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The Journal of Clinical Investigation Aug 2023BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.
Topics: Adult; Animals; Child; Humans; Fragile X Syndrome; Single-Blind Method; Learning; Language; Cleft Palate; Indoles; Malignant Hyperthermia; Myotonia Congenita
PubMed: 37651202
DOI: 10.1172/JCI171723 -
Journal of Anesthesia Jun 2024Anesthetic management of pediatric patients poses several challenges and the optimal anesthetic agent for use in this population is still a matter of debate. We... (Review)
Review
Anesthetic management of pediatric patients poses several challenges and the optimal anesthetic agent for use in this population is still a matter of debate. We systematically searched PubMed/MEDLINE and Google Scholar from their inception for studies that investigated the role and potential applications of remimazolam, a novel ultra-short-acting benzodiazepine, in pediatric patients. Furthermore, in March 2024, an update of the literature search along with an additional post-hoc search on the EMBASE database were performed. A total of fourteen pertinent studies which spanned the 2021-2023 period explored remimazolam as either the primary or adjuvant hypnotic agent for inducing and/or maintaining general anesthesia or sedation. Preliminary evidence derived from these studies highlighted that remimazolam is a safe and effective option for both sedation and general anesthesia in pediatric patients, particularly those with concurrent mitochondrial disorders, myopathic diseases, or at risk for malignant hyperthermia. Moreover, the current evidence suggested that remimazolam may contribute to reducing preoperative anxiety and postoperative delirium in children. Its favorable pharmacodynamic and pharmacokinetic profile demonstrated potential safety, effectiveness, and ease-of-use in various perioperative pediatric contexts, making it suitable for integration into specific protocols, such as intraoperative monitoring of evoked potentials and management of difficult intubation. Notwithstanding these promising findings, further research is essential to determine optimal dosages, establish conclusive evidence of its superiority over other benzodiazepines, and elucidate the impact of genetic factors on drug metabolism.
PubMed: 38844707
DOI: 10.1007/s00540-024-03358-w -
Pediatric Emergency Care Sep 2023Hyperglycemic hyperosmolar syndrome (HHS) is an indolent process characterized by significantly increased levels of serum glucose, high osmolality, and electrolyte...
Hyperglycemic hyperosmolar syndrome (HHS) is an indolent process characterized by significantly increased levels of serum glucose, high osmolality, and electrolyte abnormalities. The incidence of HHS has steadily risen in the pediatric population over the past several years. Patients with HHS often present with profound dehydration, fatigue, and early mental status changes. Primary emergency management of HHS involves fluid replacement, hemodynamic support, correcting electrolyte derangements, and addressing complications and underlying illnesses. Insulin is not an initial therapy in HHS and should be considered only after the patient's fluids and electrolytes have been repleted. Unlike in diabetic ketoacidosis, HHS patients are not acidotic, although children may present with mixed HHS/diabetic ketoacidosis syndromes. Complications of HHS include thrombosis, rhabdomyolysis, and, rarely, malignant hyperthermia.
Topics: Child; Humans; Adolescent; Diabetic Ketoacidosis; Mental Disorders; Coma; Fatigue; Insulin
PubMed: 37642637
DOI: 10.1097/PEC.0000000000003022 -
World Journal of Emergency Medicine 2024
PubMed: 38188551
DOI: 10.5847/wjem.j.1920-8642.2024.006 -
International Journal of Molecular... Mar 2024Malignant hyperthermia (MH) is a pharmacogenetic condition of skeletal muscle that manifests in hypermetabolic responses upon exposure to volatile anaesthetics. This...
Malignant hyperthermia (MH) is a pharmacogenetic condition of skeletal muscle that manifests in hypermetabolic responses upon exposure to volatile anaesthetics. This condition is caused primarily by pathogenic variants in the calcium-release channel RYR1, which disrupts calcium signalling in skeletal muscle. However, our understanding of MH genetics is incomplete, with no variant identified in a significant number of cases and considerable phenotype diversity. In this study, we applied a transcriptomic approach to investigate the genome-wide gene expression in MH-susceptible cases using muscle biopsies taken for diagnostic testing. Baseline comparisons between muscle from MH-susceptible individuals (MHS, = 8) and non-susceptible controls (MHN, = 4) identified 822 differentially expressed genes (203 upregulated and 619 downregulated) with significant enrichment in genes associated with oxidative phosphorylation (OXPHOS) and fatty acid metabolism. Investigations of 10 OXPHOS target genes in a larger cohort (MHN: = 36; MHS: = 36) validated the reduced expression of and in MHS samples, but the remaining 8 selected were not statistically significant. Further analysis also identified evidence of a sex-linked effect in and expression, and a difference in expression across individuals with MH sub-phenotypes (trigger from in vitro halothane exposure only, MHS ( = 4); trigger to both in vitro halothane and caffeine exposure, MHS ( = 4)). Our data support a link between MH-susceptibility and dysregulated gene expression associated with mitochondrial bioenergetics, which we speculate plays a role in the phenotypic variability observed within MH.
Topics: Humans; Malignant Hyperthermia; Halothane; Oxidative Phosphorylation; Calcium; Muscle, Skeletal; Disease Susceptibility; Biopsy; Gene Expression; Muscle Contraction; Ryanodine Receptor Calcium Release Channel; Carrier Proteins
PubMed: 38542460
DOI: 10.3390/ijms25063489 -
Joint Commission Journal on Quality and... Dec 2023Latent safety threats (LSTs-characteristics of design, processes, or physical environment in health care compromising patient safety) are commonly revealed during...
BACKGROUND
Latent safety threats (LSTs-characteristics of design, processes, or physical environment in health care compromising patient safety) are commonly revealed during simulation-based training. Methods of collecting, analyzing, and classifying LSTs are underdeveloped and not standardized. Building on a large simulation program in one organization, the authors aimed to collect LSTs systematically and develop a taxonomy to classify them.
METHODS
The authors modified the Press Ganey Healthcare Performance Improvement Failure Modes Taxonomy (HPI-FMT), a standardized framework for safety event classification in health care, and used three categories: System, Individual, and Medications. The subcategories were revised to reflect simulation LST content and promote consistent data entry into a spreadsheet. Data visualization software was used to analyze LST data and generate dashboards, graphs, and executive summaries to share across the system that depicted data for individual hospitals and outpatient areas and allowed grouping, comparisons, and trending.
RESULTS
Over a year, the researchers identified 1,318 LSTs in 232 simulations across the organization-a rate of 5.7 LSTs/simulation. The top three LST subcategories were Environment/supplies/equipment (System category); Process/structure (System category); and Knowledge or unformed skill/habit (Individual category). Other important LSTs were Missing/malfunctioning supplies/equipment; Unclear or ineffective process or no process; and Unfamiliarity with supplies/equipment. When a repetitive pattern of LSTs was observed (for example, improper dantrolene use during malignant hyperthermia simulations), targeted process improvement or training was implemented.
CONCLUSION
The authors developed, implemented, and refined a systematic method of collecting, analyzing, displaying LSTs, and recommending targeted process improvements or training when LST trends were noted.
Topics: Humans; Patient Safety; Simulation Training; Inservice Training; Computer Simulation; Health Facilities
PubMed: 37748939
DOI: 10.1016/j.jcjq.2023.08.003 -
Carbohydrate Polymers May 2024Lumpectomy plus radiation is a treatment option offering better survival than conventional mastectomy for patients with early-stage breast cancer. However, successive...
Lumpectomy plus radiation is a treatment option offering better survival than conventional mastectomy for patients with early-stage breast cancer. However, successive radioactive therapy remains tedious and unsafe with severe adverse reactions and secondary injury. Herein, a composite hydrogel with pH- and photothermal double-sensitive activity is developed via physical crosslinking. The composite hydrogel incorporated with tempo-oxidized cellulose nanofiber (TOCN), polyvinyl alcohol (PVA) and a polydopamine (PDA) coating for photothermal therapy (PTT) triggered in situ release of doxorubicin (DOX) drug was utilized to optimize postoperative strategies of malignant tumors inhibition. The incorporation of TOCN significantly affects the performance of composite hydrogels. The best-performing TOCN/PVA7 was selected for drug loading and polydopamine coating by rational design. In vitro studies have demonstrated that the composite hydrogel exhibited high NIR photothermal conversion efficiency, benign cytotoxicity to L929 cells, pH-dependent release profiles, and strong MCF-7 cell inhibitory effects. Then the TOCN/PVA7-PDA@DOX hydrogel is implanted into the tumor resection cavity for local in vivo chemo-photothermal synergistical therapy to ablate residue tumor tissues. Overall, this work suggests that such a chemo-photothermal hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer.
Topics: Humans; Female; Breast Neoplasms; Cellulose, Oxidized; Photothermal Therapy; Hydrogels; Phototherapy; Hyperthermia, Induced; Mastectomy; Doxorubicin; Hydrogen-Ion Concentration
PubMed: 38431421
DOI: 10.1016/j.carbpol.2024.121931 -
Open Medicine (Warsaw, Poland) 2023Malignant hyperthermia (MH) is an inherited skeletal muscle disorder caused primarily by a genetic mutation, usually in the calcium channel gene of the muscle. This...
Malignant hyperthermia (MH) is an inherited skeletal muscle disorder caused primarily by a genetic mutation, usually in the calcium channel gene of the muscle. This mutation can lead to muscle hypersensitivity to volatile anesthetics (such as sevoflurane) and the depolarizing muscle relaxant succinylcholine, resulting in hyperthermia, muscle stiffness, metabolic disturbances, and other severe physiological reactions. This condition may prove fatal unless it is recognized in its early stages and treatment is administered promptly and aggressively. We report a 13-year-old adolescent who underwent laparoscopic appendectomy and developed MH after the use of inhalational anesthetics, manifested by unremitting hyperthermia with a maximum temperature of 44.2°C, muscle rigidity, tachycardia, hypercapnia; and malignant arrhythmias, cardiogenic shock, hyperkalemia, metabolic, and respiratory acidosis. After early and timely recognition, multidisciplinary management and administration of dantrolene, the case was successfully treated. Exome sequencing revealed a point mutation (amino acid change) on the RYR1 gene: c.12700G>C(p.Val4234Leu). Due to the lack of ready-made dantrolene in our hospital, the patient in this case received dantrolene treatment only 6 h after the first observation of high body temperature. We review the development of the disease and summarize the success of treatment and what can be done to improve the chances of saving the patient's life if dantrolene is not available in time.
PubMed: 37873543
DOI: 10.1515/med-2023-0808 -
Anticancer Research Aug 2023Hyperthermia (HT), combined with chemotherapy, has been used to treat various types of cancer. This study aimed to investigate the HT-sensitivity of malignant and...
BACKGROUND/AIM
Hyperthermia (HT), combined with chemotherapy, has been used to treat various types of cancer. This study aimed to investigate the HT-sensitivity of malignant and non-malignant cells, and then evaluate the combination effect of docetaxel (DTX) and a newly synthesized chromone derivative (compound A) with HT.
MATERIALS AND METHODS
The number of viable cells was determined using the MTT method. Cell cycle distribution was analyzed using a cell sorter, and DNA fragmentation pattern was detected using agarose gel electrophoresis.
RESULTS
Among 12 cultured cells, oral squamous cell carcinoma (OSCC), especially Ca9-22 cells, and myelogenous leukemia cells showed higher sensitivity to HT than lung carcinoma and glioblastoma cell lines, while normal oral cells were the most resistant. Cytotoxicity of DTX on Ca9-22 cells was maximum at 41-42°C and 45~60 min exposure to HT. DXT, compound A, and HT induced G/M arrest of Ca-22 cells. Mild HT enhanced the DTX- and compound A-induced subG arrest, in a synergistic fashion.
CONCLUSION
The combination G/M blockers and mild-HT can potentially be used for the treatment of OSCC.
Topics: Humans; Carcinoma, Squamous Cell; Cell Line, Tumor; Apoptosis; Mouth Neoplasms; Hyperthermia, Induced; Docetaxel
PubMed: 37500171
DOI: 10.21873/anticanres.16518 -
ACS Nano Oct 2023Photodynamic therapy (PDT) and photothermal therapy (PTT) have gained considerable attention as potential alternatives to conventional cancer treatments. However, these...
Photodynamic therapy (PDT) and photothermal therapy (PTT) have gained considerable attention as potential alternatives to conventional cancer treatments. However, these approaches remain limited by low solubility, poor stability, and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome the aforementioned limitations, we engineered biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium, and gadolinium) and the PTA bismuth selenide (NaYF:Yb/Er/Gd,BiSe) enveloped in a mesoporous silica shell that encapsulates a PS, chlorin e6 (Ce6), within its pores. NaYF:Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites Ce6 to generate cytotoxic reactive oxygen species (ROS), while BiSe efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging of the nanospheres. The mesoporous silica shell is coated with DPPC/cholesterol/DSPE-PEG to retain the encapsulated Ce6 and prevent serum protein adsorption and macrophage recognition that hinder tumor targeting. Finally, the coat is conjugated to the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into malignant cells in the mildly acidic microenvironment of tumors. The nanospheres facilitated tumor magnetic resonance and thermal and fluorescence imaging and exhibited potent NIR laser light-induced anticancer effects and via combined ROS production and localized hyperthermia, with negligible toxicity to healthy tissue, hence markedly extending survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.
PubMed: 37702397
DOI: 10.1021/acsnano.3c04564