Damrandolph9748

Buccal midazolam treatment is licensed in the European Union for prolonged acute convulsive seizures in children and adolescents, but the buccal pathway is often hampered by jaw clenching, hypersalivation, or uncontrolled swallowing. Midazolam formulations that are more secure, reliable, and faster for use are needed in the acute setting. Pharmacokinetics and comparative bioavailability of intranasally administered midazolam and two midazolam intravenous solutions administered buccally or intravenously in healthy adults were evaluated.

In this phase1, open-label, randomized, single-dose, three-period, three-sequence crossover study, 12 healthy adults (19-41years) were randomly assigned to receive 2.5mg midazolam intranasally; 2.5mg midazolam intravenously; 2.5mg midazolam buccally. Blood samples were collected for 10h post dose to determine pharmacokinetic profiles. Adverse events and vital signs were recorded.

Intranasal administration of 2.5mg midazolam demonstrated a more rapid median time to C

compared to buccal administration of midazolam (T

, 12.6min vs. 45min; C

, 38.33ng/ml vs. 24.97ng/ml). The antiepileptic effect of intranasal and buccal midazolam treatment lasted less than 4h and generally did not differ from intravenously administered midazolam. No serious adverse events or deaths were reported, and no treatment-emergent adverse events led to study discontinuation.

Intranasal administration of midazolam may be a preferable alternative to the currently approve buccal midazolam treatment for prolonged acute convulsive seizures in children and adolescents.

This study is registered at the Chinese Clinical Trial [ http//www.chictr.org.cn ] (ChiCTR2000032595) on 3 May, 2020.

This study is registered at the Chinese Clinical Trial [ http//www.chictr.org.cn ] (ChiCTR2000032595) on 3 May, 2020.The ER-resident Hsp70 paralog BiP is important in cellular homeostasis as well as in cancer cell progression. Although several BiP inhibitors have been developed, they have not succeeded in clinical trials due to toxicity issues. ER-resident co-chaperones (ERdjs) tailor the activity and specificity of BiP. Here, we report multiple-cancer analyses of BiP and ERdj genomic alterations including mRNA expression from cancer patients using available data from The Cancer Genome Atlas (TCGA). We examine the individual roles of BiP co-chaperones ERdj1-8 in mediating anticancer drug resistance through chemogenomic screening of ERdj1-8 CRISPR KO cells. In keeping with the idea that ERdjs regulate distinct facets of proteostasis, we find that each ERdj KO displays a unique signature of drug resistance. Taken together, our results demonstrate a novel way to understand functional specificity of ERdjs, suggesting a future personalized medicine approach, whereby ERdj mutation status is assessed to design an effective anticancer treatment plan.An individual's perception of risk plays an influential role in the behaviors they engage in, which could reduce or increase exposure or transmission of a certain disease. Since risk perceptions vary by social identities (e.g., gender, race/ethnicity, age) they are believed to influence the interpretation and likelihood of following guidance from risk-communication efforts. This study aims to understand how COVID-19 risk perceptions vary by social identity (with an emphasis upon socioeconomic factors), how such identities influence behavior adoption through risk-communication pathways, and how findings can be practically applied in messaging. Previous studies have investigated the role of social factors on risk perceptions, but SES has not been modeled as the main factor. Guided by the Health Belief Model and Social Determinant of Health Frameworks, findings from our 326 participants suggest those with high-risk COVID-19 perceptions identified as higher income and held more advanced educational degrees, suggesting a positive relationship between risk perceptions and SES. Individuals with high-risk perceptions more frequently reported practicing protective behaviors against COVID-19 and reported greater severity, susceptibility, barriers, benefits, trust, confidence, and health literacy in adopting behavior changes against the virus. When applying such findings to create a local risk-communication plan (logic model), it was found that messaging should be culturally relevant, in-plain language, and consistent to improve health literacy. In addition to using the most trusted and frequently used communication sources self-identified by residents, we recommend uniting trusted formal and informal community leaders to provide information in diverse pathways and formats.Hypoglycemia has emerged as a prominent complication in anti-diabetic drug therapy or negative energy balance of animals, which causes brain damage, cognitive impairment, and even death. Brain injury induced by hypoglycemia is closely related to oxidative stress and the production of reactive oxygen species (ROS). The intracellular accumulation of ROS leads to neuronal damage, even death. Ketone body β-hydroxybutyrate (BHBA) not only serves as alternative energy source for glucose in extrahepatic tissues, but is also involved in cellular signaling transduction. Previous studies showed that BHBA reduces apoptosis by inhibiting the excessive production of ROS and activation of caspase-3. However, the effects of BHBA on apoptosis induced by glucose deprivation and its related molecular mechanisms have been seldom reported. In the present study, PC12 cells and primary cortical neurons were used to establish a low glucose injury model. AG825 The effects of BHBA on the survival and apoptosis in a glucose deficient conditexpression of p-ERK was significantly increased in both PC12 cells and primary cortical neurons. Our results demonstrate that BHBA decreased the accumulation of intracellular ROS, and further inhibited cell apoptosis by mediating the p38 MAPK signaling pathway and caspase-3 apoptosis cascade during glucose deprivation. In addition, BHBA inhibited apoptosis by activating ERK phosphorylation and alleviated the damage of low glucose to PC12 cells and primary cortical neurons. These results provide new insight into the anti-apoptotic effect of BHBA in a glucose deficient condition and the related signaling cascade.Pre- and post-term children show increased autism risk. Little is known about gestational age (GA) prevalence among autistic children, and their respective autism phenotype. We compared prevalence of pre-, full- and post-term birth between a population-derived sample of N = 606 (137 females, 22.61%) autistic children and adolescents (mean age = 14.01, SD = 3.63, range 3-24) from the Netherlands Autism Register, and matched controls from the Dutch birth register. Autism phenotype and comorbid symptoms were assessed with the AQ-short and SDQ questionnaires. Using logistic regression, we found higher prevalence of pre- and post-term birth among autistic individuals but no phenotypical differences across GA groups. Autism risk was particularly elevated for post-term children, highlighting the need for closer investigation of autism on the whole GA range.Previous studies have shown reduced attention to the eyes in individuals with autism spectrum disorder (ASD). However, most eye-tracking evidence regarding this impairment has been derived from passive viewing tasks. Here, we compared the passive viewing of faces with an active task involving face identification with morphing faces. While typical controls prioritized the eyes over other facial features regardless of viewing condition, autistic children exhibited reduced eye-looking in passive viewing, but displayed increased attention allocation to the eyes when instructed to identify faces. The proportional eye-looking in ASD during facial recognition was negatively related to the autism symptoms severity. These findings provide evidence regarding the specific situations in which diminished eye-looking may rise in young ASD children.A new classification of SMARCA4-deficient tumors was proposed recently for thoracic malignancies, and the tumors have some histopathological characteristics similar to those of carcinosarcoma. We encountered a case of SMARCA4-deficient rectal carcinoma with a sarcomatoid component. A 46-year-old man presented to our hospital with a prolapsing anal mass. Colonoscopy revealed an irregular, nodular, and elevated lesion in the rectum, and the biopsy revealed a moderately differentiated adenocarcinoma. Abdominoperineal resection of the rectum was performed. A macroscopic image of the resected specimen showed a complex tumor 3.5 cm × 3 cm in size with a papillary protrusion and an irregular ulcerative lesion. Histopathological examination revealed that the tumor was composed of moderately/poorly differentiated adenocarcinoma and atypical spindle cells. The adenocarcinoma component was positive for epithelial markers (AE1/AE3 and carcinoembryonic antigen) and showed deletion of SMARCA2 and SMARCA4, while the spindle cells expressed mesenchymal markers (α-smooth muscle actin and vimentin). The pathological diagnosis was poorly differentiated adenocarcinoma with a sarcomatoid component, pT3N2bM0, stage IIIc. Although our case had histological characteristics of carcinosarcoma, immunostaining revealed a deficiency of SMARCA4. This case presented a SMARCA4-deficient colorectal carcinoma with a sarcomatoid component, which was histopathologically similar to carcinosarcoma.We report a case of donor-derived leukemia (DDL) occurring 34 months after double-unit cord blood transplantation (CBT). Molecular analysis using short tandem repeat (STR) sequences proved the acute myeloid leukemia (AML) to be of dominant cord blood origin. Karyotype was normal and molecular analysis showed WT1 and EVI1 overexpression. Cytological and molecular remission were achieved with only induction and consolidation chemotherapy. Relapse occurred after 6 years of remission from one clone with only WT1 overexpression. Potential etiologies for donor cell leukemogenesis in the recipient are discussed, including occult leukemia in the donor or genetic predisposition to hematologic malignancies, impaired immune surveillance, induced or inherited stromal abnormalities, transformation of donor cells during engraftment via altered signals of the host tissues, and fusion of donor cells with residual leukemic cells leading to acquisition of oncogenes. Although cases of DDL occurring after umbilical CBT have already been reported, very few cases have been described arising after double-unit CBT. DDL cases following CBT previously described in the literature have been reviewed.Several studies have demonstrated better hemodynamic stability of mechanically expanding valves following transcatheter aortic valve replacement (TAVR). This study aims to assess the expansion or recoil of transcatheter aortic valves using multidetector computed tomography (MDCT). This was a retrospective study. Among 873 patients who underwent TAVR with balloon-expandable (SAPIEN 3) or mechanically expanding valves (LOTUS) at Keio University Hospital between 2013 and 2020, those who underwent serial MDCT and echocardiographic assessment (pre-procedure, discharge, 6 months, 1 year, and 2 years post-TAVR) as our hospital protocol were included in this analysis (N = 30; LOTUS = 12; SAPIEN 3 = 18). The pre- and post-procedural echocardiographic data and the valve expansion rate evaluated by MDCT were compared between the groups. In LOTUS valves, late-phase expansion was observed on computed tomography (mean expansion rate, 83.8% at discharge and 86.8%, 2 years postoperative, p  less then  0.001), and a gradual increase in the aortic valve area was observed on echocardiography (aortic valve area 1.