Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal.

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

Topological Learning Approach to Characterizing Biological Membranes.

Biological membranes play key roles in cellular compartmentalization, structure, and its signaling pathways. At varying temperatures, individual membrane lipids sample from different configurations, a process that frequently leads to higher-order phase behavior and phenomena. Here, we present a persistent homology (PH)-based method for quantifying the structural features of individual and bulk lipids, providing local and contextual information on lipid tail organization. Our method leverages the mathematical machinery of algebraic topology and machine learning to infer temperature-dependent structural information on lipids from static coordinates. To train our model, we generated multiple molecular dynamics trajectories of dipalmitoyl-phosphatidylcholine membranes at varying temperatures. A fingerprint was then constructed for each set of lipid coordinates by PH filtration, in which interaction spheres were grown around the lipid atoms while tracking their intersections. The sphere filtration formed a simplicial complex that captures enduring key topological features of the configuration landscape using homology, yielding persistence data. Following fingerprint extraction for physiologically relevant temperatures, the persistence data were used to train an attention-based neural network for assignment of effective temperature values to selected membrane regions. Our persistence homology-based method captures the local structural effects, via effective temperature, of lipids adjacent to other membrane constituents, e.g., sterols and proteins. This topological learning approach can predict lipid effective temperatures from static coordinates across multiple spatial resolutions. The tool, called MembTDA, can be accessed at https://github.com/hyunp2/Memb-TDA.

Twelve-month outcomes of Kahook dual blade goniotomy combined with cataract surgery in Latino patients.

PURPOSE: To evaluate 12 month surgical outcome of Kahook Dual Blade (KDB) goniotomy in combination with cataract surgery in Latino patients with open angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: This retrospective study included 45 eyes of 40 patients who underwent KDB goniotomy combined with cataract extraction from January 2016 to September 2020 at two centers in South America. Primary outcome was surgical success defined as ≥ 20% intraocular pressure (IOP) reduction or ≥ 1 medication reduction from preoperative without additional IOP-lowering procedures and an IOP ≥ 5 mmHg or ≤ 21 mmHg. Additionally, we used 2 cutoffs values for success of IOP ≤ 18 and ≤ 15 mmHg. Secondary outcomes included: IOP, medication use, best corrected visual acuity, complications and failure-associated factors. RESULTS: Success rates at 12 months with cutoff limits of 21, 18 and 15 mmHg were 84.3%, 75.6% and 58.7%, respectively. At 12 months, mean preoperative IOP significantly decreased from 19.23 ± 0.65 mmHg on 2.3 ± 1.0 medications to 14.33 ± 0.66 mmHg on 0.6 ± 0.9 medications (p < 0.001) , with 62% of eyes free of hypotensive medication. Eyes that developed postoperative IOP spikes showed a higher risk for failure using the cutoff limit of IOP ≤ 18 mmHg with a hazard ratio of 3.6 (95% confidence interval [CI], 1.80-7.13; p < 0.001). There were no serious ocular adverse events. CONCLUSIONS: KDB combined with cataract extraction showed safety and efficacy for decreasing IOP in OAG and OHT Latino patients. Additionally, dependence on medications was reduced significantly after surgery.

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid ß Aggregates in Alzheimer's Disease.

Alzheimer's Disease (AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazamacrocycle, which dramatically increases the binding affinity toward various amyloid ß (Aß) peptide aggregates, especially for soluble Aß oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the Aß oligomers in vivo. In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the Aß species. Finally, exploiting the Cu2+-chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble Aß aggregates and can thus be used to detect and regulate various Aß species in AD.

An Allosteric Binding Site on Sortilin Regulates the Trafficking of VLDL, PCSK9, and LDLR in Hepatocytes.

ApoB lipoproteins (apo B-Lp) are produced in hepatocytes, and their secretion requires the cargo receptor sortilin. We examined the secretion of apo B-Lp-containing very low-density lipoprotein (VLDL), an LDL progenitor. Sortilin also regulates the trafficking of the subtilase PCSK9, which when secreted binds the LDL receptor (LDLR), resulting in its endocytosis and destruction at the lysosome. We show that the site 2 binding compound (cpd984) has multiple effects in hepatocytes, including (1) enhanced Apo-Lp secretion, (2) increased cellular PCSK9 retention, and (3) augmented levels of LDLR at the plasma membrane. We postulate that cpd984 enhances apo B-Lp secretion in part through binding the lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is present at higher levels on circulating VLDL form fed rats relative to after fasting. We attribute the enhanced VLDL secretion to its increased binding affinity for sortilin site 1 induced by cpd984 binding site 2. This hinders PCSK9 binding and secretion, which would subsequently prevent its binding to LDLR leading to its degradation. This suggests that site 2 is an allosteric regulator of site 1 binding. This effect is not limited to VLDL, as cpd984 augments binding of the neuropeptide neurotensin (NT) to sortilin site 1. Molecular dynamics simulations demonstrate that the C-terminus of NT (Ct-NT) stably binds site 1 through an electrostatic interaction. This was bolstered by the ability of Ct-NT to disrupt lower-affinity interactions between sortilin and the site 1 ligand PIP3. Together, these data show that binding cargo at sortilin site 1 is allosterically regulated through site 2 binding, with important ramifications for cellular lipid homeostasis involving proteins such as PCSK9 and LDLR.

Phosphatidic acid induces conformational changes in Sec18 protomers that prevent SNARE priming.

Eukaryotic cell homeostasis requires transfer of cellular components among organelles and relies on membrane fusion catalyzed by SNARE proteins. Inactive SNARE bundles are reactivated by hexameric N-ethylmaleimide-sensitive factor, vesicle-fusing ATPase (Sec18/NSF)-driven disassembly that enables a new round of membrane fusion. We previously found that phosphatidic acid (PA) binds Sec18 and thereby sequesters it from SNAREs and that PA dephosphorylation dissociates Sec18 from the membrane, allowing it to engage SNARE complexes. We now report that PA also induces conformational changes in Sec18 protomers and that hexameric Sec18 cannot bind PA membranes. Molecular dynamics (MD) analyses revealed that the D1 and D2 domains of Sec18 contain PA-binding sites and that the residues needed for PA binding are masked in hexameric Sec18. Importantly, these simulations also disclosed that a major conformational change occurs in the linker region between the D1 and D2 domains, which is distinct from the conformational changes that occur in hexameric Sec18 during SNARE priming. Together, these findings indicate that PA regulates Sec18 function by altering its architecture and stabilizing membrane-bound Sec18 protomers.

A small-molecule competitive inhibitor of phosphatidic acid binding by the AAA+ protein NSF/Sec18 blocks the SNARE-priming stage of vacuole fusion.

The homeostasis of most organelles requires membrane fusion mediated by soluble N -ethylmaleimide-sensitive factor (NSF) attachment protein receptors (SNAREs). SNAREs undergo cycles of activation and deactivation as membranes move through the fusion cycle. At the top of the cycle, inactive cis-SNARE complexes on a single membrane are activated, or primed, by the hexameric ATPase associated with the diverse cellular activities (AAA+) protein, N-ethylmaleimide-sensitive factor (NSF/Sec18), and its co-chaperone α-SNAP/Sec17. Sec18-mediated ATP hydrolysis drives the mechanical disassembly of SNAREs into individual coils, permitting a new cycle of fusion. Previously, we found that Sec18 monomers are sequestered away from SNAREs by binding phosphatidic acid (PA). Sec18 is released from the membrane when PA is hydrolyzed to diacylglycerol by the PA phosphatase Pah1. Although PA can inhibit SNARE priming, it binds other proteins and thus cannot be used as a specific tool to further probe Sec18 activity. Here, we report the discovery of a small-molecule compound, we call IPA (inhibitor of priming activity), that binds Sec18 with high affinity and blocks SNARE activation. We observed that IPA blocks SNARE priming and competes for PA binding to Sec18. Molecular dynamics simulations revealed that IPA induces a more rigid NSF/Sec18 conformation, which potentially disables the flexibility required for Sec18 to bind to PA or to activate SNAREs. We also show that IPA more potently and specifically inhibits NSF/Sec18 activity than does N-ethylmaleimide, requiring the administration of only low micromolar concentrations of IPA, demonstrating that this compound could help to further elucidate SNARE-priming dynamics.

Severe brain involvement in 5q spinal muscular atrophy type 0.

Spinal muscular atrophy (SMA) type 0 is the most severe form of SMA, associated with the SMN1 gene and manifesting at birth. Most patients die in the first weeks of life. In this work, we present 3 patients with SMA type 0 who survived >1 year and presented diffuse and progressive brain abnormalities on magnetic resonance imaging, which are not usually seen in patients with SMA. Thus, severe brain involvement may likely be the full end manifestation of an already extreme SMA phenotype caused by substantial reduction of the SMN protein in the brain. ANN NEUROL 2019;86:458-462.

Prognostic value of mean velocity at the pulmonary artery estimated by cardiovascular magnetic resonance as a prognostic predictor in a cohort of patients with new-onset heart failure with reduced ejection fraction.

BACKGROUND: Pulmonary hypertension (PH) conveys a worse prognosis in heart failure (HF), in particular when right ventricular (RV) dysfunction ensues. Cardiovascular magnetic resonance (CMR) non-invasively estimates pulmonary vascular resistance (PVR), which has shown prognostic value in HF. Importantly, RV to pulmonary artery (PA) coupling is altered early in HF, before significant rise in PV resistance occurs. The aim of this study was to assess the prognostic value of mean velocity at the pulmonary artery (mvPA), a novel non-invasive parameter determined by CMR, in HF with reduced ejection fraction (HFrEF) with and without associated PH. METHODS: Prospective inclusion of 238 patients admitted for new-onset HFrEF. MvPA was measured with CMR during index admission. The primary endpoint was defined as a composite of HF readmissions and all-cause mortality. RESULTS: During a median follow-up of 25 months, 91 patients presented with the primary endpoint. Optimal cut-off value of mvPA calculated by the receiver operator curve for the prediction of the primary endpoint was 9 cm/s. The primary endpoint occurred more frequently in patients with mvPA≤9 cm/s, as indicated by Kaplan-Meier survival curves; Log Rank 16.0, p <  0.001. Importantly, mvPA maintained its prognostic value regardless of RV function and also when considering mortality and HF readmissions separately. On Cox proportional hazard analysis, reduced mvPA≤9 cm/s emerged as an independent prognostic marker, together with NYHA III-IV/IV class, stage 3-4 renal failure and ischemic cardiomyopathy. CONCLUSIONS: In our HFrEF cohort, mvPA emerged as an independent prognostic indicator independent of RV function, allowing identification of a higher-risk population before structural damage onset. Moreover, mvPA emerged as a surrogate marker of the RV-PA unit coupling status.

Prognostic factors for discharge to home and residing at home 12 months after hip fracture: an Anoia hip study.

OBJECTIVES: Hip fracture is often associated with loss of physical function and institutionalization. The aim of this study is to describe the prognostic factors for discharge to home and residing there 12 months after a hip fracture. METHODS: A prospective study that includes patients aged ≥ 69 years that live at home before the fracture, admitted from June 1st, 2010, to May 31st, 2013. We registered the demographic data, presurgical function and cognitive assessment, surgical waiting time, type of fracture and complications during hospitalization. RESULTS: We included 273 patients (mean age 84.8 ± 6.1 years; 80% women), 130 (47.6%) were discharged directly to their own home. The predictors of discharge to home were a lower Geriatrics Dementia Scale score (OR 1.42; 95% CI 1.17-1.71; p < 0.001), a higher Barthel Index score at discharge (OR 1.07; 95% CI 1.05-1.10; p < 0.001) and a longer hospital stay (OR 1.14; 95% CI 1.02-1.27; p = 0.019). At 12 months, 169 (63.5%) were still residing at home. Predictors of residing at home 12 months after the hip fracture were age (OR 1.07; 95% CI 1.02-1.12; p = 0.010), the discharge Barthel Index score (OR 0.96; 95% CI 0.94-0.98; p < 0.001), the Geriatrics Dementia Scale score (OR 1.27; 95% CI 1.05-1.52; p = 0.013), the surgical waiting time (OR 3.42; 95% CI 1.077-10.89; p = 0.037) and Charlson comorbidity index (OR 1.27; 95% CI 1.05-1.55; p = 0.016). CONCLUSION: Prognostic factors for discharging to home and remaining there 12 months after a hip fracture are those that reflect a better health condition prior to the fracture and better functionality at the hospital discharge for hip fracture.

An Activity-Based Sensing Approach for the Detection of Cyclooxygenase-2 in Live Cells.

Cyclooxygenase-2 (COX-2) overexpression is prominent in inflammatory diseases, neurodegenerative disorders, and cancer. Directly monitoring COX-2 activity within its native environment poses an exciting approach to account for and illuminate the effect of the local environments on protein activity. Herein, we report the development of CoxFluor, the first activity-based sensing approach for monitoring COX-2 within live cells with confocal microscopy and flow cytometry. CoxFluor strategically links a natural substrate with a dye precursor to engage both the cyclooxygenase and peroxidase activities of COX-2. This catalyzes the release of resorufin and the natural product, as supported by molecular dynamics and ensemble docking. CoxFluor enabled the detection of oxygen-dependent changes in COX-2 activity that are independent of protein expression within live macrophage cells.

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase.

The human body contains endogenous cannabinoids (endocannabinoids) that elicit effects similar to those of Δ9-tetrahydrocanabinol, the principal bioactive component of cannabis. The endocannabinoid virodhamine (O-AEA) is the constitutional isomer of the well-characterized cardioprotective and anti-inflammatory endocannabinoid anandamide (AEA). The chemical structures of O-AEA and AEA contain arachidonic acid (AA) and ethanolamine; however, AA in O-AEA is connected to ethanolamine via an ester linkage, whereas AA in AEA is connected through an amide linkage. O-AEA is involved in regulating blood pressure and cardiovascular function. We show that O-AEA is found at levels 9.6-fold higher than that of AEA in porcine left ventricle. On a separate note, the cytochrome P450 (CYP) epoxygenase CYP2J2 is the most abundant CYP in the heart where it catalyzes the metabolism of AA and AA-derived eCBs to bioactive epoxides that are involved in diverse cardiovascular functions. Herein, using competitive binding studies, kinetic metabolism measurements, molecular dynamics, and wound healing assays, we have shown that O-AEA is an endogenous inhibitor of CYP2J2 epoxygenase. As a result, the role of O-AEA as an endogenous eCB inhibitor of CYP2J2 may provide a new mode of regulation to control the activity of cardiovascular CYP2J2 in vivo and suggests a potential cross-talk between the cardiovascular endocannabinoids and the cytochrome P450 system.

[Collagen VI related myopathies. When to suspect, how to identify. The contribution of muscle magnetic resonance]. / Miopatías relacionadas a colágeno VI. Cuando sospecharlas, cómo identificarlas. Aporte de la resonancia magnética muscular.

Myopathies secondary to collagen VI mutations (COLVI-M) are the most frequent in the northern hemisphere, affecting the adult and pediatric population. There are no data on its prevalence in Latin America. They are characterized by a great clinical variability, from severe phenotypes, such as Ullrich congenital muscular dystrophy (UCMD), to intermediate and mild ones such as Bethlem myopathy (BM). Its onset is also variable and extends from the neonatal period to adulthood. Given the presence of joint hypermobility, the differential diagnosis should be made with various connective tissue diseases. The classical diagnostic algorithm in many patients has been insufficient to guide the genetic study in an adequate way, and from this the muscular magnetic resonance imaging has emerged as a very useful tool for a better diagnostic approach of this and other muscular pathologies. This ob jective of this review is to study the forms of presentation, clinical characteristics, specific diagnostic study, differential diagnosis and management of one of the most frequent hereditary muscular patho logies, with emphasis on the contribution of muscle magnetic resonance imaging.

Maternal union instability and childhood mortality risk in the Global South, 2010-14.

Efforts to improve child survival in lower-income countries typically focus on fundamental factors such as economic resources and infrastructure provision, even though research from post-industrial countries confirms that family instability has important health consequences. We tested the association between maternal union instability and children's mortality risk in Africa, Latin America and the Caribbean, and Asia using children's actual experience of mortality (discrete-time probit hazard models) as well as their experience of untreated morbidity (probit regression). Children of divorced/separated mothers experience compromised survival chances, but children of mothers who have never been in a union generally do not. Among children of partnered women, those whose mothers have experienced prior union transitions have a higher mortality risk. Targeting children of mothers who have experienced union instability-regardless of current union status-may augment ongoing efforts to reduce childhood mortality, especially in Africa and Latin America where union transitions are common.

Design, development and validation of a new laryngo-pharyngeal endoscopic esthesiometer and range-finder based on the assessment of air-pulse variability determinants.

BACKGROUND: Laryngo-pharyngeal mechano-sensitivity (LPMS) is involved in dysphagia, sleep apnea, stroke, irritable larynx syndrome and cough hypersensitivity syndrome among other disorders. These conditions are associated with a wide range of airway reflex abnormalities. However, the current device for exploring LPMS is limited because it assesses only the laryngeal adductor reflex during fiber-optic endoscopic evaluations of swallowing and requires a high degree of expertise to obtain reliable results, introducing intrinsic expert variability and subjectivity. METHODS: We designed, developed and validated a new air-pulse laryngo-pharyngeal endoscopic esthesiometer with a built-in laser range-finder (LPEER) based on the evaluation and control of air-pulse variability determinants and on intrinsic observer variability and subjectivity determinants of the distance, angle and site of stimulus impact. The LPEER was designed to be capable of delivering precise and accurate stimuli with a wide range of intensities that can explore most laryngo-pharyngeal reflexes. RESULTS: We initially explored the potential factors affecting the reliability of LPMS tests and included these factors in a multiple linear regression model. The following factors significantly affected the precision and accuracy of the test (P < 0.001): the tube conducting the air-pulses, the supply pressure of the system, the duration of the air-pulses, and the distance and angle between the end of the tube conducting the air-pulses and the site of impact. To control all of these factors, an LPEER consisting of an air-pulse generator and an endoscopic laser range-finder was designed and manufactured. We assessed the precision and accuracy of the LPEER's stimulus and range-finder according to the coefficient of variation (CV) and by looking at the differences between the measured properties and the desired values, and we performed a pilot validation on ten human subjects. The air-pulses and range-finder exhibited good precision and accuracy (CV < 0.06), with differences between the desired and measured properties at <3 % and a range-finder measurement error of <1 mm. The tests in patients demonstrated obtainable and reproducible thresholds for the laryngeal adductor, cough and gag reflexes. CONCLUSIONS: The new LPEER was capable of delivering precise and accurate stimuli for exploring laryngo-pharyngeal reflexes.

Open-Source, Web-Based Dashboard Components for DICOM Connectivity.

The administration of a DICOM network within an imaging healthcare institution requires tools that allow for monitoring of connectivity and availability for adequate uptime measurements and help guide technology management strategies. We present the implementation of an open-source widget for the Dashing framework that provides basic dashboard functionality allowing for monitoring of a DICOM network using network "ping" and DICOM "C-ECHO" operations.

Amphiphilic Residues 29-44 of DREAM N-Termini Mediate Calmodulin:DREAM Complex Formation.

DREAM (downstream regulatory element antagonist modulator) is a neuronal calcium sensor that has been shown to modulate gene expression as well as to be involved in numerous neuronal processes. In this report, we show that association of calcium-bound calmodulin (CaM) with DREAM is mediated by a short amphipathic amino acid sequence located between residues 29 and 44 on DREAM. The association of CaM with a peptide analogous to DREAM(29-44) or to full-length DREAM protein is calcium-dependent with a dissociation constant of 136 nM or 3.4 µM, respectively. Thermodynamic and kinetic studies show that the observed decrease in affinity for the native protein is due to electrostatic interactions between the basic N-terminus and an electronegative surface on DREAM. These results are further supported by circular dichroism, binding studies, and molecular dynamics simulations. Additionally, fluorescence anisotropy decay measurements show a rotational correlation time of 10.8 ns for a complex of CaM with a DREAM(29-44) peptide, supporting a wraparound semispherical model with 1:1 stoichiometry. Furthermore, the interaction between an IEDANS-labeled CaM construct with DREAM is best modeled as a heterotetramer that adopts an elongated conformation with a correlation time of 45 ns in the presence of Ca(2+). We also demonstrate that association of CaM with DREAM eliminates the nonspecific interaction of DREAM with the DRE double-stranded DNA sequence of the human prodynorphin gene. This work provides molecular insight into the CaM:DREAM complex and its potential role in modulation of gene expression.

Chloral hydrate in pediatric magnetic resonance imaging: evaluation of a 10-year sedation experience administered by radiologists.

BACKGROUND: Chloral hydrate is a sedative that has been used for magnetic resonance imaging (MRI). OBJECTIVE: To evaluate the use, effectiveness and safety of chloral hydrate administered by radiologists for the sedation of children who require MRI procedures. MATERIALS AND METHODS: We retrospectively reviewed the clinical charts for all patients ages 0 - 10 years old who underwent sedation with chloral hydrate for MRI from January 2000 to December 2010. Demographic factors, dose information, indication for MRI, therapeutic failures and adverse reactions to the drug were reviewed. RESULTS: One thousand, seven hundred and three children (946 males, 757 females) with a median age of 2.5 years (range: 4 days - 9.91 years) received chloral hydrate. Moderate to deep sedation was achieved in 1,618/1,703 (95%) of the patients, 35/1,703 (2.1%) of the patients failed to achieve moderate to deep sedation, and 47/1,703 (2.8%) of the patients woke up during MRI examination. Adverse reactions were present in 31/1,703 (1.8%) of the patients. Three severe adverse reactions occurred (0.18%). A single dose of chloral hydrate (40-60 mg/kg) was administered to 1,477/1,703 patients (86.7%). An additional dose of chloral hydrate (10-20 mg/kg), given 15 min after the first dose or when the patient woke up during the MRI examination, was required in 226/1,703 patients (13.3%). The likelihood of requiring an additional dose in children older than 2 years was 2.2 times the likelihood compared to children younger than 2 years (OR = 2.2 [95%CI: 1.6-3.0]). The use of a reduced dose (<50 mg/kg) was not associated with a higher therapeutic failure rate (OR = 1.04 [95%CI 0.57-1.89]). CONCLUSION: Chloral hydrate is an appropriate sedation option for pediatric patients in MRI services when strict patient selection criteria are met. The use of a reduced dose does not affect the effectiveness of sedation. The lack of data regarding the presence of transient oxygen desaturation, the time to induce sedation and the exact duration of sedation are limitations of this study.