The association between aortic stenosis (AS) and cardiac amyloidosis (CA) is more frequent than expected. Albeit rare, CA, particularly the transthyretin (ATTR) form, is commonly found in elderly people. ATTR-CA is also the most prevalent form in patients with AS. These conditions share pathophysiological, clinical and imaging findings, making the diagnostic process very challenging. To date, a multiparametric evaluation is suggested in order to detect patients with both AS and CA and choose the best therapeutic option. Given the accuracy of modern non-invasive techniques (i.e., bone scintigraphy), early diagnosis of CA is possible. Flow-charts with the main CA findings which may help clinicians in the diagnostic process have been proposed. The prognostic impact of the combination of AS and CA is not fully known; however, new available specific treatments of ATTR-CA have changed the natural history of the disease and have some impact on the decision-making process for the management of AS. Hence the relevance of detecting these two conditions when simultaneously present. The specific features helping the detection of AS-CA association are discussed in this review, focusing on the shared pathophysiological characteristics and the common clinical and imaging hallmarks. Full article

Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs’ propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs’ propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia. Full article

Background: The pathophysiology of angina-like symptoms in myocarditis is still unclear. Perivascular fat attenuation index (pFAI) by coronary computed tomography angiography (CCTA) is a non-invasive marker of coronary inflammation (CI) in atherosclerosis. We explored the presence of CI in clinically suspected myocarditis with infarct-like presentation. Methods: We retrospectively included 15 consecutive patients (67% male, age 30 ± 10 years) with clinically suspected infarct-like myocarditis who underwent CCTA to rule out coronary artery disease. Right coronary artery (RCA) pFAI mean value was compared with that of healthy volunteers. Results: Mean RCA pFAI value was −92.8 ± 8.4 HU, similar to that of healthy volunteers (−95.2 ± 6.0, p = 0.8). We found no correlation between RCA pFAI mean values and peak Troponin I (r = −0.43, p = 0.11) and C-reactive protein at diagnosis (r = −0.25, p = 0.42). Patients with higher pFAI values showed higher biventricular end-systolic volumes (ESV) (p = 0.038 for left and p = 0.024 for right ventricle) and lower right ventricular ejection fraction (RVEF) (p = 0.038) on cardiovascular magnetic resonance. Conclusions: In clinically suspected myocarditis with infarct-like presentation, RCA pFAI values are lower than those validated in atherosclerosis. The correlation between higher pFAI values, higher biventricular ESV and lower RVEF, may suggest a role of pFAI in predicting non-atherosclerotic CI (i.e., infective/immune-mediated “endothelialitis”). Full article

Background: Meniere disease (MD) is an inner ear disorder associated with comorbidities such as autoimmune diseases or migraine. This study describes clinical and cytokine profiles in MD according to the age of onset of the condition. Methods: A cross-sectional study including 83 MD patients: 44 with early-onset MD (EOMD, <35 years old), and 39 with late-onset MD (LOMD, >50 years old), 64 patients with migraine and 55 controls was carried out. Clinical variables and cytokines levels of CCL3, CCL4, CCL18, CCL22, CXCL,1 and IL-1β were compared among the different groups. Results: CCL18 levels were higher in patients with migraine or MD than in controls. Elevated levels of IL-1β were observed in 11.4% EOMD and in 10.3% LOMD patients and these levels were not dependent on the age of individuals. EOMD had a longer duration of the disease (p = 0.004) and a higher prevalence of migraine than LOMD (p = 0.045). Conclusions: Patients with EOMD have a higher prevalence of migraine than LOMD, but migraine is not associated with any cytokine profile in patients with MD. The levels of CCL18, CCL3, and CXCL4 were different between patients with MD or migraine and controls. Full article

Background: Both obstructive sleep apnea (OSA) and metabolic syndrome (MS) promote arterial stiffening. As a basis for this study, we presumed that arterial stiffness could be assessed using the Arteriograph (TensioMed, Budapest, Hungary) to detect early modifications induced by continuous positive airway therapy (CPAP) in reversing this detrimental vascular remodeling. Arterial stiffness is increasingly acknowledged as a major cardiovascular risk factor and a marker of subclinical hypertension-mediated organ damage. The aim of this pilot study was to evaluate the arterial stiffness changes in patients with moderate–severe OSA and MS after short-term CPAP use. Methods: We performed a prospective study that included patients with moderate–severe OSA and MS who had not undergone previous CPAP therapy. All subjects underwent clinical examination and arterial stiffness assessment using the oscillometric technique with Arteriograph (TensioMed, Budapest, Hungary) detection before and after 8-week CPAP therapy. Results: 39 patients with moderate–severe OSA were included. Eight weeks of CPAP therapy significantly improved central systolic blood pressure (Δ = −11.4 mmHg, p = 0.009), aortic pulse wave velocity (aoPWV: Δ = −0.66 m/s, p = 0.03), and aortic augmentation index (aoAix: Δ = −8.25%, p = 0.01) only in patients who used the device for a minimum of 4 h/night (n = 20). Conclusions: Arterial stiffness was improved only among CPAP adherent patients and could be detected using the Arteriograph (TensioMed, Budapest, Hungary), which involves a noninvasive procedure that is easy to implement for the clinical evaluation of arterial stiffness. Full article

Background: The prevalence of chronic heart failure (CHF) in patients assisted in primary care is not well known. We investigated the prevalence of CHF, its associated factors, and its therapeutic management. Methods and findings: This was a cross-sectional, multicenter study conducted in primary care (PC) in baseline patients of the IBERICAN study (Identification of the Spanish Population at Cardiovascular and Renal Risk). CHF was defined as the presence of this condition in the medical history, classifying patients according to the type of ventricular dysfunction in CHF with preserved ejection fraction (pEF), or CHF with reduced ejection fraction (rEF). Clinical characteristics, relationship between CHF and main cardiovascular risk factors (CVRF), and drug treatments used according to ejection fraction (EF) were analyzed. Results: A total of 8066 patients were included (54.5% women), average age (SD) was 57.9 (14.8) years, of which 3.1% (95% CI: 2.3–3.7) presented CHF, without differences between men and women. CHF with pEF (61.8%; 95% CI: 55.5–67.6) was more frequent in women, and CHF with rEF (38.1%; 95% CI: 33.2–45.5) (p = 0.028) was similar in both genders (65.9%; 95% CI: 57.1–73.4 vs. 57.3%; 95% CI: 47.7–65.8) (p = 0.188). A progressive increase of the prevalence with age (15.2% in ≥80 years) and with the aggregation of CVRF was observed. The most prescribed treatments were beta-blockers (54.7%) followed by angiotensin converting enzyme inhibitors (42.8%) and angiotensin II receptor antagonists (41.3%), without differences between pEF and rEF. The variables that are most associated with the probability of suffering CHF were a personal history of left ventricular hypertrophy (OR: 5.968; p < 0.001), of atrial fibrillation (OR: 3.494; p < 0.001), and of peripheral vascular disease (OR: 2.029; p < 0.001). Conclusions: Three in every 100 patients included in the IBERICAN study presented CHF, of which two thirds had pEF. The condition increased exponentially with age and aggregation of CVRF. We did not find any differences in drug treatment according to the type of ventricular dysfunction. The treatment of HF with rEF has much room for improvement. Full article

IgA nephropathy (IgAN) is a globally well-known primary glomerular nephropathy. Hypertriglyceridemia (HTG) is one factor contributing to atherosclerosis and is a common complication of renal failure. HTG is a significant risk factor for decreased renal function in patients with IgAN. We evaluated the association of HTG with the histopathological features of IgAN patients. A total of 480 patients diagnosed with IgAN via kidney biopsy from eight university hospitals affiliated with the College of Medicine of the Catholic University of Korea were included in the final cohort. Pathological features were evaluated by eight expert pathologists with hospital consensus. HTG was defined as a serum triglyceride (TG) level of ≥150 mg/dL. In the study population analysis, the HTG group was older, with more males; higher body mass index (BMI), low-density lipoprotein cholesterol (LDL-C) and spot urine protein ratio; and lower estimated glomerular filtration rate (eGFR). In the lipid profile analysis, eGFR was negatively correlated with TGs/ high-density lipoprotein cholesterol (HDL) and triglyceride-glucose index (TyG). Proteinuria positively correlated with TGs/HDL, non-HDL/HDL, LDL/HDL, TyG, TGs and LDL. The percentages of global sclerosis (GS), segmental sclerosis (SS) and capsular adhesion (CA), and the scores for mesangial matrix expansion (MME) and mesangial cell proliferation (MCP), were more elevated in the HTG group compared to the normal TG group. Multivariable linear regression analysis showed that the percentages of global sclerosis, segmental sclerosis and capsular adhesion, as well as the scores for mesangial matrix expansion and mesangial cell proliferation, were positively associated with TG level. In binary logistic regression, the HTG group showed a higher risk for global sclerosis and segmental sclerosis. In conclusion, HTG is a significant risk factor for glomerulosclerosis in IgAN. Full article

Given the differing mechanisms thought to underlie therapeutic sub- and supra-perception-based neurostimulative modalities, Spinal Cord Stimulation (SCS) systems designed for combined delivery of these approaches may help improve analgesic outcomes and quality of life, and reduce treatment failures. This multicenter, observational case-series evaluated 188 patients with chronic back and/or leg pain implanted with an SCS device capable of sequential or simultaneous delivery of sub-perception and supra-perception stimulation programming (i.e., combination therapy) at 16 sites in Europe. Following implantation, patients were provided with an array of advanced supra-perception programs (e.g., paresthesia-based SCS using multiple independent current sources), and a custom set of sub-perception programs optimized with specific waveforms and/or field shapes. A mean overall pain score of 7.9 ± 1.7 (Standard Deviation (SD)) was reported pre-trial (Baseline). Overall pain was reduced by 4.4 ± 2.8 points (NRS) at 3-months (n = 117) and at 12 months post-implant (n = 90), respectively (p < 0.0001). Substantial quality-of-life (EQ-5D-5L) improvement as assessed at last follow-up was also observed (n = 60). These results suggest that an implanted SCS device capable of combination therapy, while also enabled with patient-specific waveform optimization and stimulation field targeting capabilities, can enable highly effective pain relief and improve quality of life in patients suffering with chronic pain. Full article

Background: The etiology of autoimmune rheumatic diseases is unknown. Endothelial dysfunction and premature atherosclerosis are commonly seen in these patients. Atherosclerosis is considered one of the main causes of cardiovascular diseases. Hypertension is considered the most important traditional cardiovascular risk. This case-control study aimed to investigate the relationship between autoimmune diseases and cardiovascular risk. Methods: This study was carried out in patients with rheumatoid arthritis, RA (n = 10), primary Sjögren syndrome, PSS (n = 10), and healthy controls (n = 10). Mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse wave velocity (PWV, an indicator of arterial stiffness) were assessed via a Vicorder device. Asymmetric dimethylarginine (ADMA) was measured via ELISA. Retinal photos were taken via a CR-2 retinal camera, and retinal microvasculature analysis was carried out. T-tests were conducted to compare the disease and control groups. ANOVA and ANOVA—ANCOVA were also used for the correction of covariates. Results: A high prevalence of hypertension was seen in RA (80% of cases) and PSS (40% of cases) compared to controls (only 20% of cases). Significant changes were seen in MBP (RA 101 ± 11 mmHg; PSS 93 ± 10 mm Hg vs. controls 88 ± 7 mmHg, p = 0.010), SBP (148 ± 16 mmHg in RA vs. 135 ± 16 mmHg in PSS vs. 128 ± 11 mmHg in control group; p = 0.007), DBP (77 ± 8 mmHg in RA, 72 ± 8 mmHg in PSS vs. 67 ± 6 mmHg in control; p = 0.010 in RA compared to the controls). Patients with PSS showed no significant difference as compared to controls (MBP: p = 0.240, SBP: p = 0.340, DBP: p = 0.190). Increased plasma ADMA was seen in RA (0.45 ± 0.069 ng/mL) and PSS (0.43 ± 0.060 ng/mL) patients as compared to controls (0.38 ± 0.059 ng/mL). ADMA in RA vs. control was statistically significant (p = 0.022). However, no differences were seen in ADMA in PSS vs. controls. PWV and retinal microvasculature did not differ across the three groups. Conclusions: The prevalence of hypertension in our cohort was very high. Similarly, signs of endothelial dysfunction were seen in autoimmune rheumatic diseases. As hypertension and endothelial dysfunction are important contributing risk factors for cardiovascular diseases, the association of hypertension and endothelial dysfunction should be monitored closely in autoimmune diseases. Full article

Pelvic inflammatory disease (PID) affects 4.4% of women aged 18–44 in the United States, and may cause infertility if it is ineffectively treated. A combination of clindamycin and gentamicin is generally used for the treatment of PID. The benefit of adding metronidazole into the treatment combination still remains unclear, and this study was designed to evaluate its effectiveness. We retrospectively included 107 women who were diagnosed with PID from May 2013 to September 2020 in a single hospital. Based on their used antibiotic regimens, the patients were divided into three groups—those who were treated with clindamycin + gentamicin (group 1, n = 46), those who took regular antibiotics plus metronidazole (group 2, n = 27), and others (group 3, n = 34). Primary outcomes included the rates of taking surgery after failed antibiotics, occurrence/rupture of tubo-ovarian abscesses, and readmission within the following 6 months of first treatment. Secondary outcomes to assess were the length of stay (LOS) and expenditure for PID. There were no significant differences in the surgical rates, readmission rates, LOS and expenditure noted between the three groups. Subgroup analysis showed that visual analogue pain scores being 5 or more would increase the LOS by 3.83 days (p < 0.001), and body temperature > 38.3 °C or more would increase the treatment total expenditure (p < 0.001). Our study results suggest that the combination of clindamycin + gentamicin is a convincible treatment protocol for PID. Full article

Background: Immune checkpoints are molecules that regulate the function of immune cells and control inflammation processes. An important role in this regard is played by TIM-3/Gal-9 and PD-1/PDL-1 interactions. Previous research performed in a mouse model of pregnancy loss confirmed that blocking TIM-3 could induce fetal loss. Similarly, the PD-1 molecule maintains protective interactions between the mother’s immune cells and the fetus. The purpose of this study was to assess the expression of these molecules on a range of T lymphocyte subpopulations from non-pregnant women with recurrent spontaneous abortion (RSA) versus healthy fertile women. Methods: PBMCs were isolated by gradient centrifugation of blood obtained from 12 healthy women and 24 women with RSA and immediately stained for flow cytometry analysis. Standard immunophenotyping of PBMC was performed with the antibodies against classical lymphocyte markers: CD3, CD4, CD8, and CD56. Immune checkpoints were investigated using antibodies against PD-1(CD279) and TIM-3(CD366). Results: We found that expression of TIM-3 was significantly decreased on CD8+ T lymphocytes in the RSA group, and expression of PD-1 was upregulated on CD4+ T lymphocytes in the RSA group in comparison to the healthy controls. Conclusions: Considering our findings, therapeutic intervention towards immune checkpoints may be a promising treatment option for recurrent spontaneous abortion. Full article

Patients with psoriatic arthritis (PsA) experience impaired health-related quality of life (HRQoL). Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA, which has been associated with improvements in dermatologic endpoints in patients with PsA. To assess the extent to which tofacitinib affects patient HRQoL via improvements in dermatologic symptoms, including itch, data were pooled from patients with PsA who received tofacitinib in phase III studies (NCT01866668 and NCT01882439). Mediation modeling assessed the indirect effects (via Itch Severity Item [ISI] and Physician’s Global Assessment of Psoriasis [PGA-PsO]) and direct effects (via all other factors) of tofacitinib treatment on dermatology-specific HRQoL (measured by Dermatology Life Quality Index [DLQI]). In the initial model, the treatment effect on DLQI was largely mediated by itch (ISI; p < 0.0001) and PGA-PsO (p < 0.01). The model was re-specified to assess the indirect effects only of itch and PGA-PsO on DLQI. Here, 17.7% of the treatment effect on DLQI was attributable to PGA-PsO (p = 0.0006), and 82.3% to itch (p < 0.0001). Tofacitinib-dependent improvements in DLQI were primarily mediated by itch relief, in addition to improvements in PGA-PsO. Full article

Previous studies have suggested that varying attention demands in dichotic listening (DL) tasks might be a clinically feasible method to distinguish ‘bottom-up’ from ‘top-down’ deficits in listening. This study aims to investigate DL processing in adults with listening difficulties (LD). We assessed the performance of a listening difficulties group (LDG) (n = 24, mean age = 24, backward digit span = 4.0) and a control group (CG) (n = 25, mean age = 29.2, backward digit span = 6.4) in DL tests involving non-forced and both right and left-forced attention. The results indicated an overall significantly worse performance of LDG compared to the CG, which was greater for forced-left condition. This same result was observed when controlling for working memory (WM) variance. Both groups presented an overall right ear advantage with no difference in terms of the magnitude of advantage. These results indicate that LD presented by the LDG might be due to a combination of sensory and cognitive deficits, with emphasis on the cognitive component. However, the WM, although impaired in the LDG group, was not the main factor in segregating both groups. The role of the additional cognitive processes such as inhibitory control in LD is discussed. Full article

The comparative efficacy and safety between lenvatinib and hepatic artery infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC) is still unclear. This multicenter historical cohort study enrolled 244 patients who were treated with HAIC (n = 173) or lenvatinib (n = 71) between 2012 and 2020. Propensity score matching (PSM) was performed, and 52 patients were selected per group. Clinical outcomes and safety were compared. Objective response rate (ORR) was not different between the two groups (26.0% vs. 23.1%, p = 0.736). Before PSM, the HAIC group had a higher proportion of Child-Pugh B and portal vein tumor, whereas the lenvatinib group had more patients with extrahepatic metastases, which was adjusted after PSM. There were no differences in progression-free survival (PFS) and overall survival (OS) after PSM (HAIC vs. lenvatinib, median PFS, 3.6 vs. 4.0 months, p = 0.706; median OS 10.8 vs. 7.9 months, p = 0.106). Multivariate Cox-regression showed that alpha-fetoprotein ≤1000 ng/mL was only an associated factor for OS after PSM in all patients (hazard ratio = 0.421, p = 0.011). Subgroup analysis for patients with a high tumor burden beyond the REFLECT eligibility criteria revealed that the HAIC group (n = 29) had a significantly longer OS than did the lenvatinib group (n = 30) (10.0 vs. 5.4 months, p = 0.004). More patients in the HAIC group achieved better liver function than those in the lenvatinib group at the time of best responses. There was no difference in the incidence of grade 3 and 4 adverse events between the two groups. Therefore, lenvatinib is comparable to HAIC in terms of ORR and OS in unresectable HCC meeting REFLECT eligibility criteria. Full article

Cardiac rehabilitation (CR) is indicated in all patients after acute myocardial infarction (AMI) to improve prognosis and exercise capacity (EC). Previous studies reported that up to a third of patients did not improve their EC after CR (non-responders). Our aim was to assess the cardiac and peripheral mechanisms of EC improvement after CR using combined exercise echocardiography and cardiopulmonary exercise testing (CPET-SE). The responders included patients with an improved EC assessed as a rise in peak oxygen uptake (VO₂) ≥ 1 mL/kg/min. Peripheral oxygen extraction was calculated as arteriovenous oxygen difference (A-VO₂Diff). Out of 41 patients (67% male, mean age 57.5 ± 10 years) after AMI with left ventricular ejection fraction (LVEF) ≥ 40%, 73% improved their EC. In responders, peak VO₂ improved by 27% from 17.9 ± 5.2 mL/kg/min to 22.7 ± 5.1 mL/kg/min, p < 0.001, while non-responders had a non-significant 5% decrease in peak VO₂. In the responder group, the peak exercise heart rate, early diastolic myocardial velocity at peak exercise, LVEF at rest and at peak exercise, and A-VO₂Diff at peak exercise increased, the minute ventilation to carbon dioxide production slope decreased, but the stroke volume and cardiac index were unchanged after CR. Non-responders had no changes in assessed parameters. EC improvement after CR of patients with preserved LVEF after AMI is associated with an increased heart rate response and better peripheral oxygen extraction during exercise. Full article