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Journal of the American Academy of... Dec 2021The majority of infantile hemangiomas (IH) can be managed conservatively, but for those requiring active treatment, management has been revolutionized in the last decade... (Review)
Review
The majority of infantile hemangiomas (IH) can be managed conservatively, but for those requiring active treatment, management has been revolutionized in the last decade by the discovery of propranolol. Patients that may require active intervention should receive specialist review, ideally before 5 weeks of age to mitigate the risk of sequelae. Propranolol can commence for most infants in the outpatient setting and the most frequently employed dosing regimen is 1 mg/kg twice daily. In the future, β-blockers with a more-selective mechanism of action, such as atenolol, show some promise. In recalcitrant lesions, systemic corticosteroids or sirolimus may be considered. For small, superficial IHs, topical timolol maleate or pulsed dye laser may be considered. Where the IH involutes with cutaneous sequelae, a range of interventions have been reported, including surgery, laser, and embolization. IHs have a well-described clinical trajectory and are readily diagnosed and managed via telemedicine. Algorithms have been constructed to stratify those patients who can be managed remotely from those who warrant in-person review during the COVID-19 pandemic.
Topics: Adrenergic beta-Antagonists; COVID-19; Hemangioma, Capillary; Humans; Infant; Nevus; Pandemics; Propranolol; SARS-CoV-2; Skin Neoplasms; Timolol; Treatment Outcome
PubMed: 34419523
DOI: 10.1016/j.jaad.2021.08.020 -
The Medical Letter on Drugs and... Jun 2023
Topics: Humans; Migraine Disorders
PubMed: 37266987
DOI: 10.58347/tml.2023.1678a -
The Medical Letter on Drugs and... May 2020
Topics: Antihypertensive Agents; Blood Pressure; Humans; Hypertension
PubMed: 32555118
DOI: No ID Found -
Clinical Toxicology (Philadelphia, Pa.) Oct 2020Beta-adrenoreceptor antagonist (beta-blocker) poisoning is a common overdose which can lead to significant morbidity and mortality. To evaluate the effects of...
Beta-adrenoreceptor antagonist (beta-blocker) poisoning is a common overdose which can lead to significant morbidity and mortality. To evaluate the effects of treatments for beta-adrenoreceptor antagonist poisoning. Searches were conducted across MEDLINE (1946-26 November 2019, Ovid); Embase (1974-26 November 2019, Ovid); and the Cochrane Central Register of Controlled Trials (CENTRAL, to 26 November 2019) utilising a combination of subject headings and free text. The search strategy identified 15, 553 citations. Two reviewers screened titles and abstracts prior to selecting 141 articles (Kappa on articles included = 0.982, 95% CI 0.980-0.985). Primary outcomes included mortality and improvement in haemodynamic parameters (e.g., heart rate, blood pressure or a composite measure able to quantitate a haemodynamic response). The risk of bias was high for all interventions. Fifteen case reports described the administration of activated charcoal and five detailed the use of gastric lavage. As there was concurrent utilisation of multiple interventions, it was difficult to draw definitive conclusions regarding the relative contribution of these interventions to mortality or survival. The use of catecholamines in treating beta-blocker toxicity was reported in 16 case reports, 3 case series and 2 animal studies. These agents most likely provided a survival benefit and improved haemodynamics. Multiple intravenous boluses of atropine were associated with improvement in heart rate and blood pressure in one case report. Intravenous calcium was associated with an improvement in haemodynamics in three out of six case reports but in association with multiple other therapies as well as in two animal studies. The use of this therapy was associated with mortality benefit in 10 case series. Two case reports showed clear haemodynamic improvement in a timeframe consistent with insulin administration (bolus then continuous infusion). Maintenance dosing ranged from 1 to 10 units/kg/h of insulin. However, it is unclear whether high-dose insulin euglycaemic therapy improved haemodynamic response above catecholamines and other inotropic agents in humans. Hypoglycaemia and hypokalemia were commonly observed adverse effects. Glucagon was associated with minor improvements in haemodynamics through an increase in heart rate in two cases series, nine case reports and five animal studies. Four case reports reported an association with improvement in haemodynamics following administration of methylene blue but in the setting of co-ingestion with amlodipine. There was variable response to intravenous lipid emulsion therapy reported in 10 case series, 5 animal studies and 21 case reports. There were four case reports showing variable response to lignocaine in arrhythmias secondary to beta-blocker toxicity. Fructose diphosphate, levosimendan and amrinone did not provide a mortality or significant haemodynamic benefit in three animal studies and nine case reports. . Veno-arterial extracorporeal membrane oxygenation was associated with improved survival in patients with severe cardiogenic shock or cardiac arrest in an observational study and four cases series. The evidence of four case reports suggest haemodialysis may assist in the management of massive overdose of specific water-soluble beta-blockers (e.g., atenolol) by improving elimination; however, a survival or haemodynamic benefit was not established. One case series and a single case report showed the utility of temporary overdrive cardiac pacing to prevent arrhythmias in sotalol toxicity. Catecholamines, vasopressors, high-dose insulin euglycaemic therapy and veno-arterial extracorporeal membrane oxygenation were associated with reduced mortality. However, it must be acknowledged that multiple treatments were often given simultaneously. Haemodynamic improvements in blood pressure and cardiac output were seen with the use of catecholamines, vasopressin and high-dose insulin euglycaemic therapy. Evidence for treatment recommendations is almost entirely drawn from very low- to low-quality studies and subject to bias. However, it is reasonable to have a graduated response to cardiovascular instability beginning with intravenous fluids, commencement of a single or a combination of catecholamine inotropes and vasopressors depending upon the type of haemodynamic compromise (bradycardia, left ventricular dysfunction, vasodilation). High-dose insulin euglycaemic therapy can be introduced as an adjunctive inotrope and lastly, more invasive methods such as veno-arterial extracorporeal membrane oxygenation should be considered in cases unresponsive to other therapies.
Topics: Adrenergic beta-Antagonists; Animals; Atropine; Catecholamines; Drug Overdose; Extracorporeal Membrane Oxygenation; Fat Emulsions, Intravenous; Hemodynamics; Humans; Insulin; Practice Guidelines as Topic
PubMed: 32310006
DOI: 10.1080/15563650.2020.1752918 -
JAMA Otolaryngology-- Head & Neck... Jul 2021Propranolol has become the first-line therapy for problematic infantile hemangiomas (IHs) that require systemic therapy. However, different adverse events have been... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Propranolol has become the first-line therapy for problematic infantile hemangiomas (IHs) that require systemic therapy. However, different adverse events have been reported during propranolol treatment. The positive efficacy and safety of atenolol raise the question of whether it could be used as a promising therapy for IH.
OBJECTIVE
To compare the efficacy and safety of propranolol vs atenolol in infants (between age 5 and 20 weeks) with problematic IHs who required systemic therapy.
DESIGN, SETTING, AND PARTICIPANTS
This was a prospective, multicenter, randomized, controlled, open-label clinical trial conducted in collaboration among 6 separate investigation sites in China from February 1, 2015, to December 31, 2018. A total of 377 patients met the criteria for inclusion and were randomized to the propranolol (190 [50.4%]) and atenolol (187 [49.6%]) groups. Data were analyzed in June 2020.
INTERVENTIONS
Participants were randomized to receive either propranolol or atenolol for at least 6 months. They completed efficacy assessments at 2 years after the initial treatment.
MAIN OUTCOMES AND MEASURES
The primary outcome was any response or nonresponse at 6 months. The key secondary outcome was changes in the hemangioma activity score.
RESULTS
Of 377 participants, 287 (76.1%) were female, and the mean (SD) age was 10.2 (4.0) weeks in the propranolol group and 9.8 (4.1) weeks in the atenolol group. After 6 months of treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and 92.5%, respectively (difference, 1.2%; 95% CI, -4.1% to 6.6%). At 1 and 4 weeks after treatment, and thereafter, the hemangioma activity score in the atenolol group aligned with the propranolol group (odds ratio, 1.034; 95% CI, 0.886-1.206). No differences between the propranolol group and atenolol group were observed in successful initial responses, quality of life scores, complete ulceration healing times, or the rebound rate. Both groups presented a similar percentage of complete/nearly complete responses at 2 years (82.1% vs 79.7%; difference, 2.4%; 95% CI, -5.9% to 10.7%). Adverse events were more common in the propranolol group (70.0% vs 44.4%; difference, 25.6%; 95% CI, 15.7%-34.8%), but the frequency of severe adverse events did not differ meaningfully between the groups.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, when compared with propranolol, atenolol had similar efficacy and fewer adverse events in the treatment of infants with problematic IHs. The results suggest that oral atenolol can be used as an alternative treatment option for patients with IH who require systemic therapy.
TRIAL REGISTRATION
ClinicalTrial.gov Identifier: NCT02342275.
Topics: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Atenolol; China; Female; Hemangioma, Capillary; Humans; Infant; Male; Propranolol; Prospective Studies
PubMed: 33856430
DOI: 10.1001/jamaoto.2021.0454 -
Inflammation Aug 2023Sepsis is a disease with a very high mortality rate, mainly involving an immune-dysregulated response due to bacterial infection. Most studies are currently limited to...
Sepsis is a disease with a very high mortality rate, mainly involving an immune-dysregulated response due to bacterial infection. Most studies are currently limited to the whole blood transcriptome level; however, at the single cell level, there is still a great deal unknown about specific cell subsets and disease markers. We obtained 29 peripheral blood single-cell sequencing data, including 66,283 cells from 10 confirmed samples of sepsis infection and 19 healthy samples. Cells related to the sepsis phenotype were identified and characterized by the "scissor" method. The regulatory relationships of sepsis-related phenotype cells in the cellular communication network were clarified using the "cell chat" method. The least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF) were used to identify sepsis signature genes of diagnostic value. External validation was performed using multiple datasets from the GEO database (GSE28750, GSE185263, GSE57065) and 40 clinical samples. Bayesian algorithm was used to calculate the regulatory network of LILRA5 co-expressed genes. The stability of atenolol-targeting LILRA5 was determined by molecular docking techniques. Ultimately, action trajectory and survival analyses demonstrate the effectiveness of atenolol-targeted LILRA5 in treating patients with sepsis. We successfully identified 1215 healthy phenotypic cells and 462 sepsis phenotypic cells. We focused on 447 monocytes of the sepsis phenotype. Among the cellular communications, there were a large number of differences between these cells and other immune cells showing a significant inflammatory phenotype compared to the healthy phenotypic cells. Together, the three machine learning algorithms identified the LILRA5 marker gene in sepsis patients, and validation results from multiple external datasets as well as real-world clinical samples demonstrated the robust diagnostic performance of LILRA5. The AUC values of LILRA5 in the external datasets GSE28750, GSE185263, and GSE57065 could reach 0.875, 0.940, and 0.980, in that order. Bayesian networks identified a large number of unknown regulatory relationships for LILRA5 co-expression. Molecular docking results demonstrated the possibility of atenolol targeting LILRA5 for the treatment of sepsis. Behavioral trajectory analysis and survival analysis demonstrate that atenolol has a desirable therapeutic effect. LILRA5 is a marker gene in sepsis patients, and atenolol can stably target LILRA5.
Topics: Humans; Atenolol; Bayes Theorem; Molecular Docking Simulation; Sepsis; Machine Learning
PubMed: 36920635
DOI: 10.1007/s10753-023-01803-8 -
Alzheimer's Research & Therapy Jan 2022Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS and multi-omics data to...
BACKGROUND
Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful.
METHODS
To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein-protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells.
RESULTS
Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861-0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862-0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD.
CONCLUSIONS
In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.
Topics: Alzheimer Disease; Animals; Artificial Intelligence; Diabetes Mellitus, Type 2; Drug Repositioning; Genome-Wide Association Study; Humans; Retrospective Studies
PubMed: 35012639
DOI: 10.1186/s13195-021-00951-z