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1.
Hum Mol Genet ; 33(5): 448-464, 2024 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-37975905

RESUMEN

Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Toward this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with a homozygous frameshift mutation (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of subretinal deposits near the optic disc, disruption of the outer retina, and neurosensorial detachment, whereas the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP and provide a toolkit and preclinical data for advancing therapeutic approaches.


Asunto(s)
Proteoglicanos , Retinitis Pigmentosa , Humanos , Animales , Ratones , Adulto , Proteoglicanos/genética , Retina , Mutación , Retinitis Pigmentosa/genética , Progresión de la Enfermedad
2.
Hum Mol Genet ; 30(8): 644-657, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-33709122

RESUMEN

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is required for nuclear nicotinamide adenine mononucleotide (NAD+) biosynthesis in all nucleated cells, and despite its functional ubiquity, mutations in this gene lead to an isolated retinal degeneration. The mechanisms underlying how mutant NMNAT1 causes disease are not well understood, nor is the reason why the pathology is confined to the retina. Using a mouse model of NMNAT1-associated retinal degeneration that harbors the p.Val9Met mutation, we tested the hypothesis that decreased function of mutant NMNAT1 has a greater effect on the levels of NAD+ in the retina than elsewhere in the body. Measurements by liquid chromatography with tandem mass spectrometry showed an early and sustained decrease of NAD+ in mutant retinas that was not observed in other tissues. To understand how consumers of nuclear NAD+ are affected by the reduced availability of NAD+ in mutant retinas, poly(ADP-ribose) polymerase (PARP) and nuclear sirtuin activity were evaluated. PARP activity was elevated during disease progression, as evidenced by overproduction of poly(ADP-ribose) (PAR) in photoreceptors, whereas histone deacetylation activity of nuclear sirtuins was not altered. We hypothesized that PARP could be activated because of elevated levels of oxidative stress; however, we did not observe oxidative DNA damage, lipid peroxidation, or a low glutathione to oxidized glutathione ratio. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed that photoreceptors appear to ultimately die by apoptosis, although the low NAD+ levels and overproduction of PAR suggest that cell death may include aspects of the parthanatos cell death pathway.


Asunto(s)
Modelos Animales de Enfermedad , Mutación , NAD/metabolismo , Nicotinamida-Nucleótido Adenililtransferasa/genética , Poli Adenosina Difosfato Ribosa/metabolismo , Retina/metabolismo , Degeneración Retiniana/genética , Animales , Apoptosis/genética , Cromatografía Liquida , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Nicotinamida-Nucleótido Adenililtransferasa/metabolismo , Estrés Oxidativo , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Degeneración Retiniana/metabolismo , Sirtuinas/metabolismo , Espectrometría de Masas en Tándem
3.
Anesthesiology ; 138(3): 264-273, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36538355

RESUMEN

BACKGROUND: The authors previously reported a broad suite of individualized Risk Stratification Index 3.0 (Health Data Analytics Institute, Inc., USA) models for various meaningful outcomes in patients admitted to a hospital for medical or surgical reasons. The models used International Classification of Diseases, Tenth Revision, trajectories and were restricted to information available at hospital admission, including coding history in the previous year. The models were developed and validated in Medicare patients, mostly age 65 yr or older. The authors sought to determine how well their models predict utilization outcomes and adverse events in younger and healthier populations. METHODS: The authors' analysis was based on All Payer Claims for surgical and medical hospital admissions from Utah and Oregon. Endpoints included unplanned hospital admissions, in-hospital mortality, acute kidney injury, sepsis, pneumonia, respiratory failure, and a composite of major cardiac complications. They prospectively applied previously developed Risk Stratification Index 3.0 models to the younger and healthier 2017 Utah and Oregon state populations and compared the results to their previous out-of-sample Medicare validation analysis. RESULTS: In the Utah dataset, there were 55,109 All Payer Claims admissions across 40,710 patients. In the Oregon dataset, there were 21,213 admissions from 16,951 patients. Model performance on the two state datasets was similar or better than in Medicare patients, with an average area under the curve of 0.83 (0.71 to 0.91). Model calibration was reasonable with an R2 of 0.93 (0.84 to 0.97) for Utah and 0.85 (0.71 to 0.91) for Oregon. The mean sensitivity for the highest 5% risk population was 28% (17 to 44) for Utah and 37% (20 to 56) for Oregon. CONCLUSIONS: Predictive analytical modeling based on administrative claims history provides individualized risk profiles at hospital admission that may help guide patient management. Similar predictive performance in Medicare and in younger and healthier populations indicates that Risk Stratification Index 3.0 models are valid across a broad range of adult hospital admissions.


Asunto(s)
Hospitalización , Medicare , Adulto , Humanos , Anciano , Estados Unidos , Hospitales , Factores de Riesgo , Medición de Riesgo
4.
Anesthesiology ; 137(6): 673-686, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36129680

RESUMEN

BACKGROUND: Risk stratification helps guide appropriate clinical care. Our goal was to develop and validate a broad suite of predictive tools based on International Classification of Diseases, Tenth Revision, diagnostic and procedural codes for predicting adverse events and care utilization outcomes for hospitalized patients. METHODS: Endpoints included unplanned hospital admissions, discharge status, excess length of stay, in-hospital and 90-day mortality, acute kidney injury, sepsis, pneumonia, respiratory failure, and a composite of major cardiac complications. Patient demographic and coding history in the year before admission provided features used to predict utilization and adverse events through 90 days after admission. Models were trained and refined on 2017 to 2018 Medicare admissions data using an 80 to 20 learn to test split sample. Models were then prospectively tested on 2019 out-of-sample Medicare admissions. Predictions based on logistic regression were compared with those from five commonly used machine learning methods using a limited dataset. RESULTS: The 2017 to 2018 development set included 9,085,968 patients who had 18,899,224 inpatient admissions, and there were 5,336,265 patients who had 9,205,835 inpatient admissions in the 2019 validation dataset. Model performance on the validation set had an average area under the curve of 0.76 (range, 0.70 to 0.82). Model calibration was strong with an average R 2 for the 99% of patients at lowest risk of 1.00. Excess length of stay had a root-mean-square error of 0.19 and R 2 of 0.99. The mean sensitivity for the highest 5% risk population was 19.2% (range, 11.6 to 30.1); for positive predictive value, it was 37.2% (14.6 to 87.7); and for lift (enrichment ratio), it was 3.8 (2.3 to 6.1). Predictive accuracies from regression and machine learning techniques were generally similar. CONCLUSIONS: Predictive analytical modeling based on administrative claims history can provide individualized risk profiles at hospital admission that may help guide patient management. Similar results from six different modeling approaches suggest that we have identified both the value and ceiling for predictive information derived from medical claims history.


Asunto(s)
Hospitalización , Medicare , Humanos , Anciano , Estados Unidos/epidemiología , Modelos Logísticos , Medición de Riesgo , Hospitales , Estudios Retrospectivos
5.
Hum Mol Genet ; 27(11): 2012-2024, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29659833

RESUMEN

Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outersegments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography (ERG) responses by 1 month and complete outer-nuclear layer (ONL) degeneration by 2 months. We investigated molecular mechanisms of degeneration and show that IFT172 protein reduction leads to mislocalization of specific photoreceptor outersegment (OS) proteins (RHO, RP1, IFT139), aberrant light-driven translocation of alpha transducin and altered localization of glioma-associated oncogene family member 1 (GLI1). This mouse model exhibits key features of the retinal phenotype observed in patients with IFT172-associated blindness and can be used for in vivo testing of ciliopathy therapies.


Asunto(s)
Proteínas Portadoras/genética , Cilios/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Degeneración Retiniana/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Cilios/patología , Proteínas del Citoesqueleto , Modelos Animales de Enfermedad , Electrorretinografía , Humanos , Ratones , Ratones Noqueados , Mutación , Retina/diagnóstico por imagen , Retina/patología , Degeneración Retiniana/diagnóstico por imagen , Degeneración Retiniana/patología , Células Fotorreceptoras Retinianas Bastones/patología , Proteína con Dedos de Zinc GLI1/genética
6.
Adv Exp Med Biol ; 1185: 323-327, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31884632

RESUMEN

Parthanatos is a programmed cell death pathway mediated by the effects of pathogenically high levels of poly(ADP-ribose) polymerase 1 (PARP1) activity. This process underlies a broad range of diseases affecting many tissues and organs across the body, including the retina. This chapter reviews mechanisms that are currently understood to drive parthanatos in the context of retinal diseases associated with this form of cell death. Toxicity of upregulated poly(ADP-ribose) (PAR) content, NAD+ and ATP depletion, translocation of apoptosis-inducing factor (AIF) to the nucleus, and loss of glycolytic function are discussed. Since therapies that preserve vulnerable cells remain elusive for the vast majority of retinal diseases, pharmacologically blocking parthanatos may be an effective treatment strategy for cases in which this process contributes to pathogenesis.


Asunto(s)
Parthanatos , Enfermedades de la Retina/patología , Factor Inductor de la Apoptosis , Humanos , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli Adenosina Difosfato Ribosa , Transporte de Proteínas
7.
Am J Pathol ; 186(7): 1925-1938, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27207593

RESUMEN

The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would provide a resource for testing treatment options. To this end, we identified two separate N-ethyl-N-nitrosourea-generated mouse lines that harbor either a p.V9M or a p.D243G mutation. Both mouse models recapitulate key aspects of the human disease and confirm the pathogenicity of mutant NMNAT1. Homozygous Nmnat1 mutant mice develop a rapidly progressing chorioretinal disease that begins with photoreceptor degeneration and includes attenuation of the retinal vasculature, optic atrophy, and retinal pigment epithelium loss. Retinal function deteriorates in both mouse lines, and, in the more rapidly progressing homozygous Nmnat1(V9M) mutant mice, the electroretinogram becomes undetectable and the pupillary light response weakens. These mouse models offer an opportunity for investigating the cellular mechanisms underlying disease pathogenesis, evaluating potential therapies for NMNAT1-Leber congenital amaurosis, and conducting in situ studies on NMNAT1 function and NAD(+) metabolism.


Asunto(s)
Modelos Animales de Enfermedad , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/fisiopatología , Nicotinamida-Nucleótido Adenililtransferasa/genética , Animales , Genotipo , Humanos , Ratones , Ratones Mutantes , Reacción en Cadena de la Polimerasa
8.
Vis Neurosci ; 31(1): 25-37, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24801621

RESUMEN

Specific variants of human long-wavelength (L) and middle-wavelength (M) cone opsin genes have recently been associated with a variety of vision disorders caused by cone malfunction, including red-green color vision deficiency, blue cone monochromacy, myopia, and cone dystrophy. Strikingly, unlike disease-causing mutations in rhodopsin, most of the cone opsin alleles that are associated with vision disorders do not have deleterious point mutations. Instead, specific combinations of normal polymorphisms that arose by genetic recombination between the genes encoding L and M opsins appear to cause disease. Knockout/knock-in mice promise to make it possible to study how these deleterious cone opsin variants affect the structure, function, and viability of the cone photoreceptors. Ideally, we would like to evaluate different variants that cause vision disorders in humans against a control pigment that is not associated with vision disorders, and each variant should be expressed as the sole photopigment in each mouse cone, as is the case in humans. To evaluate the feasibility of this approach, we created a line of mice to serve as the control in the analysis of disease-causing mutations by replacing exon 2 through 6 of the mouse M-opsin gene with the corresponding cDNA for a human L-opsin variant that is associated with normal vision. Experiments reported here establish that the resulting pigment, which differs from the endogenous mouse M opsin at 35 amino acid positions, functions normally in mouse cones. This pigment was evaluated in mice with and without coexpression of the mouse short wavelength (S) opsin. Here, the creation and validation of two lines of genetically engineered mice that can be used to study disease-causing variants of human L/M-opsins, in vivo, are described.


Asunto(s)
Modelos Animales , Opsinas/genética , Secuencia de Aminoácidos , Animales , Electrorretinografía , Técnicas de Genotipaje , Humanos , Inmunohistoquímica , Ratones , Ratones Noqueados , Opsinas/química , ARN Mensajero/aislamiento & purificación , Proteínas Recombinantes , Transcripción Genética
9.
J Opt Soc Am A Opt Image Sci Vis ; 31(4): A208-13, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24695171

RESUMEN

The electroretinogram (ERG) provides information about outer retina function in both clinical and research applications. ERG components elicited by light increments and decrements can be separated using a long-flash paradigm in which periods of light ON and OFF are alternated. Here, the ON-OFF ERG is combined with a silent substitution technique to elicit responses from individual cone photoreceptor classes by modulating the intensities of three color lights between the two periods. The results focus on the short wavelength (S) cone pathways since they are vulnerable to disease and because there are many unanswered questions about S-cone ON and OFF circuitry.


Asunto(s)
Percepción de Color/fisiología , Electrorretinografía/métodos , Células Fotorreceptoras Retinianas Conos/citología , Transducción de Señal , Animales , Humanos , Papio
10.
J Bone Joint Surg Am ; 105(3): 214-222, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36723465

RESUMEN

BACKGROUND: Spine surgery has demonstrated cost-effectiveness in reducing pain and restoring function, but the impact of spine surgery relative to nonsurgical care on longer-term outcomes has been less well described. Our objective was to compare single-level surgical treatment for lumbar stenosis, with or without spondylolisthesis, and nonsurgical treatment with respect to patient mortality, resource utilization, and health-care payments over the first 2 years following initial treatment. METHODS: A retrospective review of the Medicare National Database Fee for Service Files from 2011 to 2017 was performed. A 2-year prediction of mortality risk (risk stratification index, RSI) was used as a measure of patient baseline health. Patients (88%) were matched by RSI and demographics. Mortality, spine-related health-care utilization, and 2-year total Medicare payments for patients undergoing surgical treatment were compared with matched patients undergoing nonsurgical treatment. RESULTS: We identified 61,534 patients with stenosis alone and 83,813 with stenosis and spondylolisthesis. Surgical treatment was associated with 28% lower 2-year mortality compared with matched patients undergoing nonsurgical treatment. Total Medicare payments were significantly lower for patients with stenosis alone undergoing laminectomy alone and for patients with stenosis and spondylolisthesis undergoing laminectomy with or without fusion compared with patients undergoing nonsurgical treatment. There was no significant difference in mortality when fusion or laminectomy was compared with combined fusion and laminectomy. However, laminectomy alone was associated with significantly lower 2-year payments when treating stenosis with or without spondylolisthesis. CONCLUSIONS: Surgical treatment for stenosis with or without spondylolisthesis within the Medicare population was associated with significantly lower mortality and total medical payments at 2 years compared with nonsurgical treatment, although residual confounding could have contributed to these findings. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Asunto(s)
Fusión Vertebral , Estenosis Espinal , Espondilolistesis , Humanos , Anciano , Estados Unidos , Constricción Patológica , Espondilolistesis/cirugía , Espondilolistesis/complicaciones , Estenosis Espinal/cirugía , Estenosis Espinal/complicaciones , Vértebras Lumbares/cirugía , Resultado del Tratamiento , Medicare , Laminectomía , Descompresión Quirúrgica
11.
Anesthesiology ; 116(6): 1195-203, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22546967

RESUMEN

BACKGROUND: Low mean arterial pressure (MAP) and deep hypnosis have been associated with complications and mortality. The normal response to high minimum alveolar concentration (MAC) fraction of anesthetics is hypotension and low Bispectral Index (BIS) scores. Low MAP and/or BIS at lower MAC fractions may represent anesthetic sensitivity. The authors sought to characterize the effect of the triple low state (low MAP and low BIS during a low MAC fraction) on duration of hospitalization and 30-day all-cause mortality. METHODS: Mean intraoperative MAP, BIS, and MAC were determined for 24,120 noncardiac surgery patients at the Cleveland Clinic, Cleveland, Ohio. The hazard ratios associated with combinations of MAP, BIS, and MAC values greater or less than a reference value were determined. The authors also evaluated the association between cumulative triple low minutes, and excess length-of-stay and 30-day mortality. RESULTS: Means (±SD) defining the reference, low, and high states were 87 ± 5 mmHg (MAP), 46 ± 4 (BIS), and 0.56 ± 0.11 (MAC). Triple lows were associated with prolonged length of stay (hazard ratio 1.5, 95% CI 1.3-1.7). Thirty-day mortality was doubled in double low combinations and quadrupled in the triple low group. Triple low duration ≥60 min quadrupled 30-day mortality compared with ≤15 min. Excess length of stay increased progressively from ≤15 min to ≥60 min of triple low. CONCLUSIONS: The occurrence of low MAP during low MAC fraction was a strong and highly significant predictor for mortality. When these occurrences were combined with low BIS, mortality risk was even greater. The values defining the triple low state were well within the range that many anesthesiologists tolerate routinely.


Asunto(s)
Anestesia por Inhalación , Anestésicos por Inhalación/metabolismo , Monitores de Conciencia , Hipotensión/mortalidad , Tiempo de Internación , Alveolos Pulmonares/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Anestesia General , Anestésicos por Inhalación/farmacocinética , Índice de Masa Corporal , Femenino , Mortalidad Hospitalaria , Humanos , Hipotensión/complicaciones , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Adulto Joven
12.
JAMA Ophthalmol ; 140(12): 1193-1200, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36301519

RESUMEN

Importance: Approximately 70% of crew members who complete long-duration missions to the International Space Station develop signs of optic disc edema, a hallmark finding of spaceflight-associated neuro-ocular syndrome. The onset and magnitude of edema differ across individuals, and the reason for this variability remains unknown. Identifying risk factors for spaceflight-induced disc edema is important because this condition may become more severe during extended-duration missions to the moon and Mars and could be associated with irreversible vision loss. Objective: To assess whether preflight indicators of crowded optic nerve head morphology, other ocular measures (such as choroid thickness and axial length), body weight, body mass index, sex, age, and previous flight experience are associated with optic disc edema development. Design, Setting, and Participants: This cohort study analyzed ocular, body weight, and demographic data collected from 31 US and international crew members before, during, and after spaceflight at the NASA Johnson Space Center and International Space Station. Ocular factors assessed included preflight and in-flight peripapillary total retinal thickness, minimum rim width, optic cup volume, mean cup depth, mean cup width, cup-disc ratio, Bruch membrane opening area, retinal nerve fiber layer thickness, choroid thickness, axial length, and refractive error. In addition, body weight, body mass index, sex, age, and previous spaceflight experience were assessed for associations with optic disc edema development. The data were analyzed from August 2021 to June 2022. Exposure: Approximately 6 to 12 months of spaceflight. Main Outcomes and Measures: In-flight increases in peripapillary total retinal thickness. Linear mixed models were used to assess for associations between a wide range of risk factors and in-flight increases in peripapillary total retinal thickness, which is a sensitive objective measure for detecting optic disc edema. Results: This study included 31 International Space Station crew members with a mean (SD) age of 46.9 (6.0) years (25 men [80.6%]). During spaceflight, mean (SE) peripapillary total retinal thickness increased from 392.0 (5.8) µm to 430.2 (9.6) µm (P < .001), and greater individual changes were associated with smaller preflight cup volume (slope [SE], -62.8 [18.9]; P = .002), shallower preflight cup depth (slope [SE], -0.11 [0.03]; P < .001), and narrower preflight cup width (slope [SE], -0.03 [0.01]; P = .03). No associations were observed between changes in peripapillary total retinal thickness and any other variable evaluated. Conclusions and Relevance: Findings of this cohort study suggest that smaller optic cup morphology may be associated with optic disc edema development during spaceflight. Crew members with this cup profile may benefit from enhanced ophthalmic monitoring during spaceflight and use of countermeasures against spaceflight-associated neuro-ocular syndrome.


Asunto(s)
Papiledema , Vuelo Espacial , Masculino , Humanos , Persona de Mediana Edad , Papiledema/diagnóstico , Papiledema/etiología , Estudios de Cohortes , Edema , Peso Corporal
13.
PLoS One ; 17(2): e0262264, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35108291

RESUMEN

We estimated excess mortality in Medicare recipients in the United States with probable and confirmed Covid-19 infections in the general community and amongst residents of long-term care (LTC) facilities. We considered 28,389,098 Medicare and dual-eligible recipients from one year before February 29, 2020 through September 30, 2020, with mortality followed through November 30th, 2020. Probable and confirmed Covid-19 diagnoses, presumably mostly symptomatic, were determined from ICD-10 codes. We developed a Risk Stratification Index (RSI) mortality model which was applied prospectively to establish baseline mortality risk. Excess deaths attributable to Covid-19 were estimated by comparing actual-to-expected deaths based on historical (2017-2019) comparisons and in closely matched concurrent (2020) cohorts with and without Covid-19. Overall, 677,100 (2.4%) beneficiaries had confirmed Covid-19 and 2,917,604 (10.3%) had probable Covid-19. A total of 472,329 confirmed cases were community living and 204,771 were in LTC. Mortality following a probable or confirmed diagnosis in the community increased from an expected incidence of about 4.0% to actual incidence of 7.5%. In long-term care facilities, the corresponding increase was from 20.3% to 24.6%. The absolute increase was therefore similar at 3-4% in the community and in LTC residents. The percentage increase was far greater in the community (89.5%) than among patients in chronic care facilities (21.1%) who had higher baseline risk of mortality. The LTC population without probable or confirmed Covid-19 diagnoses experienced 38,932 excess deaths (34.8%) compared to historical estimates. Limitations in access to Covid-19 testing and disease under-reporting in LTC patients probably were important factors, although social isolation and disruption in usual care presumably also contributed. Remarkably, there were 31,360 (5.4%) fewer deaths than expected in community dwellers without probable or confirmed Covid-19 diagnoses. Disruptions to the healthcare system and avoided medical care were thus apparently offset by other factors, representing overall benefit. The Covid-19 pandemic had marked effects on mortality, but the effects were highly context-dependent.


Asunto(s)
COVID-19/mortalidad , Medicare/tendencias , Anciano , Anciano de 80 o más Años , COVID-19/economía , Femenino , Humanos , Incidencia , Beneficios del Seguro/tendencias , Cuidados a Largo Plazo/tendencias , Masculino , Mortalidad , Factores de Riesgo , SARS-CoV-2/patogenicidad , Instituciones de Cuidados Especializados de Enfermería/tendencias , Estados Unidos
14.
JAMA Ophthalmol ; 140(8): 763-770, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35708665

RESUMEN

Importance: Countermeasures that reverse the headward fluid shift experienced in weightlessness have the potential to mitigate spaceflight-associated neuro-ocular syndrome. This study investigated whether use of the countermeasure lower-body negative pressure during spaceflight was associated with changes in ocular structure. Objective: To determine whether changes to the optic nerve head and retina during spaceflight can be mitigated by brief in-flight application of 25-mm Hg lower-body negative pressure. Design, Setting, and Participants: In the National Aeronautics and Space Administration's "Fluid Shifts Study," a prospective cohort study, optical coherence tomography scans of the optic nerve head and macula were obtained from US and international crew members before flight, in-flight, and up to 180 days after return to Earth. In-flight scans were obtained both under normal weightless conditions and 10 to 20 minutes into lower-body negative pressure exposure. Preflight and postflight data were collected in the seated, supine, and head-down tilt postures. Crew members completed 6- to 12-month missions that took place on the International Space Station. Data were analyzed from 2016 to 2021. Interventions or Exposures: Spaceflight and lower-body negative pressure. Main Outcomes and Measures: Changes in minimum rim width, optic cup volume, Bruch membrane opening height, peripapillary total retinal thickness, and macular thickness. Results: Mean (SD) flight duration for the 14 crew members (mean [SD] age, 45 [6] years; 11 male crew members [79%]) was 214 (72) days. Ocular changes on flight day 150, as compared with preflight seated, included an increase in minimum rim width (33.8 µm; 95% CI, 27.9-39.7 µm; P < .001), decrease in cup volume (0.038 mm3; 95% CI, 0.030-0.046 mm3; P < .001), posterior displacement of Bruch membrane opening (-9.0 µm; 95% CI, -15.7 to -2.2 µm; P = .009), and decrease in macular thickness (fovea to 500 µm, 5.1 µm; 95% CI, 3.5-6.8 µm; P < .001). Brief exposure to lower-body negative pressure did not affect these parameters. Conclusions and Relevance: Results of this cohort study suggest that peripapillary tissue thickening, decreased cup volume, and mild central macular thinning were associated with long-duration spaceflight. Acute exposure to 25-mm Hg lower-body negative pressure did not alter optic nerve head or retinal morphology, suggesting that longer durations of a fluid shift reversal may be needed to mitigate spaceflight-induced changes and/or other factors are involved.


Asunto(s)
Disco Óptico , Vuelo Espacial , Estudios de Cohortes , Transferencias de Fluidos Corporales/fisiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Retina/diagnóstico por imagen , Vuelo Espacial/métodos
15.
JAMA Netw Open ; 4(5): e2111113, 2021 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-34019086

RESUMEN

Importance: Immunotherapy is now a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC), but its uptake and effectiveness among older patients outside clinical trials remain poorly understood. Objective: To understand treatment patterns and evaluate the overall survival associated with checkpoint inhibitor immunotherapy, cytotoxic chemotherapy, and combined chemoimmunotherapy for older patients who have advanced NSCLC and Medicare coverage. Design, Setting, and Participants: This retrospective cohort study included Medicare-insured patients in the US aged 66 to 89 years who initiated first palliative-intent systemic therapy for lung cancer between January 1, 2016, and December 31, 2018. Survival follow-up continued through March 31, 2020. A total of 19 529 patients who had advanced lung cancer and were insured by a Medicare fee-for-service plan were included in the analysis. Exposures: Regimens included pembrolizumab monotherapy (n = 3079), combined platinum-based drug (ie, cisplatin or carboplatin [hereinafter, platinum]) and pemetrexed disodium (n = 5159), combined platinum and a taxane (ie, paclitaxel, nab-paclitaxel, or docetaxel) (n = 9866), and combined platinum, pemetrexed, and pembrolizumab (n = 1425), as ascertained using Medicare claims from the Centers for Medicare & Medicaid Services. Main Outcomes and Measures: The primary outcome was overall survival, which was measured using the restricted mean survival time (RMST) with propensity score adjustment for clinical and sociodemographic characteristics. Median survival was also reported for comparison with outcomes from registrational trials. Results: A total of 19 529 patients (54% male, 46% female; median age, 73.8 [interquartile range, 69.9-78.4] years) were identified for analysis. The uptake of pembrolizumab-containing regimens in the Medicare population was rapid, increasing from 0.7% of first-line treatments in the second quarter of 2016 to 42.4% in the third quarter of 2018. Patients who were older (≥70 years, 2484 [81%]), were female (1577 [51%]), and/or had higher Risk Stratification Index scores (highest quintile, 922 [30%]) were more likely to receive single-agent pembrolizumab than chemotherapy. After propensity score adjustment, pembrolizumab was associated with survival similar to platinum/pemetrexed (RMST difference, -0.2 [95% CI, -0.5 to 0.2] months) or platinum/taxane (RMST difference, -0.7 [95% CI, -1.0 to -0.4] months). Patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy also had adjusted survival similar to those receiving platinum/pemetrexed chemotherapy (RMST difference, 0.5 [95% CI, 0.1-0.9] months). The unadjusted median survival was 11.4 (95% CI, 10.5-12.3) months among patients receiving single-agent pembrolizumab, approximately 15 months shorter than observed among pembrolizumab-treated participants in the KEYNOTE-024 trial. The unadjusted median survival was 12.9 (95% CI, 11.8-14.0) months among patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy, approximately 10 months shorter than observed among platinum/pemetrexed/pembrolizumab-treated participants in the KEYNOTE-189 trial. Conclusions and Relevance: Immunotherapy has been incorporated rapidly into treatment for patients with advanced NSCLC. However, survival estimates in the Medicare population are much shorter than those reported in registrational trials. These results provide contemporary estimates of survival for older patients with advanced NSCLC treated in routine practice, facilitating patient-centered decision-making.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Inhibidores de Puntos de Control Inmunológico/sangre , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Anciano , Anciano de 80 o más Años , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Masculino , Medicare/estadística & datos numéricos , Pemetrexed/uso terapéutico , Estudios Retrospectivos , Análisis de Supervivencia , Taxoides/uso terapéutico , Estados Unidos
16.
Physiol Rep ; 9(15): e14977, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34355874

RESUMEN

Spaceflight associated neuro-ocular syndrome (SANS) is hypothesized to develop as a consequence of the chronic headward fluid shift that occurs in sustained weightlessness. We exposed healthy subjects (n = 24) to strict 6° head-down tilt bed rest (HDTBR), an analog of weightlessness that generates a sustained headward fluid shift, and we monitored for ocular changes similar to findings that develop in SANS. Two-thirds of the subjects received a daily 30-min exposure to artificial gravity (AG, 1 g at center of mass, ~0.3 g at eye level) during HDTBR by either continuous (cAG, n = 8) or intermittent (iAG, n = 8) short-arm centrifugation to investigate whether this intervention would attenuate headward fluid shift-induced ocular changes. Optical coherence tomography images were acquired to quantify changes in peripapillary total retinal thickness (TRT), retinal nerve fiber layer thickness, and choroidal thickness, and to detect chorioretinal folds. Intraocular pressure (IOP), optical biometry, and standard automated perimetry data were collected. TRT increased by 35.9 µm (95% CI, 19.9-51.9 µm, p < 0.0001), 36.5 µm (95% CI, 4.7-68.2 µm, p = 0.01), and 27.6 µm (95% CI, 8.8-46.3 µm, p = 0.0005) at HDTBR day 58 in the control, cAG, and iAG groups, respectively. Chorioretinal folds developed in six subjects across the groups, despite small increases in IOP. Visual function outcomes did not change. These findings validate strict HDTBR without elevated ambient CO2 as a model for investigating SANS and suggest that a fluid shift reversal of longer duration and/or greater magnitude at the eye may be required to prevent or mitigate SANS.


Asunto(s)
Reposo en Cama/efectos adversos , Enfermedades de la Coroides/patología , Inclinación de Cabeza/efectos adversos , Papiledema/patología , Enfermedades de la Retina/patología , Simulación de Ingravidez/efectos adversos , Adulto , Estudios de Casos y Controles , Enfermedades de la Coroides/etiología , Femenino , Humanos , Masculino , Papiledema/etiología , Enfermedades de la Retina/etiología
17.
J Appl Physiol (1985) ; 130(6): 1766-1777, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33856253

RESUMEN

Head-to-foot gravitationally induced hydrostatic pressure gradients in the upright posture on Earth are absent in weightlessness. This results in a relative headward fluid shift in the vascular and cerebrospinal fluid compartments and may underlie multiple physiological consequences of spaceflight, including the spaceflight-associated neuro-ocular syndrome. Here, we tested three mechanical countermeasures [lower body negative pressure (LBNP), venoconstrictive thigh cuffs (VTC), and impedance threshold device (ITD) resistive inspiratory breathing] individually and in combination to reduce a posture-induced headward fluid shift as a ground-based spaceflight analog. Ten healthy subjects (5 male) underwent baseline measures (seated and supine postures) followed by countermeasure exposure in the supine posture. Noninvasive measurements included ultrasound [internal jugular veins (IJV) cross-sectional area, cardiac stroke volume, optic nerve sheath diameter, noninvasive IJV pressure], transient evoked otoacoustic emissions (OAE; intracranial pressure index), intraocular pressure, choroidal thickness from optical coherence tomography imaging, and brachial blood pressure. Compared with the supine posture, IJV area decreased 48% with application of LBNP [mean ratio: 0.52, 95% confidence interval (CI): 0.44-0.60, P < 0.001], 31% with VTC (mean ratio: 0.69, 95% CI: 0.55-0.87, P < 0.001), and 56% with ITD (mean ratio: 0.44, 95% CI: 0.12-1.70, P = 0.46), measured at end-inspiration. LBNP was the only individual countermeasure to decrease the OAE phase angle (Δ -12.9 degrees, 95% CI: -25 to -0.9, P = 0.027), and use of combined countermeasures did not result in greater effects. Thus, LBNP, and to a lesser extent VTC and ITD, represents promising headward fluid shift countermeasures but will require future testing in analog and spaceflight environments.NEW & NOTEWORTHY As a weightlessness-induced headward fluid shift is hypothesized to be a primary factor underlying several physiological consequences of spaceflight, countermeasures aimed at reversing the fluid shift will likely be crucial during exploration-class spaceflight missions. Here, we tested three mechanical countermeasures individually and in various combinations to reduce a posture-induced headward fluid shift as a ground-based spaceflight analog.


Asunto(s)
Vuelo Espacial , Ingravidez , Transferencias de Fluidos Corporales , Humanos , Presión Intracraneal , Presión Negativa de la Región Corporal Inferior , Masculino , Ingravidez/efectos adversos
18.
J Appl Physiol (1985) ; 131(2): 613-620, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34166098

RESUMEN

Spaceflight-associated neuro-ocular syndrome (SANS) develops during long-duration (>1 mo) spaceflight presumably because of chronic exposure to a headward fluid shift that occurs in weightlessness. We aimed to determine whether reversing this headward fluid shift with acute application of lower body negative pressure (LBNP) can influence outcome measures at the eye. Intraocular pressure (IOP) and subfoveal choroidal thickness were therefore evaluated by tonometry and optical coherence tomography (OCT), respectively, in 14 International Space Station crewmembers before flight in the seated, supine, and 15° head-down tilt (HDT) postures and during spaceflight, without and with application of 25 mmHg LBNP. IOP in the preflight seated posture was 14.4 mmHg (95% CI, 13.5-15.2 mmHg), and spaceflight elevated this value by 1.3 mmHg (95% CI, 0.7-1.8 mmHg, P < 0.001). Acute exposure to LBNP during spaceflight reduced IOP to 14.2 mmHg (95% CI, 13.4-15.0 mmHg), which was equivalent to that of the seated posture (P > 0.99), indicating that venous fluid redistribution by LBNP can influence ocular outcome variables during spaceflight. Choroidal thickness during spaceflight (374 µm, 95% CI, 325-423 µm) increased by 35 µm (95% CI, 25-45 µm, P < 0.001), compared with the preflight seated posture (339 µm, 95% CI, 289-388 µm). Acute use of LBNP during spaceflight did not affect choroidal thickness (381 µm, 95% CI, 331-430 µm, P = 0.99). The finding that transmission of reduced venous pressure by LBNP did not decrease choroidal thickness suggests that engorgement of this tissue during spaceflight may reflect changes that are secondary to the chronic cerebral venous congestion associated with spaceflight.NEW & NOTEWORTHY Spaceflight induces a chronic headward fluid shift that is believed to underlie ocular changes observed in astronauts. The present study demonstrates, for the first time, that reversing this headward fluid shift via application of lower body negative pressure (LBNP) during spaceflight may alter the ocular venous system, as evidenced by a decrease in intraocular pressure. This finding indicates that LBNP has the potential to be an effective countermeasure against the headward fluid shift during spaceflight, which may then be beneficial in preventing or reversing associated ocular changes.


Asunto(s)
Vuelo Espacial , Ingravidez , Coroides , Humanos , Presión Intraocular , Presión Negativa de la Región Corporal Inferior , Tonometría Ocular , Ingravidez/efectos adversos
19.
Mol Ther Methods Clin Dev ; 18: 582-594, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32775493

RESUMEN

No treatment is available for nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1)-associated retinal degeneration, an inherited disease that leads to severe vision loss early in life. Although the causative gene, NMNAT1, plays an essential role in nuclear nicotinamide adenine dinucleotide (NAD)+ metabolism in tissues throughout the body, NMNAT1-associated disease is isolated to the retina. Since this condition is recessive, supplementing the retina with a normal copy of NMNAT1 should protect vulnerable cells from disease progression. We tested this hypothesis in a mouse model that harbors the p.Val9Met mutation in Nmnat1 and consequently develops a retinal degenerative phenotype that recapitulates key features of the human disease. Gene augmentation therapy, delivered by subretinal injection of adeno-associated virus (AAV) carrying a normal human copy of NMNAT1, rescued retinal structure and function. Due to the early-onset profile of the phenotype, a rapidly activating self-complementary AAV was required to initiate transgene expression during the narrow therapeutic window. These data represent the first proof of concept for a therapy to treat patients with NMNAT1-associated disease.

20.
Psychiatry Res ; 169(2): 132-8, 2009 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-19709754

RESUMEN

We examined the Antidepressant Treatment Response (ATR) index as a predictor of differential response and remission to escitalopram, bupropion, or a combination of the two medications, in subjects with major depressive disorder (MDD). Three hundred seventy-five subjects had a baseline quantitative electroencephalographic (QEEG) study preceding 1 week of treatment with escitalopram, 10 mg, after which a second QEEG was performed and the ATR index was calculated. Subjects then were randomized to continue escitalopram, switch to bupropion, or receive a combination of the two. Clinical response was assessed using the 17-item Hamilton Depression Rating Scale at 49 days of treatment. Accuracy of ATR in predicting response and remission was calculated. There were no significant differences between response and remission rates in the three treatment groups. A single ATR threshold was useful for predicting differential response to either escitalopram or bupropion monotherapy. Subjects with ATR values above the threshold were more than 2.4 times as likely to respond to escitalopram as those with low ATR values (68% vs. 28%). Subjects with ATR values below the threshold who were switched to bupropion treatment were 1.9 times as likely to respond to bupropion alone as those who remained on escitalopram treatment (53% vs. 28%). The ATR index did not provide a useful prediction of response to combination treatment. The ATR index may prove useful in predicting responsiveness to different antidepressant medications.


Asunto(s)
Antidepresivos de Segunda Generación/uso terapéutico , Bupropión/uso terapéutico , Citalopram/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Electroencefalografía/efectos de los fármacos , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Escalas de Valoración Psiquiátrica , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
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