few specific cells with stem cell properties, including self-renewal and multi-lineage cell differentiation. The origins of the endometriosis-initiating stem cells were thought to be the bone marrow, uterine endometrium, and other tissues. Based on the implantation or metastatic theory in combination with the initial stem cell theory, one or a few multipotent stem/progenitor cells present in the eutopic endometrium or bone marrow translocate to ectopic sites via fallopian tubes during menstruation, vasculolymphatic routes, or through direct migration and invasion. Subsequently, they give rise to endometriotic lesions followed by differentiation into various cell components of endometriosis, including glandular and stromal cells. Recent somatic mutation analyses of deep infiltrating endometriosis, endometrioma, and eutopic normal endometrium using next-generation sequencing techniques have redefined the stem cell theory. It is now proposed that stem/progenitor cells of at least two different origins—epithelium and stroma—sequentially, differentially, but coordinately contribute to the genesis of endometriosis. The dual stem cell theory on how two (or more) stem/progenitor cells differentially and coordinately participate in the establishment of endometriotic lesions remains to be elucidated. Furthermore, the stem/progenitor cells involved in this theory also remain to be identified. Given that the origin of endometriosis is eutopic endometrium, the candidate cells for endometriotic epithelium-initiating cells are likely to be endometrial epithelial cells positive for either N-cadherin or SSEA-1 or both. The candidate cells for endometriotic stroma-initiating cells may be endometrial mesenchymal stem cells positive for SUSD2. Endometrial side population cells are also a possible candidate because they contain unipotent or multipotent cells capable of behaving as endometrial epithelial and stromal stem/progenitor cells. Full article

Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemoresistance development. Full article

Targeted radiation therapy (TRT) is a strategy increasingly adopted for the treatment of different types of cancer. The urge for optimization, as stated by the European Council Directive (2013/59/EURATOM), requires the implementation of a personalized dosimetric approach, similar to what already happens in external beam radiation therapy (EBRT). The purpose of this paper is to provide a thorough introduction to the field of personalized dosimetry in TRT, explaining its rationale in the context of optimization and describing the currently available methodologies. After listing the main therapies currently employed, the clinical workflow for the absorbed dose calculation is described, based on works of the most experienced authors in the literature and recent guidelines. Moreover, the widespread software packages for internal dosimetry are presented and critical aspects discussed. Overall, a selection of the most important and recent articles about this topic is provided. Full article

Myocarditis is an inflammatory heart disease induced by infectious and non-infectious causes frequently triggering immune-mediated pathologic mechanisms leading to myocardial damage and dysfunction. In approximately half of the patients, acute myocarditis resolves spontaneously while in the remaining cases, it may evolve into serious complications including inflammatory cardiomyopathy, arrhythmias, death, or heart transplantation. Due to the large variability in clinical presentation, unpredictable course of the disease, and lack of established causative treatment, myocarditis represents a challenging diagnosis in modern cardiology. Moreover, an increase in the incidence of myocarditis and inflammatory cardiomyopathy has been observed in recent years. However, there is a growing potential of available non-invasive diagnostic methods (biomarkers, serum anti-heart autoantibodies (AHA), microRNAs, speckle tracking echocardiography, cardiac magnetic resonance T1 and T2 tissue mapping, positron emission tomography), which may refine the diagnostic workup and/or noninvasive follow-up. Personalized management should include the use of endomyocardial biopsy and AHA, which may allow the etiopathogenetic subsets of myocarditis (infectious, non-infectious, and/or immune-mediated) to be distinguished and implementation of disease-specific therapies. In this review, we summarize current knowledge on myocarditis and inflammatory cardiomyopathy, and outline some practical diagnostic, therapeutic, and follow-up algorithms to facilitate comprehensive individualized management of these patients. Full article

The Paris System (TPS) for Reporting Urinary Cytology is a standardized, evidence-based reporting system, comprising seven diagnostic categories: nondiagnostic, negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), suspicious for high-grade urothelial carcinoma (SHGUC), HGUC, low-grade urothelial neoplasm (LGUN), and other malignancies. This study aimed to calculate the pooled risk of high-grade malignancy (ROHM) of each category and demonstrate the diagnostic accuracy of urine cytology reported with TPS. Four databases (PubMed, Embase, Scopus, Web of Science) were searched. Specific inclusion and exclusion criteria were applied, while data were extracted and analyzed both qualitatively and quantitatively. The pooled ROHM was 17.70% for the nondiagnostic category (95% CI, 0.0650; 0.3997), 13.04% for the NHGUC (95% CI, 0.0932; 0.1796), 38.65% for the AUC (95% CI, 0.3042; 0.4759), 12.45% for the LGUN (95% CI, 0.0431; 0.3101), 76.89 for the SHGUC (95% CI, 0.7063; 0.8216), and 91.79% for the HGUC and other malignancies (95% CI, 0.8722; 0.9482). A summary ROC curve was created and the Area Under the Curve (AUC) was 0.849, while the pooled sensitivity was 0.669 (95% CI, 0.589; 0.741) and false-positive rate was 0.101 (95% CI, 0.063; 0.158). In addition, the pooled DOR of the included studies was 21.258 (95% CI, 14.336; 31.522). TPS assigns each sample into a diagnostic category linked with a specific ROHM, guiding clinical management. Full article

The future development of personalized medicine depends on a vast exchange of data from different sources, as well as harmonized integrative analysis of large-scale clinical health and sample data. Computational-modelling approaches play a key role in the analysis of the underlying molecular processes and pathways that characterize human biology, but they also lead to a more profound understanding of the mechanisms and factors that drive diseases; hence, they allow personalized treatment strategies that are guided by central clinical questions. However, despite the growing popularity of computational-modelling approaches in different stakeholder communities, there are still many hurdles to overcome for their clinical routine implementation in the future. Especially the integration of heterogeneous data from multiple sources and types are challenging tasks that require clear guidelines that also have to comply with high ethical and legal standards. Here, we discuss the most relevant computational models for personalized medicine in detail that can be considered as best-practice guidelines for application in clinical care. We define specific challenges and provide applicable guidelines and recommendations for study design, data acquisition, and operation as well as for model validation and clinical translation and other research areas. Full article

Background: The objective of this work was to describe the technique of exclusive lipofilling in breast reconstruction after total mastectomy, to evaluate the satisfaction and quality of life of the patients, and to explore current literature on the subject. Methods: We conducted a retrospective observational multicentric study from January 2013 to April 2020. The modalities of surgery, esthetic result, and patient satisfaction were evaluated with the breast reconstruction module of BREAST-Q. Results: Complete data were available for 37 patients. The mean number of sessions was 2.2 (standard deviation 1.1), spread over an average of 6.8 months (SD 6.9). The average total volume of fat transferred was 566.4 mL. The complication rate was 18.9%. No severe complication was observed (Clavien–Dindo 3/4). Two patients were diagnosed with recurrence, in a metastatic mode (5.4%). The average satisfaction rate was 68.4% (SD 24.8) for psychosocial well-being and 64.5% (SD 24.1) for sexual well-being. The satisfaction rate was 60.2% (SD 20.9) for the image of the reconstructed breast and 82.7% (SD 21.9) for locoregional comfort. Conclusions: Breast reconstruction by exclusive lipofilling after total mastectomy provides satisfactory quality of life scores. The simplicity of the surgical technique and equipment required, and the high satisfaction rate confirm that lipofilling should be included in the panel of choice of breast reconstruction techniques. Full article

Epidemiological studies aimed at defining the association of thyroid diseases with extra-thyroidal malignancies (EM) have aroused considerable interest in the possibility of revealing common genetic and environmental factors underlying disease etiology and progression. Over the years, multiple lines of evidence indicated a significant relationship between thyroid carcinomas and other primary EM, especially breast cancer. For the latter, a prominent association was also found with benign thyroid diseases. In particular, a meta-analysis revealed an increased risk of breast cancer in patients with autoimmune thyroiditis, and our recent work demonstrated that the odds ratio (OR) for breast cancer was raised in both thyroid autoantibody-positive and -negative patients. However, the OR was significantly lower for thyroid autoantibody-positive patients compared to the negative ones. This is in agreement with findings showing that the development of thyroid autoimmunity in cancer patients receiving immunotherapy is associated with better outcome and supports clinical evidence that breast cancer patients with thyroid autoimmunity have longer disease-free interval and overall survival. These results seem to suggest that factors other than oncologic treatments may play a role in the initiation and progression of a second primary malignancy. The molecular links between thyroid autoimmunity and breast cancer remain, however, unidentified, and different hypotheses have been proposed. Here, we will review the epidemiological, clinical, and experimental data relating thyroid diseases and breast cancer, as well as the possible hormonal and molecular mechanisms underlying such associations. Full article

The interest in regenerative medicine is increasing, and it is a dynamically developing branch of aesthetic surgery. Biocompatible and autologous-derived products such as platelet-rich plasma or adult mesenchymal stem cells are often used for aesthetic purposes. Their application originates from wound healing and orthopaedics. Adipose-derived stem cells are a powerful agent in skin rejuvenation. They secrete growth factors and anti-inflammatory cytokines, stimulate tissue regeneration by promoting the secretion of extracellular proteins and secrete antioxidants that neutralize free radicals. In an office procedure, without cell incubation and counting, the obtained product is stromal vascular fraction, which consists of not only stem cells but also other numerous active cells such as pericytes, preadipocytes, immune cells, and extra-cellular matrix. Adipose-derived stem cells, when injected into dermis, improved skin density and overall skin appearance, and increased skin hydration and number of capillary vessels. The main limitation of mesenchymal stem cell transfers is the survival of the graft. The final outcomes are dependent on many factors, including the age of the patient, technique of fat tissue harvesting, technique of lipoaspirate preparation, and technique of fat graft injection. It is very difficult to compare available studies because of the differences and multitude of techniques used. Fat harvesting is associated with potentially life-threatening complications, such as massive bleeding, embolism, or clots. However, most of the side effects are mild and transient: primarily hematomas, oedema, and mild pain. Mesenchymal stem cells that do not proliferate when injected into dermis promote neoangiogenesis, that is why respectful caution should be taken in the case of oncologic patients. A longer clinical observation on a higher number of participants should be performed to develop reliable indications and guidelines for transferring ADSCs. Full article

Post-transplant diabetes is a frequent complication after transplantation. Moreover, patients suffering from post-transplant diabetes have increased cardiovascular morbidity and reduced survival. Pathogenesis mainly involves beta-cell dysfunction in presence of insulin resistance. Both pre- and post-transplant risk factors are well-described, and some of them may be corrected or prevented. However, the frequency of post-transplant diabetes has not decreased in recent years. We realized a critical appraisal of preventive measures to reduce post-transplant diabetes. Full article

Biomarkers that predict likely response or resistance to specific therapies are critical in personalising treatment for cancer patients. Such biomarkers are now available for an increasing number of anti-cancer therapies, especially targeted therapy and immunotherapy. The gold-standard method for determining predictive biomarkers requires tumour tissue. Obtaining tissue, however, is not always possible and even if possible, the amount or quality of tissue obtained may be inadequate for biomarker analysis. Tumour DNA, however, can be released into the bloodstream, giving rise to what is referred to as circulating tumour DNA (ctDNA). In contrast to tissue, blood can be obtained from effectively all patients in a minimally invasive and safe manner. Other advantages of blood over tissue for biomarker testing include a shorter turn-around time and an ability to perform serial measurements. Furthermore, blood should provide a more complete profile of mutations present in heterogeneous tumours than a single-needle tissue biopsy. A limitation of blood vis-à-vis tissue, however, is lower sensitivity and, thus, the possibility of missing an actionable mutation. Despite this limitation, blood-based predictive biomarkers, such as mutant EGFR for predicting response to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer and mutant PIK3CA for predicting response to alpelisib in combination with fulvestrant in advanced breast cancer, may be used when tissue is unavailable. Although tissue remains the gold standard for detecting predictive biomarkers, it is likely that several further blood-based assays will soon be validated and used when tissue is unavailable or unsuitable for analysis. Full article

Asthma is a complex multifactorial and heterogeneous respiratory disease. Although genetics is a strong risk factor of asthma, external and internal exposures and their interactions with genetic factors also play important roles in the pathophysiology of asthma. Over the past decades, the application of high-throughput omics approaches has emerged and been applied to the field of asthma research for screening biomarkers such as genes, transcript, proteins, and metabolites in an unbiased fashion. Leveraging large-scale studies representative of diverse population-based omics data and integrating with clinical data has led to better profiling of asthma risk. Yet, to date, no omic-driven endotypes have been translated into clinical practice and management of asthma. In this article, we provide an overview of the current status of omics studies of asthma, namely, genomics, transcriptomics, epigenomics, proteomics, exposomics, and metabolomics. The current development of the multi-omics integrations of asthma is also briefly discussed. Biomarker discovery following multi-omics profiling could be challenging but useful for better disease phenotyping and endotyping that can translate into advances in asthma management and clinical care, ultimately leading to successful precision medicine approaches. 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

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

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

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

Objective: The use of hyperthermic intraperitoneal chemotherapy (HIPEC) as a treatment for epithelial ovarian cancer remains controversial. Our study aims to analyze the overall survival and disease-free survival for the use of HIPEC as a treatment for advanced epithelial ovarian cancer after neoadjuvant chemotherapy. Methods: A systematic review and meta-analysis was carried out using PubMed, Cochrane, Web of Science, and ClinicalTrials.gov. A total of six studies were used, comprising a total of 674 patients. Results: The results of our meta-analysis of all studies analyzed together (observational and randomized controlled trials (RCT)) did not achieve significant results. Contrary to the OS (HR = 0.56, 95% IC = 0.33–0.95, p = 0.03) and DFS (HR = 0.61, 95% IC = 0.43–0.86, p < 0.01) of the RCT analyzed separately, a clear impact on survival was suggested. The subgroup analysis showed that studies making use of higher temperatures (≥42 °C) for a shorter period of time (≤60 min) achieved better results for both OS and DFS, as well as the use of cisplatin as the form of chemotherapy in HIPEC. Moreover, the use of HIPEC did not increase high-grade complications. Conclusions: The addition of HIPEC to cytoreductive surgery demonstrates an improvement in OS and DFS for patients with epithelial ovarian cancer in advanced stages, without an increase in the number of complications. The use of cisplatin as chemotherapy in HIPEC obtained better results. Full article

The functional disease of the esophago-gastric junction (EGJ) is one of the most common health problems. It often happens that patients suffering from GERD need surgical management. The laparoscopic fundoplication has been considered the gold standard surgical treatment for functional diseases of the EGJ. The aim of our meta-analysis is to investigate functional outcomes after robotic fundoplication compared with conventional laparoscopic fundoplication. A prospective search of online databases was performed by two independent reviewers using the search string “robotic and laparoscopic fundoplication”, including all the articles from 1996 to December 2021. The risk of bias within each study was assessed with the Cochrane ROBINS-I and RoB 2.0 tools. Statistical analysis was performed using Review Manager version 5.4. In addition, sixteen studies were included in the final analysis, involving only four RCTs. The primary endpoints were functional outcomes after laparoscopic (LF) and robotic fundoplication (RF). No significant differences between the two groups were found in 30-day readmission rates (p = 0.73), persistence of symptomatology at follow-up (p = 0.60), recurrence (p = 0.36), and reoperation (p = 0.81). The laparoscopic fundoplication represents the gold standard treatment for the functional disease of the EGJ. According to our results, the robotic approach seems to be safe and feasible as well. Further randomized controlled studies are required to better evaluate the advantages of robotic fundoplication. Full article

Background: In recent years, physical exercise has been investigated for its potential as a therapeutic tool in patients with end-stage renal disease (ESRD) undergoing hemodialysis maintenance treatment (HD). It has been shown that regular practice of moderate-intensity exercise can improve certain aspects of immune function and exert anti-inflammatory effects, having been associated with low levels of pro-inflammatory cytokines and high levels of anti-inflammatory cytokines. Purpose: The aim of this review is to examine the studies carried out in this population that analyzed the effect of intradialytic exercise on the inflammatory state and evaluate which exercise modality is most effective. Methods: The search was carried out in the MEDLINE, CINAHL Web of Science and Cochrane Central Register of Controlled Trials databases from inception to June 2022. The PEDro scale was used to assess methodological quality, and the Cochrane Risk of Bias Tool and MINORS were used to evaluate the risk of bias. The quality of evidence was assessed with GRADE scale. The outcome measures were systemic inflammation biomarkers. Results: Mixed results were found in terms of improving inflammation biomarkers, such as CRP, IL-6 or TNFα, after exercise. Aerobic exercise seems to improve systemic inflammation when performed at medium intensity while resistance training produced better outcomes when performed at high intensity. However, some studies reported no differences after exercise and these results should be taken with caution. Conclusions: The low quality of the evidence suggests that aerobic and resistance exercise during HD treatment improves systemic inflammation biomarkers in patients with ESRD. In any case, interventions that increase physical activity in patients with ESRD are of vital importance as sedentary behaviors are associated with mortality. More studies are needed to affirm solid conclusions and to make intervention parameters, such as modality, dose, intensity or duration, sufficiently clear. Full article

Background: Anorexia nervosa (AN) has high rates of enduring disease and mortality. Currently, there is insufficient knowledge on the predictors of relapse after weight normalization and this is why a systematic literature review was performed. Methods: PubMed, EMBASE, PsychInfo, and Cochrane databases were searched for literature published until 13 July 2021. All study designs were eligible for inclusion if they focused on predictors of relapse after weight normalization in AN. Individual study definitions of relapse were used, and in general, this was either a drop in BMI and/or reccurrence of AN symptoms. Results: The database search identified 11,507 publications, leaving 9511 publications after the removal of duplicates and after a review of abstracts and titles; 191 were selected for full-text review. Nineteen publications met the criteria and included 1398 AN patients and 39 healthy controls (HC) from adults and adolescents (ages range 11–73 years). The majority used a prospective observational study design (12 studies), a few used a retrospective observational design (6 studies), and only one was a non-randomized control trial (NRCT). Sample sizes ranged from 16 to 191 participants. BMI or measures of body fat and leptin levels at discharge were the strongest predictors of relapse with an approximate relapse rate of 50% at 12 months. Other predictors included signs of eating disorder psychopathology at discharge. Conclusions: BMI at the end of treatment is a predictor of relapse in AN, which is why treatment should target a BMI well above 20. Together with the time to relapse, these outcomes are important to include in the evaluation of current and novel treatments in AN and for benchmarking. Full article

Background: New-onset atrial fibrillation (NOAF) is a common complication in patients with sepsis, although its prevalence and impact on outcomes are still unclear. We aim to provide a systematic review and meta-analysis on the prevalence of NOAF in patients with sepsis, and its impact on in-hospital mortality and intensive care unit (ICU) mortality. Methods: PubMed and EMBASE were systematically searched on 26 December 2021. Studies reporting on the prevalence of NOAF and/or its impact on in-hospital mortality or ICU mortality in patients with sepsis or septic shock were included. The pooled prevalence and 95% confidence intervals (CI) were calculated, as well as the risk ratios (RR), 95%CI and 95% prediction intervals (PI) for outcomes. Subgroup analyses and meta-regressions were performed to account for heterogeneity. Results: Among 4988 records retrieved from the literature search, 22 articles were included. Across 207,847 patients with sepsis, NOAF was found in 13.5% (95%CI: 8.9–20.1%), with high heterogeneity between studies; significant subgroup differences were observed, according to the geographical location, study design and sample size of the included studies. A multivariable meta-regression model showed that sample size and geographical location account for most of the heterogeneity. NOAF patients showed an increased risk of both in-hospital mortality (RR: 1.69, 95%CI: 1.47–1.96, 95%PI: 1.15–2.50) and ICU mortality (RR: 2.12, 95%CI: 1.86–2.43, 95%PI: 1.71–2.63), with moderate to no heterogeneity between the included studies. Conclusions: NOAF is a common complication during sepsis, being present in one out of seven individuals. Patients with NOAF are at a higher risk of adverse events during sepsis, and may need specific therapeutical interventions. Full article

Background: Endoscopic combined intrarenal surgery (ECIRS) adds ureteroscopic vision to percutaneous nephrolithotomy (PCNL), which can be helpful when dealing with complex renal stones. Yet, there is still no consensus on the superiority of ECIRS. We aimed to critically analyze the available evidence of studies comparing efficacy, safety, bleeding risk, and efficiency of ECIRS and PCNL. Methods: We searched for studies comparing efficacy (initial and final stone-free rate), safety (postoperative fever, overall and severe complications), efficiency (operative time and hospital stay) and bleeding risk between ECIRS and PCNL. Meta-analysis was performed. Results: Seven studies (919 patients) were identified. ECIRS provided a significantly higher initial stone-free rate, higher final stone-free rate, lower overall complications, lower severe complications, and lower rate of requiring blood transfusion. There was no difference between the two groups in terms of postoperative fever, hemoglobin drop, operative time, and hospital stay. In the subgroup analysis, both minimally invasive and conventional ECIRS were associated with a higher stone-free rate and lower complication outcomes. Conclusions: When treating complex renal stones, ECIRS has a better stone-free rate, fewer complications, and requires fewer blood transfusions compared with PCNL. Subgroups either with minimally invasive or conventional intervention showed a consistent trend. Full article

Screening for latent tuberculosis infection (LTBI) is mandatory before commencing tumor necrosis factor (TNF)-α inhibitor use. However, the impact of immunosuppressive therapy (IST), including corticosteroids and immunomodulators, on the performance of LTBI screening in patients with inflammatory bowel disease (IBD) has not been fully elucidated. We searched all relevant studies published before November 2021 that examined the performance of interferon γ release assays (IGRAs) and tuberculin skin tests (TSTs) in patients with IBD who received IST, using the Medline, EMBASE, and Cochrane Library databases. We performed meta-analyses of positive or indeterminate rates of IGRA or TST according to IST and calculated the concordance rates between IGRA and TST results. A total of 20 studies with 4045 patients were included in the meta-analysis. The IGRA-positive rate was lower in patients on IST than in those not on IST (odds ratio (OR) (95% confidence interval (CI)) = 0.55 (0.39–0.78)), whereas the IGRA-indeterminate rate was higher in patients on IST than in those not on IST (OR (95% CI) = 2.91 (1.36–6.24)). The TST-positive rate did not differ between the on-IST and not-on-IST groups (OR (95% CI) = 0.87 (0.51–1.50)). The concordance rate between IGRA and TST was 83.3% (95% CI, 78.5–88.1%). The IGRA-negative/TST-positive rate tended to be higher than that the IGRA-positive/TST-negative rate (9.5% vs. 5.8%, respectively), although the difference was not statistically significant. In conclusion, IGRA results were negatively affected by IST in patients with IBD, supporting requirements that IGRA should be performed before initiating IST. The use of both an IGRA and TST in patients with IBD on IST may improve the diagnosis rate of LTBI. Full article

Abdominal adhesions are a risk factor for conversion to open surgery. An advantage of robotic surgery is the lower rate of unplanned conversions. A systematic review was conducted using the terms “laparoscopic” and “robotic”. Inclusion criteria were: comparative studies evaluating patients undergoing laparoscopic and robotic surgery; reporting data on conversion to open surgery for each group due to adhesions and studies including at least five patients in each group. The main outcomes were the conversion rates due to adhesions and surgeons’ expertise (novice vs. expert). The meta-analysis included 70 studies from different surgical specialities with 14,329 procedures (6472 robotic and 7857 laparoscopic). The robotic approach was associated with a reduced risk of conversion (OR 1.53, 95% CI 1.12–2.10, p = 0.007). The analysis of the procedures performed by “expert surgeons” showed a statistically significant difference in favour of robotic surgery (OR 1.48, 95% CI 1.03–2.12, p = 0.03). A reduced conversion rate due to adhesions with the robotic approach was observed in patients undergoing colorectal cancer surgery (OR 2.62, 95% CI 1.20–5.72, p = 0.02). The robotic approach could be a valid option in patients with abdominal adhesions, especially in the subgroup of those undergoing colorectal cancer resection performed by expert surgeons. Full article

While randomized trials typically lack sufficient statistical power to identify predictors and moderators of outcome, ”individual participant data” (IPD) meta-analyses, which combine primary data of multiple randomized trials, can increase the statistical power to identify predictors and moderators of outcome. We conducted a systematic review of IPD meta-analyses on psychological treatments of depression to provide an overview of predictors and moderators identified. We included 10 (eight pairwise and two network) IPD meta-analyses. Six meta-analyses showed that higher baseline depression severity was associated with better outcomes, and two found that older age was associated with better outcomes. Because power was high in most IPD meta-analyses, non-significant findings are also of interest because they indicate that these variables are probably not relevant as predictors and moderators. We did not find in any IPD meta-analysis that gender, education level, or relationship status were significant predictors or moderators. This review shows that IPD meta-analyses on psychological treatments can identify predictors and moderators of treatment effects and thereby contribute considerably to the development of personalized treatments of depression. Full article