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Summary Background Studies have reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased incidence of cardiovascular disease (CVD). However, the magnitude of the risk and whether this risk changes with the severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CVD events. Methods We systematically searched PubMed, Scopus, and Web of Science from database inception to July 1, 2021, to identify eligible observational studies examining the risk of incident CVD events amongst adult (age ≥18 years) individuals with and without NAFLD and in which NAFLD was diagnosed by imaging, International Classification of Diseases codes, or liver biopsy. The primary outcomes were CVD death, non-fatal CVD events, or both. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95% CIs. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on Open Science Framework, number osf.io/5z7gf. Findings We identified 36 longitudinal studies with aggregate data on 5 802 226 middle-aged individuals (mean age 53 years [SD 7]) and 99 668 incident cases of fatal and non-fatal CVD events over a median follow-up of 6·5 years (IQR 5·0–10·2). NAFLD was associated with a moderately increased risk of fatal or non-fatal CVD events (pooled random-effects HR 1·45, 95% CI 1·31–1·61; I2=86·18%). This risk markedly increased across the severity of NAFLD, especially the stage of fibrosis (pooled random-effects HR 2·50, 95% CI 1·68–3·72; I2=73·84%). All risks were independent of age, sex, adiposity measures, diabetes, and other common cardiometabolic risk factors. Sensitivity analyses did not modify these results. Interpretation NAFLD is associated with an increased long-term risk of fatal or non-fatal CVD events. CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage. These results provide evidence that NAFLD might be an independent risk factor for CVD morbidity and mortality. Funding None.

Liver health is a key determinant of cardiovascular risk (CVR). Hepatic fibrosis is the shared common result of chronic hepatitis, irrespective of aetiology. Fibrosis profoundly distorts liver tissue architecture and perturbs hepatic physiology, dictates the course of chronic liver disease and is increasingly recognized as a CVR factor. The relative weights of pre-diabetes and hepatic fibrosis as risk factors for major adverse cardiac events (MACE) in patients with HCV remain an open issue. Sasso and Colleagues answered this research question by treating approximately half of 770 HCV positive pre-diabetic patients with direct antiviral agents (DAAs), while the rest served as historical controls. Data have shown that achieving HCV clearance with DAAs was associated with a 60% reduced risk of MACE, thereby implying that this antiviral strategy is recommended in HCV positive pre-diabetic patients, regardless of the severity of liver disease and concurrent CVR factors. This study paves the way for additional studies addressing the molecular patho-mechanisms and changes in the clinical spectrum involved in cardio-metabolic protection following HCV eradication in patients with pre-diabetes.

Aims Ceramides exert several biological activities that may contribute to the pathophysiology of cardiovascular disease and heart failure (HF). The association between plasma levels of distinct ceramides (that have been previously associated with increased cardiovascular risk) and cardiovascular mortality in patients with chronic HF has received little attention. Methods and results In a post hoc ancillary analysis of the Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure (GISSI‐HF; NCT00336336) trial, we randomly selected a sample of 200 ambulatory patients with chronic HF who died due to cardiovascular causes and 200 patients who were alive at the end of the trial (after a median follow‐up period of 3.9 years). We measured baseline plasma concentrations of six previously identified high‐risk ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) and their individual plasma ratios with Cer(d18:1/24:0)]. Patients who died due to cardiovascular causes had significantly (P

We performed a cross-sectional study to investigate the prevalence of Diffuse Idiopathic Skeletal Hyperostosis (DISH) through Dual-Energy X-ray absorptiometry (DXA) Vertebral Fracture Assessment (VFA) in a group of post-menopausal women with Type 2 Diabetes Mellitus (T2DM). We also explored several biomarkers of bone turnover metabolism, including Wnt pathway modulators. DXA-VFA was performed to detect the presence of DISH. Serum samples were collected from all patients at the time of study recruitment. 16 different serum biomarkers were tested between the two subgroups. Given the exploratory nature of the study, we did not adjust for multiplicity. At VFA analysis, among 96 individuals enrolled in the study 20 (20.8%) showed features of DISH. No statistically significant difference was found for BMD values, between the DISH and NO-DISH subgroups. Concerning blood biomarkers, DISH patients showed a significant difference only in the sclerostin serum levels (32 vs 35.5 pmol/L, for the DISH and NO-DISH subgroup, respectively; p = 0.010). After adjustment for confounding factors, sclerostin serum levels remained significantly lower in DISH group (p = 0.002). We demonstrated a non-negligible prevalence of DISH in a population of post-menopausal women affected by T2DM and suggested low serum sclerostin as a possible key feature associated with DISH presence. In addition, we propose DXA-VFA analysis, whose radiation dose is considerably lower than conventional radiography, as a viable diagnostic and prognostic mean to obtain data not only on bone health, but also for the screening for DISH in subjects at risk.

Aim Emerging evidence suggests that specific plasma ceramides are involved in the pathophysiology of cardiovascular disease (CVD) and other inflammation-associated diseases. However, scarce information is currently available on the association between distinct plasma ceramides (that have been associated with increased cardiovascular morbidity and mortality) and plasma high-sensitivity C-reactive protein (hs-CRP) concentrations in patients with type 2 diabetes mellitus (T2DM), a group of individuals at high risk of developing CVD and other chronic inflammation-related conditions. Methods We measured six previously identified high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), Cer(d18:1/24:1)] in 92 postmenopausal women with T2DM attending the diabetes outpatient service over a 3-month period. Plasma ceramide levels were measured using targeted liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay. Results Plasma hs-CRP levels were positively associated with all measured ceramides in univariable linear regression analyses. However, only plasma Cer(d18:1/16:0) (standard β coefficient: 0.27, P = 0.015), Cer(d18:1/22:0) (standard β coefficient: 0.25, P = 0.032) and Cer(d18:1/24:1) (standard β coefficient: 0.30, P = 0.007) remained significantly associated with increased plasma hs-CRP levels after adjusting for age, adiposity measures, diabetes duration, HbA1c, insulin resistance, smoking, hypertension, plasma LDL cholesterol, estimated glomerular filtration rate, preexisting ischaemic heart disease and use of lipid-lowering, antihypertensive, antiplatelet or hypoglycaemic drugs. Conclusion In postmenopausal women with T2DM, elevated levels of specific plasma ceramides are associated with higher plasma hs-CRP levels independent of established cardiovascular risk factors, diabetes-related variables and other potential confounding factors.

The aim of this review was to identify the imaging methods at our disposal to optimally manage posterior uveitis at the present time. The focus was put on methods that have become available since the 1990s, some 30 years after fluorescein angiography had revolutionised imaging of posterior uveitis in particular imaging of the retinal vascular structures in the 1960s. We have focussed our review on precise imaging methods that have been standardised and validated and can be used universally thanks to commercially produced and available instruments for the diagnosis and follow-up of posterior uveitis. The second part of this imaging review will deal with invasive imaging methods and in particular ocular angiography.摘要: 本文旨在确认当前可行的影像学方法, 以优化后葡萄膜炎的治疗。聚焦于自20世纪90年代以来可行的方法, 30年前荧光素血管造影术对后葡萄膜炎的成像进行了变革, 尤其是20世纪60年代针对视网膜血管结构的成像。本综述着重阐述已标准化及被验证的精确的成像方法, 商业化生产它们得以普遍使用, 且可用于后葡萄膜炎的诊断及随访。本文的第二部分将讨论侵入性影像学方法, 尤其是眼血管造影术。.

At present, there is scarce information regarding the global prevalence of chronic liver disease in individuals with coronavirus disease 2019 (COVID-19) disease, which is becoming a global pandemic. The aim of this study was to assess the overall prevalence of chronic liver disease among patients with COVID-19 disease by meta-analysing data in observational studies and to investigate the relationship between liver damage and COVID-19 disease. We included 11 observational studies for a total of 2034 adult individuals (median age 49 years [IQR 45-54], 57.2% men). The overall prevalence of chronic liver disease at baseline was 3% (95% CI 2%-4%; I2 = 29.1%). Individuals with severe COVID-19 disease had relevant alterations of liver enzymes and coagulative profile, probably due to the innate immune response against the virus. Further studies are needed to better investigate the causes of liver injury in patients with COVID-19 disease and the effect of treatment for COVID-19 on the liver.

Background Recent cohort studies evaluated the association between some previously identified high-risk ceramides [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] and risk of major adverse cardiovascular events in adult population. Objective The objective of this meta-analysis was to investigate the magnitude of such associations. Methods We searched publication databases using appropriate keywords to identify cohort studies (published up to July 30, 2019), in which association between previously identified high-risk ceramides and major adverse cardiovascular events was reported. Data from eligible studies were extracted and meta-analysis was performed using random-effects modeling. Results Seven cohort studies with aggregate data on 29,818 individuals (2736 new cases of cardiovascular events over a median follow-up of 6 years) were included. Higher plasma levels of Cer(d18:1/16:0) (random effects hazard ratio [HR] per standard deviation 1.21, 95% confidence interval [CI] 1.11–1.32, I2 = 88%), Cer(d18:1/18:0) (HR 1.19, 95% CI 1.10–1.27, I2 = 68%), and Cer(d18:1/24:1) (HR 1.17, 95% CI 1.08–1.27, I2 = 83%) were associated with major adverse cardiovascular events. Conversely, no association with plasma levels of Cer(d18:1/22:0) (HR 1.14 95% CI 0.88–1.47, I2 = 88%) and Cer(d18:1/24:0) (HR 0.97, 95% CI 0.89–1.05, I2 = 73%) was found. Subgroup analyses did not substantially modify the findings. Conclusions Higher plasma levels of Cer(d18:1/16:0), Cer(d18:1/18:0) and Cer(d18:1/24:1) were associated with major adverse cardiovascular events, whereas plasma levels of Cer(d18:1/22:0) and Cer(d18:1/24:0) were not. Additional research is required to elucidate the different role of ceramides on pathways involved in cardiovascular disease.

Chronic kidney disease (CKD) is a disease regularly seen in clinical practice. At present, CKD is described as a change of kidney structure and/or function and it is classified in relation to cause, values of glomerular filtration rate and albuminuria category. Seeing that CKD is closely linked to the development of end-stage renal disease and other comorbidities, the determination of additional independent predictors for CKD is clinically necessary. At present, there is evidence associating non-alcoholic fatty liver disease (NAFLD) with CKD, thereby suggesting that NAFLD patients may require intensive surveillance to reduce their risk of CKD. In 2008, genome-wide association studies documented an association between the variant rs738409 (C > G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene (mainly implicated in the lipid regulation) and the entire spectrum of NAFLD (i.e., liver steatosis, non-alcoholic steatohepatitis, fibrosis, and hepatocellular carcinoma). In the last years, accumulating epidemiological evidence suggests the existence of a relationship between PNPLA3 rs738409 and risk of CKD, indicating that rs738409 may also contribute to the kidney injury. This is of particular scientific interest, as such association may explain, at least in part, the epidemiological association between liver and kidney disease. In this narrative review, we will discuss the accumulating evidence regarding the association between PNPLA3 rs738409 and risk of CKD, the putative biological mechanisms underpinning such relationship, and the possible future perspective.

Background: Diabetic foot ulceration is a severe complication of diabetes characterized by chronic inflammation and impaired wound healing. This study aimed to evaluate the effect of a medical device gel based on adelmidrol + trans-traumatic acid in the healing process of diabetic foot ulcers. Methods: Thirty-seven diabetic patients with foot ulcers of mild/moderate grade were treated with the gel daily for 4 weeks on the affected area. The following parameters were evaluated at baseline and weekly: 1) wound area, measured by drawing a map of the ulcer and then calculated with photo editing software tools, and 2) clinical appearance of the ulcer, assessed by recording the presence/absence of dry/wet necrosis, infection, fibrin, neoepithelium, exudate, redness, and granulation tissue. Results: Topical treatment led to progressive healing of diabetic foot ulcers with a significant reduction of the wound area and an improvement in the clinical appearance of the ulcers. No treatment-related adverse events were observed. Conclusions: The results of this open-label study show the potential benefits of adelmidrol + trans-traumatic acid topical administration to promote reepithelialization of diabetic foot ulcers. Further studies are needed to confirm the observed results.

Aim. - Recent observational studies assessed the association between non-alcoholic fatty liver disease (NAFLD) and lung function in adults, but the magnitude of this association remains uncertain. We estimated the magnitude of the association between NAFLD and lung function on spirometry (predicted forced expiratory volume in 1 sec [FEV1] and forced vital capacity [FVC]).Methods. - We searched publication databases using predefined keywords to identify studies (published up to October 4, 2018), in which NAFLD was diagnosed by imaging or biochemistry (no studies with biopsy-proven NAFLD were available). Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling.Results. - Six observational studies (5 cross-sectional and 1 longitudinal) with aggregate data on 133,707 individuals (27.8% with NAFLD) of predominantly Asian ethnicity (74.6%) were included in the final analysis. There were significant differences in predicted FEV1 (n = 5 studies; pooled weighted mean difference [WMD]: -2.43%, 95%CI -3.28 to -1.58; I2 = 69.7%) and predicted FVC (pooled WMD: -2.96%, 95%CI -4.75 to -1.17; I2 = 91.7%) between individuals with and without NAFLD. Decreased FEV1 and FVC at baseline were also independently associated with a ~15% increased risk of incident NAFLD (n = 1 study in Korean individuals). Subgroup analyses did not materially modify these findings.Conclusions. - NAFLD is associated with significant reductions of both FEV1 and FVC in Asian and United States adults, and such small, but significant, reductions of lung volumes at baseline may be also associated with increased NAFLD incidence in Asian individuals. Further research is needed to better elucidate the link between NAFLD and impaired lung volumes.

BackgroundNonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD.AimsWe examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors.MethodsWe recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system.ResultsThe overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75–0.88] vs. 0.77 [0.70–0.84] without SNPs; p = 0.047).ConclusionsNAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD.

Background & Aims We examined the diagnostic performance of plasma N‐terminal propeptide of type III procollagen (PIIINP) levels, aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis‐4 (FIB‐4) score for predicting non‐alcoholic steatohepatitis (NASH) and liver fibrosis stage in children/adolescents with non‐alcoholic fatty liver disease (NAFLD). Methods We enrolled 204 children/adolescents with biopsy‐proven NAFLD at the "Bambino Gesù" Children's Hospital. We measured plasma PIIINP levels using a commercially available enzyme‐linked immunosorbent assay kit and calculated APRI and FIB‐4 scores using standard methods. Results Children with NASH had higher plasma PIIINP levels, APRI and FIB‐4 scores compared with those without NASH (all P < .001). However, PIIINP levels had much better diagnostic performance and accuracy than APRI and FIB‐4 scores for predicting liver fibrosis stage. PIIINP levels correlated with the total NAFLD activity score (NAS) and its constituent components (P < .0001). The risk of either NASH or F ≥ 2 fibrosis progressively increased with increasing PIIINP levels (P < .0001), independent of age, gender, adiposity measures, insulin resistance, NAS score and the patatin‐like phospholipase domain‐containing protein‐3 rs738409 polymorphism. For every 3.6 ng/mL increase in PIIINP levels, the likelihood of having F ≥ 2 fibrosis increased by ~14‐fold (adjusted‐odds ratio 14.1, 95% CI 5.50‐35.8, P < .0001) after adjustment for the aforementioned risk factors. The area under the receiver operating characteristics curve was 0.921 (95% CI 0.87‐0.97) for F ≥ 2 fibrosis, and 0.993 (95% CI 0.98‐1.0) for F3 fibrosis respectively. Conclusions Unlike APRI and FIB‐4 scores, plasma PIIINP levels are a promising, non‐invasive biomarker for diagnosing liver fibrosis stage in children/adolescents with biopsy‐proven NAFLD.

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD.

Background & aims Recent studies examined the association between non-alcoholic fatty liver disease (NAFLD) and risk of atrial fibrillation (AF) in adults, but the findings have been inconsistent. We provided a quantitative estimate of the magnitude of the association between NAFLD and risk of AF. Methods We searched publication databases using predefined keywords to identify observational studies (published up to December 14, 2018), in which NAFLD was diagnosed by biopsy, imaging or biochemistry and AF was diagnosed by medical history and electrocardiograms. Data from selected studies were extracted and meta-analysis was performed using random-effects modelling. Results Nine cross-sectional and longitudinal studies were included in the final analysis (n = 364 919 individuals). Meta-analysis of data from 5 cross-sectional studies showed that NAFLD was associated with an increased risk of prevalent AF (random-effects odds ratio 2.07, 95% CI 1.38-3.10; I2 = 54.7%), independent of age, sex, body mass index, hypertension and other common AF risk factors. This risk was particularly high among patients with established diabetes (n = 1 study; random-effects odds ratio 5.17, 95% CI 2.05-13.02). Meta-analysis of data from 4 longitudinal studies showed that NAFLD was independently associated with a 10-year increased risk of incident AF only in type 2 diabetic patients (n = 1 study; random-effects hazard ratio 4.96, 95% CI 1.42-17.28). Sensitivity analyses did not modify these findings. Funnel plots did not reveal significant publication bias. Conclusions NAFLD is associated with an increased risk of AF in middle-aged and elderly individuals (especially in those with type 2 diabetes). However, the observational design of the eligible studies does not allow for proving causality.

Background and aim: AZOOR is a rare disease characterized by loss of zones of outer retinal function, first described by J Donald Gass in 1993. Symptoms include acute onset photopsias and subjective visual field losses. The syndrome is characterized by a normal fundus appearance, scotomas and electroretinographic changes pointing towards outer retinal dysfunction. Evolution, response to immunosuppressive treatment and outcome are difficult to predict. The aim of this small case series was to identify the morphological changes and sequence of events in AZOOR thanks to multimodal imaging. Methods: Charts of AZOOR patients seen in the Centre for Ophthalmic Specialized care (COS, Lausanne, Switzerland) were analyzed by multimodal imaging including fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICGA), blue light fundus autofluorescence (BL-FAF) and spectral domain optical coherence tomography (SD-OCT) in addition to a complete ophthalmological examination including visual field testing and microperimetry, as well as OCT angiography (OCT-A) and ganglion-cell complex analysis when available. Cases and Results: Three AZOOR patients with a mean follow-up of 47 ± 25.5 months were included following the clinical definitions laid down by J Donald Gass. The primary damage was identified at the level of the photoreceptor outer segments with an intact choriocapillaris and retinal pigment epithelium (RPE) layer, these structures being only secondarily involved with progression of the disease. Conclusion: Although AZOOR has often been included within white dot syndromes, some of which are now known to be choriocapillaris diseases (choriocapillaritis entities), our findings clearly commend to differentiate AZOOR from entities such as MEWDS (Multiple evanescent white dot syndrome), APMPPE (Acute Posterior Multifocal Placoid Pigment Epitheliopathy), MFC (Multifocal Choroiditis) and others, as the damage to photoreceptors is primary in AZOOR (a retinopathy) and secondary in choriocapillaritis (a choriocapillaropathy).

Background and aims Cardiovascular disease (CVD) is the leading cause of death in patients with non-alcoholic fatty liver disease (NAFLD), both with and without type 2 diabetes mellitus (T2DM). Cardiac autonomic dysfunction is a risk factor for CVD morbidity and mortality. The aim of this pilot study was to assess whether there is an association between NAFLD and impaired cardiac autonomic function. Methods and results Among the first 4979 participants from the Cooperative Health Research in South Tyrol (CHRIS) study, we randomly recruited 173 individuals with T2DM and 183 age- and sex-matched nondiabetic controls. Participants underwent ultrasonography and vibration-controlled transient elastography (Fibroscan®, Echosens) to assess hepatic steatosis and liver stiffness. The low-to-high-frequency (LF/HF) power ratio and other heart rate variability (HRV) measures were calculated from a 20-min resting electrocardiogram (ECG) to derive a measure of cardiac sympathetic/parasympathetic imbalance. Among the 356 individuals recruited for the study, 117 had NAFLD and T2DM, 56 had T2DM alone, 68 had NAFLD alone, and 115 subjects had neither condition. Individuals with T2DM and NAFLD (adjusted odds ratio [OR] 4.29, 95% confidence intervals [CI] 1.90–10.6) and individuals with NAFLD alone (adjusted OR 3.41, 95% CI 1.59–7.29), but not those with T2DM alone, had a substantially increased risk of having cardiac sympathetic/parasympathetic imbalance, compared with those without NAFLD and T2DM. Logistic regression models were adjusted for age, sex, body mass index (BMI), hypertension, dyslipidemia, insulin resistance, hemoglobin A1c (HbA1c), C-reactive protein (CRP), and Fibroscan®-measured liver stiffness. Conclusions NAFLD was associated with cardiac sympathetic/parasympathetic imbalance, regardless of the presence or absence of T2DM, liver stiffness, and other potential confounding factors.

The choroid was poorly accessible to imaging investigation until the last decade of the last century. With the availability of more precise imaging methods such as indocyanine green angiography (ICGA) and, later, optical coherence tomography (OCT), enhanced depth OCT (EDI-OCT), and OCT angiography (OCTA), appraisal of choroidal inflammation has substantially gained in accuracy. This allowed to precisely determine which structures were touched in the different non-infectious choroiditis entities and made it possible to classify this group of diseases, ICGA signs, mainly hypofluorescent lesions, were identified and described. Previous publications have divided angiographic findings into two main sets of signs: (1) irregular “geographic” hypofluorescent areas corresponding to choriocapillaris non-perfusion and (2) round more regular, hypofluorescent dark dots more evenly distributed in the fundus corresponding to more deep choroidal stromal foci. These distinct findings allowed to subdivide and classify choroiditis into choriocapillaritis and stromal choroiditis. Additional signs were identified from EDI-OCT and OCTA examination supporting the classification of choroiditis into choriocapillaritis and stromal choroiditis. Results: Diseases involving principally the choriocapillaris included Multiple Evanescent White Dot Syndrome (MEWDS), Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE), Idiopathic Multifocal Choroiditis (MFC), and Serpiginous Choroiditis (SC) as well as mixed forms. Diseases primarily involving the choroidal stroma included HLA-A29 Birdshot Retinochoroiditis (BRC), Vogt-Koyanagi-Harada disease (VKH), Sympathetic Ophthalmia (SO), and Sarcoidosis chorioretinitis (SARC). Thanks to new imaging investigations of the choroid, it is now possible to classify and understand the diverse clinicopathological mechanisms in the group of non-infectious choroiditis entities.

To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: −3.92%, 95% confidence intervals (CI) −6.27% to −1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52–6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation.

Background Concern exists about durability of stent grafts used to bridge aortic grafts to visceral and renal arteries during fenestrated and branched endovascular aneurysm repair (F/B-EVAR). There are no guidelines regarding the ideal technique for joining target vessels (TVs). Methods We systematically reviewed data published from 2014 to 2019 using PRISMA guidelines and PICO models. Keywords were searched in MEDLINE, EMBASE, and Cochrane Library. All articles were screened by two authors (a third author in case of discrepancies). Only original articles regarding F/B-EVAR in complex aortic aneurysm, reporting the number and type of TVs mated, the onset of bridging stent complications, and reinterventions on TVs were included. Analysis included quality assessment scoring, types of stent grafts, and complications related to bridging stents. Results 19 studies were included with 2,796 patients and 9556 TV; 4,797 renal arteries (50.2%), 4,174 visceral arteries (43.6%), and undefined TV (n = 585; 6.1%) were bridged. Balloon-expandable stent-grafts (B-EXP) were used in 40.9% and self-expandable (S-EXP) in 22.7% and undefined stents in 36.3%. The included studies had quality assessment scores ranging between 11/15 and 15/15, with high grade of accordance on reporting general results, but a low grade of accordance on reporting detailed data. Despite study heterogeneity, high-volume analysis confirmed a higher rate of complication in renal arteries than visceral arteries, 6% (95% CI 4–8) vs. 2% (95% CI 1–3), respectively. The rate of reinterventions was similar, 3% (95% CI 2–4) and 2% (95% CI 1–3). S-EXP versus B-EXP stent complication was 4% (95% CI 2–7) vs. 3% (95% CI 2–5), respectively. Conclusions This systematic review underlines the low grade of accordance in reporting detailed data of bridging stents in F/B-EVAR. Renal TVs were more prone to complications, with an equivalent reintervention rate to visceral TVs. As to B-EVAR, the choice of B-EXP over S-EXP is still uncertain.

ObjectiveFollow-up studies have shown that non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of incident diabetes, but currently, it is uncertain whether this risk changes with increasing severity of NAFLD. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident diabetes.DesignWe systematically searched PubMed, Scopus and Web of Science databases from January 2000 to June 2020 using predefined keywords to identify observational studies with a follow-up duration of at least 1 year, in which NAFLD was diagnosed by imaging techniques or biopsy. Meta-analysis was performed using random-effects modelling.Results33 studies with 501 022 individuals (30.8% with NAFLD) and 27 953 cases of incident diabetes over a median of 5 years (IQR: 4.0–19 years) were included. Patients with NAFLD had a higher risk of incident diabetes than those without NAFLD (n=26 studies; random-effects HR 2.19, 95% CI 1.93 to 2.48; I2=91.2%). Patients with more ‘severe’ NAFLD were also more likely to develop incident diabetes (n=9 studies; random-effects HR 2.69, 95% CI 2.08 to 3.49; I2=69%). This risk markedly increased across the severity of liver fibrosis (n=5 studies; random-effects HR 3.42, 95% CI 2.29 to 5.11; I2=44.6%). All risks were independent of age, sex, adiposity measures and other common metabolic risk factors. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias.ConclusionThis updated meta-analysis shows that NAFLD is associated with a ~2.2-fold increased risk of incident diabetes. This risk parallels the underlying severity of NAFLD.

Previous studies showed a significant association between lower plasma adiponectin levels and higher risk of adverse cardiovascular outcomes in patients with and without type 2 diabetes mellitus (T2DM). Presently, it is uncertain whether lower plasma adiponectin levels are associated with greater plasma thrombin generation in patients with T2DM. We studied 82 middle-aged men with non-insulin-treated T2DM [mean age ± SD: 64.1 ± 8 years; median duration of diabetes: 12.5 (inter-quartile range 6–19) years; mean hemoglobin A1c 7.0 ± 0.7%], consecutively attending our diabetes outpatient service over a 6-month period. Using the newly developed fully automated thrombin generation analyzer ST Genesia®, we measured the plasma parameters lag time (LT), time to peak (TP), peak height (PH) and endogenous thrombin potential (ETP) in all participants. In univariable linear regression analyses, lower plasma adiponectin levels were significantly associated with higher plasma thrombin generation parameters, as reflected by higher values of PH (Pearson’s r coefficient = − 0.228, p = 0.039) and EPT (r = − 0.293, p = 0.007). Plasma adiponectin levels were not significantly associated with other thrombin generation parameters (LT and TP). Notably, the significant associations of plasma adiponectin levels with thrombin PH and EPT values persisted after adjustment for age and adiposity measures, but they were lost after additional adjustment for plasma triglycerides. Our findings show for the first time the existence of a significant association between lower levels of plasma adiponectin and greater plasma thrombin generation (as assessed by the ST Genesia® analyzer) in men with non-insulin-treated T2DM, which appears to be largely mediated by plasma triglycerides.

Background and aim The association between non-alcoholic fatty liver (NAFL) and the variant rs641738 within the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene is currently uncertain, especially in the paediatric population. We examined whether there is an association between this genetic variant and NAFL in a large multicentre, hospital-based cohort of Italian overweight/obese children. Methods and results We studied 1760 overweight or obese children [mean age (SD): 11.1(2.9) years, z-body mass index (zBMI) 3.2(0.9)], who underwent ultrasonography for the diagnosis of NAFL. A subgroup of these children (n = 182) also underwent liver biopsy. Genotyping of the MBOAT7 rs641738 polymorphism was performed by TaqMan-Based RT-PCR system in each subject. Overall, 1131 (64.3%) children had ultrasound-detected NAFL; 528 (30%) had rs641738 CC genotype, 849 (48.2%) had rs641738 CT genotype, and 383 (21.8%) had rs641738 TT genotype, respectively. In the whole cohort, the interaction of MBOAT7 genotypes with zBMI was not associated with NAFL after adjustment for age, sex, serum triglycerides, serum alanine aminotransferase levels and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genotype (adjusted-odds ratio 1.02 [95% CI 0.98–1.06]). Similarly, no association was found between MBOAT7 genotypes and NAFL after stratification by obesity status. MBOAT7 genotypes were not associated with the presence of non-alcoholic steatohepatitis or the stage of liver fibrosis in a subgroup of 182 children with biopsy-proven NAFLD. Conclusions The results of this study did not show any significant contribution of MBOAT7 rs641738 polymorphism to the risk of having either NAFL on ultrasonography or NASH on histology in a large hospital-based cohort of Italian overweight/obese children.

ObjectiveStudies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD.DesignWe systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling.Results13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate 2, with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; I2=60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias.ConclusionThis large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.

Aims To estimate the prevalence of established diabetes and its association with the clinical severity and in-hospital mortality associated with COVID-19. Data synthesis We systematically searched PubMed, Scopus and Web of Science, from 1st January 2020 to 15th May 2020, for observational studies of patients admitted to hospital with COVID-19. Meta-analysis was performed using random-effects modeling. A total of 83 eligible studies with 78,874 hospitalized patients with laboratory-confirmed COVID-19 were included. The pooled prevalence of established diabetes was 14.34% (95% CI 12.62-16.06%). However, the prevalence of diabetes was higher in non-Asian vs. Asian countries (23.34% [95% CI 16.40-30.28] vs. 11.06% [95% CI 9.73-12.39]), and in patients aged ≥60 years vs. those aged, Highlights • Little is known about the association of diabetes with the clinical severity and in-hospital mortality associated with COVID-19. • We meta-analyzed 83 observational studies for a total of 78,874 in-patients with COVID-19. • Pre-existing diabetes was associated with a two to three times greater risk of severe/critical illness and in-hospital mortality associated with COVID-19.

To assess the overall prevalence of clinical signs, symptoms, and radiological findings in children and/or adolescents with COVID-19. We systematically researched in PubMed, Scopus and Web of Science databases observational studies describing COVID-19 in children and/or adolescents until April 11, 2020. Data regarding clinical and radiological features were extracted from eligible studies and meta-analysis was performed using random-effects modeling. We examined 19 eligible studies for a total of 2855 children and/or adolescents with COVID-19. Approximately 47% of subjects had fever (95% confidence interval [CI] 22−72%; I2 = 98.6%), 37% cough (95%CI 15−63%; I2 = 98.6%), 4% diarrhea (95%CI 0−12%; I2 = 92.2%), 2% nasal congestion (95%CI 0−7%; I2 = 87.7%), 1% dyspnea (95%CI 0−7%; I2 = 91.5%) and 0% abdominal pain (95%CI 0−1%; I2 = 76.3%). Subjects presented mild symptoms in 79% (95%CI 65−91%; I2 = 93.5%) of cases, whereas only 4% (95%CI 1−9%; I2 = 76.4%) were critical. Among those with pneumonia on computed tomography, 26.4% (95%CI 13−41%; I2 = 80.8%) presented a unilateral involvement, 16% (95%CI 5−29%, I2 = 81.2%) had bilateral involvement and 9% (95%CI 0−24%; I2 = 88.7%) had interstitial pneumonia. Children and/or adolescents tend to have a mild COVID-19 course with a good prognosis.

The World Health Organization recently declared the outbreak of severe acute respiratory syndrome coronavirus 2 disease (COVID-19) a global pandemic (1). It is known that people with diabetes have a higher overall risk of infection resulting from multiple perturbations of innate immunity (2). Presently, it remains uncertain whether people with diabetes are also at higher risk of infection and, especially, at greater severity of illness associated with COVID-19. A recent meta-analysis of 30 observational studies (most of which were preprint studies that have yet to be reviewed) showed that pre-existing diabetes is significantly associated with poorer in-hospital outcomes (3), but none of the included studies have examined whether the impact of diabetes on COVID-19 severity is independent of age, sex and metabolic comorbidities, such as obesity and hypertension. Therefore, in this retrospective study, we aimed to examine the association between diabetes and severity of COVID-19 illness (irrespective of metabolic comorbidities) among in-patients with confirmed COVID-19.

Objective— It is known that specific plasma ceramides are associated with stress-induced reversible myocardial perfusion defects in patients with established or suspected coronary artery disease undergoing myocardial perfusion scintigraphy (MPS). However, it is currently uncertain whether plasma ceramides are also associated with reduced poststress myocardial perfusion in these patients. Approach and Results— We measured 6 previously identified high-risk plasma ceramide species (ceramide [d18:1/16:0], ceramide [d18:1/18:0], ceramide [d18:1/20:0], ceramide [d18:1/22:0], ceramide [d18:1/24:0], and ceramide [d18:1/24:1]) in 167 consecutive patients with established or suspected coronary artery disease undergoing stress MPS for clinical indications. Plasma ceramides were measured by a targeted liquid chromatography–tandem mass spectrometry assay both at baseline and after MPS. Multivariable linear regression analysis was undertaken to examine the associations (standardized B coefficients) between plasma ceramides and the percentage of poststress myocardial perfusion after adjustment for multiple cardiovascular risk factors. Seventy-eight patients had stress-induced myocardial ischemia on MPS (mainly located in the anteroapical wall). Of the 6 measured plasma ceramides, higher levels of basal ceramide (d18:1/18:0; B=−0.182; P =0.019), ceramide (d18:1/20:0; B=−0.224; P =0.004), ceramide (d18:1/22:0; B=−0.163; P =0.035), and ceramide (d18:1/24:1; B=−0.20; P =0.010) were associated with lower poststress anteroapical wall perfusion. Notably, these significant associations persisted even after adjustment for conventional cardiovascular risk factors, previous coronary artery disease, electrocardiographic left bundle branch block, left ventricular ejection fraction and type of stress testing. Similar results were observed for poststress plasma ceramides. Conclusions— Higher circulating levels of specific ceramides, both at baseline and after stress, were independently associated with lower poststress anteroapical wall perfusion in patients with suspected or established coronary artery disease referred for clinically indicated MPS.

In choroiditis, fundoscopic examination is very limited. Only the choroidal foci of sufficient importance causing yellow-white discoloration can be visible through the retinal pigment epithelium (RPE). This is the reason why several inflammatory choroidal entities, with different pathophysiologic mechanisms, were grouped under the general term “white dot syndromes”.1 With the advent of indocyanine green angiography (ICGA), we gained access to the choroidal compartment which allowed the differentiation between the two main mechanisms at the origin of choroidal inflammatory pathology: choriocapillaris diseases (inflammatory choriocapillaropathies/choriocapillaritis) and stromal diseases (stromal choroiditis). Primary inflammatory choriocapillaropathies include multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), idiopathic multifocal choroiditis (MFC), serpiginous choroiditis as well as acute macular neuroretinopathy such as acute zonal occult outer retinopathy (AZOOR).2, 3 In these conditions, ICGA shows patchy or geographic hypofluorescent areas of variable sizes more clearly visible on the late frames. These areas correspond to areas of hypo or non-perfusion of the choriocapillaris. Recently, optical coherence tomography angiography (OCT-A), a new imaging technique which allows visualization of the retinal and choroidal vasculature, was developed. It has the advantage of being fast and easy to acquire, non-invasive, and depth-selective.4 OCT-A of active lesions of APMPPE and serpiginous choroiditis revealed areas of non-perfused choriocapillaris which corresponded topographically to hypofluorescent areas in ICGA,5, 6 supporting the theory of choriocapillaris hypo and/or non-perfusion as the origin of these diseases. However, a recent study by Pichi et al.7 has created doubt about choriocapillaritis being the origin of the morphological and functional alterations in MEWDS,7 as OCT-A seems not to show any alterations in choriocapillaris circulation. We present in detail the reasons why choriocapillaritis should not be discarded as the origin of the pathological lesions in MEWDS.

The prognostic impact of hyperuricemia on long-term clinical outcomes in patients with chronic heart failure (HF) has been investigated in observational registries and clinical trials, but the results have been often inconclusive. We examined the prognostic impact of elevated serum uric acid levels on long-term clinical outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial.CLINICALTRIALS.NCT00336336.We assessed the rates of all-cause death, cardiovascular death, cardiovascular hospitalization and the composite of all-cause death or cardiovascular hospitalization over a median follow-up of 3.9 years among 6683 ambulatory patients with chronic HF.Patients in the 3rd serum uric acid tertile (7.2 mg/dl) had a nearly 1.8-fold increased risk of both all-cause death and cardiovascular death, and a nearly 1.5-fold increased risk of cardiovascular hospitalization and of the composite endpoint compared to those in the 1st uric acid tertile (5.7 mg/dl). Beyond serum uric acid ≥ 7 mg/dl the risk of outcomes increased sharply and linearly. The significant association between elevated serum uric acid levels and adverse outcomes persisted after adjustment for multiple established cardiovascular risk factors, HF etiology, left ventricular ejection fraction, medication use and other potential confounders, with an adjusted hazard ratio of 1.37 (95% CI 1.22-1.55) for all-cause death, 1.48 (1.29-1.69) for cardiovascular death, 1.19 (1.09-1.30) for cardiovascular hospitalization and 1.21 (1.11-1.31) for the composite endpoint, respectively.Elevated serum uric acid levels are independently associated with poor long-term survival and increased risk of cardiovascular hospitalization in patients with chronic HF.

Aims It is known that type 2 diabetic patients are at high risk of atrial fibrillation (AF). However, the early echocardiographic determinants of AF vulnerability in this patient population remain poorly known. Methods We followed-up for 2years a sample of 180 consecutive outpatients with type 2 diabetes, who were free from AF and ischemic heart disease at baseline. All patients underwent a baseline echocardiographic-Doppler evaluation with tissue Doppler and 2-D strain analysis. Standard electrocardiograms were performed twice per year, and a diagnosis of incident AF was confirmed in affected patients by a single cardiologist. Results Over the 2-year follow-up period, 14 (7.8%) patients developed incident AF. In univariate analyses, echocardiographic predictors of new-onset AF were greater indexed cardiac mass, larger indexed left atrial volume (LAVI), lower global longitudinal strain (LS SYS ), lower global diastolic strain rate during early phase of diastole (SR E ), lower global diastolic strain rate during late phase of diastole (SR L ), and higher E/SR E ratio. Multivariate logistic regression analysis showed that lower LS SYS remained the only significant predictor of new-onset AF (adjusted-odds ratio 1.63, 95%CI 1.17–2.27; p Conclusions This is the first prospective study to show that early LS SYS impairment independently predicts the risk of new-onset AF in type 2 diabetic patients with preserved ejection fraction and without ischemic heart disease. Future larger prospective studies are needed to confirm these findings.

Aim: Recent prospective studies have identified distinct plasma ceramides as strong predictors of major adverse cardiovascular events in patients with established or suspected coronary artery disease (CAD). Currently, it is uncertain whether higher levels of distinct plasma ceramides are also associated with greater angiographic severity of coronary-artery stenoses in this patient population.Methods: We measured six previously identified high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD, who underwent urgent or elective coronary angiography.Results: Approximately 77% of patients had a significant stenosis (≥50%) in one or more of the main coronary arteries, the majority of whom (~60%) had a significant stenosis in the left anterior descending (LAD) artery. Of the six measured plasma ceramides, higher levels of plasma Cer(d18:1/20:0) (adjusted-odds ratio 1.39, 95%CI 1.0-1.99), Cer(d18:1/22:0) (adjusted-odds ratio 1.57, 95%CI 1.08-2.29) and Cer(d18:1/24:0) (adjusted-odds ratio 1.59, 95%CI 1.08-2.32) were significantly associated with the presence of LAD stenosis ≥ 50%, after adjustment for age, sex, smoking, pre-existing CAD, hypertension, diabetes, dyslipidaemia, lipid-lowering therapy, estimated glomerular filtration rate and plasma C-reactive protein levels. Almost identical results were found even after excluding patients (n=15) with acute ST-elevation myocardial infarction. Similar results were also found when patients were categorized according to Gensini severity score.Conclusion: Our cross-sectional study shows for the first time that higher levels of specific plasma ceramides are independently associated with a greater severity of coronary-artery stenoses in the LAD artery in patients who had suspected or established CAD.

We demonstrate in 351 diabetic patients with steatosis that NAFLD fibrosis score (NFS), a rapid and affordable score to diagnose hepatic fibrosis, identifies patients at higher risk of advanced fibrosis and vascular diabetic complications (especially peripheral neuropathy), pointing NFS as a first-line vascular and hepatic screening in diabetic patients. (C) 2020 Elsevier Inc. All rights reserved.

Despite the widely accepted benefits, at present, gender equity is a challenge for women, also in science.1 In this context, according to the UN Educational, Scientific, and Cultural Organization's Women in Science data, women represented approximately 30% of researchers in 2018, whereas nearly 75% of trainees, health workers, and faculty involved in global health were characterized by women in the same year.2 In neurology, the analysis of the American Academy of Neurology (AAN) Report led to estimate that in 2016, women were approximately 32% of all US neurologists, whereas in 2008, they were nearly 25%.3 In addition, it also appears that women researchers are much less represented than men among editorial boards of various scientific journals.4,5 In 2011, Amrein et al.4 reported that women represented approximately 18% of all editorial board members of 60 top-ranked journals, whereas they decreased to less than 15% when considering the top 5 neurology journals.

OBJECTIVE Right ventricle and pulmonary artery pressure have received less attention in type 1 diabetes compared to the left ventricle. The aim of the present study was to compare right heart performance and the estimated peak systolic pulmonary artery pressure in young non complicated patients with type 1 diabetes with healthy controls. RESEARCH DESIGN AND METHODS Ninety-three patients with type 1 diabetes without cardiovascular and respiratory diseases were recruited and compared to 56 healthy controls. All subjects were evaluated with a comprehensive trans-thoracic echocardiography and pulmonary peak systolic arterial pressure was estimated with an established formula based on pulmonary artery acceleration time. RESULTS None of the subjects showed alterations of either systolic or diastolic function of the left ventricle. The estimated peak systolic pulmonary artery pressure was significantly higher in patients with type 1 diabetes compared to controls (38.5 ± 8.6 vs 35.4 ± 6.7, p = 0.019). The highest value of EPSPAP was observed in smoker female patients with type 1 diabetes. Basal and mid cavity diameter of the right ventricle were higher in patients with type 1 diabetes. In the multivariate analyses, factors associated with EPSPAP were female sex, body mass index, mid cavity diameter and, with an inverse correlation, HDL cholesterol. CONCLUSIONS The present study suggests that young, uncomplicated patients with type 1 diabetes have a higher estimated peak systolic pulmonary artery pressure. Future studies are needed to better define the mechanisms underlying this alteration and its clinical consequences.

The diagnosis of peripheral neuropathies can be challenging with consequent difficulties in patients' management. The aim of this study was to explore the current diagnostic role of sural nerve biopsy and to compare pathological findings with serum neurofilament light chain levels (NfL) as biomarkers of axonal damage. We collected demographic, clinical, and paraclinical data of patients referred over 1 year to the Neurology Unit, University of Verona, Italy, to perform nerve biopsy for diagnostic purposes, and we analyzed NfL levels in available paired sera using a high sensitive technique (Quanterix, Simoa). Eighty-two patients were identified (37.8% females, median age 65.5 years). Neuropathy onset was frequently insidious (68.3%) with a slowly progressive course (76.8%). Lower limbs were usually involved (81.7%), with a predominance of sensory over motor symptoms (74.4% vs 42.7%). The most common neuropathological findings were a demyelinating pattern (76.8%), clusters of regenerations (58.5%), and unmyelinated fibers involvement on ultrastructural evaluation (52.4%). A definite pathological diagnosis was achieved in 29 cases, and in 20.7% of patients, the referral clinical diagnosis was modified. Coexistent hematological conditions and hepatitis were diagnostic confounding factors (p = 0.012 and 0.034, respectively). In the analyzed paired sera (n = 37), an inverse despite not significant relationship between NfL values and fiber density was observed (Spearman's rho - 0.312, p = 0.056). In addition, we noted increased serum NfL values of patients with active axonal degeneration. Nerve biopsy remains a useful diagnostic investigation to achieve a correct diagnosis and guide patients' management in selected cases of peripheral neuropathy. Serum NfL is an accessible and potential valuable marker of axonal damage in these conditions.