Early onset left ventricular remodeling in juvenile systemic lupus erythematosus; Insight from 3-dimensional speckle tracking echocardiography.

BACKGROUND: Early diagnosis and treatment of myocardial affection in patients with systemic lupus erythematosus (SLE) are crucial. OBJECTIVES: To evaluate the ventricular systolic function in juvenile-onset systemic lupus erythematosus (j-SLE) patients by 3-D speckle tracking echocardiography (3D-STE) and to determine the predictors of left ventricular (LV) dysfunction if present. METHODS: Twenty-six SLE patients without heart failure and 21 healthy controls were studied by standard echocardiogram and 3D-STE. Conventional parameters included LV ejection fraction (EF), fractional shortening (FS), and mitral annular plane systolic excursion (MAPSE). Global LV strain (GLS) and global area strain (GAS) were obtained by 3D-STE. Medical records, including diagnosis criteria, duration of disease, and SLE disease activity index (SLEDAI) were evaluated. RESULTS: The mean age was similar in patients and controls 11.42 vs 11.48 years p = 0.93. The mean duration of the disease was 1.87 ± 1.02 years and SLEDAI ranged from 0 to 9. By conventional and tissue Doppler imaging echocardiography, only MAPSE was significantly lower in SLE patients compared to controls (14.56 vs 18.46 mm, p < 0.001). By 3D speckle tracking echocardiography, GLS and GAS were significantly reduced in SLE patients compared to controls (-15.07 vs -19.9.4%, -34.6% vs -39.7%, respectively, p < 0.001). Multiple linear regression and ROC analyses indicated that the SLEDAI score was the only predictive factor for the left ventricular remodeling. CONCLUSIONS: These results indicate that early subclinical LV dysfunction occur in jSLE patients even with normal EF and SLE disease activity might be a potential driver for LV deformation.

Kaempferol ameliorates symptoms of metabolic syndrome by improving blood lipid profile and glucose tolerance.

Kaempferol (KPF) is a dietary polyphenol reported to have various beneficial effects on human health. However, its molecular mechanisms in regulating lipid and glucose metabolism are not fully understood. This study examined the effects of KPF on obesity, dyslipidemia, and diabetes in Tsumura, Suzuki, Obese Diabetes mice. The 6-week administration of KPF decreased fat weight, serum total cholesterol, and low-density lipoproteins (LDLs); increased high-density lipoproteins (HDLs); and improved glucose tolerance. Additionally, KPF increased LDL receptor (LDLR) and apolipoprotein A1 (ApoA1) gene expression and decreased serum resistin levels. These findings suggest that the decrease in LDL and the increase in HDL caused by KPF may be due to increases in hepatic LDLR and ApoA1 expression, respectively. Furthermore, it is possible that the improvement in glucose tolerance by KPF may occur via resistin reduction. These mechanisms may be parts of complex mechanism by which KPF improves metabolic syndrome.

Colon-specific tablets containing 5-fluorouracil microsponges for colon cancer targeting.

Most anticancer medications undergo major first-pass metabolism in the intestinal wall, the liver, or both. 5-fluorouracil (5-FU) is known to have erratic oral bioavailability due to first-pass metabolism. The present study aimed to develop 5-FU-loaded microsponges (MS) compressed in enteric-coated tablets as a new colon targeting to colorectal cancer. MS was prepared as a controlled release system for 5-FU and characterized for drug encapsulation efficiency, and surface morphology. Further, hydroxypropyl methylcellulose (HPMC) was mixed with pectin and characterized for their flow as a tablet coat enclosing the core tablets of 5-FU-MS. Moreover, in vitro drug release behavior was studied in different pH media, while the X-ray imaging was used to monitor the in vivo movement of prepared tablets containing 5-FU-MS throughout the GI system. The results showed that MS were spherical in shape and have several pores on their surfaces. The encapsulation efficiency was from 71.80 ± 1.62% - 101.3 ± 2.60%, while the particle size was from 53.11 ± 41.03 - 118.12 ± 48.21 nm. The formulated tablets were fulfilling all official and other specifications and exhibited sustained release of 5-FU only inside the colon. The in vivo human volunteer study of X-ray has shown that the tablets ultimately reached the colon without disturbing in the upper GI system. The obtained carrier formulation is considered as a novel system to deliver 5-FU to the colon tumor with 100% targeting without any drug release in the upper GIT or first-pass metabolism.

Sterilized bifidobacteria suppressed fat accumulation and blood glucose level.

Probiotics such as Lactobacillus and Bifidobacterium improve the balance of intestinal microflora and have various physiological functions beneficial to human health. It is not always known whether the ingested microbial cells are viable- or killed. However, even sterilized bacterial cells are functional. Bacterial cell functions are strain-specific and their modes of action are still poorly understood. The aim of this study was to elucidate the roles of sterilized bifidobacteria in obesity and lipid metabolism. To this end, mice were orally ingested sterilized bacteria. Male C57BL/6J mice aged 7 wks were raised on a high-fat diet and received oral sterilized bifidobacteria for 4 wks. Although the amount of food they ingested did not change in response to bifidobacteria administration, both weight gain and epididymal body fat mass were significantly reduced. In addition, the elevated blood glucose, triglyceride, and total cholesterol levels observed in the mice on the high-fat diet all decreased in response to bifidobacteria treatment. Hepatic triglyceride levels also decreased. Furthermore, oral glucose tolerance and insulin resistance tests indicated that sterilized bifidobacteria improved glucose tolerance and diminished insulin resistance. Sterilized bifidobacteria also decreased blood lipopolysaccharides and altered intestinal flora. The present study indicates that in mice on a high-fat diet, sterilized bifidobacteria suppressed fat accumulation, improved insulin resistance, and lowered blood glucose levels.

Elevated Hemi-diaphragms as a Cause of ST-segment Elevation: A case report and review of literature.

While ST-segment elevation (STE) on ECG is widely recognized as representing myocardial infarction or injury such as coronary occlusion or pericarditis, STE may occasionally ensue from non-cardiac etiologies. Indeed, gastrointestinal disorders causing STE are not well documented in the literature. We present a case wherein extreme abdominal distension and hemi-diaphragm elevation resulted in extrinsic cardiac and epicardial coronary compression manifesting as STE. Subsequent relief of the abdominal distension resulted in resolution of STE representing a noncoronary cause of STE. A brief literature review, illustrating the importance of considering abdominal etiologies as a cause of STE is provided.

Antimicrobial activity of essential oil and aqueous and ethanol extracts of Teucrium polium L. subsp. gabesianum (L.H.) from Tunisia.

The antimicrobial effects of essential oil, ethanol and aqueous extracts of Teucrium polium L. were investigated against 13 microorganisms. Extracts and essential oil were obtained from maceration, decoction and hydrodistillation respectively. Samples were tested for their antimicrobial activity using the disk diffusion, the agar dilution and the agar incorporation method. Essential oil was analysed using GC/MS, results showed that ß-pinene (35.97%) and α-pinene (13.32%) were the main components. Furthermore, essential oil exhibited the highest antimicrobial activity, it was most effective against Proteus mirabilis, Staphylococcus aureus and Citrobacter freundei where inhibition zone ranged between 15 and 25 mm, and with the microbial inhibitory concentration (MIC) values of 0.078-0.156 mg/ml. The oil and ethanol extract showed the best antifungal activity against Microsporum canis, Scopulariopsis brevicaulis, and Trichophyton rubrum with the inhibition percentage (I%) ranging from 18.94 to 100%. However, none of the samples exhibited antifungal activity against Aspergillus fumigatus. In this study, the obtained results showed significant effects of essential oils and ethanol extracts of T. polium which may used as a substitute to the synthetic drugs against certain microbial diseases.

Thrombolysis for Right Atrial Thrombus-in-Transit in a Patient With Massive Pulmonary Embolism.

Right atrial thrombus is a rare entity frequently encountered in patients with pulmonary embolism. Although the existing guidelines do not offer a clear statement for the management of right atrial thrombus and pulmonary embolism, this condition is associated with worse outcomes. We present a case of a 79-year-old patient presenting with signs suggestive of massive pulmonary embolism who was found to have a right atrial thrombus on transthoracic echocardiogram and was successfully treated with systemic thrombolysis. Despite the lack of data from randomized studies, right atrial thombi in transit should be considered a severe form of thromboembolic disease often requiring aggressive treatment, particularly in patients with severe right ventricular dysfunction.

Amber (Succinite) Extract Enhances Glucose Uptake through the Up-Regulation of ATP and Down-Regulation of ROS in Mouse C2C12 Cells.

Traditionally, amber (Succinite) has been used to alleviate all types of pain, skin allergies, and headaches. However, no studies have been conducted on its antidiabetic and antioxidant effects. In this study, differentiated skeletal muscle C2C12 cells were used to demonstrate the protective effects of amber (AMB) against H2O2-induced cell death. In addition, the effects of AMB on glucose uptake and ATP production were investigated. Our results showed that AMB at 10, 25, and 50 µg/mL suppressed the elevation of ROS production induced by H2O2 in a dose-dependent manner. Moreover, AMB enhanced glucose utilization in C2C12 cells through the improvement of ATP production and an increase in PGC-1α gene expression resulting in an amelioration of mitochondrial activity. On the other hand, AMB significantly increased the gene expression of glucose transporters GLUT4 and GLUT1. Our finding suggests that AMB can be used as a natural supplement for diabetes treatment and for the promotion of skeletal muscle function.

Automated sign language detection and classification using reptile search algorithm with hybrid deep learning.

Sign language recognition (SLR) contains the capability to convert sign language gestures into spoken or written language. This technology is helpful for deaf persons or hard of hearing by providing them with a way to interact with people who do not know sign language. It is also be utilized for automatic captioning in live events and videos. There are distinct methods of SLR comprising deep learning (DL), computer vision (CV), and machine learning (ML). One general approach utilises cameras for capturing the signer's hand and body movements and processing the video data for recognizing the gestures. One of challenges with SLR comprises the variability in sign language through various cultures and individuals, the difficulty of certain signs, and require for realtime processing. This study introduces an Automated Sign Language Detection and Classification using Reptile Search Algorithm with Hybrid Deep Learning (SLDC-RSAHDL). The presented SLDC-RSAHDL technique detects and classifies different types of signs using DL and metaheuristic optimizers. In the SLDC-RSAHDL technique, MobileNet feature extractor is utilized to produce feature vectors, and its hyperparameters can be adjusted by manta ray foraging optimization (MRFO) technique. For sign language classification, the SLDC-RSAHDL technique applies HDL model, which incorporates the design of Convolutional Neural Network (CNN) and Long-Short Term Memory (LSTM). At last, the RSA was exploited for the optimal hyperparameter selection of the HDL model, which resulted in an improved detection rate. The experimental result analysis of the SLDC-RSAHDL technique on sign language dataset demonstrates the improved performance of the SLDC-RSAHDL system over other existing DL techniques.

Machine learning and deep learning approaches in IoT.

The internet is a booming sector for exchanging information because of all the gadgets in today's world. Attacks on Internet of Things (IoT) devices are alarming as these devices evolve. The two primary areas of the IoT that should be secure in terms of authentication, authorization, and data privacy are the IoMT (Internet of Medical Things) and the IoV (Internet of Vehicles). IoMT and IoV devices monitor real-time healthcare and traffic trends to protect an individual's life. With the proliferation of these devices comes a rise in security assaults and threats, necessitating the deployment of an IPS (intrusion prevention system) for these systems. As a result, machine learning and deep learning technologies are utilized to identify and control security in IoMT and IoV devices. This research study aims to investigate the research fields of current IoT security research trends. Papers about the domain were searched, and the top 50 papers were selected. In addition, research objectives are specified concerning the problem, which leads to research questions. After evaluating the associated research, data is retrieved from digital archives. Furthermore, based on the findings of this SLR, a taxonomy of IoT subdomains has been given. This article also identifies the difficult areas and suggests ideas for further research in the IoT.

Effect of 17-Hydroxyprogesterone Caproate on Interleukin-6 and Tumor necrosis factor-alpha in expectantly managed early-onset preeclampsia.

The study aimed to evaluate the effect of 17 hydroxy progesterone (17-OHPC) on interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in expectantly managed early-onset preeclampsia (PE). A randomized open-label controlled study included women who were diagnosed as early-onset PE if they assigned to expectant management according to the American College of Obstetricians and Gynecologists (ACOG) 2013 criteria for diagnosis of severity of PE. Patients were randomized into Group A (40 patients) received 17-OHPC 250 mg intra-muscular at admission and every 7 days thereafter and Group B (40 patients) was given the usual conservative measures of early-onset PE as a control group. Blood samples were obtained from all participants for measurements of TNF-α and IL-6 levels at admission and repeated at termination of pregnancy. The primary outcome was the mean difference between TNF-α and IL-6 levels before and after treatment in both groups. TNF-α and IL-6 levels at admission were not different between the two groups. However, there was a significant difference concerning these inflammatory biomarkers within the same group at admission and at termination (p < 0.001), with significant decline of IL-6 and TNF-α level in the 17-OHPC treated group and significant rise of IL-6 and TNF-α in the control group. There was a strong positive correlation between systolic blood pressure (SBP) at admission and TNF-α level (r= 0.867, p=0.017), and moderately positive significant correlation between diastolic blood pressure (DBP) at admission and TNF-α (r=0.610, p < 0.001). There was a mild positive significant correlation between IL-6 levels and SBP (r= 0.231, p=0.039), and DBP (r= 0.203, p= 0.041) at admission. In conclusion, 17-OHPC has no effect in improving maternal or neonatal outcomes in conservatively managed early onset PE, although it alters the inflammatory markers levels (IL-6 and TNF-α) that could improve the pathogenesis of PE.

Leveraging Marine Predators Algorithm with Deep Learning for Lung and Colon Cancer Diagnosis.

Cancer is a deadly disease caused by various biochemical abnormalities and genetic diseases. Colon and lung cancer have developed as two major causes of disability and death in human beings. The histopathological detection of these malignancies is a vital element in determining the optimal solution. Timely and initial diagnosis of the sickness on either front diminishes the possibility of death. Deep learning (DL) and machine learning (ML) methods are used to hasten such cancer recognition, allowing the research community to examine more patients in a much shorter period and at a less cost. This study introduces a marine predator's algorithm with deep learning as a lung and colon cancer classification (MPADL-LC3) technique. The presented MPADL-LC3 technique aims to properly discriminate different types of lung and colon cancer on histopathological images. To accomplish this, the MPADL-LC3 technique employs CLAHE-based contrast enhancement as a pre-processing step. In addition, the MPADL-LC3 technique applies MobileNet to derive feature vector generation. Meanwhile, the MPADL-LC3 technique employs MPA as a hyperparameter optimizer. Furthermore, deep belief networks (DBN) can be applied for lung and color classification. The simulation values of the MPADL-LC3 technique were examined on benchmark datasets. The comparison study highlighted the enhanced outcomes of the MPADL-LC3 system in terms of different measures.

The pharmacodynamics of vecuronium in chronic renal failure patients: the impact of different priming doses.

PURPOSE: The concept of priming was introduced to facilitate a faster onset of nondepolarizing neuromuscular blocker for endotracheal intubation. Vecuronium is still very much in use for most chronic renal failure patients posted for renal transplantation. The aim of this study was to examine the pharmacodynamics of vecuronium without and with preceding different small doses. METHODS: One hundred chronic renal failure patients were assigned into four groups according to the used vecuronium priming regimen. The first control group (V(0)-group), where no priming dose was given. The other three priming groups (V(10)- , V(15)- , and V(20)-groups), where 10%, 15%, and 20% of ED(95) of vecuronium were administrated 5 min prior to the remaining intubating dose (2 × ED(95)) of vecuronium. Neuromuscular blockade was measured via acceleromyographic response of the ulnar nerve. Train-of-four (TOF) ratio was measured every minute during priming interval. Any unpleasant symptoms during precurarization were recorded. Lag time and onset time (from injection of intubating dose) were recorded. Endotracheal intubation condition was scored blindly. The duration and recovery times were also recorded. RESULTS: The significant higher incidence of symptoms of paresis was encountered in V(20)-group in comparison with other two priming groups. TOF ratio started to decrease significantly at the first minute in V(20)-group, at the second minute in V(15)-group, and at the third minute in V(10)-group, till the fourth minute in the priming interval. Although TOF ratio was still above 0.90 in V(10)-group, it was below 0.80 in V(20)-group. Priming groups did not show significant intergroup difference in onset time. However, duration and recovery times were significantly longer in priming groups in comparison with V(0)-group without priming. CONCLUSION: Priming the chronic renal failure patients with 10% of ED(95) vecuronium dose acquit the best pharmacodynamics with the fewest signs of muscle weakness. Larger vecuronium priming doses are unfavorable and convey no more clinical utility.

Synthesis and Characterization of Polyethylene Glycol-Grafted Photoreactive Polyethylene Glycols for Antibiofouling Applications.

Notably, antibiofouling is an important and predominant technique adopted to improve the surfaces of biomaterials. In this study, polyethylene glycol-grafted polyethylene glycols bearing azidophenyl groups were synthesized and immobilized on polystyrene surfaces via photoirradiation. The prepared polymers were found to be highly soluble in water, and photoimmobilization with fluorescent proteins was confirmed based on micropatterning using a photomask. These polymers suppressed nonspecific interactions between proteins and cells on the substrate. Considering that photoimmobilization can be adopted for the covalent bond modification of various surfaces, the developed water-soluble and highly antibiofouling polymers appear to be useful in biomaterial preparation.

Development and Characterization of Furfuryl-Gelatin Electrospun Scaffolds for Cardiac Tissue Engineering.

In this study, three types of electrospun scaffolds, including furfuryl-gelatin (f-gelatin) alone, f-gelatin with polycaprolactone (PCL) in a 1:1 ratio, and coaxial scaffolds with PCL (core) and f-gelatin (sheath), were developed for tissue engineering applications. Scaffolds were developed through single nozzle electrospinning and coaxial electrospinning, respectively, to serve as scaffolds for cardiac tissue engineering. Uniform fibrous structures were revealed in the scaffolds with significantly varying average fiber diameters of 760 ± 80 nm (f-gelatin), 420 ± 110 nm [f-gelatin and PCL (1:1)], and 810 ± 60 nm (coaxial f-gelatin > PCL) via scanning electron microscopy. The distinction between the core and the sheath of the fibers of the coaxial f-gelatin > PCL electrospun fibrous scaffolds was revealed by transmission electron microscopy. Thermal analysis and Fourier transformed infrared (FTIR) spectroscopy revealed no interactions between the polymers in the blended electrospun scaffolds. The varied blending methods led to significant differences in the elastic moduli of the electrospun scaffolds with the coaxial f-gelatin > PCL revealing the highest elastic modulus of all scaffolds (164 ± 3.85 kPa). All scaffolds exhibited excellent biocompatibility by supporting the adhesion and proliferation of human AC16 cardiomyocytes cells. The biocompatibility of the coaxial f-gelatin > PCL scaffolds with superior elastic modulus was assessed further through adhesion and functionality of human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes, thereby demonstrating the potential of the coaxially spun scaffolds as an ideal platform for developing cardiac tissue-on-a-chip models. Our results demonstrate a facile approach to produce visible light cross-linkable, hybrid, biodegradable nanofibrous scaffold biomaterials, which can serve as platforms for cardiac tissue engineered models.

Stabilization and Movable Ligand-Modification by Folate-Appended Polyrotaxanes for Systemic Delivery of siRNA Polyplex.

To achieve a systemic targeted delivery of siRNA using polymeric carriers, there is a dilemma between ligand modification and stabilization of the polyplex. Namely, ligand modification often leads to destabilization of the polyplex in the blood circulation. In fact, we previously developed cyclodextrin (CD)/polyamidoamine dendrimer conjugates (CDE) as siRNA carriers, and the interaction of CDE/siRNA was decreased by the conjugation with folate-polyethylene glycol, leading to the destabilization. To overcome this dilemma, in this study, folate-appended polyrotaxanes (Fol-PRX) were developed. Fol-PRX stabilized CDE/siRNA polyplex by intermolecularly connecting CDE molecules through a host-guest interaction between adamantane at the terminals of Fol-PRX and ß-CD in the polyplex. Moreover, the intermolecular connection of the polyplex with Fol-PRX provided movable folate moieties on the surface. As a result, Fol-PRXs enhanced the in vivo antitumor activity of the polyplex after intravenous administration, suggesting their utility as the dual-functional materials for systemic delivery of siRNA polyplexes.

The impact of timing of maximal crystalloid hydration on early graft function during kidney transplantation.

BACKGROUND: Early graft function is crucial for successful kidney transplantation. Maintaining adequate hydration is complicated by rapid movement of water to the extravascular space. We designed this study to test the effect of maximal hydration during graft ischemia time on early renal function. METHODS: Forty adult patients with chronic renal failure underwent renal transplantation from related living donors. Study subjects were randomly assigned 1 of 2 regimens for intraoperative hydration. The constant infusion rate group received normal saline 0.9% at an infusion rate 10 to 12 mL . kg(-1) . h(-1) from the start of surgery until the renal vessels were unclamped after vascular anastomosis. The central venous pressure target (CVPT) group received normal saline 0.9% titrated to maintain a specific central venous pressure (CVP). The target CVP from the start of surgery until clamping of the donor renal vessels was 5 mm Hg except for the interval from clamping of the renal vessels until the end of renal vascular anastomosis, when the target CVP was 15 mm Hg. Perioperative hemodynamics, infused saline volumes, rate of infusion, onset of diuresis, graft turgidity, urine volume, and renal function during the first 5 postoperative days were recorded. RESULTS: At the end of renal ischemia time, both groups had received approximately 3 L crystalloid solution. The CVPT group achieved the highest peak of intravascular volume expansion with an average infusion rate of 48.3 mL . min(-1) during 48 +/- 12 minutes of renal ischemia. The CVPT group had better graft function, required fewer vasopressors and diuretics, and had less postoperative tissue edema than the constant infusion rate group. CONCLUSIONS: Hydration directed toward maintaining a given CVP during kidney transplantation produced a more stable hemodynamic profile and promoted diuresis. The calculated infusion rate of approximately 45 to 50 mL . min(-1), within an hour ischemia time, seems feasible to enhance early graft function. A larger trial with long-term follow-up of renal function is warranted to confirm the clinical benefit of titrating IV crystalloid administration to maintain a given CVP in this population.

Effect of inactivated Bifidobacterium longum intake on obese diabetes model mice (TSOD).

Obesity and diabetes have been increasing at an alarming rate worldwide. Studies have shown the futility of chemical drugs in the treatment of obesity and diabetes. Bifidobacterium longum (BL), a common member of the gut microbiota throughout the human lifespan, has been widely reported to play a role in host health and disease. Here, we evaluated the effects of inactivated cells of BL (IBL) on obesity and blood glucose levels in TSOD mice by administering IBL orally for 5 weeks. The treated mice showed a significant decrease of body weight gain, adipose tissue mass and blood glucose levels, as well as a significant reduction in blood glucose during an oral glucose tolerance test. The treatment also resulted in reduced levels of cholesterol, triglycerides, and NEFA. Moreover, serum and urine analysis showed low creatinine levels in IBL-treated mice. These data demonstrate that IBL may have the potential to prevent obesity and diabetes.

Robotic laparoscopic radical cystectomy inhalational versus total intravenous anesthesia: a pilot study.

BACKGROUND: Robotic assistance may refine laparoscopic radical cystectomy. Steep Trendelenburg tilt (TT) and pneumoperitoneum (PP) are challenging anesthesia maneuvers. In view of those maneuvers, would inhalational anesthesia or total intravenous anesthesia (TIVA) be the more appropriate anesthetic management for this kind of surgery? This issue is under consideration in this clinical trial. METHODS: 15 patients scheduled for robotic laparoscopic radical cystectomy (RLRC) were randomly allocated into two groups to be anesthetized by either isoflurane anesthesia (ISO n = 8) or ketamine-midazolam-fentanyl total intravenous anesthesia (TIVA n = 7). The hemo-respiratory dynamics, oxygenation and biochemical variables were monitored taking into consideration the system organ function as primary outcomes, and operative conditions and recovery profile as secondary outcomes. RESULTS: The PP and TT increased the mean arterial and airway pressures and decreased lung compliance, and were associated with respiratory acidemia, while changes in heart rate remained within normal range. The duration of PP was shorter in TIVA patients but mean arterial pressure was higher than ISO group. ISO was associated with increased plasma concentrations ofprothrombin, fibrinogen and aspartate aminotransferase. CONCLUSIONS: Though the number of patients is small in this study (n = 15), it nevertheless brings to light the advantages of TIVA during the robotic laparoscopic radical cystectomy (RLRC), by shortening the duration of PP without an increase in prothrombin and fibrinogen concentrations. A lager number of clinical trial are needed to further clarify this issue.