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1.
Artículo en Inglés | MEDLINE | ID: mdl-38574825

RESUMEN

BACKGROUND: Allergic sensitization and low lung function in early childhood are risk factors for subsequent wheezing and asthma. However, it is unclear how allergic sensitization affects lung function over time. OBJECTIVE: We sought to test whether allergy influences lung function and whether these factors synergistically increase the risk of continued wheezing in childhood. METHODS: We analyzed longitudinal measurements of lung function (spirometry and impulse oscillometry) and allergic sensitization (aeroallergen skin tests and serum allergen-specific IgE) throughout early childhood in the Urban Environmental and Childhood Asthma study, which included high-risk urban children living in disadvantaged neighborhoods. Intraclass correlation coefficients were calculated to assess lung function stability. Cluster analysis identified low, medium, and high allergy trajectories, which were compared with lung function and wheezing episodes in linear regression models. A variable selection model assessed predictors at age 5 years for continued wheezing through age 12 years. RESULTS: Lung function adjusted for growth was stable (intraclass correlation coefficient, 0.5-0.7) from age 5 to 12 years and unrelated to allergy trajectory. Lung function and allergic sensitization were associated with wheezing episodes in an additive fashion. In children with asthma, measuring lung function at age 5 years added little to the medical history for predicting future wheezing episodes through age 12 years. CONCLUSIONS: In high-risk urban children, age-related trajectories of allergic sensitization were not associated with lung function development; however, both indicators were related to continued wheezing. These results underscore the importance of understanding early-life factors that negatively affect lung development and suggest that treating allergic sensitization may not alter lung function development in early to mid-childhood.

2.
J Intensive Care Med ; 37(7): 917-924, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34541951

RESUMEN

Purpose: Data on the use of transesophageal echocardiography (TEE) by intensivist physicians (IP) and emergency physicians (EP) are limited. This study aims to characterize the use of TEE by IPs and EPs in critically ill patients at a single center in the United States. Materials and Methods: Retrospective chart review of all critical care TEEs performed from January 1, 2016 to January 31, 2021. The personnel performing the exams, location of the exams, characteristics of exams, complications, and outcome of the patients were reviewed. Results: A total of 396 examinations was reviewed. TEE was performed by IPs (92%) and EPs (9%). The location of TEE included: intensive care unit (87%), emergency department (11%), and prehospital (2%) settings. The most common indications for TEE were: hemodynamic instability/shock (44%), cardiac arrest (23%), and extracorporeal membrane oxygenation (ECMO) facilitation, adjustment, or weaning (21%). The most common diagnosis based on TEE were: normal TEE (25%), left ventricular dysfunction (19%), and vasodilatory shock (15%). A management change resulted from 89% of exams performed. Complications occurred in 2% of critical care TEEs. Conclusion: TEE can be successfully performed by IPs and EPs on critically ill patients in multiple clinical settings. TEE frequently informed management changes with few complications.


Asunto(s)
Enfermedad Crítica , Médicos , Cuidados Críticos , Enfermedad Crítica/terapia , Ecocardiografía Transesofágica/efectos adversos , Humanos , Estudios Retrospectivos
3.
J Pediatr Nurs ; 30(4): 611-5, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25482982

RESUMEN

Recent statistics show an increasing trend of electronic cigarette usage among adolescents. Despite common misconceptions, electronic cigarette use does not reduce cigarette use among adolescents and can potentially increase cigarette dependence via nicotine addiction and modeling of smoking behaviors. Pediatric nurses and health care providers should be aware of the popularity and safety concerns of electronic cigarettes so that they can properly provide education regarding the possible negative health effects of adolescent electronic cigarette use, raise awareness of this public health concern, and impact policies in their communities.


Asunto(s)
Conducta del Adolescente , Sistemas Electrónicos de Liberación de Nicotina/efectos adversos , Enfermería Pediátrica , Asunción de Riesgos , Adolescente , Humanos
4.
J Inj Violence Res ; 16(1)2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38439555

RESUMEN

BACKGROUND: Drowning is a worldwide problem. Scholarly publications about drowning prevention play a crucial role in bringing data to policy makers and prevention specialists. This study presents a bibliometric analysis of published articles related to unintentional drowning prevention included in the comprehensive, curated injury literature database, SafetyLit®. METHODS: Thorough searches of drowning-related search terms in English and non- English translations identified articles published in journals between 2000 and 2022. RESULTS: There was a 3-fold increase in publications between 2000 and 2022, with 2,937 articles published in 941 journals. Articles were published in 20 different languages. Five journals published 16% of the articles and sixty-one top journals published 50% of the articles. Eighty-nine percent of the top journals were included in PubMed; 82% were indexed in MEDLINE®; and professional areas of expertise of article authors spanned 18 categories. CONCLUSIONS: This study can facilitate journal selection for drowning researchers to ultimately increase the publication of scientific literature globally.

5.
Inj Epidemiol ; 11(1): 23, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38858694

RESUMEN

BACKGROUND: Sport-related injuries and illnesses can negatively impact athlete welfare at all standards of participation in team sports. Injury and illness surveillance (IIS), and the development of monitoring systems, initiates the sequence of injury and illness prevention. Operational IIS monitoring systems help to appraise epidemiological estimates of injury and illness incidence and burden in various athlete populations. However, the methodological underpinnings of various monitoring systems are not harmonized or widely documented, with the presence of efficient and successful programmes rarely showcased at non-elite levels. The aim is to provide a framework that guides the development of IIS, which will enhance overall surveillance, to indirectly inform injury prevention strategies. METHODS: The process involved all members of the research group initially discussing the research gaps, scope of the project, and the aims of the article. Unique experiences were shared, and specific and global challenges and barriers to IIS at all standards of team sport participation were identified. A tiered system of data collection with corresponding content were produced, with experiences and guidance provided throughout the article. RESULTS: The literature has been reviewed and using first-hand experience in conducting IIS programmes in complex and diverse sport settings, the authors have identified key enablers and barriers for best practise as time, technological and human resources, reporter/practitioner training, and medical expertise. Areas of greatest importance regarding the conducting of IIS have been outlined, providing guidance and recommendations across all levels of team sport participation. These areas include definitions, data context, collection procedures, handling, security, ethics, storage, dissemination, quality, compliance, and analysis. Given the barriers to IIS, 3-tiered levels of data collection and content have been proposed. The levels indicate data collection variables, with a focus on sufficiency and achievability, aiming to support the successful conducting of IIS in team sports across all standards of participation. Future opportunities in IIS have been discussed, with several predictive measures and analytical techniques expanded upon. CONCLUSIONS: The framework provides universal guidance for implementing IIS monitoring systems, facilitating athletes, coaches, parents/guardians, governing bodies and practitioners to implement IIS processes, identify challenges, complete analysis, and interpret outcomes at all standards of participation.

6.
NEJM Evid ; 3(6): EVIDoa2300311, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38804779

RESUMEN

BACKGROUND: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption. METHODS: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months. RESULTS: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 µg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 µg/l. Adverse events were uncommon, and the majority were related to the food challenge. CONCLUSIONS: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.).


Asunto(s)
Arachis , Hipersensibilidad al Cacahuete , Humanos , Hipersensibilidad al Cacahuete/prevención & control , Hipersensibilidad al Cacahuete/inmunología , Hipersensibilidad al Cacahuete/epidemiología , Estudios de Seguimiento , Arachis/inmunología , Femenino , Masculino , Preescolar , Lactante , Adolescente , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Niño , Tolerancia Inmunológica
7.
Inj Epidemiol ; 10(Suppl 1): 65, 2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38093267

RESUMEN

BACKGROUND: Drowning is the leading cause of death for toddlers. When caregivers are knowledgeable about water safety, they can provide the best protection against drowning. The aim of this study is to survey caregivers of toddlers to better understand factors associated with water safety knowledge, attitudes about pool supervision, and toddler water competency skills. METHODS: An online survey of 650 parents/caregivers of 1-4-year-old toddlers asked about the caregiver's water safety and swimming background and views on pool supervision. Surveys included a true/false section of ten basic water safety knowledge questions. Caregivers also reported on toddler swim lesson history and whether their toddler could perform six standard water competency skills. Linear regression identified factors predictive of water safety knowledge. RESULTS: On average, caregivers selected the correct answer on six out of ten water safety knowledge questions. Water safety knowledge was predicted by the relationship of the caregiver to the toddler, gender, race, education, prior CPR training, caregiver swim capability, and reported pool supervision style. On average, caregivers reported that their toddler could perform half of the water competency skills. The majority of the toddlers had taken swimming lessons. One third of caregivers believed that after a toddler has had swimming lessons, they don't need to be watched as closely when they are in a pool. CONCLUSIONS: Findings suggest that water safety knowledge is poor and that there are misconceptions about toddler supervision needs. Efforts are needed to improve water safety knowledge and to change perceptions about supervision among caregivers of toddlers.

8.
Front Aging ; 4: 1090087, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37214774

RESUMEN

Deterioration in movement and posture often occurs with aging. Yet there may be approaches to movement training that can maintain posture and movement coordination patterns as we age. The Alexander Technique is a non-exercise-based approach that aims to improve everyday movement and posture by increasing awareness and modulating whole-body postural muscle activity. This study assessed whether nineteen 55-72-year-old Alexander Technique teachers showed different posture and movement coordination patterns than twenty age-matched controls during a standing and walking protocol using 3D inertial sensors. During upright stance, Alexander Technique teachers showed lower centroidal sway frequency at the ankle (p = .04) and lower normalized jerk at the sternum (p = .05) than controls. During gait, Alexander Technique teachers had more symmetrical gait cycles (p = .04), more symmetrical arm swing velocity (p = .01), greater arm swing velocity (p < .01), greater arm swing range of motion (p = .02), and lower range of acceleration of the torso in the frontal plane (p = .03) than controls. Smoother control of upright posture, more stable torso motion, and less restrained arm mobility suggest that Alexander Technique training may counter movement degradation that is found with aging. Results highlight the important balance between mobility and stability within the torso and limbs.

9.
Inj Epidemiol ; 10(Suppl 1): 64, 2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-38087381

RESUMEN

Drowning is a major public health issue internationally. In August 2022, a report was released by members of the Central Texas Drowning Prevention Action Team that provided data on drowning fatalities in Texas between 2006 and 2020 and offered recommendations for drowning prevention actions. The information in the Texas drowning report is an important contribution to the field of injury prevention. The aim of this editorial is to allow the information in the report to be available to a wider audience and potentially used as a model for other states.

10.
R Soc Open Sci ; 10(9): 230444, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37711143

RESUMEN

We tested whether Shoshone pupfish Cyprinodon nevadensis shoshone and Amargosa River pupfish C. n. amargosae respond behaviourally to conspecific chemical alarm cues released when epidermal tissue is damaged by a predator. We found that both subspecies reduced activity and vertical position in the water column in response to alarm cues. We then tested if pupfish can use alarm cue to acquire recognition of a novel predator. We trained pupfish with (1) water + odour of largemouth bass fed a diet of earthworms, (2) alarm cues from skin extract (epidermal alarm cues) + odour of bass fed a diet of earthworms, or (3) water + odour of bass fed a diet of pupfish (dietary alarm cues). Pupfish responded to epidermal alarm cues but not to dietary alarm cues. Pupfish were retested with the odour of bass that were fed an earthworm diet. Pupfish that had previously received epidermal alarm cues reduced vertical position and activity relative to the other two treatments. This is the first demonstration of acquired recognition of a novel predator by a pupfish, the first report of partial predator naiveté, and opens the possibility of predator-recognition training as a tool for management and conservation of endangered desert fishes.

11.
Healthc Financ Manage ; 66(8): 70-7, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22931029

RESUMEN

Implementing an effective clinical integration program requires deliberate investment of time and resources in five key areas: Physician leadership, Physician-led care management, Quality monitoring, Patient information and data sharing, Payer engagement.


Asunto(s)
Organizaciones Responsables por la Atención , Integración de Sistemas , Gestión de la Información/organización & administración , Reembolso de Seguro de Salud , Liderazgo , Registro Médico Coordinado , Innovación Organizacional , Rol del Médico , Control de Calidad , Estados Unidos
12.
Int J Crit Illn Inj Sci ; 12(4): 184-189, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36779217

RESUMEN

Background: Groups of children swimming during summer camp or child care are generally monitored by a small number of lifeguards and staff. The high child-to-staff ratio can make pool monitoring less effective, increasing drowning risk. The aim of this study is to evaluate novel drowning detection technology that could supplement pool monitoring. Methods: The WAVE™ Drowning Detection System was deployed at a camp pool for 8 weeks. The WAVE™ Drowning Detection System entails headbands worn by swimmers that send alerts to vibrating staff bracelets and audible alarms when submerged for a period of time. Data on the number of alerts were collected, and staff were surveyed. Results: One or two alerts were initiated every hour. Staff reported that risky underwater play and exiting the pool area were top reasons for alerts. Staff found the awareness brought to risky pool behavior useful and had a neutral attitude about false alarms. Staff found the system easy to learn and use but suggested headband fit and comfort could be improved. Staff believed the system could help save someone's life. Conclusions: The WAVE system is low-risk, easy-to-use technology that may supplement lifeguard monitoring of large groups of children in pools.

13.
Mol Ther Methods Clin Dev ; 25: 476-489, 2022 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-35615708

RESUMEN

Gene therapy is a rapidly developing field, and adeno-associated viruses (AAVs) are a leading viral-vector candidate for therapeutic gene delivery. Newly engineered AAVs with improved abilities are now entering the clinic. It has proven challenging, however, to predict the translational potential of gene therapies developed in animal models due to cross-species differences. Human retinal explants are the only available model of fully developed human retinal tissue and are thus important for the validation of candidate AAV vectors. In this study, we evaluated 18 wild-type and engineered AAV capsids in human retinal explants using a recently developed single-cell RNA sequencing (RNA-seq) AAV engineering pipeline (scAAVengr). Human retinal explants retained the same major cell types as fresh retina, with similar expression of cell-specific markers except for a photoreceptor population with altered expression of photoreceptor-specific genes. The efficiency and tropism of AAVs in human explants were quantified with single-cell resolution. The top-performing serotypes, K91, K912, and 7m8, were further validated in non-human primate and human retinal explants. Together, this study provides detailed information about the transcriptome profiles of retinal explants and quantifies the infectivity of leading AAV serotypes in human retina, accelerating the translation of retinal gene therapies to the clinic.

14.
Inj Epidemiol ; 9(Suppl 1): 40, 2022 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-36544224

RESUMEN

BACKGROUND: Drowning is a leading cause of unintentional injury-related death for toddlers within the USA. Keeping toddlers within arm's reach while swimming is recommended, yet many caregivers do not. Possibly, caregivers' attitudes are shaped by their expectations about whether they could quickly save a child. The aims of this study are to 1) explore caregivers' views of arm's reach pool supervision in various scenarios and 2) understand whether perceptions of arm's reach pool supervision are impacted by the caregiver's self-reported capability to swim the length of a standard pool. RESULTS: Caregivers generally showed agreement with arm's reach pool supervision; however, arm's reach supervision was viewed as less necessary when a toddler was in shallow water, wearing a flotation device, or with an older child or teen. There was a significant effect of caregiver swimming capability on perceptions of arm's reach pool supervision, with non-swimmers and the strongest swimmers showing more positive perceptions of arm's reach pool supervision than caregivers reporting poor swimming capability. Female caregivers showed significantly more agreement with arm's reach pool supervision compared with male caregivers. Grandparents and parents showed significantly more agreement with arm's reach pool supervision than siblings. CONCLUSIONS: Caregivers' views about what constitutes appropriate supervision are impacted by gender, the relationship to the toddler, and the caregiver's swimming capability. Findings suggest that a caregiver's ability to offer close supervision or respond in an emergency may influence their attitudes about what constitutes appropriate supervision. Caregivers may view arm's reach pool supervision as less necessary when additional layers of protection are in place.

15.
Nat Commun ; 13(1): 2300, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35484108

RESUMEN

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett's esophagus compared to 40 Barrett's patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett's tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett's versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett's esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.


Asunto(s)
Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Adenocarcinoma/patología , Esófago de Barrett/genética , Esófago de Barrett/patología , Progresión de la Enfermedad , Neoplasias Esofágicas/patología , Humanos
16.
Arch Phys Med Rehabil ; 92(7): 1053-9, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21704784

RESUMEN

OBJECTIVE: To examine sex differences in lumbopelvic motion and symptom behavior during hip medial rotation in people with low back pain (LBP). We hypothesized that men would demonstrate greater and earlier lumbopelvic motion and would be more likely to report increased symptoms compared with women. DESIGN: Cross-sectional observational study. SETTING: University musculoskeletal analysis laboratory. PARTICIPANTS: Persons with chronic LBP (N=59; 30 men, 29 women) were recruited from the community and a university-based physical therapy clinic. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Lumbopelvic rotation range of motion, amount of hip rotation completed before the start of lumbopelvic motion, and provocation of LBP symptoms during the test of prone hip medial rotation were measured. RESULTS: Men demonstrated significantly more lumbopelvic rotation (men, 10.0°±5.1°; women, 4.5°±3.9°; P<.001) and completed less hip rotation before the start of lumbopelvic motion (men, 5.4°±3.8°; women, 16.0°±13.2°; P<.001) compared with women. Additionally, a significantly greater percentage of men (60.0%) than women (34.5%; P=.050) reported increased symptoms with hip medial rotation. CONCLUSIONS: Men could be at greater risk than women for experiencing LBP symptoms related to hip medial rotation as a result of greater and earlier lumbopelvic motion.


Asunto(s)
Dolor de la Región Lumbar/fisiopatología , Movimiento/fisiología , Rango del Movimiento Articular/fisiología , Adulto , Enfermedad Crónica , Estudios Transversales , Femenino , Articulación de la Cadera/fisiología , Humanos , Dolor de la Región Lumbar/rehabilitación , Región Lumbosacra/fisiopatología , Masculino , Persona de Mediana Edad , Pelvis/fisiopatología , Rotación , Factores Sexuales
17.
Healthc Financ Manage ; 65(4): 56-66, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21548429

RESUMEN

When assessing the financial implications of a physician alignment and clinical integration initiative, a hospital should measure the initiative's potential ROI, perhaps best using a combination of net present value and payback period. The hospital should compare its own historical and projected performance with rating agency median benchmarks for key financial indicators of profitability, debt service, capital and cash flow, and liquidity. The hospital should also consider potential indirect benefits, such as retained outpatient/ancillary revenue, increased inpatient revenue, improved cost control, and improved quality and reporting transparency.


Asunto(s)
Financiación del Capital , Prestación Integrada de Atención de Salud , Economía Hospitalaria/organización & administración , Prestación Integrada de Atención de Salud/economía , Relaciones Médico-Hospital , Estados Unidos
18.
Crit Care Clin ; 37(3): 501-516, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34053703

RESUMEN

Over the last 2 decades, prescription and nonprescription substance use has significantly increased. In this article, 3 particular drug classes-opioids, sedatives, and hypnotics-are discussed. For each class, a brief history of the agent, a description of relevant pharmacology, the clinical presentation of overdose, the management of specific drug overdoses, and a summary of salient points are presented. The intent is to provide a clinically relevant and comprehensive approach to understanding these potential substance exposures in order to provide a framework for management of opioid, sedative, and hypnotic overdoses.


Asunto(s)
Sobredosis de Droga , Preparaciones Farmacéuticas , Analgésicos Opioides/efectos adversos , Benzodiazepinas , Humanos , Hipnóticos y Sedantes/efectos adversos
19.
J Inj Violence Res ; 13(2)2021 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-34519279

RESUMEN

BACKGROUND: In the U.S., drowning is a leading cause of death for toddlers. One important layer of protection against submersion injuries and fatalities is parent or caregiver supervision. The aims of this study are to explore current supervisory behavior of caregivers, determine how caregivers view com-mon supervision distractions, like cell phones and grilling, and identify what factors shape the quality of supervision that is given when swimming with their toddler at a swimming pool. METHODS: This cross-sectional study used the MTurk online platform to survey 650 caregivers of toddlers (1-4 yrs old) about their supervision behavior, their drowning knowledge, their perceptions of arm's reach supervision, the water competency of their toddler, and other background information. Regression analysis was used to identify factors that predicted report-ed supervision behavior. RESULTS: The average supervision behavior score for caregivers indicated an attitude between neutral and disagreement with allowing distractions for themselves while supervising their toddler in a swimming pool. High water safety knowledge and positive perceptions of arm's reach supervision were the biggest predictors of attentive supervision behavior. Having a home pool, higher education level, and believing their toddler had greater water competency were predictive of less attentive supervision behavior. CONCLUSIONS: Results suggest that supervision behavior while toddlers are in a swimming pool may be inade-quate. Low water safety knowledge and attitudes about what constitutes quality supervision are related to pool supervision behavior and changing these may reduce drowning risk. Caregivers should be encouraged to not reduce supervision as their toddlers gain water competency and if they have a home pool.

20.
Elife ; 102021 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-34664552

RESUMEN

Background: Adeno-associated virus (AAV)-mediated gene therapies are rapidly advancing to the clinic, and AAV engineering has resulted in vectors with increased ability to deliver therapeutic genes. Although the choice of vector is critical, quantitative comparison of AAVs, especially in large animals, remains challenging. Methods: Here, we developed an efficient single-cell AAV engineering pipeline (scAAVengr) to simultaneously quantify and rank efficiency of competing AAV vectors across all cell types in the same animal. Results: To demonstrate proof-of-concept for the scAAVengr workflow, we quantified - with cell-type resolution - the abilities of naturally occurring and newly engineered AAVs to mediate gene expression in primate retina following intravitreal injection. A top performing variant identified using this pipeline, K912, was used to deliver SaCas9 and edit the rhodopsin gene in macaque retina, resulting in editing efficiency similar to infection rates detected by the scAAVengr workflow. scAAVengr was then used to identify top-performing AAV variants in mouse brain, heart, and liver following systemic injection. Conclusions: These results validate scAAVengr as a powerful method for development of AAV vectors. Funding: This work was supported by funding from the Ford Foundation, NEI/NIH, Research to Prevent Blindness, Foundation Fighting Blindness, UPMC Immune Transplant and Therapy Center, and the Van Sloun fund for canine genetic research.


Gene therapy is an experimental approach to treating disease that involves altering faulty genes or replacing them with new, working copies. Most often, the new genetic material is delivered into cells using a modified virus that no longer causes disease, called a viral vector. Virus-mediated gene therapies are currently being explored for degenerative eye diseases, such as retinitis pigmentosa, and neurological disorders, like Alzheimer's and Parkinson's disease. A number of gene therapies have also been approved for treating some rare cancers, blood disorders and a childhood form of motor neuron disease. Despite the promise of virus-mediated gene therapy, there are significant hurdles to its widespread success. Viral vectors need to deliver enough genetic material to the right cells without triggering an immune response or causing serious side effects. Selecting an optimal vector is key to achieving this. A type of viruses called adeno-associated viruses (AAV) are prime candidates, partly because they can be easily engineered. However, accurately comparing the safety and efficacy of newly engineered AAVs is difficult, due to variation between test subjects and the labor and cost involved in careful testing. Öztürk et al. addressed this issue by developing an experimental pipeline called scAAVengr for comparing gene therapy vectors head-to-head. The process involves tagging potential AAV vectors with unique genetic barcodes, which can then be detected and quantified in individual cells using a technique called single-cell RNA sequencing. This means that when several vectors are used to infect lab-grown cells or a test animal at the same time, they can be tracked. The vectors can then be ranked on their ability to infect specific cell types and deliver useful genetic material. Using scAAVengr, Öztürk et al. compared viral vectors designed to target the light-sensitive cells of the retina, which allow animals to see. First, a set of promising viral vectors were evaluated using the scAAVengr pipeline in the eyes of marmosets and macaques, two small primates. Precise levels and locations of gene delivery were quantified. The top-performing vector was then identified and used to deliver Cas9, a genome editing tool, to primate retinas. Öztürk et al. also used scAAVengr to compare viral vectors in mice, analysing the vectors' ability to deliver their genetic cargo to the brain, heart, and liver. These experiments demonstrated that scAAVengr can be used to evaluate vectors in multiple tissues and in different organisms. In summary, this work outlines a method for identifying and precisely quantifying the performance of top-performing viral vectors for gene therapy. By aiding the selection of optimal viral vectors, the scAAVengr pipeline could help to improve the success of preclinical studies and early clinical trials testing gene therapies.


Asunto(s)
Dependovirus/fisiología , Perfilación de la Expresión Génica/métodos , Macaca fascicularis/fisiología , Retina/fisiología , Transcriptoma , Transducción Genética , Animales , Vectores Genéticos
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