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J. Clin. Med., Volume 8, Issue 8 (August 2019)

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Open AccessArticle
Peptide Antagonists for P-selectin Discriminate between Sulfatide-Dependent Platelet Aggregation and PSGL-1-Mediated Cell Adhesion
J. Clin. Med. 2019, 8(8), 1266; https://doi.org/10.3390/jcm8081266 (registering DOI)
Received: 18 July 2019 / Revised: 8 August 2019 / Accepted: 16 August 2019 / Published: 20 August 2019
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Abstract
Background: Membrane-exposed sulfatides are proposed to contribute to P-selectin-dependent platelet aggregation. Here, we demonstrated that P-selectin-mediated platelet aggregation on a collagen-coated surface under flow indeed depended on sulfatides and that this interaction differed considerably from the interaction of P-selectin with P-selectin Glycoprotein Ligand-1 [...] Read more.
Background: Membrane-exposed sulfatides are proposed to contribute to P-selectin-dependent platelet aggregation. Here, we demonstrated that P-selectin-mediated platelet aggregation on a collagen-coated surface under flow indeed depended on sulfatides and that this interaction differed considerably from the interaction of P-selectin with P-selectin Glycoprotein Ligand-1 (PSGL-1), which underlies leukocyte-endothelium adhesion. Methods and Results: Upon platelet activation, sulfatides were translocated to the platelet surface to form focal hot-spots. Interestingly, P-selectin was observed to exclusively interact with liposomes with a sulfatide density higher than 21% (w/w), indicating that the binding profile of P-selectin for sulfatide-rich liposomes was dependent on sulfatide density. Sulfatide-liposome binding to P-selectin and sulfatide/P-selectin-dependent platelet aggregation was blunted by peptide antagonists, carrying the EWVDV motif within N-terminal extensions, such as CDVEWVDVSC (half maximal inhibitory concentration IC50 = 0.2 μM), but not by the EWVDV core motif itself (IC50 > 1000 μM), albeit both being equally potent inhibitors of PSGL-1/P-selectin interaction (IC50 = 7–12 μM). Conclusions: Our data suggest that the sulfatide/P-selectin interaction implicates multiple binding pockets, which only partly overlap with that of PSGL-1. These observations open ways to selectively interfere with sulfatide/P-selectin-dependent platelet aggregation without affecting PSGL-1-dependent cell adhesion. Full article
Open AccessArticle
Does the Implementation of a Quality Improvement Care Bundle Reduce the Incidence of Acute Kidney Injury in Patients Undergoing Emergency Laparotomy?
J. Clin. Med. 2019, 8(8), 1265; https://doi.org/10.3390/jcm8081265 (registering DOI)
Received: 17 May 2019 / Revised: 16 July 2019 / Accepted: 17 July 2019 / Published: 20 August 2019
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Abstract
Purpose: Previous work has demonstrated a survival improvement following the introduction of an enhanced recovery protocol in patients undergoing emergency laparotomy (the emergency laparotomy pathway quality improvement care (ELPQuiC) bundle). Implementation of this bundle increased the use of intra-operative goal directed fluid therapy [...] Read more.
Purpose: Previous work has demonstrated a survival improvement following the introduction of an enhanced recovery protocol in patients undergoing emergency laparotomy (the emergency laparotomy pathway quality improvement care (ELPQuiC) bundle). Implementation of this bundle increased the use of intra-operative goal directed fluid therapy and ICU admission, both evidence-based strategies recommended to improve kidney outcomes. The aim of this study was to determine if the observed mortality benefit could be explained by a difference in the incidence of AKI pre- and post-implementation of the protocol. Method: The primary outcome was the incidence of AKI in the pre- and post-ELPQuiC bundle patient population in four acute trusts in the United Kingdom. Secondary outcomes included the KDIGO stage specific incidence of AKI. Serum creatinine values were obtained retrospectively at baseline, in the post-operative period and the maximum recorded creatinine between day 1 and day 30 were obtained. Results: A total of 303 patients pre-ELPQuiC bundle and 426 patients post-ELPQuiC bundle implementation were identified across the four centres. The overall AKI incidence was 18.4% in the pre-bundle group versus 19.8% in the post bundle group p = 0.653. No significant differences were observed between the groups. Conclusions: Despite this multi-centre cohort study demonstrating an overall survival benefit, implementation of the quality improvement care bundle did not affect the incidence of AKI. Full article
Open AccessArticle
Pulmonary Rehabilitation Reduces Subjective Fatigue in COPD: A Responder Analysis
J. Clin. Med. 2019, 8(8), 1264; https://doi.org/10.3390/jcm8081264 (registering DOI)
Received: 12 July 2019 / Revised: 13 August 2019 / Accepted: 16 August 2019 / Published: 20 August 2019
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Abstract
To date, it remains unknown which patients report a clinically-relevant improvement in fatigue following pulmonary rehabilitation (PR). The purpose of this study was to identify and characterize these responders. Demographics, lung function, anxiety (anxiety subscale of the 90-item symptom checklist (SCL-90-A)), depression (Beck [...] Read more.
To date, it remains unknown which patients report a clinically-relevant improvement in fatigue following pulmonary rehabilitation (PR). The purpose of this study was to identify and characterize these responders. Demographics, lung function, anxiety (anxiety subscale of the 90-item symptom checklist (SCL-90-A)), depression (Beck depression inventory for primary care (BDI-PC)), exercise tolerance (six-minute walking distance test (6MWD)), and health status (Nijmegen clinical screening instrument (NCSI)) were assessed before and after a 12-week PR programme. Fatigue was assessed using the checklist individual strength (CIS)-Fatigue. Patients with a decline ≥ 10 points (minimally clinically important difference, MCID) on the CIS-Fatigue were defined as responders. Chronic obstructive pulmonary disease (COPD) patients (n = 446, 61 ± 9 years, 53% male, forced expiratory volume in 1 second (FEV1) 43% ± 18% predicted, 75% severe fatigue) were included. Mean change in fatigue after PR was 10 ± 12 points (p < 0.01) and exceeded the MCID. In total, 56% were identified as fatigue responders. Baseline CIS-Fatigue (45 ± 7 vs. 38 ± 9 points, respectively, p < 0.001) and health-related quality-of-life (HRQoL; p < 0.001) were different between responders and non-responders. No differences were found in demographics, baseline anxiety, depression, lung function, 6MWD, and dyspnoea (p-values > 0.01). Responders on fatigue reported a greater improvement in anxiety, depression, 6MWD, dyspnoea (all p-values < 0.001), and most health status parameters. PR reduces fatigue in COPD. Responders on fatigue have worse fatigue and HRQoL scores at baseline, and are also likely to be responders on other outcomes of PR. Full article
Open AccessArticle
The Importance of Sex Differences on Outcome after Major Trauma: Clinical Outcome in Women Versus Men
J. Clin. Med. 2019, 8(8), 1263; https://doi.org/10.3390/jcm8081263 (registering DOI)
Received: 8 July 2019 / Revised: 7 August 2019 / Accepted: 16 August 2019 / Published: 20 August 2019
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Abstract
Purpose: The purpose of this study was to evaluate epidemiological and clinically relevant sex-related differences in polytraumatized patients at a Level 1 Trauma Center. Methods: 646 adult patients (210 females and 436 males) who were classified as polytraumatized (at the point of admission) [...] Read more.
Purpose: The purpose of this study was to evaluate epidemiological and clinically relevant sex-related differences in polytraumatized patients at a Level 1 Trauma Center. Methods: 646 adult patients (210 females and 436 males) who were classified as polytraumatized (at the point of admission) and treated at our Level I Trauma Center were reviewed and included in this study. Demographic data as well as mechanism of injury, injury severity, injury pattern, frequency of preclinical intubation, hemodynamic variables on admission, time of mechanical ventilation and of intensive care unit (ICU) treatment, as well as the incidence of acute respiratory distress syndrome (ARDS), multi organ failure (MOF), and mortality were extracted and analyzed. Results: A total of 210 female and 436 male patients formed the basis of this report. Females showed a higher mean age (44.6 vs. 38.3 years; p < 0.0001) than their male counterparts. Women were more likely to be injured as passengers or by suicidal falls whereas men were more likely to suffer trauma as motorcyclists. Following ICU treatment, female patients resided significantly longer at the casualty ward than men (27.1 days vs. 20.4 days, p = 0.013) although there was no significant difference regarding injury severity, hemodynamic variables on admission, and incidence of MOF, ARDS, and mortality. Conclusion: The positive correlation of higher age and longer in-hospital stay in female trauma victims seems to show women at risk for a prolonged in-hospital rehabilitation time. A better understanding of the impact of major trauma in women (but also men) will be an important component of efforts to improve trauma care and long-term outcome. Full article
(This article belongs to the Section Orthopedics)
Open AccessArticle
Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency
J. Clin. Med. 2019, 8(8), 1262; https://doi.org/10.3390/jcm8081262 (registering DOI)
Received: 25 July 2019 / Revised: 9 August 2019 / Accepted: 15 August 2019 / Published: 20 August 2019
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Abstract
Complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase) is the largest complex of the mitochondrial oxidative phosphorylation system (OXPHOS) system. Forty-four subunits encoded in nuclear and mitochondrial genomes compose this multiprotein complex, its assembly being a highly complex process involving at least 15 [...] Read more.
Complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase) is the largest complex of the mitochondrial oxidative phosphorylation system (OXPHOS) system. Forty-four subunits encoded in nuclear and mitochondrial genomes compose this multiprotein complex, its assembly being a highly complex process involving at least 15 additional nuclear encoded assembly factors. Complex I deficiency is a mitochondrial disorder usually associated with early-onset severe multisystem disorders characterized by highly variable clinical manifestations. Flavin adenine dinucleotide (FAD)-dependent oxidoreductase domain-containing protein 1 (FOXRED1) is a complex I assembly factor. To date, only five patients with mitochondrial complex I deficiency due to mutations in FOXRED1 have been characterized. Here, we describe a child with ataxia, epilepsy and psychomotor developmental delay carrying two heterozygous FOXRED1 variants, c.920G>A (p.Gly307Glu) and c.733+1G>A. We demonstrate the molecular mechanism supporting the pathogenicity of the FOXRED1 variants, showing a clear deficiency of complex I activity. The reduction in the steady-state level of complex I holoenzyme in patient fibroblasts, confirmed the pathogenicity of the variants and showed the molecular mechanism behind their pathogenicity. A comparison of the clinical presentation of the index case with the previously described cases allowed deepening our knowledge about the clinical variability associated with FOXRED1 defects. Full article
(This article belongs to the Section Neuroscience)
Open AccessReview
Antibody Therapies for Acute Myeloid Leukemia: Unconjugated, Toxin-Conjugated, Radio-Conjugated and Multivalent Formats
J. Clin. Med. 2019, 8(8), 1261; https://doi.org/10.3390/jcm8081261 (registering DOI)
Received: 1 July 2019 / Revised: 13 August 2019 / Accepted: 16 August 2019 / Published: 20 August 2019
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Abstract
In recent decades, therapy for acute myeloid leukemia (AML) has remained relatively unchanged, with chemotherapy regimens primarily consisting of an induction regimen based on a daunorubicin and cytarabine backbone, followed by consolidation chemotherapy. Patients who are relapsed or refractory can be treated with [...] Read more.
In recent decades, therapy for acute myeloid leukemia (AML) has remained relatively unchanged, with chemotherapy regimens primarily consisting of an induction regimen based on a daunorubicin and cytarabine backbone, followed by consolidation chemotherapy. Patients who are relapsed or refractory can be treated with allogeneic hematopoietic stem-cell transplantation with modest benefits to event-free and overall survival. Other modalities of immunotherapy include antibody therapies, which hold considerable promise and can be categorized into unconjugated classical antibodies, multivalent recombinant antibodies (bi-, tri- and quad-specific), toxin-conjugated antibodies and radio-conjugated antibodies. While unconjugated antibodies can facilitate Natural Killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), bi- and tri-specific antibodies can engage either NK cells or T-cells to redirect cytotoxicity against AML targets in a highly efficient manner, similarly to classic ADCC. Finally, toxin-conjugated and radio-conjugated antibodies can increase the potency of antibody therapies. Several AML tumour-associated antigens are at the forefront of targeted therapy development, which include CD33, CD123, CD13, CLL-1 and CD38 and which may be present on both AML blasts and leukemic stem cells. This review focused on antibody therapies for AML, including pre-clinical studies of these agents and those that are either entering or have been tested in early phase clinical trials. Antibodies for checkpoint inhibition and microenvironment targeting in AML were excluded from this review. Full article
(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)
Open AccessArticle
Sedentary Time, Physical Activity, and Sleep Duration: Associations with Body Composition in Fibromyalgia. The Al-Andalus Project
J. Clin. Med. 2019, 8(8), 1260; https://doi.org/10.3390/jcm8081260 (registering DOI)
Received: 19 July 2019 / Revised: 14 August 2019 / Accepted: 16 August 2019 / Published: 20 August 2019
PDF Full-text (271 KB) | XML Full-text | Supplementary Files
Abstract
To explore the individual–independent relationships of sedentary time (ST) and physical activity (PA) (light and moderate-to-vigorous intensity (MVPA)), with sleep duration and body composition (waist circumference, body mass index (BMI), body fat percentage, and muscle mass index) in women with fibromyalgia, and to [...] Read more.
To explore the individual–independent relationships of sedentary time (ST) and physical activity (PA) (light and moderate-to-vigorous intensity (MVPA)), with sleep duration and body composition (waist circumference, body mass index (BMI), body fat percentage, and muscle mass index) in women with fibromyalgia, and to determine whether these associations are independent of physical fitness. This cross-sectional study involved 385 women with fibromyalgia. ST and PA were assessed by triaxial accelerometry, sleep duration was self-reported. Waist circumference was measured using an anthropometric tape, and body weight, body fat percentage, and muscle mass were estimated using a bio-impedance analyzer. In individual regression models, ST and sleep were directly associated with waist circumference, BMI, and body fat percentage (β between 0.10 and 0.25; all p < 0.05). Light PA and MVPA were inversely associated with waist circumference, BMI, and body fat percentage (β between −0.23 and −0.12; all p < 0.05). In multiple linear regression models, ST (β between 0.17 and 0.23), light PA (β between −0.16 and −0.21), and sleep duration (β between 0.11 and 0.14) were independently associated with waist circumference, BMI, and body fat percentage (all p < 0.05). MVPA was associated with waist circumference independent of light physical activity (LPA) and sleep duration (β = −0.11; p < 0.05). Except for MVPA, these associations were independent of physical fitness. These results suggest that longer ST and sleep duration, and lower PA levels (especially light intensity PA), are independently associated with greater adiposity, but not muscle mass, in women with fibromyalgia. These associations are, overall, independent of physical fitness. Full article
(This article belongs to the Section Epidemiology & Public Health)
Open AccessArticle
Cytokine Profile in Patients with Aseptic Loosening of Total Hip Replacements and Its Relation to Metal Release and Metal Allergy
J. Clin. Med. 2019, 8(8), 1259; https://doi.org/10.3390/jcm8081259 (registering DOI)
Received: 19 July 2019 / Revised: 6 August 2019 / Accepted: 9 August 2019 / Published: 20 August 2019
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Abstract
Metal release from total hip replacements (THRs) is associated with aseptic loosening (AL). It has been proposed that the underlying immunological response is caused by a delayed type IV hypersensitivity-like reaction to metals, i.e., metal allergy. The purpose of this study was to [...] Read more.
Metal release from total hip replacements (THRs) is associated with aseptic loosening (AL). It has been proposed that the underlying immunological response is caused by a delayed type IV hypersensitivity-like reaction to metals, i.e., metal allergy. The purpose of this study was to investigate the immunological response in patients with AL in relation to metal release and the prevalence of metal allergy. THR patients undergoing revision surgery due to AL or mechanical implant failures were included in the study along with a control group consisting of primary THR patients. Comprehensive cytokine analyses were performed on serum and periimplant tissue samples along with metal analysis using inductive coupled plasma mass spectrometry (ICP-MS). Patient patch testing was done with a series of metals related to orthopedic implant. A distinct cytokine profile was found in the periimplant tissue of patients with AL. Significantly increased levels of the proinflammatory cytokines IL-1β, IL-2, IL-8, IFN-γ and TNF-α, but also the anti-inflammatory IL-10 were detected. A general increase of metal concentrations in the periimplant tissue was observed in both revision groups, while Cr was significantly increased in patient serum with AL. No difference in the prevalence of metal sensitivity was established by patch testing. Increased levels of IL-1β, IL-8, and TNF-α point to an innate immune response. However, the presence of IL-2 and IFN-γ indicates additional involvement of T cell-mediated response in patients with AL, although this could not be detected by patch testing. Full article
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Open AccessArticle
Prediction of Transplant-Free Survival through Albumin-Bilirubin Score in Primary Biliary Cholangitis
J. Clin. Med. 2019, 8(8), 1258; https://doi.org/10.3390/jcm8081258
Received: 12 July 2019 / Revised: 13 August 2019 / Accepted: 16 August 2019 / Published: 19 August 2019
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Abstract
Albumin–bilirubin (ALBI) grade is defined using the ALBI score, which is calculated based on total serum bilirubin and albumin. This study aimed to evaluate the diagnostic ability of the ALBI score for determining hepatic fibrosis stage and transplant-free survival in primary biliary cholangitis [...] Read more.
Albumin–bilirubin (ALBI) grade is defined using the ALBI score, which is calculated based on total serum bilirubin and albumin. This study aimed to evaluate the diagnostic ability of the ALBI score for determining hepatic fibrosis stage and transplant-free survival in primary biliary cholangitis (PBC) patients. A total of 181 Japanese patients with biopsy-proven or serologically diagnosed PBC were enrolled. The pathological stage was assessed using the Scheuer classification. The ALBI score differentiated fibrosis in stage 4 from that of 3 in the biopsy-proven cohort (p < 0.05). With an ALBI score cut-off value of −1.679, the sensitivity and specificity were 100% and 91.1%, respectively, with a likelihood ratio of 12.3 to differentiate stage 4 from stages 1–3. The ALBI score at the beginning of ursodeoxycholic acid (UDCA) prescription correlated with the two prognostic scores calculated after 1-year UDCA treatment. Kaplan–Meier analysis showed that the baseline ALBI score differentiated liver transplant-free survival (p < 0.05). The ALBI score presented a greater hazard ratio for transplant-free survival than aspartate aminotransferase-to-platelet ratio index (APRI) in Cox proportional hazard model. In conclusion, ALBI score indicates pathological stage in Japanese PBC patients and scores before UDCA prescription predict better liver transplant-free survival, which correlated well with the two major prognostic scores. The prognosis-predicting ability of the ALBI score might surpass that of APRI. Full article
(This article belongs to the Special Issue Liver Transplantation)
Open AccessArticle
Low Muscle Mass as a Prognostic Factor for Early Postoperative Outcomes in Pediatric Patients Undergoing the Fontan Operation: A Retrospective Cohort Study
J. Clin. Med. 2019, 8(8), 1257; https://doi.org/10.3390/jcm8081257
Received: 8 July 2019 / Revised: 15 August 2019 / Accepted: 16 August 2019 / Published: 19 August 2019
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Abstract
The impact of low muscle mass on pediatric cardiac patients remains unclear. We investigated the impact of low muscle mass on early postoperative outcomes in patients undergoing the Fontan operation. The electronic medical records of 74 patients (aged <18 years) who underwent the [...] Read more.
The impact of low muscle mass on pediatric cardiac patients remains unclear. We investigated the impact of low muscle mass on early postoperative outcomes in patients undergoing the Fontan operation. The electronic medical records of 74 patients (aged <18 years) who underwent the Fontan operation were retrospectively reviewed. The cross-sectional areas of the erector spinae and pectoralis muscles were measured using preoperative chest computed tomography (CT), normalized to the body surface area, and combined to obtain the total skeletal muscle index (TSMI). Low muscle mass was defined as a TSMI value lower than the median TSMI for the second quintile. The incidence of major postoperative complications was higher in patients with low muscle mass than in those with high muscle mass (48% (15/31) versus 14% (6/43); P = 0.003). Multivariable analyses revealed that a higher TSMI was associated with a lower likelihood of an increased duration of intensive care unit (>5 days) and hospital stay (>14 days) (odds ratio (OR) 0.86; 95% confidence interval (CI) 0.77–0.96; P = 0.006 and OR 0.92; 95% CI 0.85–0.99; P = 0.035 per 1 cm2/m2 increase in TSMI) and incidence of major postoperative complications (OR 0.90; 95% CI 0.82–0.99; P = 0.039 per 1 cm2/m2 increase in TSMI). Preoperative low muscle mass was associated with poor early postoperative outcomes in pediatric patients undergoing the Fontan operation. Full article
(This article belongs to the Special Issue Anesthesia for the High-Risk Patient)
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Open AccessArticle
Systemic Sclerosis Serum Steers the Differentiation of Adipose-Derived Stem Cells Toward Profibrotic Myofibroblasts: Pathophysiologic Implications
J. Clin. Med. 2019, 8(8), 1256; https://doi.org/10.3390/jcm8081256
Received: 19 July 2019 / Revised: 6 August 2019 / Accepted: 16 August 2019 / Published: 19 August 2019
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Abstract
Systemic sclerosis (SSc; scleroderma) is characterized by life-threatening progressive multiorgan fibrosis orchestrated by profibrotic myofibroblasts originating from different sources. Because recent data demonstrated that the majority of myofibroblasts in a murine scleroderma model arise from adipocytic progenitors through the adipocyte-myofibroblast transition process, we [...] Read more.
Systemic sclerosis (SSc; scleroderma) is characterized by life-threatening progressive multiorgan fibrosis orchestrated by profibrotic myofibroblasts originating from different sources. Because recent data demonstrated that the majority of myofibroblasts in a murine scleroderma model arise from adipocytic progenitors through the adipocyte-myofibroblast transition process, we sought to determine whether the SSc microenvironment may affect the differentiation potential of adipose-derived stem cells (ADSC). Normal human ADSC from three donors were treated with serum from SSc patients (n = 6), serum from healthy individuals (n = 6), or recombinant human transforming growth factor-β1 (TGFβ1) as positive control of myofibroblastic phenotype induction. ADSC were subjected to in vitro adipogenic differentiation for up to 21 days in the presence of different stimuli followed by lipid content quantification. In selected experiments, adipocytic and mesenchymal/myofibroblast marker gene and protein expression levels were assessed by Real-Time PCR, immunoblotting and immunofluorescence after administration of different stimuli for 72 and 96 h, respectively. Cell contractile phenotype was assayed by collagen gel contraction assay. Likewise stimulation with TGFβ1, SSc serum was able to significantly inhibit the adipocyte differentiation of ADSC as testified by a strong decrease in red-colored lipid droplets after 21 days of adipogenic induction. Treatment of ADSC either with SSc serum or TGFβ1 resulted in the acquisition of a myofibroblast-like phenotype characterized by a reduced expression of the adipocytic markers perilipin and adiponectin, a significant upregulation of the mesenchymal/myofibroblast markers α-SMA+ stress fibers, S100A4 and type I collagen, and an ability to effectively contract collagen gels. In SSc, the pathologic environment may favor the differentiation of ADSC into profibrotic and contractile myofibroblast-like cells. These findings strengthen the notion that the generation of myofibroblasts from ADSC may be relevant in SSc pathophysiology potentially representing a new target for the prevention/treatment of multiorgan fibrosis. Full article
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Open AccessArticle
Oral Health in Adults with Congenital Heart Disease
J. Clin. Med. 2019, 8(8), 1255; https://doi.org/10.3390/jcm8081255
Received: 19 July 2019 / Revised: 12 August 2019 / Accepted: 16 August 2019 / Published: 19 August 2019
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Abstract
Oral bacteria and odontogenic oral infections are responsible for a high portion of cases with infective endocarditis. Hence, oral health in patients with congenital heart disease (CHD) gains particular importance. This case-control study compared the oral health status in 112 adults with CHD [...] Read more.
Oral bacteria and odontogenic oral infections are responsible for a high portion of cases with infective endocarditis. Hence, oral health in patients with congenital heart disease (CHD) gains particular importance. This case-control study compared the oral health status in 112 adults with CHD and 168 healthy control subjects. In addition, the patient group was stratified according to the complexity of the heart defect and the recommendation for antibiotic prophylaxis during invasive dental procedures. Considering caries experience, a significantly lower mean DMFT (decayed missing filled teeth) score (7.91 ± 6.63 vs. 13.6 ± 8.15; p < 0.0001) was found in patients with CHD compared to healthy controls. Healthy controls had a higher average number of decayed teeth (0.33 ± 0.76 vs. 1.76 ± 2.61; p < 0.0001). In female subjects a significant lower relative amount of teeth with apical periodontitis was found among CHD patients (3.4% ± 0.9%) as compared to healthy controls (5.6% ± 1.9%) (p = 0.053). Regarding periodontal health, patients with CHD had lower rate of sulcus bleeding (0.32 ± 0.65 vs. 0.71 ± 0.60; p < 0.0001) and less alveolar bone loss than heart healthy individuals (% root length: multi rooted teeth: 8.97 ± 10.64 vs. 23.22 ± 20.70; p < 0.0001; single rooted teeth: 5.59 ± 6.25 vs. 17.30 ± 17.17; p = 0.003). On the contrary, CHD patients presented with higher amount of plaque in comparison to healthy controls (Quigley & Hein index: 2.22 ± 0.67 vs. 1.25 ± 0.72; p < 0.0001). Based on the current results, it can be concluded that adults with CHD have better oral health than heart healthy individuals. Full article
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Open AccessReview
Kidney Disease in HIV Infection
J. Clin. Med. 2019, 8(8), 1254; https://doi.org/10.3390/jcm8081254
Received: 13 July 2019 / Revised: 7 August 2019 / Accepted: 12 August 2019 / Published: 19 August 2019
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Abstract
Antiretroviral therapy (ART) has significantly improved life expectancy of infected subjects, generating a new epidemiological setting of people aging withHuman Immunodeficiency Virus (HIV). People living with HIV (PLWH), having longer life expectancy, now face several age-related conditions as well as side effects of [...] Read more.
Antiretroviral therapy (ART) has significantly improved life expectancy of infected subjects, generating a new epidemiological setting of people aging withHuman Immunodeficiency Virus (HIV). People living with HIV (PLWH), having longer life expectancy, now face several age-related conditions as well as side effects of long-term exposure of ART. Chronic kidney disease (CKD) is a common comorbidity in this population. CKD is a relentlessly progressive disease that may evolve toward end-stage renal disease (ESRD) and significantly affect quality of life and risk of death. Herein, we review current understanding of renal involvement in PLWH, mechanisms and risk factors for CKD as well as strategies for early recognition of renal dysfunction and best care of CKD. Full article
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Open AccessArticle
Multi-Omics Characterization of the Spontaneous Mesenchymal–Epithelial Transition in the PMC42 Breast Cancer Cell Lines
J. Clin. Med. 2019, 8(8), 1253; https://doi.org/10.3390/jcm8081253
Received: 10 July 2019 / Revised: 15 August 2019 / Accepted: 15 August 2019 / Published: 19 August 2019
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Abstract
Epithelial–mesenchymal plasticity (EMP), encompassing epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), are considered critical events for cancer metastasis. We investigated chromosomal heterogeneity and chromosomal instability (CIN) profiles of two sister PMC42 breast cancer (BC) cell lines to assess the relationship between their karyotypes [...] Read more.
Epithelial–mesenchymal plasticity (EMP), encompassing epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), are considered critical events for cancer metastasis. We investigated chromosomal heterogeneity and chromosomal instability (CIN) profiles of two sister PMC42 breast cancer (BC) cell lines to assess the relationship between their karyotypes and EMP phenotypic plasticity. Karyotyping by GTG banding and exome sequencing were aligned with SWATH quantitative proteomics and existing RNA-sequencing data from the two PMC42 cell lines; the mesenchymal, parental PMC42-ET cell line and the spontaneously epithelially shifted PMC42-LA daughter cell line. These morphologically distinct PMC42 cell lines were also compared with five other BC cell lines (MDA-MB-231, SUM-159, T47D, MCF-7 and MDA-MB-468) for their expression of EMP and cell surface markers, and stemness and metabolic profiles. The findings suggest that the epithelially shifted cell line has a significantly altered ploidy of chromosomes 3 and 13, which is reflected in their transcriptomic and proteomic expression profiles. Loss of the TGFβR2 gene from chromosome 3 in the epithelial daughter cell line inhibits its EMT induction by TGF-β stimulus. Thus, integrative ‘omics’ characterization established that the PMC42 system is a relevant MET model and provides insights into the regulation of phenotypic plasticity in breast cancer. Full article
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Open AccessCommunication
Blood Flow Restriction Increases the Neural Activation of the Knee Extensors During Very Low-Intensity Leg Extension Exercise in Cardiovascular Patients: A Pilot Study
J. Clin. Med. 2019, 8(8), 1252; https://doi.org/10.3390/jcm8081252
Received: 5 July 2019 / Revised: 14 August 2019 / Accepted: 15 August 2019 / Published: 19 August 2019
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Abstract
Blood flow restriction (BFR) has the potential to augment muscle activation, which underlies strengthening and hypertrophic effects of exercise on skeletal muscle. We quantified the effects of BFR on muscle activation in the rectus femoris (RF), the vastus lateralis (VL), and the vastus [...] Read more.
Blood flow restriction (BFR) has the potential to augment muscle activation, which underlies strengthening and hypertrophic effects of exercise on skeletal muscle. We quantified the effects of BFR on muscle activation in the rectus femoris (RF), the vastus lateralis (VL), and the vastus medialis (VM) in concentric and eccentric contraction phases of low-intensity (10% and 20% of one repetition maximum) leg extension in seven cardiovascular patients who performed leg extension in four conditions: at 10% and 20% intensities with and without BFR. Each condition consisted of three sets of 30 trials with 30 s of rest between sets and 5 min of rest between conditions. Electromyographic activity (EMG) from RF, VL, and VM for 30 repetitions was divided into blocks of 10 trials and averaged for each block in each muscle. At 10% intensity, BFR increased EMG of all muscles across the three blocks in both concentric and eccentric contraction phases. At 20% intensity, EMG activity in response to BFR tended to not to increase further than what it was at 10% intensity. We concluded that very low 10% intensity exercise with BFR may maximize the benefits of BFR on muscle activation and minimize exercise burden on cardiovascular patients. Full article
(This article belongs to the Section Epidemiology & Public Health)
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Open AccessArticle
Comparison of Radiographic Progression-Free Survival and PSA Response on Sequential Treatment Using Abiraterone and Enzalutamide for Newly Diagnosed Castration-Resistant Prostate Cancer: A Propensity Score Matched Analysis from Multicenter Cohort
J. Clin. Med. 2019, 8(8), 1251; https://doi.org/10.3390/jcm8081251
Received: 28 June 2019 / Revised: 31 July 2019 / Accepted: 16 August 2019 / Published: 19 August 2019
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Abstract
Background: There is emerging evidence that radiographic progression-free survival (rPFS) is highly correlated with overall survival (OS), potentially serving as an indicator of treatment outcome for castration-resistant prostate cancer (CRPC). The objective of this study is to assess rPFS and prostate specific [...] Read more.
Background: There is emerging evidence that radiographic progression-free survival (rPFS) is highly correlated with overall survival (OS), potentially serving as an indicator of treatment outcome for castration-resistant prostate cancer (CRPC). The objective of this study is to assess rPFS and prostate specific antigen (PSA) response in sequential treatment using androgen signaling inhibitors (ASIs) including abiraterone and enzalutamide in newly diagnosed CRPC. Methods: Propensity score matching was performed to reduce bias by confounding factors between first-line ASIs. The primary endpoints of the study included rPFS, time to PSA progression (TTPP), and PSA response. Results: A paired-matched group of 184 patients were identified. From the initiation of first-line ASIs, there was no significant difference in rPFS, TTPP, and PSA response between treatment arms. From the initiation of second-line ASIs, enzalutamide following abiraterone consistently exhibited longer rPFS (median: 7 and 15 months, p = 0.04), TTPP, and better PSA response compared to the reverse, whereas OS did not reach significance (median: 14 and 23 months, p = 0.35). Conclusion: Although the effect of ASIs as the first line was similar, the extent of cross-resistance might differ towards less resistance in enzalutamide following abiraterone than the reverse. Full article
(This article belongs to the Section Oncology)
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Open AccessArticle
Mechanical Ventilation Strategies Targeting Different Magnitudes of Collapse and Tidal Recruitment in Porcine Acid Aspiration-Induced Lung Injury
J. Clin. Med. 2019, 8(8), 1250; https://doi.org/10.3390/jcm8081250
Received: 25 June 2019 / Revised: 6 August 2019 / Accepted: 14 August 2019 / Published: 18 August 2019
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Abstract
Reducing ventilator-associated lung injury by individualized mechanical ventilation (MV) in patients with Acute Respiratory Distress Syndrome (ARDS) remains a matter of research. We randomly assigned 27 pigs with acid aspiration-induced ARDS to three different MV protocols for 24 h, targeting different magnitudes of [...] Read more.
Reducing ventilator-associated lung injury by individualized mechanical ventilation (MV) in patients with Acute Respiratory Distress Syndrome (ARDS) remains a matter of research. We randomly assigned 27 pigs with acid aspiration-induced ARDS to three different MV protocols for 24 h, targeting different magnitudes of collapse and tidal recruitment (collapse&TR): the ARDS-network (ARDSnet) group with low positive end-expiratory pressure (PEEP) protocol (permissive collapse&TR); the Open Lung Concept (OLC) group, PaO2/FiO2 >400 mmHg, indicating collapse&TR <10%; and the minimized collapse&TR monitored by Electrical Impedance Tomography (EIT) group, standard deviation of regional ventilation delay, SDRVD. We analyzed cardiorespiratory parameters, computed tomography (CT), EIT, and post-mortem histology. Mean PEEP over post-randomization measurements was significantly lower in the ARDSnet group at 6.8 ± 1.0 cmH2O compared to the EIT (21.1 ± 2.6 cmH2O) and OLC (18.7 ± 3.2 cmH2O) groups (general linear model (GLM) p < 0.001). Collapse&TR and SDRVD, averaged over all post-randomization measurements, were significantly lower in the EIT and OLC groups than in the ARDSnet group (collapse p < 0.001, TR p = 0.006, SDRVD p < 0.004). Global histological diffuse alveolar damage (DAD) scores in the ARDSnet group (10.1 ± 4.3) exceeded those in the EIT (8.4 ± 3.7) and OLC groups (6.3 ± 3.3) (p = 0.16). Sub-scores for edema and inflammation differed significantly (ANOVA p < 0.05). In a clinically realistic model of early ARDS with recruitable and nonrecruitable collapse, mechanical ventilation involving recruitment and high-PEEP reduced collapse&TR and resulted in improved hemodynamic and physiological conditions with a tendency to reduced histologic lung damage. Full article
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Open AccessArticle
Short-Term Postoperative Outcomes between 4% Icodextrin Solution and Hyaluronic Acid- Carboxymethyl Cellulose Membrane during Emergency Cesarean Section
J. Clin. Med. 2019, 8(8), 1249; https://doi.org/10.3390/jcm8081249
Received: 2 July 2019 / Revised: 7 August 2019 / Accepted: 16 August 2019 / Published: 18 August 2019
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Abstract
Emergency cesarean sections are associated with more postoperative complications than with elective cesarean sections. Seprafilm and Adept are commonly used adhesion reduction devices and have been applied in abdominal or pelvic surgery for a long time. This study focuses on comparing the short-term [...] Read more.
Emergency cesarean sections are associated with more postoperative complications than with elective cesarean sections. Seprafilm and Adept are commonly used adhesion reduction devices and have been applied in abdominal or pelvic surgery for a long time. This study focuses on comparing the short-term postoperative outcomes of emergency cesarean sections between two groups. We performed a retrospective study that included all patients who received emergency caesarean sections from the same surgeon at MacKay Memorial Hospital between August 2014 and November 2017, We analyzed the overall cases and conducted a subgroup analysis of cases with contaminated or dirty/infected wounds in regard to the rates of surgical-site infection (SSI), bandemia, delayed flatus passage, and length of hospital stay. The two groups were similar with respect to the rates of SSI, bandemia, and length of hospital stay. However, Seprafilm was associated with higher risk of delayed flatus passage over 48 h (OR: 2.67, 95% CI = 2.16–7.64, p = 0.001). It also needs less time for recovery of the digestive system and less medical management postoperatively. In cases of contaminated or dirty/infected wounds, Adept user also had significantly lower rates (10.3% vs. 32%, p = 0.048, OR: 4.12, CI = 1.09–15.61) of postcesarean metritis. Full article
(This article belongs to the Section Obstetrics & Gynecology)
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Open AccessArticle
Aseptic Ligatures Induce Marginal Peri-Implant Bone Loss—An 8-Week Trial in Rabbits
J. Clin. Med. 2019, 8(8), 1248; https://doi.org/10.3390/jcm8081248
Received: 16 July 2019 / Revised: 15 August 2019 / Accepted: 16 August 2019 / Published: 18 August 2019
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Abstract
The clinical value of ligature-induced experimental peri-implantitis studies has been questioned due to the artificial nature of the model. Despite repeated claims that ligatures of silk, cotton and other materials may not induce bone resorption by themselves; a recent review showed that the [...] Read more.
The clinical value of ligature-induced experimental peri-implantitis studies has been questioned due to the artificial nature of the model. Despite repeated claims that ligatures of silk, cotton and other materials may not induce bone resorption by themselves; a recent review showed that the tissue reaction toward them has not been investigated. Hence, the current study aimed to explore the hard and soft tissue reactions toward commonly used ligature materials. A total of 60 dental implants were inserted into the femur (n = 20) and tibia (n = 40) of 10 rabbits. The femoral implants were ligated with sterile 3-0 braided silk in one leg and sterile cotton retraction chord in the other leg. The tibial implants were ligated with silk or left as non-ligated controls. All wounds were closed in layers. After a healing time of 8 weeks, femoral (silk versus cotton) and proximal tibial (silk versus non-ligated control) implants were investigated histologically. Distal tibial (silk versus non-ligated control) implants were investigated with real time polymerase chain reaction (qPCR). The distance from the implant-top to first bone contact point was longer for silk ligated implants compared to non-ligated controls (p = 0.007), but did not vary between cotton and silk. The ligatures triggered an immunological reaction with cell infiltrates in close contact with the ligature materials, adjacent soft tissue encapsulation and bone resorption. qPCR further demonstrated an upregulated immune response toward the silk ligatures compared to non-ligated controls. Silk and cotton ligatures provoke foreign body reactions of soft tissue encapsulation type and bone resorption around implants in the absence of plaque. Full article
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Open AccessArticle
Early Neurological Assessment in Infants with Hypoxic Ischemic Encephalopathy Treated with Therapeutic Hypothermia
J. Clin. Med. 2019, 8(8), 1247; https://doi.org/10.3390/jcm8081247
Received: 1 July 2019 / Revised: 22 July 2019 / Accepted: 12 August 2019 / Published: 18 August 2019
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Abstract
Early neurological assessment in infants with hypoxic ischemic encephalopathy (HIE) treated with hypothermia has not been systematically explored. The aims of the present study were to assess whether the Hammersmith Infant Neurological Examination (HINE) is a good tool to predict later neurodevelopmental outcomes [...] Read more.
Early neurological assessment in infants with hypoxic ischemic encephalopathy (HIE) treated with hypothermia has not been systematically explored. The aims of the present study were to assess whether the Hammersmith Infant Neurological Examination (HINE) is a good tool to predict later neurodevelopmental outcomes at 2 year from birth in this population of infants. A total of 41 term born infants with HIE treated with hypothermia performed the HINE at 12 months and a neurodevelopmental assessment at 24 months. All the infants who had a global HINE score between 67 and 78 were able to walk independently at 2 years and reported a normal developmental quotient; language disorders were observed in a limited number of infants. HINE scores <67 were always associated with motor impairment. In conclusion, the HINE confirms its role as one of the early neurological examination tools for the diagnosis of high risk infants, even in infants with HIE treated with hypothermia. These results can be useful for clinicians involved in the follow up of these infants for early identification of motor disabilities and in planning appropriate intervention. Full article
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Open AccessArticle
Local and Widespread Pressure Pain Hyperalgesia Is Not Side Specific in Females with Unilateral Neck Pain that Can Be Reproduced during Passive Neck Rotation
J. Clin. Med. 2019, 8(8), 1246; https://doi.org/10.3390/jcm8081246
Received: 25 June 2019 / Revised: 9 August 2019 / Accepted: 14 August 2019 / Published: 18 August 2019
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Abstract
Current evidence for widespread hyperalgesia in non-specific neck pain (NSNP) is unclear. It is currently recommended to group NSNP patients according to pain-provoking movements. The aim of this study was to investigate local and widespread pain sensitivity in females with unilateral NSNP that [...] Read more.
Current evidence for widespread hyperalgesia in non-specific neck pain (NSNP) is unclear. It is currently recommended to group NSNP patients according to pain-provoking movements. The aim of this study was to investigate local and widespread pain sensitivity in females with unilateral NSNP that is reproducible during passive neck rotation compared with matched controls, and to compare the side specific effect of pain location on pressure pain sensitivity among females with unilateral NSNP. Thirty-six females with unilateral NSNP evoked during passive ipsilateral (n = 20) or contralateral (n = 16) rotation toward the painful side were compared with 20 controls. Participants reported their pain intensity at rest and during passive neck rotation and completed the Neck Disability Index. Pressure pain thresholds (PPTs) were assessed bilaterally over the anterior scalene; the sternocleidomastoid; the levator scapulae; lateral to the spinous process of C6; the median, ulnar, and radial nerves; and the tibialis anterior. The ANOVA revealed lower PPTs in females with unilateral NSNP compared with the controls (all at p < 0.001), but no differences were found between the sides, nor was there any Group × side interaction. Among females with NSNP, those with higher pain intensity during ipsilateral rotation toward the painful side showed lower PPTs over the anterior scalene, median nerve, ulnar nerve, and tibialis anterior (all, p < 0.05) than females with higher pain intensity during contralateral rotation toward the painful side. These findings demonstrated bilateral local and widespread pressure pain hyperalgesia in females with unilateral NSNP that was reproducible during passive neck rotation compared with controls. There was no side specific effect of pain location on PPTs among females with unilateral NSNP. Full article
(This article belongs to the Section Anesthesiology)
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Open AccessBrief Report
The State of Lupus Clinical Trials: Minority Participation Needed
J. Clin. Med. 2019, 8(8), 1245; https://doi.org/10.3390/jcm8081245
Received: 31 July 2019 / Revised: 12 August 2019 / Accepted: 15 August 2019 / Published: 17 August 2019
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Abstract
In the United States, the reported prevalence of lupus is 100,000 to 500,000 patients. Lupus disproportionately affects minority populations, including African Americans and Latinos, and the associated health disparities are substantial. Women are at a higher risk of lupus than men and lupus [...] Read more.
In the United States, the reported prevalence of lupus is 100,000 to 500,000 patients. Lupus disproportionately affects minority populations, including African Americans and Latinos, and the associated health disparities are substantial. Women are at a higher risk of lupus than men and lupus prevalence is the highest in African Americans and Latinos compared to non-Hispanic whites. African Americans and Latinos also have increased disease symptom severity, experience more lupus-related complications, and have a two- to three-fold mortality rate compared to non-Hispanic Whites. Lupus clinical trials offer opportunities for quality care and can result in new treatment options, but African Americans and Latinos are underrepresented in clinical trials because of substantial patient- and provider-side barriers. In conjunction with the limited knowledge of clinical trials that potential participants may have, the healthcare staff approaching participants have limited time to adequately educate and explain the aspects of clinical trials. Indeed, ninety percent of clinical trials fail to meet their recruitment goals on time, so a multi-faceted approach is necessary to address the issue of low minority participation in clinical trials. Full article
Open AccessArticle
Molecular Profiling of Cutaneous Lupus Lesions Identifies Subgroups Distinct from Clinical Phenotypes
J. Clin. Med. 2019, 8(8), 1244; https://doi.org/10.3390/jcm8081244
Received: 29 July 2019 / Revised: 14 August 2019 / Accepted: 16 August 2019 / Published: 17 August 2019
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Abstract
Cutaneous lupus erythematosus (CLE) is a common manifestation of systemic lupus erythematosus (SLE), and CLE can also develop without systemic involvement. CLE can be difficult to treat and negatively contributes to quality of life. Despite the importance of CLE, our knowledge of what [...] Read more.
Cutaneous lupus erythematosus (CLE) is a common manifestation of systemic lupus erythematosus (SLE), and CLE can also develop without systemic involvement. CLE can be difficult to treat and negatively contributes to quality of life. Despite the importance of CLE, our knowledge of what differentiates cutaneous lupus subtypes is limited. Here, we utilized a large cohort of 90 CLE lesional biopsies to compare discoid lupus erythematosus (DLE) and subacute cutaneous lupus (SCLE) in patients with and without associated SLE in order to discern the drivers of disease activity and possibly uncover better treatment targets. Overall, we found that DLE and SCLE share many differentially expressed genes (DEG) reflecting type I interferon (IFN) signaling and repression of EGFR pathways. No differences between CLE only and SLE-associated CLE lesions were found. Of note, DLE uniquely expresses an IFN-γ node. Unbiased cluster analysis of the DEGs identified two groups separated by neutrophilic vs. monocytic signatures that did not sort the patients based on clinical phenotype or disease activity. This suggests that unbiased analysis of the pathobiology of CLE lesions may be important for personalized medicine and targeted therapeutic decision making. Full article
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Open AccessArticle
Left Atrial Strain to Identify Diastolic Dysfunction in Children with Cardiomyopathies
J. Clin. Med. 2019, 8(8), 1243; https://doi.org/10.3390/jcm8081243
Received: 6 July 2019 / Revised: 23 July 2019 / Accepted: 12 August 2019 / Published: 17 August 2019
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Abstract
Background: Left ventricular (LV) diastolic dysfunction (DD) carries worse prognosis in childhood. 2-dimensional (2-D) left atrial (LA) strain accurately categorizes DD in adults but its role in children is unknown. Thus, the aim of this study is to investigate whether LA strain and [...] Read more.
Background: Left ventricular (LV) diastolic dysfunction (DD) carries worse prognosis in childhood. 2-dimensional (2-D) left atrial (LA) strain accurately categorizes DD in adults but its role in children is unknown. Thus, the aim of this study is to investigate whether LA strain and strain rate could diagnose and classify DD in children with dilated (CMD), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies (CM). Methods and Results: The study includes 136 children (aged 8.8 ± 6 years): 44 with DCM, 40 with HCM, 7 with RCM and 45 healthy controls (CTRL). They underwent standard echocardiographic examination and 2-D speckle-tracking analyses (LV longitudinal peak systolic strain (LS), LA peak systolic strain and strain rate). No significant differences in mitral E/A and pulmonary S/D ratios were observed among the four groups. Although E/E’ and indexed left atrial volumes were found to be significantly higher in HCM, DCM and RCM compared to CTRL (p < 0.001), they showed no significant difference among the three CM groups. LV LS values were significantly reduced in CM vs CTRL (p < 0.001) and in DCM vs HCM (p < 0.01), with no other differences between the remaining groups. LA peak systolic strain and strain rate values showed a steady and significant decrease with worsening of DD. Receiver Operating Characteristics (ROC) curves showed area under the curve of 0.976 (p < 0.001) for LA strain and 0.946 (p < 0.001) for LA strain rate, to distinguish CTRL from CMs. Conclusions: LA strain and strain rate could be a promising tool to better understand and classify DD in children with cardiomyopathies, opening the way to its clinical use. Full article
(This article belongs to the Section Cardiology)
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Open AccessArticle
Changes in Circulating Lysyl Oxidase-Like-2 (LOXL2) Levels, HOMA, and Fibrosis after Sustained Virological Response by Direct Antiviral Therapy
J. Clin. Med. 2019, 8(8), 1242; https://doi.org/10.3390/jcm8081242
Received: 1 July 2019 / Revised: 9 August 2019 / Accepted: 13 August 2019 / Published: 17 August 2019
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Abstract
Background: we aimed to assess the influence of metabolic syndrome on fibrosis regression (using liver-stiffness measurement (LSM) and serological scores) and the relationship with the expression of lysyl oxidase-like-2 as a potential goal of antifibrotic therapy. Methods: We included 271 patients treated with [...] Read more.
Background: we aimed to assess the influence of metabolic syndrome on fibrosis regression (using liver-stiffness measurement (LSM) and serological scores) and the relationship with the expression of lysyl oxidase-like-2 as a potential goal of antifibrotic therapy. Methods: We included 271 patients treated with Direct Antiviral Therapy (DAAs) in our hospital who achieved a sustained virological response (SVR); physical examination, blood tests, and LSM were made at baseline (B) and 24 months (24 M) after SVR. Hemodynamic studies and transjugular liver biopsies were performed on 13 patients. Results: At B, 68 patients were F1 (25.1%); F2 n = 59 (21.7%); F3 n = 44 (16.05%); and 100 were F4 (36.9%). Although the LSM (absolute value) improved in 82% of patients (n = 222), it progressed in 17.5% of patients (n = 48). At 24 M, 48 patients met the metabolic syndrome (MetS) criteria and there was an increase in patients with a BMI of >25 kg/m2 (p < 0.001). At B and 24 M, a BMI of >25 kg/m2 is a risk factor for significant fibrosis or steatosis at 24 M (p < 0.05) and progression on LSM (p < 0.001), as well as MetS at B and 24 M (OR 4.1 IC (1.4–11.7), p = 0.008; and OR 5.4 IC (1.9–15.4), p = 0.001, respectively). Regarding the correlation between LSM and the liver biopsy, we found that only six out of 13 patients had a matching LSM and biopsy. We found a statistically significant decrease in LOXL2 levels at 24 M with respect to B (p < 0.001) with higher serological value in patients with elastography of >9 kPa vs. <9 kPa (p = 0.046). Conclusion: Regression of LSM was reached in 82% of patients. Downregulated LOXL2 was demonstrated post-SVR, with overexpression in cirrhotic patients being a potential therapy goal in selected patients. Full article
(This article belongs to the Section Gastroenterology & Hepato-Pancreato-Biliary Medicine)
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Open AccessArticle
Risk-Aware Machine Learning Classifier for Skin Lesion Diagnosis
J. Clin. Med. 2019, 8(8), 1241; https://doi.org/10.3390/jcm8081241
Received: 16 June 2019 / Revised: 12 August 2019 / Accepted: 15 August 2019 / Published: 17 August 2019
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Abstract
Knowing when a machine learning system is not confident about its prediction is crucial in medical domains where safety is critical. Ideally, a machine learning algorithm should make a prediction only when it is highly certain about its competency, and refer the case [...] Read more.
Knowing when a machine learning system is not confident about its prediction is crucial in medical domains where safety is critical. Ideally, a machine learning algorithm should make a prediction only when it is highly certain about its competency, and refer the case to physicians otherwise. In this paper, we investigate how Bayesian deep learning can improve the performance of the machine–physician team in the skin lesion classification task. We used the publicly available HAM10000 dataset, which includes samples from seven common skin lesion categories: Melanoma (MEL), Melanocytic Nevi (NV), Basal Cell Carcinoma (BCC), Actinic Keratoses and Intraepithelial Carcinoma (AKIEC), Benign Keratosis (BKL), Dermatofibroma (DF), and Vascular (VASC) lesions. Our experimental results show that Bayesian deep networks can boost the diagnostic performance of the standard DenseNet-169 model from 81.35% to 83.59% without incurring additional parameters or heavy computation. More importantly, a hybrid physician–machine workflow reaches a classification accuracy of 90 % while only referring 35 % of the cases to physicians. The findings are expected to generalize to other medical diagnosis applications. We believe that the availability of risk-aware machine learning methods will enable a wider adoption of machine learning technology in clinical settings. Full article
(This article belongs to the Special Issue The Future of Artificial Intelligence in Clinical Medicine)
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Open AccessArticle
Patients with Heart Failure and Preserved Ejection Fraction Are at Risk of Gastrointestinal Bleeding
J. Clin. Med. 2019, 8(8), 1240; https://doi.org/10.3390/jcm8081240
Received: 14 July 2019 / Revised: 11 August 2019 / Accepted: 14 August 2019 / Published: 17 August 2019
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Abstract
Aims. Two thirds of patients with heart failure and preserved ejection fraction (HFpEF) have an indication for oral anticoagulation (OAC) to prevent thromboembolic events. However, evidence regarding the safety of OAC in HFpEF is limited. Therefore, our aim was to describe bleeding events [...] Read more.
Aims. Two thirds of patients with heart failure and preserved ejection fraction (HFpEF) have an indication for oral anticoagulation (OAC) to prevent thromboembolic events. However, evidence regarding the safety of OAC in HFpEF is limited. Therefore, our aim was to describe bleeding events and to find predictors of bleeding in a large HFpEF cohort. Methods and Results. We recorded bleeding events in a prospective HFpEF cohort. Out of 328 patients (median age 71 years (interquartile range (IQR) 67–77)), 64.6% (n = 212) were treated with OAC. Of those, 65.1% (n = 138) received vitamin-K-antagonists (VKA) and 34.9% (n = 72) non-vitamin K oral anticoagulants (NOACs). During a median follow-up time of 42 (IQR 17–63) months, a total of 54 bleeding events occurred. Patients on OAC experienced more bleeding events (n = 49 (23.1%) versus n = 5 (4.3%), p < 0.001). Major drivers of events were gastrointestinal (GI) bleeding (n = 18 (36.7%)]. HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score (hazard ratios (HR) of 2.15 (95% confidence interval (CI) 1.65–2.79, p < 0.001)) was the strongest independent predictor for overall bleeding. In the subgroup of GI bleeding, mean right atrial pressure (mRAP: HR of 1.13 (95% CI 1.03–1.25, p = 0.013)) and HAS-BLED score (HR of 1.74 (95% CI 1.15–2.64, p = 0.009)] remained significantly associatiated with bleeding events after adjustment. mRAP provided additional prognostic value beyond the HAS-BLED score with an improvement from 0.63 to 0.71 (95% CI 0.58–0.84, p for comparison 0.032), by C-statistic. This additional prognostic value was confirmed by significant improvements in net reclassification index (61.3%, p = 0.019) and integrated discrimination improvement (3.4%, p = 0.015). Conclusion. OAC-treated HFpEF patients are at high risk of GI bleeding. High mRAP as an indicator of advanced stage of disease was predictive for GI bleeding events and provided additional risk stratification information beyond that obtained by HAS-BLED score. Full article
(This article belongs to the Special Issue Acute and Chronic Heart Failure)
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Open AccessArticle
From Research to Practice: Ten Lessons in Delivering Digital Mental Health Services
J. Clin. Med. 2019, 8(8), 1239; https://doi.org/10.3390/jcm8081239
Received: 16 July 2019 / Revised: 10 August 2019 / Accepted: 15 August 2019 / Published: 17 August 2019
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Abstract
There is a large body of research showing that psychological treatment can be effectively delivered via the internet, and Digital Mental Health Services (DMHS) are now delivering those interventions in routine care. However, not all attempts to translate these research outcomes into routine [...] Read more.
There is a large body of research showing that psychological treatment can be effectively delivered via the internet, and Digital Mental Health Services (DMHS) are now delivering those interventions in routine care. However, not all attempts to translate these research outcomes into routine care have been successful. This paper draws on the experience of successful DMHS in Australia and Canada to describe ten lessons learned while establishing and delivering internet-delivered cognitive behavioural therapy (ICBT) and other mental health services as part of routine care. These lessons include learnings at four levels of analysis, including lessons learned working with (1) consumers, (2) therapists, (3) when operating DMHS, and (4) working within healthcare systems. Key themes include recognising that DMHS should provide not only treatment but also information and assessment services, that DMHS require robust systems for training and supervising therapists, that specialist skills are required to operate DMHS, and that the outcome data from DMHS can inform future mental health policy. We also confirm that operating such clinics is particularly challenging in the evolving funding, policy, and regulatory context, as well as increasing expectations from consumers about DMHS. Notwithstanding the difficulties of delivering DMHS, we conclude that the benefits of such services for the broader community significantly outweigh the challenges. Full article
Open AccessArticle
Association between Secondhand Smoke Exposure and Hypertension in 106,268 Korean Self-Reported Never-Smokers Verified by Cotinine
J. Clin. Med. 2019, 8(8), 1238; https://doi.org/10.3390/jcm8081238
Received: 26 June 2019 / Revised: 13 August 2019 / Accepted: 15 August 2019 / Published: 16 August 2019
Viewed by 203 | PDF Full-text (307 KB) | Supplementary Files
Abstract
: No study has reported the relationship between secondhand smoke (SHS) exposure and hypertension in self-reported never-smokers verified by nicotine metabolite. The aim of this study is to determine the relationship between SHS exposure and hypertension in self-reported and cotinine-verified never-smokers. A total [...] Read more.
: No study has reported the relationship between secondhand smoke (SHS) exposure and hypertension in self-reported never-smokers verified by nicotine metabolite. The aim of this study is to determine the relationship between SHS exposure and hypertension in self-reported and cotinine-verified never-smokers. A total of 106,268 self-reported never-smokers, verified as nonsmokers by urinary cotinine, who participated in Kangbuk Samsung Cohort study (KSCS) between 2012 and 2016 were included. Cotinine-verified nonsmokers were defined as individuals having urinary cotinine <50 ng/mL. SHS exposure was defined as current exposure to passive smoke indoors at home or the workplace. The multivariate regression model revealed that SHS exposure was associated with hypertension (odds ratio (OR) (95% confidence interval (CI)), 1.16 (1.08, 1.24)). Current SHS exposure that has been exposed to home SHS (1.22 (1.11, 1.33)) as well as current SHS exposure only at the workplace (1.15 (1.02, 1.29)) significantly increased the ORs for hypertension compared to no SHS exposure. There was no significant gender interaction for the relationships between SHS exposure and hypertension. This study showed that SHS exposure was significantly associated with hypertension in self-reported never-smokers verified as nonsmokers by urinary cotinine, suggesting necessity of health program and stricter smoking regulation to reduce the risk of hypertension. Full article
(This article belongs to the Section Epidemiology & Public Health)
Open AccessViewpoint
Rheumatoid Arthritis Treatment. A Back to the Drawing Board Project or High Expectations for Low Unmet Needs?
J. Clin. Med. 2019, 8(8), 1237; https://doi.org/10.3390/jcm8081237
Received: 5 July 2019 / Accepted: 15 August 2019 / Published: 16 August 2019
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Abstract
Despite the significant progress in Rheumatoid Arthritis (RA) therapeutics, there are several reports in the literature claiming that the size of unmet needs in RA is large. In the era before biologics, there was indeed a significant number of patients who did not [...] Read more.
Despite the significant progress in Rheumatoid Arthritis (RA) therapeutics, there are several reports in the literature claiming that the size of unmet needs in RA is large. In the era before biologics, there was indeed a significant number of patients who did not achieve low disease activity (LDA) or disease remission due to limited therapeutic choices in the doctors’ armamentarium. Treatment wise, great progress has been achieved over the last decades with the discovery and introduction in therapeutics of new molecules, such as the biological (b) disease-modifying anti-rheumatic drugs (DMARDs), and the targeted synthetic (ts) DMARDs. Today, with such a plethora of conventional synthetic (cs) DMARDs, tsDMARDs, and bDMARDs, why are we unable to successfully treat RA patients? What is wrong? However, a new drug for RA does not mean it is necessary to switch to a new treatment. It is very easy to change and switch therapies when the patient complains about pain and stiffness. In this setting, it is obligatory to rule out other comorbidities and disorders that may be the cause of the pain first. Thus, clinicians must have a deep knowledge of the drug therapy and be able to adjust the treatment when needed. A minute clinical examination must be carried out on every visit with close monitoring of the patient. A treat-to-target (T2T) approach and the application of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) recommendations and strategies should minimize the unmet needs. Full article
(This article belongs to the Section Immunology)
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