RESUMEN
Protein-protein complexes power the majority of cellular processes. Interfering with the formation of such complexes using well-designed mimics is a difficult, yet actively pursued, research endeavor. Due to the limited availability of results on the conformational preferences of oligosaccharides compared to polypeptides, the former have been much less explored than the latter as protein mimics, despite interesting ADMET characteristics. In this work, the conformational landscapes of a series of 956 substituted glucopyranose oligomers of lengths 3 to 12 designed as protein interface mimics are revealed using microsecond-time-scale, enhanced-sampling molecular dynamics simulations. Deep convolutional networks are trained on these large conformational ensembles, to predict the stability of longer oligosaccharide structures from those of their constituent trimer motifs. Deep generative adversarial networks are then designed to suggest plausible conformations for oligosaccharide mimics of arbitrary length and substituent sequences that can subsequently be used as input to docking simulations. Analyzing the performance of the neural networks also yields insights into the intricate collective effects that dominate oligosaccharide conformational dynamics.
Asunto(s)
Simulación de Dinámica Molecular , Proteínas , Proteínas/química , Oligosacáridos/química , Conformación Molecular , Redes Neurales de la ComputaciónRESUMEN
To power the specific recognition and binding of protein partners into functional complexes, a wealth of information about the structure and function of the partners is necessarily encoded into the global shape of protein-protein interfaces and their local topological features. To identify whether this is the case, this study uses convolutional deep learning methods (typically leveraged for 2D image recognition) on 3D voxel representations of protein-protein interfaces colored by burial depth. A novel two-stage network fed with voxelizations of each interface at two distinct resolutions achieves balance between performance and computational cost. From the shape of the interfaces, the network tries to predict the presence of secondary structure motifs at the interface and the molecular function of the corresponding complex. Secondary structure and certain classes of function are found to be very well predicted, validating the hypothesis that interface shape is a conveyor of higher-level information. Interface patterns triggering the recognition of specific classes are also identified and described.
Asunto(s)
Aprendizaje Profundo , Redes Neurales de la Computación , Estructura Secundaria de Proteína , ProteínasRESUMEN
BACKGROUND: Cardiovascular severe maternal morbidity (CSMM) is rising and has become the leading cause of maternal mortality. Research using administrative data sets may allow for better understanding of this critical group of diseases. OBJECTIVE: To validate a composite variable of CSMM for use in epidemiologic studies. METHODS: We analysed delivery hospitalisations at an obstetric teaching hospital from 2007 to 2017. We utilised a subset of indicators developed by the Centers for Disease Control and Prevention based on ICD codes to form the composite variable for CSMM. Two expert clinicians manually reviewed all qualifying events using a standardised tool to determine whether these represented true CSMM events. Additionally, we estimated the number of CSMM cases among delivery hospitalisations without qualifying ICD codes by manually reviewing all hospitalisations with severe preeclampsia, a population at high risk of CSMM, and a random sample of 1000 hospitalisations without severe preeclampsia. We estimated validity of the composite variable. RESULTS: Among 91 355 admissions for delivery, we captured 113 potential CSMM cases using qualifying ICD codes. Of these, 65 (57.5%) were true CSMM cases. Indicators for acute myocardial infarction, cardiac arrest, and cardioversion had the highest true-positive rates (100% for all). We found an additional 70 CSMM cases in the 2102 admissions with severe preeclampsia and a single CSMM case in the random sample. Assuming a rate of 1 CSMM case per 1000 deliveries in the remaining cohort, the composite variable had a positive predictive value of 57.5% (95% CI 47,9, 66.8), a negative predictive value of 99.8% (95% CI 99.8, 99.9), a sensitivity of 29.0% (95% CI 23.2, 35.4), and a specificity of 100% (95% CI 99.9, 100.0). CONCLUSION: A novel composite variable for CSMM had reasonable PPV but limited sensitivity. This composite variable may enable epidemiologic studies geared towards reducing maternal morbidity and mortality.
Asunto(s)
Parto Obstétrico , Cardioversión Eléctrica/estadística & datos numéricos , Paro Cardíaco , Clasificación Internacional de Enfermedades/normas , Mortalidad Materna , Evaluación de Resultado en la Atención de Salud , Preeclampsia , Complicaciones Cardiovasculares del Embarazo , Adulto , Parto Obstétrico/efectos adversos , Parto Obstétrico/estadística & datos numéricos , Estudios Epidemiológicos , Femenino , Paro Cardíaco/epidemiología , Paro Cardíaco/terapia , Hospitalización/estadística & datos numéricos , Humanos , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/normas , Preeclampsia/diagnóstico , Preeclampsia/epidemiología , Embarazo , Complicaciones Cardiovasculares del Embarazo/diagnóstico , Complicaciones Cardiovasculares del Embarazo/mortalidad , Complicaciones Cardiovasculares del Embarazo/terapia , Embarazo de Alto Riesgo , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
Pyoverdines are Pseudomonas aeruginosa's primary siderophores. These molecules, composed of a fluorescent chromophore attached to a peptide chain of 6-14 amino acids, are synthesized by the bacterium to scavenge iron (essential to its survival and growth) from its environment. Hijacking the siderophore pathway to use pyoverdine-antibiotic compounds in a Trojan horse approach has shown promise but remains very challenging because of the synthetic efforts involved. Indeed, both possible approaches (grafting an antibiotic on pyoverdine harvested from Pseudomonas or designing a total synthesis route) are costly, time-consuming and low-yield tasks. Designing comparatively simple analogs featuring the salient properties of the original siderophore is thus crucial for the conception of novel antibiotics to fight bacterial resistance. In this work, we focus on the replacement of the pyoverdine chromophore, a major roadblock on the synthetic pathway. We propose three simpler analogs and evaluate their ability to complex iron and interact with the FpvA transporter using molecular modeling techniques. Based on these results, we discuss the role of the native chromophore's main features (polycyclicity, positive charge, flexibility) on pyoverdine's ability to bind iron and be recognized by membrane transporter FpvA and propose guidelines for the design of effective synthetic siderophores.
Asunto(s)
Oligopéptidos/metabolismo , Pseudomonas aeruginosa/metabolismo , Sideróforos/metabolismo , Proteínas Bacterianas/metabolismo , Hierro/metabolismoRESUMEN
Pyoverdines, the primary siderophores of Pseudomonas bacteria, scavenge the iron essential to bacterial life in the outside medium and transport it back into the periplasm. Despite their relative simplicity, pyoverdines feature remarkably flexible recognition characteristics whose origins at the atomistic level remain only partially understood: the ability to bind other metals than ferric iron, the capacity of outer membrane transporters to recognize and internalize noncognate pyoverdines from other pseudomonads One of the less examined factors behind this polymorphic recognition lies in the ability for pyoverdines to bind iron with two distinct chiralities, at the cost of a conformational switch. Herein, we use free energy simulations to study how the stereochemistry of the iron chelating groups influences the structure and dynamics of two common pyoverdines and impacts their recognition by the FpvA membrane transporter of P. aeruginosa. We show that conformational preferences for one metal binding chirality over the other, observed in solution depending on the nature of the pyoverdine, are canceled out by the FpvA transporter, which recognizes both chiralities equally well for both pyoverdines under study. However, FpvA discriminates between pyoverdines by altering the kinetics of stereoisomer interconversion. We present structural causes of this intriguing recognition mechanism and discuss its possible significance in the context of the competitive scavenging of iron.
Asunto(s)
Proteínas Bacterianas/metabolismo , Hierro/química , Oligopéptidos/química , Pseudomonas aeruginosa/metabolismo , Proteínas Bacterianas/química , Sitios de Unión , Enlace de Hidrógeno , Hierro/metabolismo , Modelos Moleculares , Oligopéptidos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Estereoisomerismo , TermodinámicaRESUMEN
BACKGROUND: Supervised injection facilities (SIFs) are legally sanctioned environments for people to inject drugs under medical supervision. SIFs currently operate in ten countries, but to date, no SIF has been opened in the USA. In light of increasing overdose mortality in the USA, this study evaluated willingness to use a SIF among youth who report non-medical prescription opioid (NMPO) use. METHODS: Between January 2015 and February 2016, youth with recent NMPO use were recruited to participate in the Rhode Island Young Adult Prescription Drug Study (RAPiDS). We explored factors associated with willingness to use a SIF among participants who had injected drugs or were at risk of initiating injection drug use (defined as having a sex partner who injects drugs or having a close friend who injects). RESULTS: Among 54 eligible participants, the median age was 26 (IQR = 24-28), 70.4% were male, and 74.1% were white. Among all participants, when asked if they would use a SIF, 63.0% answered "Yes", 31.5% answered "No", and 5.6% were unsure. Among the 31 participants reporting injection drug use in the last six months, 27 (87.1%) reported willingness to use a SIF; 15 of the 19 (78.9%) who injected less than daily reported willingness, while all 12 (100.0%) of the participants who injected daily reported willingness. Compared to participants who were unwilling or were unsure, participants willing to use a SIF were also more likely to have been homeless in the last six months, have accidentally overdosed, have used heroin, have used fentanyl non-medically, and typically use prescription opioids alone. CONCLUSIONS: Among young adults who use prescription opioids non-medically and inject drugs or are at risk of initiating injection drug use, more than six in ten reported willingness to use a SIF. Established risk factors for overdose, including homelessness, history of overdose, daily injection drug use, heroin use, and fentanyl misuse, were associated with higher SIF acceptability, indicating that young people at the highest risk of overdose might ultimately be the same individuals to use the facility. Supervised injection facilities merit consideration to reduce overdose mortality in the USA.
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Analgésicos Opioides , Abuso de Medicamentos/estadística & datos numéricos , Programas de Intercambio de Agujas/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Abuso de Sustancias por Vía Intravenosa/rehabilitación , Adulto , Estudios Transversales , Femenino , Reducción del Daño , Humanos , Masculino , Rhode IslandRESUMEN
Highly specific transcriptional regulation depends on the cooperative association of transcription factors into enhanceosomes. Usually, their DNA-binding cooperativity originates from either direct interactions or DNA-mediated allostery. Here, we performed unbiased molecular simulations followed by simulations of protein-DNA unbinding and free energy profiling to study the cooperative DNA recognition by OCT4 and SOX2, key components of enhanceosomes in pluripotent cells. We found that SOX2 influences the orientation and dynamics of the DNA-bound configuration of OCT4. In addition SOX2 modifies the unbinding free energy profiles of both DNA-binding domains of OCT4, the POU specific and POU homeodomain, despite interacting directly only with the first. Thus, we demonstrate that the OCT4-SOX2 cooperativity is modulated by an interplay between protein-protein interactions and DNA-mediated allostery. Further, we estimated the change in OCT4-DNA binding free energy due to the cooperativity with SOX2, observed a good agreement with experimental measurements, and found that SOX2 affects the relative DNA-binding strength of the two OCT4 domains. Based on these findings, we propose that available interaction partners in different biological contexts modulate the DNA exploration routes of multi-domain transcription factors such as OCT4. We consider the OCT4-SOX2 cooperativity as a paradigm of how specificity of transcriptional regulation is achieved through concerted modulation of protein-DNA recognition by different types of interactions.
Asunto(s)
ADN/química , ADN/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/química , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factores de Transcripción SOXB1/química , Factores de Transcripción SOXB1/metabolismo , Regulación Alostérica , Simulación de Dinámica Molecular , Células Madre Pluripotentes , Unión ProteicaRESUMEN
Bacterial lectins are nonenzymatic sugar-binding proteins involved in the formation of biofilms and the onset of virulence. The weakness of individual sugar-lectin interactions is compensated by the potentially large number of simultaneous copies of such contacts, resulting in high overall sugar-lectin affinities and marked specificities. Therapeutic compounds functionalized with sugar residues can compete with the host glycans for binding to lectins only if they are able to take advantage of this multivalent binding mechanism. Glycopeptide dendrimers, featuring treelike topologies with sugar moieties at their leaves, have already shown great promise in this regard. However, optimizing the dendrimers' amino acid sequence is necessary to match the dynamics of the lectin active sites with that of the multivalent ligands. This work combines long-time-scale coarse-grained simulations of dendrimers and lectins with a reasoned exploration of the dendrimer sequence space in an attempt to suggest sequences that could maximize multivalent binding to the galactose-specific bacterial lectin LecA. These candidates are validated by simulations of mixed dendrimer/lectin solutions, and the effects of the dendrimers on lectin dynamics are discussed. This approach is an attractive first step in the conception of therapeutic compounds based on the dendrimer scaffold and contributes to the understanding of the various classes of multivalency that underpin the ubiquitous "sugar code".
Asunto(s)
Adhesinas Bacterianas/metabolismo , Dendrímeros/metabolismo , Glicopéptidos/química , Glicopéptidos/metabolismo , Adhesinas Bacterianas/química , Secuencia de Aminoácidos , Dominio Catalítico , Diseño de Fármacos , Glicopéptidos/uso terapéutico , Simulación de Dinámica Molecular , Unión ProteicaRESUMEN
The Gram-negative bacterium Pseudomonas aeruginosa, a ubiquitous human opportunistic pathogen, has developed resistances to multiple antibiotics. It uses its primary native siderophore, pyoverdine, to scavenge the iron essential to its growth in the outside medium and transport it back into its cytoplasm. The FpvA receptor on the bacterial outer membrane recognizes and internalizes pyoverdine bearing its iron payload, but can also bind pyoverdines from other Pseudomonads or synthetic analogues. Pyoverdine derivatives could therefore be used as vectors to deliver antibiotics into the bacterium. In this study, we use molecular dynamics and free energy calculations to characterize the mechanisms and thermodynamics of the recognition of the native pyoverdines of P. aeruginosa and P. fluorescens by FpvA. Based on these results, we delineate the features that pyoverdines with high affinity for FpvA should possess. In particular, we show that (i) the dynamics and interaction of the unbound pyoverdines with water should be optimized with equal care as the interface contacts in the complex with FpvA; (ii) the C-terminal extremity of the pyoverdine chain, which appears to play no role in the bound complex, is involved in the intermediate stages of recognition; and (iii) the length and cyclicity of the pyoverdine chain can be used to fine-tune the kinetics of the recognition mechanism.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/metabolismo , Simulación de Dinámica Molecular , Oligopéptidos/metabolismo , Pseudomonas aeruginosa/metabolismo , Proteínas de la Membrana Bacteriana Externa/química , Sitios de Unión , Oligopéptidos/química , Estructura Terciaria de Proteína , TermodinámicaRESUMEN
Ubiquitin is a highly conserved, highly represented protein acting as a regulating signal in numerous cellular processes. It leverages a single hydrophobic binding patch to recognize and bind a large variety of protein domains with remarkable specificity, but can also self-assemble into chains of poly-diubiquitin units in which these interfaces are sequestered, profoundly altering the individual monomers' recognition characteristics. Despite numerous studies, the origins of this varied specificity and the competition between substrates for the binding of the ubiquitin interface patch remain under heated debate. This study uses enhanced sampling all-atom molecular dynamics to simulate the unbinding of complexes of mono- or K48-linked diubiquitin bound to several ubiquitin-associated domains, providing insights into the mechanism and free energetics of ubiquitin recognition and binding. The implications for the subtle tradeoff between the stability of the polyubiquitin signal and its easy recognition by target protein assemblies are discussed, as is the enhanced affinity of the latter for long polyubiquitin chains compared to isolated mono- or diubiquitin.
Asunto(s)
Simulación de Dinámica Molecular , Ubiquitina/metabolismo , Secuencia de Aminoácidos , Datos de Secuencia Molecular , Unión Proteica , Estructura Terciaria de Proteína , Solventes/química , Termodinámica , Ubiquitina/química , Agua/químicaRESUMEN
Atomic-scale molecular dynamics and free energy calculations in explicit aqueous solvent are used to study the complex mechanism by which a molecule can intercalate between successive base pairs of the DNA double helix. We have analyzed the intercalation pathway for the anticancer drug daunomycin using two different methods: metadynamics and umbrella sampling. The resulting free energy pathways are found to be consistent with one another and point, within an equilibrium free energy context, to a three-step process. Daunomycin initially binds in the minor groove of DNA. An activated step then leads to rotation of the drug, coupled with DNA deformation that opens a wedge between the base pairs, bends DNA toward the major groove, and forms a metastable intermediate that resembles structures seen within the interfaces between DNA and minor-groove-binding proteins. Finally, crossing a small free energy barrier leads to further rotation of daunomycin and full intercalation of the drug, reestablishing stacking with the flanking base pairs and straightening the double helix.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , ADN/metabolismo , Daunorrubicina/farmacología , Sustancias Intercalantes/farmacología , ADN/química , Simulación de Dinámica Molecular , TermodinámicaRESUMEN
The present paper aims at providing a fundamental insight into the interaction between a lithium salt and an inorganic filler in a perspective of lithium mobility. Through a synergistic approach, coupling experimental results and molecular dynamics simulations, the influence of the surface chemical state of the nanosilica Stöber-type on the dissociation of LiTFSI and its impact on the lithium conduction properties are studied. For this purpose, the surface modification of silica nanoparticles was performed by different methods such as calcination, lithiation and capping with organosilane. The impact of the surface modification on the dissociation of the lithium salt is further investigated by electrochemical impedance spectroscopy after impregnation of the material with a defined amount of lithium salt. The combined experimental and in silico analyses of the results, performed for the first time on such systems, allow a detailed understanding of the interaction between the salt and the support and should prove itself useful for the future design of hybrid polymer electrolytes in new generation batteries.
Asunto(s)
Litio , Nanopartículas , Suministros de Energía Eléctrica , Electrólitos/química , Litio/química , Dióxido de SilicioRESUMEN
BACKGROUND: Women with preeclampsia are at increased short-term risk of adverse cardiovascular outcomes during pregnancy and the early postpartum period. We aimed to develop and internally validate a risk assessment tool to predict acute cardiovascular morbidity in preeclampsia. METHODS: The study was conducted at an academic obstetrics hospital. Participants with preeclampsia at delivery from 2007 to 2017 were included. A model to predict acute cardiovascular morbidity at delivery and within 6 weeks after delivery was developed and evaluated. The primary composite outcome included pulmonary edema/acute heart failure, myocardial infarction, aneurysm, cardiac arrest/ventricular fibrillation, heart failure/arrest during surgery or procedure, cerebrovascular disorders, cardiogenic shock, conversion of cardiac rhythm, and difficult-to-control severe hypertension. We assessed model discrimination and calibration. We used bootstrapping for internal validation. RESULTS: A total of 4171 participants with preeclampsia were included. The final model comprised 8 variables. Predictors positively associated with acute cardiovascular morbidity (presented as odds ratio with 95% confidence interval) were: gestational age at delivery (20-36 weeks: 5.36 [3.67-7.82]; 37-38 weeks: 1.75 [1.16-2.64]), maternal age (≥ 40 years: 1.65 [1.00-2.72]; 35-39 years: 1.49 [1.07-2.09]), and previous caesarean delivery (1.47 [1.01-2.13]). The model had an area under the receiver operating characteristic curve of 0.72 (95% CI 0.69-0.74). Moreover, it was adequately calibrated and performed well on internal validation. CONCLUSIONS: This risk prediction tool identified women with preeclampsia at highest risk of acute cardiovascular morbidity. If externally validated, this tool may facilitate early interventions aimed at preventing adverse cardiovascular outcomes in pregnancy and postpartum.
Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Preeclampsia , Adulto , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Progresión de la Enfermedad , Femenino , Edad Gestacional , Humanos , Lactante , Preeclampsia/epidemiología , Embarazo , Curva ROCRESUMEN
The accurate description and analysis of protein-protein interfaces remains a challenging task. Traditional definitions, based on atomic contacts or changes in solvent accessibility, tend to over- or underpredict the interface itself and cannot discriminate active from less relevant parts. We here extend a fast, parameter-free and purely geometric definition of protein interfaces and introduce the shelling order of Voronoi facets as a novel measure for an atom's depth inside the interface. Our analysis of 54 protein-protein complexes reveals a strong correlation between Voronoi Shelling Order (VSO) and water dynamics. High Voronoi Shelling Orders coincide with residues that were found shielded from bulk water fluctuations in a recent molecular dynamics study. Yet, VSO predicts such "dry" residues without consideration of forcefields or dynamics at a dramatically reduced cost. The interface center is enriched in hydrophobic residues. Yet, this hydrophobic centering is not universal and does not mirror the far stronger geometric bias of water fluxes. The seemingly complex water dynamics at protein interfaces appears thus largely controlled by geometry. Sequence analysis supports the functional relevance of dry residues and residues with high VSO, both of which tend to be more conserved. On closer inspection, the spatial distribution of conservation argues against the arbitrary dissection into core or rim and thus refines previous results. Voronoi Shelling Order reveals clear geometric patterns in protein interface composition, function and dynamics and facilitates the comparative analysis of protein-protein interactions.
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Biología Computacional/métodos , Proteínas/química , Modelos Moleculares , Unión ProteicaRESUMEN
The SRY gene on the Y chromosome is a necessary and sufficient condition for the development of the male phenotype and is involved in sex-reversal pathologies. The associated SRY protein also represents a convenient model system for the study of indirect protein-DNA recognition mechanisms, in which the local plasticity of DNA may play a more important role than direct interactions between the protein and the DNA bases. Using a novel, low-bias restraint methodology, we have performed molecular dynamics simulations of the controlled dissociation of SRY from its cognate DNA sequence. The resulting free energy profile provides a detailed view of protein-DNA binding and identifies a metastable intermediate state.
Asunto(s)
ADN/química , ADN/metabolismo , Proteína de la Región Y Determinante del Sexo/química , Proteína de la Región Y Determinante del Sexo/metabolismo , Sitios de Unión , Dominios HMG-Box , Modelos Moleculares , Estructura Secundaria de Proteína , TermodinámicaRESUMEN
We use a physics-based approach termed ADAPT to analyse the sequence-specific interactions of three proteins which bind to DNA on the side of the minor groove. The analysis is able to estimate the binding energy for all potential sequences, overcoming the combinatorial problem via a divide-and-conquer approach which breaks the protein-DNA interface down into a series of overlapping oligomeric fragments. All possible base sequences are studied for each fragment. Energy minimisation with an all-atom representation and a conventional force field allows for conformational adaptation of the DNA and of the protein side chains for each new sequence. As a result, the analysis depends linearly on the length of the binding site and complexes as large as the nucleosome can be treated, although this requires access to grid computing facilities. The results on the three complexes studied are in good agreement with experiment. Although they all involve significant DNA deformation, it is found that this does not necessarily imply that the recognition will be dominated by the sequence-dependent mechanical properties of DNA.
Asunto(s)
Proteínas de Unión al ADN/química , ADN/química , Secuencia de Bases , Sitios de Unión , Unión Proteica , Proteína de la Región Y Determinante del Sexo/química , Proteína de Unión a TATA-Box/química , TermodinámicaRESUMEN
The plasticity of membranes plays an important functional role in cells, cell components, and micelles, where bending, budding, and remodeling implement numerous recognition and communication processes. Comparatively, molecular simulation methods to induce, control, and quantitatively characterize such deformations remain scarce. This work defines a novel collective coordinate associated with membrane bending, which strives to combine realism (by preserving the notion of local atomic curvatures) and low computational cost (allowing its evaluation at every time step of a molecular dynamics simulation). Enhanced sampling simulations along this conformational coordinate provide convenient access to the underlying bending free energy landscape. To showcase its potential, the method is applied to three state-of-the-art problems: the determination of the bending free energy landscape of a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) bilayer, the formation of a POPE liposome, and the study of the influence of the Pseudomonas quinolone signal on the budding of Gram-negative bacterial outer membranes.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/química , Membrana Dobles de Lípidos/química , Simulación de Dinámica Molecular , Fosfatidiletanolaminas/química , Liposomas/química , Conformación Molecular , Quinolonas/químicaRESUMEN
Non-medical prescription opioid (NMPO) use and depression frequently co-occur and are mutually reinforcing in adults, yet NMPO use and depression in younger populations has been under-studied. We examined the prevalence and correlates of depressive symptomology among NMPO-using young adults. The Rhode Island Young Adult Prescription Drug Study (RAPiDS) recruited young adults in Rhode Island who reported past 30-day NMPO use. We administered the Center for Epidemiologic Studies Short Depression Scale (CES-D 10), and used modified Poisson regression to identify the independent correlates of depressive symptomology (CES-D 10 score ≥10). Over half (59.8%, n = 119) screened positive for depressive symptomology. In modified Poisson regression analysis, diagnostic history of depressive disorder and childhood verbal abuse were associated with depressive symptomology. Participants with depressive symptomology were more likely to report using prescription opioids non-medically to feel less depressed or anxious, to avoid withdrawal symptoms, and as a substitute when other drugs are not available. Among young adult NMPO users, depressive symptomology is prevalent and associated with distinct motivations for engaging in NMPO use and represents a potential subgroup for intervention. Improving guidelines with tools such as screening for depressive symptomology among young adult NMPO users may help prevent NMPO-related harms.
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Analgésicos Opioides , Depresión/epidemiología , Motivación , Trastornos Relacionados con Opioides/epidemiología , Mal Uso de Medicamentos de Venta con Receta/estadística & datos numéricos , Adolescente , Adulto , Comorbilidad , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Prevalencia , Rhode Island/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Benzodiazepine use dramatically increases the risk of unintentional overdose among people who use opioids non-medically. However, little is known about the patterns of co-occurring benzodiazepine and opioid use among young adults in the United States. METHODS: The Rhode Island Young Adult Prescription Drug Study (RAPiDS) was a cross-sectional study from January 2015-February 2016. RAPiDS recruited 200 young adults aged 18-29 who reported past 30-day non-medical prescription opioid (NMPO) use. Using Wilcoxon rank sum test and Fisher's exact test, we examined correlates associated with regular prescribed and non-medical use (defined as at least monthly) of benzodiazepines among NMPO users in Rhode Island. RESULTS: Among participants, 171 (85.5%) reported lifetime benzodiazepine use and 125 (62.5%) reported regular benzodiazepine use. Nearly all (n=121, 96.8%) reported non-medical use and 43 (34.4%) reported prescribed use. Compared to the 75 participants who did not regularly use benzodiazepines, participants who reported regular use were more likely to be white (66.3% vs. 58.0%, p=0.03), have ever been incarcerated (52.8% vs. 37.3%, p=0.04), and have ever been diagnosed with a psychiatric disorder (bipolar: 29.6% vs. 16.0%, p=0.04; anxiety: 56.8 vs. 36.0%, p=0.01). Although the association was marginally significant, accidental overdose was higher among those who were prescribed the benzodiazepine they used most frequently compared to those who were not (41.9% vs. 24.4%, p=0.06). CONCLUSION: Benzodiazepine use and misuse are highly prevalent among young adult NMPO users. Harm reduction and prevention programs for this population are urgently needed.
Asunto(s)
Analgésicos Opioides/efectos adversos , Benzodiazepinas/efectos adversos , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/psicología , Mal Uso de Medicamentos de Venta con Receta/efectos adversos , Mal Uso de Medicamentos de Venta con Receta/psicología , Adolescente , Adulto , Analgésicos Opioides/uso terapéutico , Benzodiazepinas/uso terapéutico , Estudios Transversales , Femenino , Reducción del Daño , Humanos , Masculino , Trastornos del Humor/diagnóstico , Trastornos del Humor/epidemiología , Trastornos del Humor/psicología , Trastornos Relacionados con Opioides/diagnóstico , Prevalencia , Rhode Island/epidemiología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Though the full implications of a Trump presidency for ongoing health care and criminal justice reform efforts remain uncertain, whatever policy changes are made will be particularly salient for the South, which experiences the highest incarceration rates, highest uninsured rates, and worst health outcomes in the United States. The passage of the Affordable Care Act (ACA) in 2010 was a watershed event and many states have taken advantage of opportunities created by the ACA to expand healthcare coverage to their poorest residents, and to develop partnerships between health and justice systems. Yet to date, only four have taken advantage of the benefits of healthcare reform. Expanding Medicaid would provide Southern states with the opportunity to significantly impact health outcomes for criminal justice-involved individuals. In the context of an uncertain policy landscape, we suggest the use of three strategies, focusing on advancing incremental change while safeguarding existing gains, rebranding Medicaid as a local or statewide initiative, and linking Medicaid expansion to criminal justice reform, in order to implement Medicaid expansion across the South.