Journal of Clinical Medicine — Open Access Journal

Inhibitors of sodium–glucose cotransporter 2 (SGLT2) have emerged as practice-changing treatments for patients with type 2 diabetes, reducing both the risk of cardiovascular events and kidney events. However, regarding the latter, caution is warranted, as these kidney endpoints are defined using glomerular filtration rate estimations based on creatinine, the non-enzymatic product of creatine residing in muscles. Creatinine-based estimations of the glomerular filtration rate are only valid if the treatment has no effect on changes in muscle mass over time. Yet, circumstantial evidence suggests that treatment with SGLT2 inhibitors does result in a loss of muscle mass, rendering serum creatinine-based kidney endpoints invalid. Currently, it cannot be excluded that the described renoprotective effect of SGLT2 inhibitors is in part or in whole the consequence of a loss of muscle mass. Post-hoc analyses of existing trials or new trials based on kidney function markers independent of muscle mass can provide more definitive answers on the proposed renoprotective effects of SGLT2 inhibitors. Full article

Clinical evidence indicates that innate immune cells may contribute to acute coronary syndrome (ACS). Our prospective study aimed at investigating the association of neutrophil phenotypes with ACS. 108 patients were categorized into chronic stable coronary artery disease (n = 37), unstable angina (UA) (n = 19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n = 25), and ST-Elevation Myocardial Infarction (STEMI) (n = 27). At the time of inclusion, blood neutrophil subpopulations were analysed by flow cytometry. Differential blood cell count and plasma levels of neutrophilic soluble markers were recorded at admission and, for half of patients, at six-month follow-up. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio than stable and UA patients (p < 0.0001), which normalized at six-month post-MI. Atypical low-density neutrophils were detected in the blood of the four patient groups. STEMI patients were characterized by elevated percentages of band cells compared to the other patients (p = 0.019). Multivariable logistic regression analysis revealed that plasma levels of total myeloperoxidase was associated with STEMI compared to stable (OR: 1.434; 95% CI: 1.119–1.837; P < 0.0001), UA (1.47; 1.146–1.886; p = 0.002), and NSTEMI (1.213; 1.1–1.134; p = 0.0001) patients, while increased neutrophil side scatter (SSC) signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033–14.184; p = 0.045). Hence, changes in neutrophil phenotype are concomitant to ACS. Full article

Sickle-cell disease (SCD) is a worldwide distributed hemoglobinopathy, characterized by hemolytic anemia associated with vaso-occlusive events. These result in acute and chronic multiorgan damage. Bone is early involved, leading to long-term disability, chronic pain and fractures. Here, we carried out a retrospective study to evaluate sickle bone disease (SBD) in a cohort of adults with SCD. We assessed bone density, metabolism and turnover. We also evaluated the presence of fractures and the correlation between SCD severity and skeletal manifestations. A total of 71 patients with SCD were analyzed. The mean age of population was 39 ± 10 years, 56% of which were females. We found osteoporosis in a range between 7% and 18% with a high incidence of vertebral fractures. LDH and AST were predictive for the severity of vertebral fractures, while bone density was not. Noteworthy, we identified -1.4 Standard Deviations T-score as the cutoff for detecting the presence of fractures in patients with SCD. Collectively our data allowed us to develop an algorithm for the management of SBD, which may be useful in daily clinical practice to early intersect and treat SBD. Full article

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease, worldwide, and oxidative stress has been recognized as a key factor in the pathogenesis and progression of DN. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has the most important contribution to reactive oxygen species generation during the development of DN. Bioactive compound use has emerged as a potential approach to reduce chronic renal failure. Therefore, a red orange and lemon extract (RLE) rich in anthocyanins was chosen in our study, to reduce the toxic renal effects during the development of DN in Zucker diabetic fatty rat (ZDF). RLE effects were examined daily for 24 weeks, through gavage, in ZDF rats treated with RLE (90 mg/kg). At the end of the experiment, ZDF rats treated with RLE showed a reduction of the diabetes-associated up-regulation of both NOX4 and the p47-phox and p22-phox subunits, and restored the BAX/BCL-2 ratio respect to ZDF rats. Furthermore, RLE was able to reduce the oxidative DNA damage measured in urine samples in ZDF rats. This study showed that RLE could prevent the renal damage induced by DN through its capacity to inhibit NOX4 and apoptosis mechanisms. Full article

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia and associated with the disruption of circadian rhythm. The study aimed to assess the relationship between hypoxia-inducible factor (HIF) subunits, circadian clock proteins, and polysomnography (PSG) variables, in healthy individuals and severe OSA patients. The study included 20 individuals, who underwent PSG and were divided into severe OSA group (n = 10; AHI ≥ 30) and healthy control (n = 10; AHI < 5) based on apnea-hypopnea index (AHI). All participants had their peripheral blood collected in the evening before and the morning after the PSG. HIF-1α, HIF-1β, BMAL1, CLOCK, CRY1, and PER1 protein concertation measurements were performed using ELISA. In a multivariate general linear model with the concentration of all circadian clock proteins as dependent variables, evening HIF-1α protein level was the only significant covariant (p = 0.025). Corrected models were significant for morning and evening PER1 (p = 0.008 and p = 0.006, respectively), evening (p = 0.043), and evening BMAL protein level (p = 0.046). In corrected models, evening HIF-1α protein level had an influence only on the evening PER1 protein level. Results suggest that OSA patients are at risk for developing circadian clock disruption. This process might be mediated by subunit α of HIF-1, as its increased protein level is associated with overexpression of circadian clock proteins. Full article

Context: Affecting older and even some younger adults, neurodegenerative disease represents a global public health concern and has been identified as a research priority. To date, most anti-aging interventions have examined older adults, but little is known about the effects of polyphenol interventions on brain-related aging processes in healthy young and middle-aged adults. Objective: This systematic review and meta-analysis aimed to evaluate the acute and chronic effects of (poly)phenol-rich diet supplementation on cognitive function and brain health in young and middle-aged adults. In July 2019, two electronic databases (PubMed and Web of Science) were used to search for relevant trials examining the effect of acute or chronic (poly)phenol-rich supplementation on cognitive function and neuroprotective measures in young and middle-aged adults (<60 years old). A total of 4303 records were screened by two researchers using the PICOS criteria. Fifteen high quality (mean PEDro score = 8.8 ± 0.58) trials with 401 total participants were included in the final analyses. Information on treatment, study design, characteristics of participants, outcomes and used tools were extracted following PRISMA guidelines. When items were shown to be sufficiently comparable, a random-effects meta-analysis was used to pool estimates across studies. Effect size (ES) and its 95% confidence interval (CI) was calculated. The meta-analysis indicated that (poly)phenol supplementation significantly increased brain-derived neurotrophic factor (ES = 3.259, p = 0.033), which was accompanied by higher performance in serial (7s) subtraction (ES = 1.467, p = 0.001) and decreases in simple reaction time (ES = −0.926, p = 0.015) and mental fatigue (ES = −3.521 p = 0.010). Data related to cognitive function were skewed towards an effect from acute compared to chronic polyphenol intervention; data related to BDNF were skewed toward an effect from higher bioavailability phenolic components. Conclusion: This meta-analysis provides promising findings regarding the usefulness of polyphenol-rich intervention as an inexpensive approach for enhancing circulation of pro-cognitive neurotrophic factors. These beneficial effects appear to depend on the supplementation protocols. An early acute and/or chronic application of low- to high-dose phenolic components with high bioavailability rates (≥30%) at a younger age appear to provide more promising effects. Full article

Multiple sclerosis (MS) is an inflammatory disease mainly affecting the central nervous system. In MS, abnormal immune mechanisms induce acute inflammation, demyelination, axonal loss, and the formation of central nervous system plaques. The long-term treatment involves options to modify the disease progression, whereas the treatment for the acute relapse has its focus in the administration of high-dose intravenous methylprednisolone (up to 1000 mg daily) over a period of three to five days as a first step. If symptoms of the acute relapse persist, it is defined as glucocorticosteroid-unresponsive, and immunomodulation by apheresis is recommended. However, several national and international guidelines have no uniform recommendations on using plasma exchange (PE) nor immunoadsorption (IA) in this case. A systematic review and meta-analysis was conducted, including observational studies or randomized controlled trials that investigated the effect of PE or IA on different courses of MS and neuromyelitis optica (NMO). One thousand, three hundred and eighty-three patients were included in the evaluation. Therapy response in relapsing-remitting MS and clinically isolated syndrome was 76.6% (95%CI 63.7–89.8%) in PE- and 80.6% (95%CI 69.3–91.8%) in IA-treated patients. Based on the recent literature, PE and IA may be considered as equal treatment possibilities in patients suffering from acute, glucocorticosteroid-unresponsive MS relapses. Full article

Background and Aims: The mechanisms of interindividual variation of lipid regulation by statins, such as the low-density lipoprotein cholesterol (LDL) lowering effects, are not fully understood yet. Here, we used a gut microbiota depleted mouse model to investigate the relation between the gut microbiota and the regulatory property of atorvastatin on blood lipids. Methods: Mice (C57BL/6) with intact gut microbiota or antibiotic induced abiotic mice (ABS) were put on standard chow diet (SCD) or high fat diet (HFD) for six weeks. Atorvastatin (10 mg/kg body weight/day) or a control vehicle were applied per gavage for the last four weeks of dietary treatment. Blood lipids including total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and sphingolipids were measured to probe microbiota-dependent effects of atorvastatin. The expression of genes involved in hepatic and intestinal cholesterol metabolism was analyzed with qRT-PCR. The alteration of the microbiota profile was examined using 16S rRNA qPCR in mice with intact gut microbiota. Results: HFD feeding significantly increased total blood cholesterol and LDL levels, as compared to SCD in both mice with intact and depleted gut microbiota. The cholesterol lowering effect of atorvastatin was significantly attenuated in mice with depleted gut microbiota. Moreover, we observed a global shift in the abundance of several sphingolipids upon atorvastatin treatment which was absent in gut microbiota depleted mice. The regulatory effect of atorvastatin on the expression of distinct hepatic and intestinal cholesterol-regulating genes, including Ldlr, Srebp2 and Npc1l1 was altered upon depletion of gut microbiota. In response to HFD feeding, the relative abundance of the bacterial phyla Bacteroidetes decreased, while the abundance of Firmicutes increased. The altered ratio between Firmicutes to Bacteroidetes was partly reversed in HFD fed mice treated with atorvastatin. Conclusions: Our findings support a regulatory impact of atorvastatin on the gut microbial profile and, in turn, demonstrate a crucial role of the gut microbiome for atorvastatin-related effects on blood lipids. These results provide novel insights into potential microbiota-dependent mechanisms of lipid regulation by statins, which may account for variable response to statin treatment. Full article

We investigated the role of near infrared spectroscopy (NIRS) in identifying delayed cerebral ischemia (DCI) in patients with subarachnoid hemorrhage (SAH). We measured the cerebral regional oxygen saturation (rSO2) continuously for 14 days. The differences in rSO2 according to DCI were analyzed. We also compared the diagnostic accuracy of NIRS and transcranial Doppler ultrasonography (TCD) for DCI detection using the area under receiver operator characteristic (ROC) curve. Fifty-two patients treated with coil embolization were enrolled, including 18 with DCI (34.6%) and 34 without DCI (65.4%). Significant differences in rSO2 levels were observed from days 7 to 9. The rSO2 level was 60.95 (58.10–62.30) at day 7 in the DCI vs. 63.90 (62.50–67.10) in the non-DCI patients. By day 8, it was 59.50 (56.90–64.50) in the DCI vs. 63.30 (59.70–68.70) in the non-DCI cases. By day 9, it was 61.85 (59.40–65.20) in the DCI vs. 66.00 (62.70–68.30) in the non-DCI. A decline of >12.7% in SO2 rate yielded a sensitivity of 94.44% (95% CI: 72.7–99.9%) and a specificity of 70.59% (95% CI: 52.5–84.9%) for identifying DCI. Changes in NIRS tended to yield better diagnostic accuracy than TCD, but were not statistically significant. NIRS is a feasible method for real-time detection of DCI. Full article

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy. Full article

Background: Classification of colorectal neoplasms during colonoscopic examination is important to avoid unnecessary endoscopic biopsy or resection. This study aimed to develop and validate deep learning models that automatically classify colorectal lesions histologically on white-light colonoscopy images. Methods: White-light colonoscopy images of colorectal lesions exhibiting pathological results were collected and classified into seven categories: stages T1-4 colorectal cancer (CRC), high-grade dysplasia (HGD), tubular adenoma (TA), and non-neoplasms. The images were then re-classified into four categories including advanced CRC, early CRC/HGD, TA, and non-neoplasms. Two convolutional neural network models were trained, and the performances were evaluated in an internal test dataset and an external validation dataset. Results: In total, 3828 images were collected from 1339 patients. The mean accuracies of ResNet-152 model for the seven-category and four-category classification were 60.2% and 67.3% in the internal test dataset, and 74.7% and 79.2% in the external validation dataset, respectively, including 240 images. In the external validation, ResNet-152 outperformed two endoscopists for four-category classification, and showed a higher mean area under the curve (AUC) for detecting TA+ lesions (0.818) compared to the worst-performing endoscopist. The mean AUC for detecting HGD+ lesions reached 0.876 by Inception-ResNet-v2. Conclusions: A deep learning model presented promising performance in classifying colorectal lesions on white-light colonoscopy images; this model could help endoscopists build optimal treatment strategies. Full article

The 12-month mortality rate in patients undergoing hematopoietic stem cell transplantation (HSCT) remains high, especially with respect to transplant-related mortality (TRM), which includes mortality due to infection complications through the aplasia phase. The aim of this study was to determine whether the administration of Pentaglobin^® could decrease TRM by lowering sepsis onset or weakening sepsis through the aplasia phase. One hundred and ninety-nine pediatric patients who had undergone HSCT were enrolled in our retrospective study. The patients were divided into two groups: the Pentaglobin group, which had received Pentaglobin^® in addition to the standard antibiotic treatment protocol established for the aplasia phase, and the Control group, which received only the standard treatment. As compared to the control group outcome, Pentaglobin^® led to a significant decrease in the days of temperature increase (p < 0.001) and a reduced infection-related mortality rate (p = 0.04). In addition, the number of antibiotics used to control infections, and the number of antibiotic therapy changes needed following first-line drug failure, were significantly lowered in the Pentaglobin group as compared to the control group (p < 0.0001). With respect to the onset of new infections following the primary infection detected, the Pentaglobin group showed a significant reduction for bacterial events, as compared to the control group (p < 0.03). Pentaglobin^® use in patients undergoing HSCT seems to produce a significant decrease in infection-associated TRM rate. Full article

Postoperative delirium is a common complication after liver transplantation (LT). A high model for end-stage liver disease (MELD) score is an independent risk factor for postoperative delirium, but it is unclear which of the components of this score are risk indicators. The aim of this study was to analyze the incidence of postoperative delirium according to the preoperative serum bilirubin level, a component of the MELD score, in patients who underwent LT. The medical records of 325 patients who underwent LT from January 2010 to February 2019 at a single university hospital were retrospectively reviewed. The patients were divided into two groups: those who experienced postoperative delirium (Delirium group, n = 69) and those who did not (Control group, n = 256). Data on the patients’ demographic characteristics, perioperative management, and postoperative complications were collected. Mean preoperative bilirubin level was higher in the Delirium group than in the Control group (p < 0.0001). In the Delirium group, 54 (78.26%) patients had preoperative bilirubin levels above 3.5 mg/dL. In the multivariate analysis, preoperative bilirubin above 3.5 mg/dL was associated with postoperative delirium (p = 0.002). Therefore, preoperative hyperbilirubinemia is an independent risk factor for postoperative delirium. Full article

Objectives: The prevalence of elbow joint arthritis in rheumatoid arthritis (RA) assessed by ultrasound has not yet been investigated. Methods: We investigated 102 patients with RA and 50 patients without rheumatological disease. Both elbow joints were examined by ultrasound for effusion, hypervascularization, and enthesitis. A clinical examination was performed, and Disease Activity Score in 28 joints (DAS28), and visual analog scale for pain (VASp) were recorded. Arthritis was defined as joint effusion (≥grade II) and synovial hyperperfusion. Results: The RA cohort versus the control group displayed a joint effusion in 54.9% vs. 6.9%, a hypervascularization in 6.8% vs. 0%. Arthritis was detected in 36 RA patients (35.29%) and no one in the control group. Four (3.8%) RA patients and one (1%) control displayed enthesitis. The RA cohort showed a significant correlation between movement restriction and joint effusion (p-value = 0.001) as well as DAS28 (p-value = 0.02) and between DAS28 and ultrasound detected arthritis (p-value = 0.022). In an overall analysis, a highly significant correlation of VASp with movement restriction (MR) (p-value ≤ 0.001), the presence of joint effusion (p-value ≤ 0.001), and the diagnosis of RA (p-value ≤ 0.001) were observed. Interrater analysis of ultrasound imaging showed good agreement with Cohen’s kappa of 0.896. Conclusion: The prevalence of elbow arthritis in RA seems to be high, with 35.29%. Movement restriction is a good indicator, but not in all RA patients (32 vs. 70 patients without MR) compared to the control group (5 vs. 45 patients without MR). Reported pain correlates with joint effusion and MR (p-value ≤ 0.001). Full article

The gut microbiota has been linked to blood lipids. However, the relationship between the gut microbiome and other lipid markers like apolipoproteins A1 (apoA1) and B (apoB) as well as classical lipid markers in Asians remain unclear. Here, we examined the associations between gut microbial diversity and taxonomic compositions with both apolipoproteins and lipid markers in a large number of Korean patients. The fecal 16S rRNA gene sequencing data from 1141 subjects were analyzed and subjects were categorized into control group (G0) or abnormal group (G1) according to blood lipid measurements. The microbial diversity and several taxa of the gut microbiota were significantly associated with triglyceride, apoA1, and apoB levels, but not with total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. The alpha diversity of the gut microbiota was inversely associated with high triglyceride level. Interestingly, G1 of apoA1 showed increased microbial richness and distinct microbial community compared with G0 of apoA1. A high abundance of Fusobacteria and low abundance of Oscillospira were found in the hypertriglyceridemia group. In this large-scale study, we identified associations of gut microbiota with apolipoproteins and classical lipid markers, indicating that the gut microbiota may be an important target for regulating blood lipids. Full article

In midlife, women experience hormonal changes due to menopausal transition. A decrease especially in estradiol has been hypothesized to cause loss of muscle mass. This study investigated the effect of menopausal transition on changes in lean and muscle mass, from the total body to the muscle fiber level, among 47–55-year-old women. Data were used from the Estrogenic Regulation of Muscle Apoptosis (ERMA) study, where 234 women were followed from perimenopause to early postmenopause. Hormone levels (estradiol and follicle stimulating hormone), total and regional body composition (dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) scans), physical activity level (self-reported and accelerometer-measured) and muscle fiber properties (muscle biopsy) were assessed at baseline and at early postmenopause. Significant decreases were seen in lean body mass (LBM), lean body mass index (LBMI), appendicular lean mass (ALM), appendicular lean mass index (ALMI), leg lean mass and thigh muscle cross-sectional area (CSA). Menopausal status was a significant predictor for all tested muscle mass variables, while physical activity was an additional significant contributor for LBM, ALM, ALMI, leg lean mass and relative muscle CSA. Menopausal transition was associated with loss of muscle mass at multiple anatomical levels, while physical activity was beneficial for the maintenance of skeletal muscle mass. Full article

At least one ultrasound is recommended to predict fetal growth restriction and low birthweight earlier in pregnancy. However, in low-income countries, imaging equipment and trained manpower are scarce. Hence, we developed and validated a model and risk score to predict low birthweight using maternal characteristics during pregnancy, for use in resource limited settings. We developed the model using a prospective cohort of 379 pregnant women in South Ethiopia. A stepwise multivariable analysis was done to develop the prediction model. To improve the clinical utility, we developed a simplified risk score to classify pregnant women at high- or low-risk of low birthweight. The accuracy of the model was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration plot. All accuracy measures were internally validated using the bootstrapping technique. We evaluated the clinical impact of the model using a decision curve analysis across various threshold probabilities. Age at pregnancy, underweight, anemia, height, gravidity, and presence of comorbidity remained in the final multivariable prediction model. The AUC of the model was 0.83 (95% confidence interval: 0.78 to 0.88). The decision curve analysis indicated the model provides a higher net benefit across ranges of threshold probabilities. In general, this study showed the possibility of predicting low birthweight using maternal characteristics during pregnancy. The model could help to identify pregnant women at higher risk of having a low birthweight baby. This feasible prediction model would offer an opportunity to reduce obstetric-related complications, thus improving the overall maternal and child healthcare in low- and middle-income countries. Full article

Background: A convergent association between polycystic ovary syndrome (PCOS) and periodontal disease, in particular chronic periodontitis (CP), has recently been proposed. The underlying molecular mechanisms of this association are not fully understood, though it is thought that chronic inflammation is responsible. Therefore, the aim of this study was to evaluate the association between periodontal disease—gingivitis and CP—and PCOS. Materials and Methods: The PICO (Participants, Intervention, Control, and Outcomes) question was as follows: “Is there an association between PCOS and CP?” A systematic review of three databases—PubMed, Embase and Scopus—was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Original studies in human cohorts carried out in the last 10 years and including a control group were eligible for inclusion. Letters to the editor, case reports, and reviews were not considered. Results: Ten articles met all the selection criteria and provided a positive answer to the PICO question. Our review of these articles revealed an association between CP and PCOS, since periodontal parameters were altered more frequently in patients with these conditions than in healthy young women. This altered periodontal response in PCOS was associated with a proinflammatory status that seemed to increase susceptibility to periodontal disease. Conclusion: Patients with PCOS appear to be more susceptible to developing periodontal diseases than women without the pathology. Full article

Periodontitis is a common chronic inflammatory disease which could have an important impact on blood pressure (BP). This study aimed to explore (a) the association between periodontal health and BP in a large representative cohort, (b) the predictive value of diagnosis of periodontitis in undiagnosed raised BP and (c) whether age is a mediator of this relationship. In total, 1057 randomly recruited individuals (mean age, 60.9 ± 16.3 years, 57.7% women) underwent periodontal clinical assessment and one-single BP measurement using an automated sphygmomanometer device. Logistic and linear regression models were used to estimate the odds of hypertension based on periodontitis case definitions. Mediation analysis was performed to understand the effect of age on the association of periodontitis with hypertension. Adjusted logistic model for gender, smoking habits and body mass index confirmed the association between high BP and periodontitis (OR = 2.31, 95%CI: 1.75–3.04, p < 0.001). Among 168 participants with undiagnosed high BP (15.9% of the study sample), 62.5% had periodontitis (n = 105). In this study, the association between periodontitis with both systolic blood pressure (SBP) (77.6%, p < 0.001) and diastolic blood pressure (DBP) (66.0%, p < 0.001) was mediated by age. Periodontitis is closely linked to BP in a representative Portuguese population. Full article