Journal of Clinical Medicine — Open Access Journal

Cardiac patients who engage in ≥150 min of moderate- to vigorous-intensity physical activity (MVPA)/week have lower mortality, yet MVPA declines even following cardiac rehabilitation (CR), and is lower in women. A randomized trial of nine socioecological theory-based exercise facilitation contacts over 50 weeks versus usual care (1:1 parallel arms) was undertaken (NCT01658683). The tertiary objective, as presented in this paper, was to test whether the intervention impacted socioecological elements, and in turn their association with MVPA. The 449 participants wore an accelerometer and completed questionnaires post-CR, and 26, 52 and 78 weeks later. At 52 weeks, exercise task self-efficacy was significantly greater in the intervention arm (p = 0.01), but no other differences were observed except more encouragement from other cardiac patients at 26 weeks (favoring controls). Among women adherent to the intervention, the group in whom the intervention was proven effective, physical activity (PA) intentions at 26 weeks were significantly greater in the intervention arm (p = 0.04), with no other differences. There were some differences in socioecological elements associated with MVPA by arm. There were also some differences by sex, with MVPA more often associated with exercise benefits/barriers in men, versus with working and the physical environment in women. Full article

Type 1 diabetes mellitus (T1DM) is caused by the autoimmune targeting of pancreatic β-cells, and, in the advanced stage, severe hypoinsulinemia due to islet destruction. In patients with T1DM, continuous exogenous insulin therapy cannot be avoided. However, an insufficient dose of insulin easily induces extreme hyperglycemia or diabetic ketoacidosis, and intensive insulin therapy may cause hypoglycemic symptoms including hypoglycemic shock. While these insulin therapies are efficacious in most patients, some additional therapies are warranted to support the control of blood glucose levels and reduce the risk of hypoglycemia in patients who respond poorly despite receiving appropriate treatment. There has been a recent gain in the popularity of cellular therapies using mesenchymal stromal cells (MSCs) in various clinical fields, owing to their multipotentiality, capacity for self-renewal, and regenerative and immunomodulatory potential. In particular, adipose tissue-derived MSCs (ADMSCs) have become a focus in the clinical setting due to the abundance and easy isolation of these cells. In this review, we outline the possible therapeutic benefits of ADMSC for the treatment of T1DM. Full article

Chordomas is rare malignant bone tumors thought to arise from remnants of embryonic notochord along the spine, frequently at the skull base and sacrum. Although chordoma is slow growing tumors, while are extremely recurrent, and aggressive, as well as the rate of prognosis remains poorly. Radical surgery and high-dose radiation are the most used treatments. Currently, there is no effective chemotherapeutic standard for chordomas. The Hedgehog (HH) pathway adjusts various processes included in expansion and differentiation of tissues and organs throughout the fetus’s life, furthermore cell growth and differentiation in the adult organism, of the cell in an adult organism, in which acute anesthesia is involved in multiple cancers. To study the role of signaling the hedgehog in the base of the skull and sacrum chordomas, the expression of SHH and GLI-1 levels were detected immuno histochemically, Additionally, PTCH-1 and GLI-1 expressions were distinguished by in- Situ- hybridization. Based on the findings presented herein, it is likely that the HH signal cascade was revealed even in cranial, where consecoently spinal chordoma and their recurrences play an important role. Our staining exhibited a canonical, ligand- dependent and autocrine Hedgehog signaling in skull base and sacrum chordomas including relapse. Due to the high levels of SHH and GLI-1 expression in all investigated chordoma samples, the study suggests a possible autocrine ligand-dependent activation of the canonical HH signaling cascade. A paracrine or non-canonical pathway cannot be excluded. Our results suggest that Hedgehog-inhibitors, like SHH-, GLI- and SMO- inhibitors, might serve as a potential and effective target for the treatment of chordomas. Full article

(1) Background: A functional shunt is critical to hemodialysis, but the ideal timing of shunt cannulation is still not established. In this study, we assessed the association between ideal puncture timing and shunt survival. (2) Methods: This retrospective cohort study using data from the Taiwan Health and Welfare database, which included 26885 hemodialysis patients with arteriovenous fistulas from 1 July 2008 to 30 June 2012. Fistulas were categorized by functional maturation time, defined as the time from the date of shunt construction to the first successful cannulation. Functional cumulative survival, measured as the duration from the first puncture to shunt abandonment, was mainly regarded. (3) Results: The fistulas created between 91 and 180 days prior to the first cannulation had significantly greater cumulative functional survival (HR 0.883; 95% CI 0.792–0.984), and there was no more benefit on their survival from waiting more than 180 days (HR 0.957; 95% CI 0.853–1.073) for shunt maturity. (4) Conclusions: Our results showed that to achieve better long-term shunt survivals, fistulas should be constructed at least 90 days before starting hemodialysis. Notably, there was no additional benefit on waiting more than 180 days prior to cannulation. Full article

The World Health Organization (WHO) defines glycogen-rich clear cell carcinoma (GRCC) of the breast as a carcinoma with glycogen accumulation in more than 90% of its tumor cells. Due to the rarity of this disease, its reported survival and clinical associations have been inconsistent due to reliance on case reports and limited case series. As a result, the prognostic implication of this cancer subtype remains unclear. Using the U.S. Surveillance, Epidemiology, and End Results (SEER) program database, we compared the incidence, demographics and prognostic factors of 155 cases of GRCC of the breast to 1,251,584 cases of other (non-GRCC) breast carcinomas. We demonstrate that GRCC is more likely to be identified as high grade, advanced stage, and more likely to have triple negative receptor status. GRCC cases display a poorer prognosis than non-GRCC carcinomas of the breast irrespective of age, AJCC staging, tumor grade, joint hormone receptor/human epidermal growth factor receptor 2 (HER2) status, and treatment. Similar to non-GRCC carcinomas, older age and higher American Joint Committee on Cancer (AJCC)/TNM staging were associated with poorer prognosis for GRCC, while treatment with surgery and radiation were associated with improved survival. Radiation, specifically in the setting of breast-conserving surgery, further improved survival compared to surgery alone. Our study highlights the poorer prognosis associated with glycogen accumulation in breast cancers and hence stresses the importance of identifying this more aggressive tumor type. Full article

Uterus transplantation (UTx) is now a possible approach for women with absolute uterine factor infertility to deliver a child, following the first successful delivery by Brännström et al. in Sweden in September 2014. This remarkable achievement attracted major attention worldwide and caused many countries to prepare for UTx, including countries in Asia. To date, three groups have performed UTx in humans in Asia, and many others are aiming for the clinical application of UTx with accumulation of basic experimental data. Therefore, it is likely that UTx will expand rapidly in Asia in the near future, although this will depend on ethical, social and religious views in each country. With this background, herein we summarize the current progress of UTx in East, Southeast and South Asia, with the purpose of increasing understanding of the current status of basic and clinical UTx research in each country and sharing progress and knowledge to ensure future development of UTx research in Asia. Full article

Amiodarone is recommended for shock-refractory ventricular arrhythmia during resuscitation; however, it is unknown whether amiodarone is effective for preventing ventricular arrhythmia recurrence in out-of-hospital cardiac arrest (OHCA) survivors treated with targeted temperature management (TTM). We investigated the effectiveness of prophylactic amiodarone in preventing ventricular arrhythmia recurrence in OHCA survivors. Data of consecutive adult non-traumatic OHCA survivors treated with TTM between 2010 and 2016 were extracted from prospective cardiac arrest registries of four tertiary care hospitals. The prophylactic amiodarone group was matched in a 1:1 ratio by using propensity scores. The primary outcome was ventricular arrhythmia recurrence requiring defibrillation during TTM. Among 295 patients with an initially shockable rhythm and 149 patients with initially non-shockable-turned-shockable rhythm, 124 patients (27.9%) received prophylactic amiodarone infusion. The incidence of ventricular arrhythmia recurrence was 11.26% (50/444). Multivariate analysis showed prophylactic amiodarone therapy to be the independent factor associated with ventricular arrhythmia recurrence (odds ratio 1.95, 95% CI 1.04–3.65, p = 0.04), however, no such association was observed (odds ratio 1.32, 95% CI 0.57–3.04, p = 0.51) after propensity score matching. In this propensity-score-matched study, prophylactic amiodarone infusion had no effect on preventing ventricular arrhythmia recurrence in OHCA survivors with shockable cardiac arrest. Prophylactic amiodarone administration must be considered carefully. Full article

We analyzed the capacities of pertinent parameters (determined by single-energy non-contrast computed tomography [NCCT]) and urinary pH to predict uric acid stones. We reviewed the medical records of 501 patients whose stones were removed surgically or passed spontaneously between December 2014 and April 2016. Qualifying participants (n = 420) were stratified by the nature of the stone (calcium oxalate, uric acid, or infectious). Based on NCCT, we determined maximal stone length (MSL), mean stone density (MSD), and stone heterogeneity index (SHI) using Hounsfield units (HU) and calculated the variant coefficient of stone density (VCSD = SHI/MSD × 100). Urinary pH was also ascertained. Mean patient age was 55.55 ± 15.46 years. MSD (448.59 ± 173.21 HU), SHI (100.81 ± 77.37 HU), and VCSD (22.58 ± 10.55) proved to be significantly lower in uric acid versus other types of stones, as did urinary pH (5.33 ± 0.56; all p < 0.001). Receiver operating characteristic (ROC) curves depicting predictability of uric acid stones yielded area under ROC curve (AUC) values for MSD, SHI, VCSD, and urinary pH of 0.806 (95% CI: 0.761–0.850), 0.893 (95% CI: 0.855–0.931), 0.782 (95% CI: 0.726–0.839), and 0.797 (95% CI: 0.749–0.846), respectively, with corresponding cutpoints of 572.3 HU, 140.4 HU, 25.79, and 6.0. Among these four parameters, SHI was verifiably (DeLong’s test) the most effective predictor of uric acid stones (all p < 0.001). Compared with MSD, VCSD, and urinary pH, SHI may better predict uric acid stones, using a cutpoint of 140.4 HU. Full article

Subthreshold micropulse laser treatment has been intensively used for selected retinal diseases in the last decade; however, the exact mechanism of the action of lasers in the subthreshold micropulse mode is not yet fully understood. This kind of treatment is safe and cheap, and contrary to classic laser photocoagulation, it leaves the retinal cells intact. A modern theory of micropulse laser interaction with retinal tissue and a possible explanation of this mechanism are presented in this review. The authors present all the relevant literature on the application of micropulse lasers in different retinal disorders. The efficacy of this treatment is analyzed on the basis of available studies and then placed in the perspective of other therapeutic methods that are used in retinal diseases. Full article

Standard methods for detecting chronic lung allograft dysfunction (CLAD) and rejection have poor sensitivity and specificity and have conventionally required bronchoscopies and biopsies. Plasma cell-free DNA (cfDNA) has been shown to be increased in various types of allograft injury in transplant recipients and CXCL10 has been reported to be increased in the lung tissue of patients undergoing CLAD. This study used a novel cfDNA and CXCL10 assay to evaluate the noninvasive assessment of CLAD phenotype and prediction of survival from bronchoalveolar lavage (BAL) fluid. A total of 60 BAL samples (20 with bronchiolitis obliterans (BOS), 20 with restrictive allograft syndrome (RAS), and 20 with stable allografts (STA)) were collected from 60 unique lung transplant patients; cfDNA and CXCL10 were measured by the ELISA-based KIT assay. Median cfDNA was significantly higher in BOS patients (6739 genomic equivalents (GE)/mL) versus STA (2920 GE/mL) and RAS (4174 GE/mL) (p < 0.01 all comparisons). Likelihood ratio tests revealed a significant association of overall survival with cfDNA (p = 0.0083), CXCL10 (p = 0.0146), and the interaction of cfDNA and CXCL10 (p = 0.023) based on multivariate Cox proportional hazards regression. Dichotomizing patients based on the median cfDNA level controlled for the mean level of CXCL10 revealed an over two-fold longer median overall survival time in patients with low levels of cfDNA. The KIT assay could predict allograft survival with superior performance compared with traditional biomarkers. These data support the pursuit of larger prospective studies to evaluate the predictive performance of cfDNA and CXCL10 prior to lung allograft failure. Full article

Fused deposition modeling (FDM) is a rapidly growing three-dimensional (3D) printing technology and has great potential in medicine. Polyether-ether-ketone (PEEK) is a biocompatible high-performance polymer, which is suitable to be used as an orthopedic/dental implant material. However, the mechanical properties and biocompatibility of FDM-printed PEEK and its composites are still not clear. In this study, FDM-printed pure PEEK and carbon fiber reinforced PEEK (CFR-PEEK) composite were successfully fabricated by FDM and characterized by mechanical tests. Moreover, the sample surfaces were modified with polishing and sandblasting methods to analyze the influence of surface roughness and topography on general biocompatibility (cytotoxicity) and cell adhesion. The results indicated that the printed CFR-PEEK samples had significantly higher general mechanical strengths than the printed pure PEEK (even though there was no statistical difference in compressive strength). Both PEEK and CFR-PEEK materials showed good biocompatibility with and without surface modification. Cell densities on the “as-printed” PEEK and the CFR-PEEK sample surfaces were significantly higher than on the corresponding polished and sandblasted samples. Therefore, the FDM-printed CFR-PEEK composite with proper mechanical strengths has potential as a biomaterial for bone grafting and tissue engineering applications. Full article

(1) Background:Myocardial dysfunction in patients with sepsis is not an uncommon phenomenon, yet reported results are conflicting and there is no objective definition. Measurement of troponin may reflect the state of the heart and may correlate with echocardiographically derived data. This study aimed to evaluate the role of admission and peak troponin-I testing for the identification of sepsis-induced myocardial dysfunction (SIMD) by transthoracic echocardiography (TTE). (2) Methods:This was a retrospective cohort study using a prospective registry of septic shock at an Emergency Department from January 2011 and April 2017. All 1,776 consecutive adult septic shock patients treated with protocol-driven resuscitation bundle therapy and tested troponin-I were enrolled. SIMD was defined as left ventricular (LV) systolic/diastolic dysfunction, right ventricular (RV) diastolic dysfunction, or global/regional wall motion abnormalities (WMA). (3) Results:Of 660 (38.4%) septic shock patients with an elevated hs-TnI (≥0.04 ng/mL) at admission, 397 patients underwent TTE and 258 cases (65%) showed SIMD (LV systolic dysfunction (n = 163, 63.2%), LV diastolic dysfunction (n = 104, 40.3%), RV dysfunction (n = 97, 37.6%), and WMA (n = 186, 72.1%)). In multivariate analysis, peak hs-TnI (odds ratio 1.03, 95% confidence interval 1.01–1.06, p = 0.008) and ST-T wave changes in the electrocardiogram (odds ratio 1.82, 95% confidence interval 1.04–2.39, p = 0.013) were associated with SIMD, in contrast to hs-TnI level at admission. The area under the curve of peak hs-TnI was 0.668. When the peak hs-TnI cutoff value was 0.634 ng/mL, the sensitivity and specificity for SIMD were 58.6% and 59.1%, respectively. 4) Conclusions:About two-thirds of patients with an elevated hs-TnI level have various cardiac dysfunctions in terms of TTE. Rather than the initial level, the peak hs-TnI and ST-T change may be considered as a risk factor of SIMD. Full article

N-terminal pro b-type natriuretic peptide (NT-proBNP) was considered a prognostic factor for mortality in hemodialysis patients in previous studies. However, NT-proBNP has not been fully explored in terms of predicting other clinical outcomes in hemodialysis patients. This study aimed to investigate if NT-proBNP could predict emergency department (ED) visits, hospitalization, admission to intensive-care unit (ICU), and cardiovascular incidents in hemodialysis patients. Serum NT-proBNP and other indicators were collected in 232 hemodialysis patients. Patients were followed up for three years or until mortality. Outcomes included mortality, number of ED visits, hospitalizations, admissions to ICU, and cardiovascular events. NT-proBNP was found to predict recurrent ER visits, hospitalization, admission to ICU, cardiovascular events, and mortality, after adjusting for covariates. Time-dependent area under the curve (AUC) was used to evaluate the NT-proBNP predicting ability. Using time-dependent AUC, NT-proBNP has good predictive ability for mortality, ED visit, hospitalization, ICU admission, and cardiovascular events with the best predictive ability occurring at approximately 1 year, and 5th, 62nd, 63rd, and 63rd days respectively. AUC values for predicting mortality, hospitalization, and ICU admission decreased significantly after one year. NT-proBNP can be applied in predicting ED visits but is only suitable for the short-term. NT-proBNP may be used for predicting mortality in the long term. Full article

Tortuosity of blood vessels is a common angiographic finding that may indicate systemic disease and can be correlated with vascular pathologies. In this work, we determined whether patients with and without internal carotid artery (ICA) aneurysm presented with differences in its tortuosity descriptors. We retrospectively analysed data of 298 patients hospitalized between January 2014 and June 2018. For each patient’s imaging data, we extracted a curve representing the ICA course and measured its Relative Length (RL), Sum of Angle Metrics (SOAM), Product of Angle Distance (PAD), Triangular Index (TI), and Inflection Count Metrics (ICM). We found that patients with an ICA aneurysm had significantly lower RL (0.46 ± 0.19 vs. 0.51 ± 0.17; p = 0.023) and significantly higher SOAM (0.39 ± 0.21 vs. 0.32 ± 0.21 p = 0.003), PAD (0.38 ± 0.19 vs. 0.32 ± 0.21; p = 0.011), TI (0.30 ± 0.11 vs. 0.27 ± 0.14; p = 0.034), and ICM (0.30 ± 0.16 vs. 0.22 ± 0.12; p < 0.001). We found that that patients who presented with a subarachnoid hemorrhage had significantly higher PAD (0.46 ± 0.22 vs. 0.35 ± 0.20; p = 0.024). In conclusion, higher tortuosity of ICA is associated with ICA aneurysm presence. Full article

The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by the targeting of negative control checkpoints. The two best-known inhibitory immune checkpoints are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1). In AML, PD-1 expression is observed in T-cell subpopulations, including T regulatory lymphocytes. Increased PD-1 expression on CD8+ T lymphocytes may be one of the factors leading to dysfunction of cytotoxic T cells and inhibition of the immune response during the progressive course of AML. Upregulation of checkpoint molecules was observed after alloHSCT and therapy with hypomethylating agents, pointing to a potential clinical application in these settings. Encouraging results from recent clinical trials (a response rate above 50% in a relapsed setting) justify further clinical use. The most common clinical trials employ two PD-1 inhibitors (nivolumab and pembrolizumab) and two anti-PD-L1 (programmed death-ligand 1) monoclonal antibodies (atezolizumab and durvalumab). Several other inhibitors are under development or in early phases of clinical trials. The results of these clinical trials are awaited with great interest in, as they may allow for the established use of checkpoint inhibitors in the treatment of AML. Full article

The positive outcome of lung cancer treatment is strongly related to the earliness of the diagnosis. Thus, there is a strong requirement for technologies that could provide an early detection of cancer. The concept of early diagnosis is immediately extended to large population screening, and then, it is strongly related to non-invasiveness and low cost. Sensor technology takes advantage of the microelectronics revolution, and then, it promises to develop devices sufficiently sensitive to detect lung cancer biomarkers. A number of biosensors for the detection of cancer-related proteins have been demonstrated in recent years. At the same time, the interest is growing towards the analysis of volatile metabolites that could be measured directly from the breath. In this paper, a review of the state-of-the-art of biosensors and volatile compound sensors is presented. Full article

The authors identified that chemo-brain was induced after trastuzumab (TZB) therapy. In addition, atorvastatin (ATV) could rescue chemo-brain during trastuzumab (TZB) therapy. Enhanced therapeutic effect of TZB was confirmed after ATV therapy. We also investigated that there was no hair loss side effect due to ATV therapy. In an animal model, 150 μg TZB and five serial doses of 20 mg/kg ATV were administered. ¹⁸F-fluorodeoxyglucose Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) data were acquired. Statistical parametric mapping analysis and voxel-based morphometry analysis were performed to identify differences in glucose metabolism and gray matter concentration. The enhanced therapeutic efficacy of TZB after ATV treatment was assessed using a human epidermal growth factor receptor 2-positive gastric cancer model. We found a decrease in cerebral glucose metabolism and gray matter concentration in the frontal lobe following TZB therapy (p < 0.005). After subsequent ATV administration, glucose metabolism and regional gray matter concentration were rescued (p < 0.005). Cognitive impairment due to TZB and the rescue effect of ATV were confirmed using a passive avoidance test and quantitative real-time reverse transcription PCR. Furthermore, the penetration and accumulation of TZB in tumors increased by 100% after ATV co-administration, which resulted in an enhanced anti-cancer effect. Our study collectively demonstrates that ATV co-administration with TZB rescued the TZB-induced chemo-brain and enhances the therapeutic efficacy of TZB in tumors. We also showed that there was no hair loss during ATV therapy. Full article

Dihydrofolate reductase (DHFR) is an essential cellular enzyme and thereby catalyzes the
reduction of dihydrofolate to tetrahydrofolate (THF). In cancer medication, inhibition of human
DHFR (hDHFR) remains a promising strategy, as it depletes THF and slows DNA synthesis and cell
proliferation. In the current study, ligand-based pharmacophore modeling identified and evaluated
the critical chemical features of hDHFR inhibitors. A pharmacophore model (Hypo1) was generated
from known inhibitors of DHFR with a correlation coefficient (0.94), root mean square (RMS)
deviation (0.99), and total cost value (125.28). Hypo1 was comprised of four chemical features,
including two hydrogen bond donors (HDB), one hydrogen bond acceptor (HBA), and one
hydrophobic (HYP). Hypo1 was validated using Fischer's randomization, test set, and decoy set
validations, employed as a 3D query in a virtual screening at Maybridge, Chembridge, Asinex,
National Cancer Institute (NCI), and Zinc databases. Hypo1-retrieved compounds were filtered by
an absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment test and
Lipinski's rule of five, where the drug-like hit compounds were identified. The hit compounds were
docked in the active site of hDHFR and compounds with Goldfitness score was greater than 44.67
(docking score for the reference compound), clustering analysis, and hydrogen bond interactions
were identified. Furthermore, molecular dynamics (MD) simulation identified three compounds as
the best inhibitors of hDHFR with the lowest root mean square deviation (1.2 Å to 1.8 Å), hydrogen
bond interactions with hDHFR, and low binding free energy (−127 kJ/mol to −178 kJ/mol). Finally,
the toxicity prediction by computer (TOPKAT) affirmed the safety of the novel inhibitors of hDHFR
in human body. Overall, we recommend novel hit compounds of hDHFR for cancer and rheumatoid
arthritis chemotherapeutics. Full article

Tuberculosis (TB) is a serious infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance of Mtb and poor compliance to the multi-drug-resistant TB treatment protocol. New treatments are being investigated that target host intracellular processes that could be effective in fighting Mtb infections. Autophagy is an intracellular process that is involved in eliminating cellular debris, as well as intracellular pathogens. Mammalian target of rapamycin (mTOR) is an enzyme involved in inhibiting this pathway. Modulation of mTOR and the autophagy cellular machinery are being investigated as potential therapeutic targets for novel Mtb treatments. In this review, we discuss the background of Mtb pathogenesis, including its interaction with the innate and adaptive immune systems, the mTOR and autophagy pathways, the interaction of Mtb with these pathways, and finally, the drug everolimus, which targets these pathways and is a potential novel therapy for TB treatment. Full article