Journal of Clinical Medicine

Haemoptysis represents one of the most severe major bleeding manifestations in the clinical course of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). Accumulating evidence indicates that dysfunction of the pulmonary vascular bed in the setting of PAH predisposes patients to increased hemorrhagic diathesis, resulting in mild to massive and life-threatening episodes of haemoptysis. Despite major advances in PAH targeted treatment strategies, haemoptysis is still correlated with substantial morbidity and impaired quality of life, requiring a multidisciplinary approach by adult CHD experts in tertiary centres. Technological innovations in the field of diagnostic and interventional radiology enabled the application of bronchial artery embolization (BAE), a valuable tool to efficiently control haemoptysis in modern clinical practice. However, bleeding recurrences are still prevalent, implying that the optimum management of haemoptysis and its implications remain obscure. Moreover, regarding the use of oral anticoagulation in patients with haemoptysis, current guidelines do not provide a clear therapeutic strategy due to the lack of evidence. This review aims to discuss the main pathophysiological mechanisms of haemoptysis in PAH-CHD, present the clinical spectrum and the available diagnostic tools, summarize current therapeutic challenges, and propose directions for future research in this group of patients. Full article

Mitochondrial disorders are the most common inherited conditions, characterized by defects in oxidative phosphorylation and caused by mutations in nuclear or mitochondrial genes. Due to its high energy request, skeletal muscle is typically involved. According to the International Workshop of Experts in Mitochondrial Diseases held in Rome in 2016, the term Primary Mitochondrial Myopathy (PMM) should refer to those mitochondrial disorders affecting principally, but not exclusively, the skeletal muscle. The clinical presentation may include general isolated myopathy with muscle weakness, exercise intolerance, chronic ophthalmoplegia/ophthalmoparesis (cPEO) and eyelids ptosis, or multisystem conditions where there is a coexistence with extramuscular signs and symptoms. In recent years, new therapeutic targets have been identified leading to the launch of some promising clinical trials that have mainly focused on treating muscle symptoms and that require populations with defined genotype. Advantages in next-generation sequencing techniques have substantially improved diagnosis. So far, an increasing number of mutations have been identified as responsible for mitochondrial disorders. In this review, we focused on the principal molecular genetic alterations in PMM. Accordingly, we carried out a comprehensive review of the literature and briefly discussed the possible approaches which could guide the clinician to a genetic diagnosis. Full article

Background: We evaluated the risk of acute anterior uveitis (AAU) in patients with ankylosing spondylitis (AS) during treatment with tumor necrosis factor-alpha inhibitors (TNFis). Methods: This study was performed on AS patients using the Korean National Health Insurance claims database. We analyzed the first and total occurrence of AAU during the first 2 years of TNFis use according to the type of TNFis. Additionally, the occurrence of AAU was assessed in subgroups with or without prior AAU before TNFis initiation. Results: In total, 5938 AS patients initiated TNFis use between 2009 and 2017 and used them for more than 2 years. Among them, 1488 (25.1%) patients had a history of AAU before starting TNFis treatment. Compared to adalimumab, the use of etanercept (hazard ratio [HR] 1.77) increased the risk of AAU. The incidence rate ratio (IRR) of AAU with etanercept was significantly higher than that of adalimumab (IRR 1.78). The IRR of AAU was also higher for etanercept than adalimumab use in patients with (IRR 1.86) and without (IRR 2.92) a history of AAU. Conclusion: These data suggest that compared to anti-TNF-alpha monoclonal antibodies, etanercept has a higher incidence of AAU regardless of a history of AAU. Full article

People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80–102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing. Full article

The combined anteroposterior fusion with vertebral body replacement (VBR) using a wide footplate expandable cage with a minimally invasive lateral approach has been widely used for pseudoarthrosis after osteoporotic vertebral fractures. The purpose of this study is to evaluate the radiological results of combined anteroposterior surgery using VBR and to recommend the optimal procedure. Thirty-eight elderly patients were included in this study. The mean preoperative local kyphosis angle was 29.3°, and the mean correction loss angle was 6.3°. Cage subsidence was observed in ten patients (26.3%), and UIV or LIV fracture in twelve patients (31.6%). Patients with cage subsidence were compared to those without cage subsidence to determine the causal factors. The mean number of fixed vertebrae was 5.4 vertebrae with cage subsidence and 7.4 vertebrae without cage subsidence. In addition, to precisely clarify the optimal number of fixed vertebrae, those patients with two above–two below fixation were compared to those with less than two above–two below fixation, which revealed that the correction loss angle was significantly less in two above–two below fixation (p = 0.016). Based on these results, we recommend at least two above–two below fixation with VBR to minimize the correction loss angle and prevent cage subsidence. Full article

Introduction: Childhood cancer survivors (CCS) might be at high risk of additional chronic diseases due to cardiotoxic side effects. The aim of this study was to analyze long-term side effects of cancer therapy on vascular structure/function, cardiac biomarkers and on physical activity. Methods: In total, 68 asymptomatic patients aged 16–30 years with childhood cancer (diagnosed 10.6 ± 3.9 years ago) were examined from 2015–2020. (Central) blood pressure and pulse wave velocity were registered via the oscillometric method, while carotid intima-media thickness (cIMT) was measured non-invasively by ultrasound. cIMT values of patients were compared to healthy controls (n = 68; aged 22.3 ± 3.5 years). Patients’ exercise capacity was recorded. The plasma N-terminal pro-brain natriuretic protein (NTproBNP) and troponin levels were measured as cardiac biomarkers. CCS were categorized in groups with low, moderate and high anthracyclines. Results: No differences were found in cIMT between patients and controls as well as between patients with various anthracycline dosage. Patients with high dose anthracyclines showed a significant lower performance versus patients with moderate dose anthracyclines (84.4% of predicted VO2peak; p = 0.017). A total of 11.6% of CCS had abnormal NTproBNP values which correlated with received anthracycline dosage (p = 0.024; r = 0.343). Conclusion: NTproBNP levels and exercise capacity might be early markers for cardiovascular dysfunction in CCS and should be included in a follow-up protocol, while cIMT and troponin seem not to be adequate parameters. Full article

Sepsis-induced metabolic dysfunction is associated with mortality, but the signatures that differentiate variable clinical outcomes among survivors are unknown. Our aim was to determine the relationship between host metabolism and chronic critical illness (CCI) in patients with septic shock. We analyzed metabolomics data from mechanically ventilated patients with vasopressor-dependent septic shock from the placebo arm of a recently completed clinical trial. Baseline serum metabolites were measured by liquid chromatography-mass spectrometry and ¹H-nuclear magnetic resonance. We conducted a time-to-event analysis censored at 28 days. Specifically, we determined the relationship between metabolites and time to extubation and freedom from vasopressors using a competing risk survival model, with death as a competing risk. We also compared metabolite concentrations between CCI patients, defined as intensive care unit level of care ≥ 14 days, and those with rapid recovery. Elevations in two acylcarnitines and four amino acids were related to the freedom from organ support (subdistributional hazard ratio < 1 and false discovery rate < 0.05). Proline, glycine, glutamine, and methionine were also elevated in patients who developed CCI. Our work highlights the need for further testing of metabolomics to identify patients at risk of CCI and to elucidate potential mechanisms that contribute to its etiology. Full article

The increasing mortality and morbidity in patients with diabetes mellitus constitute a severe public health problem. The condition is recognized as a cause of impaired quality of life, high costs, and diminished productivity. In this study, we performed a cross-sectional analysis among 300 Polish participants with type 1 and type 2 diabetes to determine and classify risk factors associated with increased incidences of hypoglycemia. Including an open-access knowledge about the correlations between diabetes rates and human’s lifestyle, we confirm that the frequency of smoking and drinking alcohol, low BMI, inappropriate diet, low physical activity, lack of vaccination against influenza and pneumococci, and co-existence of other comorbidities such as cardiovascular diseases, thyroid diseases, hyperlipidemia, retinopathy, and asthma elevate the risk of hypoglycemia. Furthermore, hypoglycemic patients were more often malnourished, depressed, irritated, and exposed to stress. In sum, the analysis of the interaction between diabetes and sociodemographic, environmental, or other disease-related risk factors provides strategies to optimize glycemic control and reduce the incidence of hypoglycemia. Furthermore, we believe our findings may constitute a basis for promoting health by adjusting available and implementing new preventive services reducing hypoglycemic episodes in diabetic patients. Full article

The role of electrocardiography (ECG) in chronic thromboembolic pulmonary hypertension (CTEPH) diagnosis and prognosticating has not been yet established. We aimed to assess the relationships of the recommended ECG criteria of right ventricular hypertrophy (RVH) with clot localization in CTEPH patients. ECG patterns of RVH according to the American College of Cardiology Foundation were assessed in patients with newly diagnosed CTEPH. We enrolled 58 (45.3%) patients with proximal and 70 (54.7%) with distal CTEPH. Receiver-operating characteristics curves analysis indicated that the following ECG abnormalities predicted proximal CTEPH localization: R_V1 > 6 mm—AUC 0.75 (CI: 0.66–0.84, p < 0.00001); S_V6 > 3 mm—AUC 0.70 (CI: 0.60–0.79, p < 0.00001); S_I > R_I wave—AUC 0.67 (CI: 0.58–0.77, p = 0.0004); R_V1:S_V1 > 1.0—AUC 0.66 (CI: 0.56–0.76, p = 0.0009); R_V1 peak > 0.035 s (QRS < 120 ms)—AUC 0.66 (CI: 0.56–0.75, p = 0.0016); R_V1:S_V1 > R_V3(V4):S_V3(V4)—AUC-0.65 (CI: 0.54–0.75, p = 0.0081); R_aVR > 4 mm—AUC 0.62 (CI: 0.52–0.71, p = 0.002) and P_II > 2.5 mm—AUC 0.62 (CI: 0.52–0.72, p = 0.00162). Pulmonary vascular resistance significantly correlated with amplitudes of R_V1 (r = 0.34, p = 0.008), S_V6 (r = 0.53, p = 0.000027) and P_II (r = 0.44, p = 0.00007). In patients with CTEPH, only 8 out of 23 ECG RVH criteria were useful for differentiating between proximal and distal CTEPH localization and we found that R_V1 and S_V6 may contribute as potential discriminators. Full article

Addiction is a mental disorder with limited available treatment options. The therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) on it, by targeting craving in particular, has been explored with heterogenous results. This meta-analysis uses updated evidence to assess overall rTMS efficacy on craving, differential effects between addiction types clustered into three groups (depressant (alcohol, cannabis, opiate), stimulant (nicotine, cocaine, methamphetamine), and behavioral addiction (gambling, eating disorder)), and stimulation settings. Studies on substance use, gambling, and eating disorders are included, with unrestricted stimulation settings, by searching the PubMed, Embase, PsycINFO, and Cochrane databases up to 30 April 2020. A total of 34 eligible studies (42 units of analysis) were identified. Because of highly significant heterogeneity in primary results, a sensitivity analysis was performed on a remaining sample of 26 studies (30 units of analysis). Analyses performed using random effects model revealed a small effect size favoring active rTMS over shamTMS stimulation in the reduction in craving. We found a significant difference between addiction types, with a persistent small effect only for stimulant and behavioral groups. In these groups we found no difference between the different combinations of target and frequency of stimulation, but a significant correlation between number of sessions and craving reduction. In conclusion, efficacy of rTMS on craving in stimulant and behavioral addiction was highlighted, but recommendations on optimal stimulation settings and its clinical application await further research. Full article

Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented. Full article

Severe obesity increases the risk for negative outcomes in patients with coronavirus disease 2019 (COVID-19). Our objectives were to investigate the effect of BMI on in-hospital outcomes in our New York City Health and Hospitals’ ethnically diverse population, further explore this effect by age, sex, race/ethnicity, and timing of admission, and, given the relationship between COVID-19 and hyperinflammation, assess the concentrations of markers of systemic inflammation in different BMI groups. A retrospective study was conducted in hospitalized patients with COVID-19 in the public health care system of New York City from 1 March 2020 to 31 October 2020. A total of 8833 patients were included in this analysis (women: 3593, median age: 62 years). The median body mass index (BMI) was 27.9 kg/m². Both overweight and obesity were independently associated with in-hospital death. The association of overweight and obesity with death appeared to be stronger in men, younger patients, and individuals of Hispanic ethnicity. We did not observe higher concentrations of inflammatory markers in patients with obesity as compared to those without obesity. In conclusion, overweight and obesity were independently associated with in-hospital death. Obesity was not associated with higher concentrations of inflammatory markers. Full article

We evaluated the 3-year drug survival and efficacy of the biosimilar SB4/Benepali in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients, previously treated with etanercept (ETA). Drug survival rate was calculated using the Kaplan–Meier method and Cox proportional hazard models were developed to examine predictors of SB4 discontinuation. 236 patients (120 RA, 80 PsA and 36 AS), aged 60.7 ± 13.8 years and with an ETA duration of 4.1 ± 3.4 years were included. The 3-year retention rate for SB4 was 94.4%, 88% and 86% in AS, RA and PsA patients, respectively, with no difference between groups. Patients without comorbid disease had higher retention rates vs. patients with comorbid disease (90% vs. 60%, p < 0.0001). Disease activity, as measured by DAS28, DAPSA and BASDAI remained stable over the 3 years. Comorbid disease (hazard ratio; HR: 4.06, p < 0.0001) and HAQ at baseline (HR: 2.42, p = 0.0024) significantly increased the risk of SB4 discontinuation, while previous ETA duration was negatively associated with SB4 discontinuation (HR: 0.97, p = 0.0064). Forty-one (17.4%) patients left the study due to the interruption of the SB4 treatment, 31 (75.6%) discontinued due to inefficacy and 10 (24.4%) due to adverse events. This real-life study confirms the similar efficacy profile of ETA with long-term retention and a good safety profile in inflammatory arthritis patients. Full article

Despite the empirical use of human albumin during pancreatectomy to replace intraoperative volume loss while preventing fluid overload and edema, its impact on postoperative outcomes remains unclear. In addition, most previous studies have focused on the effects of therapeutic albumin usage. Here, we investigated whether preemptive administration of human albumin to prevent edema during pancreatectomy could reduce the incidence of moderate postoperative complications. Adult patients undergoing pancreatectomy were assigned to either the albumin group (n = 100) or the control group (n = 100). Regardless of the preoperative albumin level, 200 mL of 20% albumin was administered to the albumin group after induction of anesthesia. The primary outcome was the incidence of moderate postoperative complications as defined by a Clavien–Dindo classification grade ≥ 2 at discharge. Intraoperative net-fluid balance, a known risk factor of postoperative complication after pancreatectomy, was lower in the albumin group than in the control group (p = 0.030), but the incidence of moderate postoperative complications was not different between the albumin and control groups (47/100 vs. 38/100, respectively; risk ratio: 1.24, 95% CI: 0.89 to 1.71; p = 0.198). Therefore, preemptive administration of human albumin to prevent fluid overload and edema during pancreatectomy is not recommended because of its lack of apparent benefit in improving postoperative outcomes. Full article

Lipopolysaccharide, the main component of the outer membrane of Gram-negative bacteria is a highly potent endotoxin responsible for organ dysfunction in sepsis. It is present in the blood stream not only in Gram-negative infections, but also in Gram-positive and fungal infections, presumably due to sepsis-related disruption of the intestinal barrier. Various pathways, both extra- and intracellular, are involved in sensing endotoxin and non-canonical activation of caspase-mediated pyroptosis is considered to have a major role in sepsis pathophysiology. Endotoxin induces specific pathological alterations in several organs, which contributes to poor outcomes. The adverse consequences of endotoxin in the circulation support the use of anti-endotoxin therapies, yet more than 30 years of experience with endotoxin adsorption therapies have not provided clear evidence in favor of this treatment modality. The results of small studies support timely endotoxin removal guided by measuring the levels of endotoxin; unfortunately, this has not been proven in large, randomized studies. The presence of endotoxemia can be demonstrated in the majority of patients with COVID-19, yet only case reports and case series describing the effects of endotoxin removal in these patients have been published to date. The place of blood purification therapies in the treatment of septic shock has not yet been determined. Full article

Maskne, a newly coined term deriving from the contraction of mask-related acne, is a form of mechanical acne resulting from continuous textile–skin adherence and friction. Prolonged mask use heats up the face environment, thus modifying skin microbiota and sebum production. Although effective prevalence is unknown, since the pandemic began and the prolonged use of masks was extended to the general population, maskne has been a frequent topic of consultation among dermatologists. This term has been successfully introduced into common language, with more than 200,000 hashtags on social media, where it is also possible to find “home remedies” that can worsen this dermatosis. The aim of this paper is to discuss the pathogenesis, address clinicians on the correct differential diagnoses among facial dermatoses, and move towards the correct therapy. Full article

Different neurological and psychiatric disorders such as vertebrobasilar insufficiency, chronic pain syndrome, anxiety, and depression are observed in more than 90% of patients after treatment for breast cancer and may cause alterations in the functional connectivity of the default mode network. The purpose of the present study is to assess changes in the functional connectivity of the default mode network in patients after breast cancer treatment using resting state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI was performed using a 3.0T MR-scanner on patients (N = 46, women) with neurological disorders (chronic pain, dizziness, headaches, and/or tinnitus) in the late postoperative period (>12 months) after Patey radical mastectomy for breast cancer. According to the intergroup statistical analysis, there were differences in the functional connectivity of the default mode network in all 46 patients after breast cancer treatment compared to the control group (p < 0.01). The use of rs-fMRI in in breast cancer survivors allowed us to identify changes in the functional connectivity in the brain caused by neurological disorders, which correlated with a decreased quality of life in these patients. The results indicate the necessity to improve treatment and rehabilitation methods in this group of patients. Full article

In the last decade, the analysis of the medical images has evolved significantly, applications and tools capable to extract quantitative characteristics of the images beyond the discrimination capacity of the investigator’s eye being developed. The applications of this new research field, called radiomics, presented an exponential growth with direct implications in the diagnosis and prediction of response to therapy. Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with a severe prognosis, despite the aggressive multimodal treatments applied according to the guidelines. Radiomics has already proven the ability to differentiate TNBC from fibroadenoma. Radiomics features extracted from digital mammography may also distinguish between TNBC and non-TNBC. Recent research has identified three distinct subtypes of TNBC using IRM breast images voxel-level radiomics features (size/shape related features, texture features, sharpness). The correlation of these TNBC subtypes with the clinical response to neoadjuvant therapy may lead to the identification of biomarkers in order to guide the clinical decision. Furthermore, the variation of some radiomics features in the neoadjuvant settings provides a tool for the rapid evaluation of treatment efficacy. The association of radiomics features with already identified biomarkers can generate complex predictive and prognostic models. Standardization of image acquisition and also of radiomics feature extraction is required to validate this method in clinical practice. Full article

The aim of this study was to compare two different tomographs for the evaluation of the role of semiquantitative PET/CT parameters and radiomics features (RF) in the prediction of thyroid incidentalomas (TIs) at ¹⁸F-FDG imaging. A total of 221 patients with the presence of TIs were retrospectively included. After volumetric segmentation of each TI, semiquantitative parameters and RF were extracted. All of the features were tested for significant differences between the two PET scanners. The performances of all of the features in predicting the nature of TIs were analyzed by testing three classes of final logistic regression predictive models, one for each tomograph and one with both scanners together. Some RF resulted significantly different between the two scanners. PET/CT semiquantitative parameters were not able to predict the final diagnosis of TIs while GLCM-related RF (in particular GLCM entropy_log2 e GLCM entropy_log10) together with some GLRLM-related and GLZLM-related features presented the best predictive performances. In particular, GLCM entropy_log2, GLCM entropy_log10, GLZLM SZHGE, GLRLM HGRE and GLRLM HGZE resulted the RF with best performances. Our study enabled the selection of some RF able to predict the final nature of TIs discovered at ¹⁸F-FDG PET/CT imaging. Classic semiquantitative and volumetric PET/CT parameters did not reveal these abilities. Furthermore, a good overlap in the extraction of RF between the two scanners was underlined. Full article