Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many high-risk pediatric hematological malignant diseases (MD) and several nonmalignant diseases (NMD), including primary immune deficiencies. Infections must be managed to obtain better outcomes after HSCT. In this prospective observational study, viral monitoring was performed on 74 pediatric patients with MD and NMD who underwent HSCT. The incidence, risk factors, and impact of common opportunistic viral infections occurring within the first 100 days following HSCT were assessed. The viral pathogens included human herpesviruses, BK polyomavirus (BKV), adenovirus, parvovirus B19, and hepatitis B virus. In total, 52 (70%) patients had viral DNAemia, and 53% and 41% of patients developed human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) DNAemia, respectively. The risk factors were as follows negative CMV serology for any viral infections; age ≥ 2 years and negative CMV serology for HHV-6; age ≥5 years and female sex for BKV. The risk of viral infection did not significantly differ between MD and NMD, and no risk factor was identified for viral disease, likely because of the small sample numbers. However, despite the absence of symptoms, CMV DNAemia was found to increase the risk of mortality. The findings of the current study could improve the risk stratification and the management of pediatric HSCT recipients.Small molecule based inhibitors development is a growing field in medicinal chemistry. In recent years, different heterocyclic derivatives have been designed to counter the infections caused by multi-drug resistant bacteria. Indeed, small molecule inhibitors can be employed as an efficient antibacterial agents with different mechanism of action. Methicillin-resistant Staphylococcus aureus (MRSA) is becoming lethal to mankind due to easy transmission mode, rapid resistance development to existing antibiotics and affect difficult-to-treat skin and filmsy diseases. Benzimidazoles are a class of heterocyclic compounds which have capability to fight against MRSA. High biocompatibility of benzimidazoles, synergistic behaviour with antibiotics and their tunable physico-chemical properties attracted the researchers to develop new benzimidazole based antibacterial agents. The present review focus on recent developments of benzimidazole-hybrid molecules as anti MRSA agents and the results of in-vitro and in-vivo studies with possible mechanism of action and discussing structure-activity relationship (SAR) in different directions. Benzimdazoles act as DNA binding agents, enzyme inhibitors, anti-biofilm agents and showed synergistic effect with available antibiotics to achieve antibacterial activity against MRSA. This cumulative figures would help to design new benzimidazole-based MRSA growth inhibitors.Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay. We adopted activity-directed combinatorial chemical synthesis strategy to optimize this hit compound. Compound b36 was found to be the noncompetitive and the most promising one with IC50 values of 5.96 ± 0.61 μM against PHGDH. Compound b36 inhibited the proliferation of human breast cancer and ovarian cancer cells, reduced intracellular serine synthesis, damaged DNA synthesis, and induced cell cycle arrest. Collectively, our results suggest that b36 is a novel PHGDH inhibitor, which could be a promising modulator to reprogram the serine synthesis pathway and might be a potential anticancer lead worth further exploration.A new series of diverse triazoles linked to the hydroxyl group of totarol were synthesized using click chemistry approach. The structures of these compounds were elucidated by HRMS, IR and NMR spectroscopy. The structure of compound 3 g was also confirmed by x-ray single crystal diffraction. The cytotoxicity of these compounds was evaluated by the MTT method against four cancer cell lines, including fibrosarcoma HT-1080, lung carcinoma A-549 and breast adenocarcinoma (MDA-MB-231 and MCF-7), and the results indicated that all compounds showed weak to moderate activities against all cancer cell lines with IC50 values ranging from 14.44 to 46.25 μM. On the basis of our research the structure-activity relationships (SAR) of these compounds were discussed. This work provides some important hints for further structural modification of totarol towards developing novel and highly effective anticancer drugs respectively. It is interesting to note that compound 3 g indicated a very significant cytotoxicity against HT-1080 and A-549 cell lines. The molecular docking showed that compound 3 g activated the caspase-3 and inhibited tubulin by forming stable protein-ligand complexes.Increased dopaminergic activity in the striatum underlies the neurobiology of psychotic symptoms in schizophrenia (SZ). Beyond the impaired connectivity among the limbic system, the excess of dopamine could lead to inflammation and oxidative/nitrosative stress. It has been suggested that atypical antipsychotic drugs attenuate psychosis not only due to their modulatory activity on the dopaminergic/serotonergic neurotransmission but also due to their anti-inflammatory/antioxidant effects. In such a manner, we assessed the effects of the atypical antipsychotic risperidone (RISP) on the structural neuroplasticity and biochemistry of the striatum in adult rats with neonatal ventral hippocampus lesion (NVHL), which is a developmental SZ-related model. RISP administration (0.25 mg/kg, i.p.) ameliorated the neuronal atrophy and the impairments in the morphology of the dendritic spines in the spiny projection neurons (SPNs) of the ventral striatum (nucleus accumbens NAcc) in the NVHL rats. Also, RISP treatment normalized the pro-inflammatory pathways and induced the antioxidant activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this model. Our results point to the neurotrophic, anti-inflammatory, and antioxidant effects of RISP, together with its canonical antipsychotic mechanism, to enhance striatum function in animals with NVHL.
To assess the association between acute phase treatment by valproate as an adjunctive drug and risk of new onset hypothyroidism in a large cohort of patients affected by schizophrenia.

We conducted a retrospective cohort study in a psychiatric hospital in China between January 2016 and December 2018. We obtained approval from the Ethics Committee of the study hospital prior to the commencement of the study. Patients who were diagnosed with schizophrenia and admitted to the study hospital during the study period with thyroid function tests at admission and during hospitalization were included. Patients with abnormal thyroid function at admission were excluded. Hypothyroidism, defined as TSH>4.2mU/L or on L-thyroxine treatment, was the primary outcome. The primary exposure was adjunctive valproate plus atypical antipsychotics (AAPD), the secondary exposure was lithium plus AAPD and the comparison group was AAPD only. Adjusted relative risk (RR) and 95% confidence interval (CI) were estimated by log-binomial model to assess the independent association between valproate treatment and risk of hypothyroidism.

A total of 1622 eligible patients were included the final analysis. Rate of new onset hypothyroidism was 10.7% and 20.9% in AAPD only and valproate plus AAPD groups, respectively. Adjusted RR (95% CI) for valproate plus AAPD was 1.85 (1.44-2.38), with AAPD only group as reference. Similarly, adjusted RR (95% CI) for lithium plus AAPD was 1.93 (1.32-2.69).

Similar with lithium, valproate as adjunctive drug is associated with increased risk of new onset hypothyroidism during acute phase treatment for schizophrenia.
Similar with lithium, valproate as adjunctive drug is associated with increased risk of new onset hypothyroidism during acute phase treatment for schizophrenia.In the face of the COVID-19 pandemic it is important to identify factors that make people particularly vulnerable of developing mental-health issues in order to provide case-specific treatments. In this article, we examine the roles of two psychological constructs - originally put forth in the behavioral decision sciences - in predicting interindividual differences in fear responses general risk aversion (GRA) and intolerance of uncertainty (IU). We first provide a review of these constructs and illustrate why they may play important roles in shaping anxiety-related disorders. Thereafter we present an empirical study that collected survey data from 550 U.S. residents, comprising self-assessments of dispositions towards risk and uncertainty, anxiety- and depression levels, as well as demographic variables - to thus test the extent to which these psychological constructs are predictive of strong fear responses related to COVID-19 (i.e., mortal fear, racing heart). The results from Bayesian multi-model inference analyses showed that GRA and IU were more powerful predictors of fear responses than demographic variables. Moreover, the predictive power of these constructs was independent of general anxiety- and depression levels. Subsequent mediation analyses showed that the effects of GRA and IU were both direct and indirect via anxiety. We conclude by discussing possible treatment options, but also highlight that future research needs to further examine causal pathways and conceptual overlaps.While being highly effective on average, exposure-based treatments are not equally effective in all patients. The a priori identification of patients with a poor prognosis may enable the application of more personalized psychotherapeutic interventions. We aimed at identifying sociodemographic and clinical pre-treatment predictors for treatment response in spider phobia (SP). N = 174 patients with SP underwent a highly standardized virtual reality exposure therapy (VRET) at two independent sites. Analyses on group-level were used to test the efficacy. We applied a state-of-the-art machine learning protocol (Random Forests) to evaluate the predictive utility of clinical and sociodemographic predictors for a priori identification of individual treatment response assessed directly after treatment and at 6-month follow-up. https://www.selleckchem.com/products/abemaciclib.html The reliability and generalizability of predictive models was tested via external cross-validation. Our study shows that one session of VRET is highly effective on a group-level and is among the first to reveal long-term stability of this treatment effect. Individual short-term symptom reductions could be predicted above chance, but accuracies dropped to non-significance in our between-site prediction and for predictions of long-term outcomes. With performance metrics hardly exceeding chance level and the lack of generalizability in the employed between-site replication approach, our study suggests limited clinical utility of clinical and sociodemographic predictors. Predictive models including multimodal predictors may be more promising.

The risk factors of papillary thyroid carcinoma (PTC) recurrence are meaningful for patients and clinicians. Tumor mutation burden (TMB) has been a biomarker for the effectiveness of immune checkpoint inhibitor (ICI) and prognosis in cancer. However, the role of TMB and its latent significance with immune cell infiltration in PTC are still unclear. Herein, we aimed to explore the effect of TMB on PTC prognosis.

RNA-seq and DNA-seq datasets of PTC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The Gene Ontology (GO) and gene set enrichment analysis (GSEA 4.0.1) were applied further to explore potential differences in PTC patients' biological functions. The differentially expressed genes (DEGs) and immune microenvironment between the high and low TMB groups were determined.

TMB had the highest AUC score than other clinical indicators in ROC analysis on recurrence-free survival, and a higher TMB score was related to a worse prognosis. Further, GSEA showed a higher level of oxidative phosphorylation (OXPHOS) in the high TMB group, and four genes correlated with recurrence-free survival rate were identified. The abundance of CD8
T cells and M1 macrophages in the high TMB group was significantly lower than that in the low TMB group.

Our study found that TMB was a better predictor variable at evaluating the risk of PTC recurrence. Moreover, TMB-related genes conferred dramatically correlated prognosis, which was worth exploring in guiding postoperative follow-up and predicting recurrence for PTC patients.
Our study found that TMB was a better predictor variable at evaluating the risk of PTC recurrence. Moreover, TMB-related genes conferred dramatically correlated prognosis, which was worth exploring in guiding postoperative follow-up and predicting recurrence for PTC patients.Reproductive disorders, including intrauterine adhesion (IUA), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are great threats to female reproduction. Recently, mesenchymal stem cells derived-extracellular vesicles (MSC-EVs) have presented their potentials to cure these diseases, not only for the propensity ability they stemmed from the parent cells, but also for the higher biology stability and lower immunogenicity, compared to MSCs. EVs are lipid bilayer complexes, functional as mediators by transferring multiple molecules to recipient cells, such as proteins, microRNAs, lipids, and cytokines. EVs appeared to have a therapeutic effect on the female reproductive disorder, such as repairing injured endometrium, suppressing fibrosis of endometrium, regulating immunity and anti-inflammatory, and repressing apoptosis of granulosa cells (GCs) in ovaries. Although the underlying mechanisms of MSC-EVs have reached a consensus, several theories have been proposed, including promoting angiogenesis, regulating immunity, and reducing oxidate stress levels. In the current study, we summarized the current knowledge of functions of MSC-EVs on IUA, POI, and PCOS. https://www.selleckchem.com/products/abt-199.html Given the great potentials of MSC-EVs on reproductive health, the critical issues discussed will guide new insights in this rapidly expanding field.
Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection.

A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9).

Baseline RAS overactivity was present with REN elevated and AGT decr3102801.
Detailed proteomic analysis in a cohort of patients with differing severity of COVID-19 disease identified biomarkers within the complement and coagulation cascades as biomarkers for disease severity has been reported; however, it is unclear if these proteins differ sufficiently from other conditions to be considered as biomarkers.

A prospective, parallel study in T2D (n = 23) and controls (n = 23). A hyperinsulinemic clamp was performed and normoglycemia induced in T2D [4.5 ± 0.07 mmol/L (81 ± 1.2 mg/dl)] for 1-h, following which blood glucose was decreased to ≤2.0 mmol/L (36 mg/dl). Proteomic analysis for the complement and coagulation cascades were measured using Slow Off-rate Modified Aptamer (SOMA)-scan.

Thirty-four proteins were measured. At baseline, 4 of 18 were found to differ in T2D
controls for platelet degranulation [Neutrophil-activating peptide-2 (p = 0.014), Thrombospondin-1 (p = 0.012), Platelet factor-4 (p = 0.007), and Kininogen-1 (p = 0.05)], whilst 3 of 16 proteins differed for coT03102801.
https//clinicaltrials.gov/, identifier NCT03102801.
Congenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis.

We explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype.

Using the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed
for pathogenicity.

Among the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the
,
,
, or
genes in 10 infants and heterozygous variants in
,
,
, and
in 19 others. In seven cases, a heterozygous variant in the
gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them.

The systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.
The systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA1c) targets is challenging in some patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide effective reductions in HbA1c and body weight. Semaglutide is the only GLP-1RA that is available in both an injectable and oral formulation. The efficacy of once-weekly subcutaneous semaglutide and once-daily oral semaglutide has been investigated in the global SUSTAIN and PIONEER phase III clinical trial programs in a range of clinical settings, including early T2D managed with diet and exercise only, more established T2D uncontrolled on one to three oral antidiabetic drugs, and advanced disease treated with insulin. Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA1c by 1.5-1.8% after 30-56 weeks, which was significantly more than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine. Across the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA1c by 1.0-1.4%, significantly more than sitagliptin or empagliflozin, and to a similar extent as liraglutide after 26 weeks. In addition, subcutaneous semaglutide reduced body weight significantly more than all active comparators tested, while oral semaglutide reduced body weight more than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Neither formulation of semaglutide has been associated with an increased risk of hypoglycemia and both improve various measures of health-related quality of life. Semaglutide offers the benefits of a highly effective GLP-1RA in both injectable and oral formulations. Selection of the most appropriate formulation can be made on an individual basis to best suit the patient's preferences and needs.Sepsis is a common risk factor for acute kidney injury (AKI). Bone marrow-derived mesenchymal stem cells (BMSCs) bear multi-directional differentiation potential. This study explored the role of BMSCs in sepsis-induced AKI (SI-AKI). A rat model of SI-AKI was established through cecal ligation and perforation. The SI-AKI rats were injected with CM-DiL-labeled BMSCs, followed by evaluation of pathological injury of kidney tissues and kidney injury-related indicators and inflammatory factors. HK-2 cells were treated with lipopolysaccharide (LPS) to establish SI-SKI model in vitro. Levels of mitochondrial proteins, autophagy-related proteins, NLRP3 inflammasome-related protein, and expressions of Parkin and SIRT1 in renal tubular epithelial cells (RTECs) of kidney tissues and HK-2 cells were detected. The results showed that BMSCs could reach rat kidney tissues and alleviate pathological injury of SI-SKI rats. BMSCs inhibited inflammation and promoted mitophagy of RTECs and HK-2 cells in rats with SI-AKI. BMSCs upregulated expressions of Parkin and SIRT1 in HK-2 cells. Parkin silencing or SIRT1 inhibitor reversed the promoting effect of BMSCs on mitophagy. BMSCs inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin. In conclusion, BMSCs promoted mitophagy and inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin, thereby ameliorating SI-AKI.Obesity is an excess accumulation of body fat. Its progression rate has remained high in recent years. Therefore, the aim of this study was to diagnose important differentially expressed genes (DEGs) associated in its development, which may be used as novel biomarkers or potential therapeutic targets for obesity. The gene expression profile of E-MTAB-6728 was downloaded from the database. After screening DEGs in each ArrayExpress dataset, we further used the robust rank aggregation method to diagnose 876 significant DEGs including 438 up regulated and 438 down regulated genes. Functional enrichment analysis was performed. These DEGs were shown to be significantly enriched in different obesity related pathways and GO functions. Then protein-protein interaction network, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. The module analysis was performed based on the whole PPI network. We finally filtered out STAT3, CORO1C, SERPINH1, MVP, ITGB5, PCM1, SIRT1, EEF1G, PTEN and RPS2 hub genes. Hub genes were validated by ICH analysis, receiver operating curve (ROC) analysis and RT-PCR. Finally a molecular docking study was performed to find small drug molecules. The robust DEGs linked with the development of obesity were screened through the expression profile, and integrated bioinformatics analysis was conducted. Our study provides reliable molecular biomarkers for screening and diagnosis, prognosis as well as novel therapeutic targets for obesity.

Noncanonical Action involving Endocannabinoids as well as their Receptors within Key along with Side-line Synapses.
Prevalence of Campylobacter spp. in Raccoon Dogs and also Badgers inside Miyazaki Prefecture, The japanese.
QP4 or MOG antibody-positive ON without severe adverse events and the exacerbation of visual acuities.
Intestinal parasitic infection is still common in Ethiopia. Periodic evaluation of the current status of human intestinal parasitic infections (HIPIs) is a prerequisite to controlling these health threats. https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html This study is aimed at assessing the prevalence and determinant factors of HIPIs among elementary school-age children in Merawi town.

A school-based cross-sectional study design was used among 403 children. The direct wet mount method was used to diagnose the stool samples. The sociodemographic and behavioral characteristics of the respondents were collected using structured questionnaires. link= https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html The data were analyzed using the chi-square test and logistic regression.

Out of the 403 students, the overall prevalence of HIPIs was 173 (42.9%). The magnitudes of single and double infections were 39.7% and 3.2%, respectively. Seventy-two (17.9%) were positive for
, 63 (15.4%) for
, 28 (9.6%) for
, 22 (6.9%) for hookworm, and 1 (0.2%) for
. The prevalence of intestinal parasites was high in the age group in Merawi town was very high. Thus, there is a need for intensive health education for behavioral changes related to personal hygiene and mass treatment for effective control of HIPIs in the study area.
Type I diabetes (T
DM) is a genetic or autoimmune disorder, which may be stimulated by induced immune system components due to the underlying infectious diseases. This study was undertaken to find out any possible association between
infection and TIDM.

One hundred and eighty-two blood samples were taken from individuals who were referred to outpatient clinics in Shiraz city, Southern Iran, during a 6-month period. The age of type I diabetic subjects (
= 91) and the control group (
= 91) was identical, which were less than 30 years. The sera were examined for IgG and IgM antibodies by ELISA and correlated with epidemiological factors such as age, sex, and family history of diabetes.

Out of 91 diabetic patients, 54 (59.3%) were female and 37 (40.7%) were male. The highest frequency of diabetes belonged to 6-10- and 11-15-year groups (
= 0.17).
infection prevalence in diabetic and control groups was 28.6% and 7.7%, respectively (
= 0.001). A significantly positive family history of diabetes was observed between diabetic patients (31 cases, 34.1%) and the control group (3 cases, 3.3%) (
= 0.01). Interestingly, IgG positivity was seen in 13 cases (41.9%) of patients with positive family history of type I diabetes and 13 cases (21.7%) of subjects with no positive family history of type I diabetes (
= 0.04).

Our study showed a higher prevalence of
infection in type I diabetes patients. It is likely that the prevalence of TIDM decreases by increasing hygiene and preventing toxoplasmosis.
Our study showed a higher prevalence of Toxoplasma infection in type I diabetes patients. It is likely that the prevalence of TIDM decreases by increasing hygiene and preventing toxoplasmosis.[This retracts the article DOI 10.1515/tnsci-2015-0009.].
Calibrated horizontal measurements (
.
., mm) from endoscopic procedures could be utilized for advancement of evidence-based practice and personalized medicine. However, the size of an object in endoscopic images is not readily calibrated and depends on multiple factors, including the distance between the endoscope and the target surface. Additionally, acquired images may have significant non-linear distortion that would further complicate calibrated measurements. This study used a recently developed in-vivo laser-projection fiberoptic laryngoscope and proposes a method for calibrated spatial measurements.

A set of circular grids were recorded at multiple working distances. A statistical model was trained that would map from pixel length of the object, the working distance, and the spatial location of the target object into its mm length.

A detailed analysis of the performance of the proposed method is presented. The analyses have shown that the accuracy of the proposed method does not depend on the working distance and length of the target object. The estimated average magnitude of error was 0.27 mm, which is three times lower than the existing alternative.

The presented method can achieve sub-millimeter accuracy in horizontal measurement.

Evidence-based practice and personalized medicine could significantly benefit from the proposed method. Implications of the findings for other endoscopic procedures are also discussed.
Evidence-based practice and personalized medicine could significantly benefit from the proposed method. Implications of the findings for other endoscopic procedures are also discussed.Spontaneous coronary artery dissection is a serious and underreported clinical entity strongly associated with fibromuscular dysplasia (FMD). The female predominance of FMD may predispose many women to coronary artery dissection or other similar vascular pathologies. link2 We present a case of a young woman who presented with a clinical tetrad of spontaneous coronary artery dissection, cardiogenic shock requiring extracorporeal membrane oxygenation, internal carotid dissections, and subacute cerebellar infarct secondary to underlying FMD. The patient's clinical course and vascular pathology are discussed. A review of the relevant literature of previously published similar cases, the incidence of spontaneous coronary artery dissection, and issues in the clinical management of spontaneous coronary artery dissection are also included.Pheochromocytomas are tumors derived from chromaffin cells within the medulla of adrenal glands, whereas paragangliomas are tumors derived from extra-adrenal chromaffin cells of the sympathetic prevertebral and paravertebral ganglia. The growing deployment of genetic testing has shown that approximately 30% of pheochromocytoma and paraganglioma (PPGL) patients carry familial pathogenic germline mutations in known PPGL-susceptibility genes. This prompts genetic screening of their family members and leads to an increase in the detection of asymptomatic PPGLs or non-secreting tumors reported in familial cases discovered after the index patient work-up. Here, we present three case reports of affected members of a single Omani family with a history of paraganglioma and highly variable clinical presentations among the affected members. Eight out of the 16 siblings (50.0%) in the second generation of the reported family pedigree were carriers of the succinate dehydrogenase Bc.574T>C mutation, reflecting the autosomal dominant inheritance risk of paraganglioma and other associated tumors. https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html'>https://www.selleckchem.com/products/dotap-chloride.html This report highlights the complexity of managing such families and encourages further discussion regarding the management of asymptomatic PPGL-associated mutation carriers. Genetic screening has enabled the early detection of PPGLs, for which early surgical intervention can significantly impact prognosis and treatment strategies to reduce morbidity and mortality. Although PPGLs are similar tumors, they warrant distinction from each other with respect to their differences in locations, manifestations, secretory functions, genetic syndromes, and propensity to metastasize. While current guidelines are clear concerning symptomatic PPGL cases, the management of asymptomatic mutation carriers requires further elucidation.The physiological actions of thyroid hormone (TH) are mediated through TH alpha and TH beta receptors. Resistance to TH (RTH) is characterized by a lack of peripheral tissues' response to the active form of TH. TH receptor beta has been extensively studied. Mutations in this receptor were considered the main reason for TH resistance for some time up until the discovery of mutations in TH receptor alpha (TRα) that has attained more focus and interest in recent years. A 13-year-old child with classic hypothyroidism features (coarse facies, growth and developmental delay, skeletal dysplasia, generalized muscular hypertrophy, and severe constipation) associated with near-normal thyroid hormone levels, which did not support the diagnosis of hypothyroidism biochemically. link2 Therefore, progressing with whole-exome sequencing had revealed a de novo heterozygous mutation in a gene encoding TRα that establishes a diagnosis of RTHα. This case report demonstrates a rare form of TH resistance due to mutation of TRα. It also emphasizes that THs act through distinctive receptor subtypes in different target tissues. Moreover, this report aims to raise awareness about this genetic mutation, which is thought to be more common than expected. However, due to its subtle features and insidious presentation, many cases remain undiagnosed; hence, the disorder's exact incidence is unknown.Secondary ovarian involvement by renal cell carcinoma rarely occurs. Here, we describe the computed tomography and magnetic resonance imaging findings of bilateral ovarian metastases from renal cell carcinoma that demonstrated heterogeneous strong contrast enhancing tumors with flow voids around and within the tumors. In addition, the apparent diffusion coefficients of the malignant tumors were high. These findings were similar to those of renal cell carcinomas at primary and other metastatic sites.
Children's hospitals often do not have a high enough volume to justify providing radiologist staffing overnight, leading to hospitals employing teleradiology services to offer preliminary reports. link3 There is limited literature related to discrepancies between preliminary teleradiology pediatric radiologists and final interpretations.

The purpose of this study is to examine discrepancy rates for teleradiologists preliminarily interpreting pediatric exams at a children's hospital.

Eight thousand seven hundred seventy-eight consecutive preliminary reports issued by pediatric teleradiologists were reviewed. The hospital utilized a system in which local onsite radiologists rated the preliminary reports of teleradiologists following the interpretations as part of standard operating procedure. Discrepancies were also rated according to whether the discrepancy was actionable (judged to alter patient management by the final rater) or not. Rates were stratified by modality, preliminary teleradiologist reader, and fs not a predictor of discrepancy rate.Prostate cancer is the most common malignancy in men with high incidence of recurrence following treatment. Biochemical recurrence, as indicated by rising PSA levels following successful treatment of the primary disease, is a frequent encounter in routine clinical practice. link3 68Gallium-PSMA positron emission tomography/computer tomography has been widely accepted as the modality of choice with the highest impact in management of this group of patients. Pitfalls of this diagnostic technique stem from the diversity of histological entities, other than prostate tumour cells, which can demonstrate increased uptake of the radiotracer. We present a case of intracranial uptake of PSMA by meningioma in a patient with BCR, as a pitfall in imaging of prostate cancer. Knowledge of normal distribution of the tracer is of utmost importance when reading positron emission tomography/computer tomography imaging especially given the relative novelty of usage of 68Gallium-PSMA.

This paper extends earlier on socioeconomic inequality in mental health, measured by the General Health Questionnaire, to include the second national lockdown up to March 2021.
Following trials of inhaled antibiotics in adults, this study investigates the efficacy of nebulised gentamicin to improve respiratory function in children with bronchiectasis.

This is a randomised, double-blind, placebo-controlled, crossover trial of 12-week nebulised placebo/gentamicin, 6-week washout, 12-week gentamicin/placebo. Participants were children (5-15 years) with bronchiectasis, chronic infection (any pathogen), and able to perform spirometry from a hospital bronchiectasis clinic. Primary outcomes were change in forced expiratory volume in 1 s (FEV
) and hospitalisation days. Secondary outcomes included sputum bacterial density, sputum inflammatory markers, additional antibiotics and symptom severity. Analyses were on an intention-to-treat basis.

Fifteen children (mean 11.7-years-old) completed the study. There was no significant change in mean FEV
(56%/55%, P= 0.38) or annual rate of hospital admissions (1.1/0, P= 0.12) between gentamicin and placebo, respectively. However, Haemophilus influenzae sputum growth (27% vs. 80%, P= 0.002) and bacterial density (2.4 log
cfu/mL lower P< 0.001) improved with gentamicin. Sputum inflammatory markers interleukin-1β (P< 0.001), interleukin-8 (P< 0.001) and tumour necrosis factor-α (P= 0.003) were lower with gentamicin. Poor recruitment limited study power and treatment adherence was challenging for this cohort.

In this crossover study of nebulised gentamicin in children with bronchiectasis, there was a reduction in sputum bacterial density and inflammation. However, there were no major improvements in clinical outcomes and adherence was a challenge.
In this crossover study of nebulised gentamicin in children with bronchiectasis, there was a reduction in sputum bacterial density and inflammation. However, there were no major improvements in clinical outcomes and adherence was a challenge.Brain networks exhibit signatures of modular structure, which maintains a fine trade-off between wiring cost and efficiency of information transmission. Alterations in modular structure have been found in patients with obsessive-compulsive disorder (OCD). However, previous studies were focused on a single scale (i.e., modularity or intra/intermodular connectivity) for investigation. Here, we recruited 92 OCD patients and 90 healthy controls. A comprehensive analysis was performed on modular architecture alterations in the voxelwise functional connectome at the "global" (modularity), "meso" (modular segregation and within- and between-module connections), and "local" (participation coefficients, PC) scales. We also examined the correlation between modular structure metrics and clinical symptoms. The findings revealed that (1) there was no significant group difference in global modularity; (2) both primary modules (visual network, sensorimotor network) and high-order modules (dorsal attention network, frontoparietal network) exhibited lower modular segregation in OCD patients, which was mainly driven by increased numbers of between-module connections; and (3) OCD patients showed higher PC in several connectors including the bilateral middle occipital gyri, left medial orbital frontal gyrus, left superior frontal gyrus, left posterior cingulate gyrus, right superior temporal gyrus and right middle frontal gyrus, and lower PC in the right lingual gyrus. Moreover, these alterations in modular structure were associated with clinical symptoms in patients. Our findings provide further insights into the involvement of different modules in functional network dysfunction in OCD from a connectomic perspective and suggest a synergetic mechanism of module interactions that may be related to the pathophysiology of OCD.
This review aimed to synthesise the available reviews on the effects of nursing interventions on sleep quality among patients hospitalised in intensive care and non-intensive care units.

Poor sleep quality is a common fact in hospitalised patients. Nurses can contribute to the improvement of patients' sleep quality and duration.

A review of intervention reviews was carried out and reported following the PRISMA guidelines and checklist.

We systematically searched for reviews published from January 2009 to December 2019 in PubMed, CINAHL Plus, Scopus, Institute for Scientific Information Web of Science, Joanna Briggs Database of Systematic Reviews and Cochrane Central Register of Controlled Trials databases. Searches were repeated at 24 November 2020 to include the most recent evidence. A narrative synthesis of the results was conducted.

Nine reviews (representing 109 original papers) met the selection criteria and were included for critical appraisal. Overall, nursing interventions and sleep quality were poorly defined. We grouped the interventions into 3 categories (environmental, barrier and internal interventions) to provide a more comprehensive overview and examine effects of nursing interventions on inpatients sleep quality. Inconsistent results were obtained and low quality of the original articles was reported, making it difficult to establish absolute conclusions.

The impact of environmental changes on patients' sleep was positive but inconclusive, while use of earplugs and eye masks, music and acupuncture generally showed positive results with moderate quality of evidence, and no harmful effects were reported.
The impact of environmental changes on patients' sleep was positive but inconclusive, while use of earplugs and eye masks, music and acupuncture generally showed positive results with moderate quality of evidence, and no harmful effects were reported.Genetic alterations in FGF/FGFR pathway are infrequent in gastrointestinal stromal tumors (GIST), with rare cases of quadruple wildtype GISTs harboring FGFR1 gene fusions and mutations. Additionally, FGF/FGFR overexpression was shown to promote drug resistance to kinase inhibitors in GISTs. However, FGFR gene fusions have not been directly implicated as a mechanism of drug resistance in GISTs. Herein, we report a patient presenting with a primary small bowel spindle cell GIST and concurrent peritoneal and liver metastases displaying an imatinib-sensitive KIT exon 11 in-frame deletion. After an initial 9-month benefit to imatinib, the patient experienced intraabdominal peritoneal recurrence owing to secondary KIT exon 13 missense mutation and FGFR4 amplification. Despite several additional rounds of tyrosine kinase inhibitors (TKI), the patient's disease progressed after 2 years and presented with multiple peritoneal and liver metastases, including one pericolonic mass harboring secondary KIT exon 18 missense from both KIT-dependent and KIT-independent off-target activation pathways.
The purpose of this study was to investigate the effect of hypothyroidism and thyroxine replacement therapy on the prognosis of nasopharyngeal carcinoma (NPC) patients.

The clinical data of 284 NPC patients, who received intensity-modulated radiation therapy (IMRT) between January 2011 and December 2016, were retrospectively analyzed.

Hypothyroidism occurred in 38% of patients. Patients with hypothyroidism had significantly better disease-free survival (DFS) (p=0.002) and relapse-free survival (RFS) (p=0.008). Multivariate analysis showed that hypothyroidism was a positive independent prognostic factor (DFS and RFS). Among the patients with hypothyroidism, thyroxine replacement therapy did not yield inferior survival (DFS, RFS, all p > 0.05).

The NPC patients with complete response are at risk of hypothyroidism, which is attributable to escalating dose. https://www.selleckchem.com/peptide/lypressin-acetate.html These patients experienced clinical hypothyroidism could be adequately treated with thyroid hormone replacement. Further investigation of the underlying biological mechanism and potential therapeutic implications are required.
The NPC patients with complete response are at risk of hypothyroidism, which is attributable to escalating dose. These patients experienced clinical hypothyroidism could be adequately treated with thyroid hormone replacement. Further investigation of the underlying biological mechanism and potential therapeutic implications are required.Gene editing in mammalian zygotes enables us to generate genetically modified animals rapidly and efficiently. In this study, we compare multiple gene targeting strategies in rat zygotes by generating a novel knock-in reporter rat line to visualize the expression pattern of transcription factor AP-2 gamma (Tfap2c). The targeting vector is designed to replace the stop codon of Tfap2c with T2A-tdTomato sequence. We show that the combination of electroporation-mediated transduction of CRISPR/Cas9 components with adeno-associated virus-mediated transduction of the targeting vector is the most efficient in generating the targeted rat line. The Tfap2c-T2A-tdTomato fluorescence reflects the endogenous expression pattern of Tfap2c in preimplantation embryo, germline, placenta, and forebrain during rat embryo development. The reporter line generated here will be a reliable resource for identifying and purifying Tfap2c expressing cells in rats, and the gene targeting strategy we used can be widely applied for generating desired animals.
It remains unclear why some patients with the same heart rate during an atrial fibrillation (AF) have subjective symptoms, whereas others do not. We assessed the hypothesis that different responses of arterial and left atrial blood pressures to rapid stimulation may be associated with the symptoms of AF.

A total of 110 patients who underwent catheter ablation for paroxysmal AF were retrospectively studied. Asymptomatic AF was defined as a European Heart Rhythm Association score of Ⅰ for AF-related symptoms. The left atrial pressure (LAP) was measured during sinus rhythm (SR), in 10 pacing per minute (ppm) increments from 100 ppm to the Wenckebach block rate in high right atrial pacing.

Asymptomatic AF was observed in 19/110 patients (17%). Patients with symptomatic AF showed higher E/e' ratio and gradual LAP increase that was dependent on the pacing rate. Patients with asymptomatic AF had decreased LAP at 100 ppm compared that at SR, and thereafter, LAP gradually increased depending on the pacing rate. The rate of LAP change compared to that at SR was significantly lower in patients with asymptomatic AF than that in patients with symptomatic AF. The rate of LAP change was independently associated with AF symptoms.

Patients with asymptomatic AF showed lower E/e' ratio and decreased LAP at 100 ppm to rapid stimulation, followed by a steady increase in LAP afterwards. Factors other than left ventricular diastolic dysfunction may be involved in AF symptoms.
Patients with asymptomatic AF showed lower E/e' ratio and decreased LAP at 100 ppm to rapid stimulation, followed by a steady increase in LAP afterwards. Factors other than left ventricular diastolic dysfunction may be involved in AF symptoms.Glaucoma disease in humans can lead to blindness if it progresses to the point where it affects the oculus' optic nerve head. It is not easily detected since there are no symptoms, but it can be detected using tonometry, ophthalmoscopy, and perimeter. However, advances in artificial intelligence approaches have permitted machine learning techniques to diagnose at an early stage. Numerous methods have been proposed using Machine Learning to diagnose glaucoma with different data sets and techniques but these are complex methods. Although, medical imaging instruments are used as glaucoma screening methods, fundus imaging specifically is the most used screening technique for glaucoma detection. This study presents a novel DenseNet and DarkNet combination to classify normal and glaucoma affected fundus image. These frameworks have been trained and tested on three data sets of high-resolution fundus (HRF), RIM 1, and ACRIMA. A total of 658 images have been used for healthy eyes and 612 images for glaucoma-affected eyes classification.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare neurological disorder associated with a range of symptoms and functional impairments. The aim of this study was to describe the experience of AADC deficiency across five different motor milestone health states.

Qualitative interviews were conducted with caregivers of individuals with AADC deficiency in Italy, Spain, Portugal and the United States. An interview guide was developed with input from clinical experts and caregivers, and explored the symptoms and impacts of AADC deficiency. Interviews were conducted by telephone and were recorded and transcribed. Data were analysed using thematic analysis and the symptoms and impacts were compared across health states.

Fourteen caregivers took part, who provided care to 13 individuals with AADC deficiency aged 1-15years. Six individuals were in the 'no motor function' health state, one in the 'sitting unsupported' health state, one in the 'standing/stepping when fully supported' health state and h improve motor function have the potential to improve other aspects of the lives of individuals with AADC deficiency and their caregivers.
The aim of the study is to identify clinical and dosimetric factors that could predict the risk of hypothyroidism in nasopharyngeal carcinoma (NPC) patients following intensity-modulated radiotherapy (IMRT).

A total of 404 non-metastatic NPC patients were included in our study. All patients were treated with IMRT. The thyroid function were performed for all patients before and after radiation at regular intervals. The time onset for developing hypothyroidism was defined as the time interval between the completion of RT and the first recorded abnormal thyroid hormone test. The cumulative incidence rates of hypothyroidism were estimated using Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to detect the most promising factors that were associated with hypothyroidism.

Median follow up was 60.6months. The 3-, 5- and 7- year cumulative incidence rate of hypothyroidism was 39.4%, 49.1% and 54.7%, respectively. The median time to primary hypothyroidism and central hypothyroidism were 15.4months (range 2.9-83.8months) and 29.9months (range 19.8-93.6months), respectively. Univariate and multivariate analyses revealed that younger age, female gender and small thyroid volume were the most important factors in predicting the risk of hypothyroidism. Dtmean (mean dose of thyroid), V30-V50 (percentage of thyroid volume receiving a certain dose level) and VS45-VS60 (the absolute volumes of thyroid spared from various dose levels) remained statistically significant in multivariate analyses. Cutoff points of 45Gy (Dtmean), 80% (Vt40) and 5 cm
(VS45Gy) were identified to classify patients as high-risk or low-risk group.

Thyroid Vt40 highlypredicted the risk of hypothyroidism after IMRT for NPC patients. We recommended plan optimization objectives to reduce thyroid Vt40 to 80%.

Retrospectively registered.
Retrospectively registered.Plant pathogens cause yield losses in crops worldwide. Breeding for improved disease resistance and management by precision agriculture are two approaches to limit such yield losses. Both rely on detecting and quantifying signs and symptoms of plant disease. To achieve this, the field of plant phenotyping makes use of non-invasive sensor technology. Compared to invasive methods, this can offer improved throughput and allow for repeated measurements on living plants. Abiotic stress responses and yield components have been successfully measured with phenotyping technologies, whereas phenotyping methods for biotic stresses are less developed, despite the relevance of plant disease in crop production. The interactions between plants and pathogens can lead to a variety of signs (when the pathogen itself can be detected) and diverse symptoms (detectable responses of the plant). Here, we review the strengths and weaknesses of a broad range of sensor technologies that are being used for sensing of signs and symptoms on plant shoots, including monochrome, RGB, hyperspectral, fluorescence, chlorophyll fluorescence and thermal sensors, as well as Raman spectroscopy, X-ray computed tomography, and optical coherence tomography. We argue that choosing and combining appropriate sensors for each plant-pathosystem and measuring with sufficient spatial resolution can enable specific and accurate measurements of above-ground signs and symptoms of plant disease.
Gastric mucosal lesions (GML) are common in gastric diseases and seriously affect the quality of life. There are inevitable side effects in drug therapy. Acupuncture is an important part of traditional Chinese medicine. Electro-acupuncture (EA) has unique curative effect in treatment of GML. However, there are still few reports on the central mechanism of electro-acupuncture in treatment of GML. In this study, NMR metabonomics was used to explore the central metabolic change mechanism of electro-acupuncture in treatment of GML.

SD rats were randomly divided into Control, GML and EA groups. According to different intervention time, each group was further divided into 3 subgroups. This study mainly established GML model rats by 75% ethanol. Dynamic expressions of metabolites in cerebral cortex and medulla were observed by 1D
H Nuclear Magnetic Resonance (NMR) metabolomics, combined with gastric mucosal histopathological examination to evaluate the time-effect relationship of electro-acupuncture at Zusanlilectro-acupuncture can treat GML by regulating the central nervous system (CNS).

4days electro-acupuncture treatment can significantly improve gastric mucosal injury, and the curative effect tends to be stable in 7days treatment. Meanwhile, the pathogenesis of GML and the efficacy of electro-acupuncture involve metabolic pathways such as energy, neurotransmitters, cells and antioxidation, and electro-acupuncture can treat GML by regulating CNS.
4 days electro-acupuncture treatment can significantly improve gastric mucosal injury, and the curative effect tends to be stable in 7 days treatment. Meanwhile, the pathogenesis of GML and the efficacy of electro-acupuncture involve metabolic pathways such as energy, neurotransmitters, cells and antioxidation, and electro-acupuncture can treat GML by regulating CNS.
Mental illness represents a major global burden of disease worldwide. It has been hypothesised that individuals with mental illness have greater blood pressure fluctuations that lead to increased cardiovascular risk and target organ damage. This systematic review aims to (i) investigate the association between mental illness and blood pressure variability (BPV) and (ii) describe methods of BPV measurements and analysis which may affect pattern and degree of variability.

Four electronic databases were searched from inception until 2020. The quality assessment was performed using STROBE criteria. Studies were included if they investigated BPV (including either frequency or time domain analysis) in individuals with mental illness (particularly anxiety/generalised anxiety disorder, depression/major depressive disorder, panic disorder and hostility) and without hypertension. Two authors independently screened titles, abstracts and full texts. A third author resolved any disagreements.

Twelve studies met the to the deterioration of autonomic function (HRV, BPV), early therapeutic intervention in mental illness may prevent diseases associated with autonomic dysregulation and reduce the likelihood of negative cardiac outcomes. Therefore, these findings may have important implications for patients' future physical health and well-being, highlighting the need for comprehensive cardiovascular risk reduction.
Current review found that people with mental illness is significantly associated with an increased BPV regardless of age. Since mental illness can contribute to the deterioration of autonomic function (HRV, BPV), early therapeutic intervention in mental illness may prevent diseases associated with autonomic dysregulation and reduce the likelihood of negative cardiac outcomes. Therefore, these findings may have important implications for patients' future physical health and well-being, highlighting the need for comprehensive cardiovascular risk reduction.
Nod-like receptors (NLRs) are critical to innate immune activation and induction of adaptive T cell responses. Yet, their role in autoinflammatory diseases of the central nervous system (CNS) remains incompletely defined. The NLR, Nlrp12, has been reported to both inhibit and promote neuroinflammation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE), where its T cell-specific role has been investigated. Uveitis resulting from autoimmunity of the neuroretina, an extension of the CNS, involves a breach in immune privilege and entry of T cells into the eye. Here, we examined the contribution of Nlrp12 in a T cell-mediated model of uveitis, experimental autoimmune uveitis (EAU).

Mice were immunized with interphotoreceptor retinoid-binding protein peptide 1-20 (IRBP
) emulsified in Complete Freund's adjuvant, CFA. https://www.selleckchem.com/products/dihydroethidium.html Uveitis was evaluated by clinical and histopathological scoring, and comparisons were made in WT vs. Nlrp12
mice, lymphopenic Rag1
mice reconstituted witgly, a non-hematopoietic origin for Nlrp12 function was also observed. Indeed, Nlrp12 was found to be constitutively expressed in the neuroretina, where it suppressed chemokine/cytokine induction.

Our data identify a combinatorial role for Nlrp12 in dampening autoimmunity of the neuroretina. These findings could provide a pathway for development of therapies for uveitis and potentially other autoinflammatory/autoimmune diseases of the CNS.
Our data identify a combinatorial role for Nlrp12 in dampening autoimmunity of the neuroretina. These findings could provide a pathway for development of therapies for uveitis and potentially other autoinflammatory/autoimmune diseases of the CNS.
The United States requires a patent linkage system in other countries as part of free trade agreements. However, introducing a patent linkage system could be a significant barrier to the timely approval of generic drugs. This study aimed to evaluate the perceived impact of the patent linkage system in South Korea held by domestic manufacturers and analyze variations in evaluating the system according to the characteristics of domestic manufacturers.

In 2020, we conducted a questionnaire survey of 39 domestic manufacturers. The survey consisted of perceptions of the system, factors affecting patent challenges, and the perceived impact of the system. A 5-point Likert scale was used to rate each item. Domestic manufacturers were categorized into three groups based on their experience of listing a patent and acquiring first generic exclusivity.

More than half of the manufacturers surveyed had experience of listing a patent. The patent linkage system could protect the involved patents. However, manufacturersed first generic drug exclusivity through patent challenges.
The perceived impact of the patent linkage system was limited to the domestic market and generic drugs. In narrowing the impact to the effects on the domestic industry, the system had positive impacts of the system on generic manufacturers. The first generic drug exclusivity lies at the center of this positive perception. However, manufacturers perceived that the current system did not provide enough incentives for domestic manufacturers to be granted first generic drug exclusivity through patent challenges.