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1.
Ann Surg ; 277(3): 506-511, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34387207

RESUMO

OBJECTIVE: We sought to quantify the impact of injury characteristics and setting on the development of mental health conditions, comparing combat to noncombat injury mechanisms. BACKGROUND: Due to advances in combat casualty care, military service-members are surviving traumatic injuries at substantial rates. The nature and setting of traumatic injury may influence the development of subsequent mental health disorders more than clinical injury characteristics. METHODS: TRICARE claims data was used to identify servicemembers injured in combat between 2007 and 2011. Controls were servicemembers injured in a noncombat setting matched by age, sex, and injury severity. The rate of development, and time to diagnosis [in days (d)], of 3 common mental health conditions (post-traumatic stress disorder, depression, and anxiety) among combat-injured servicemembers were compared to controls. Risk factors for developing a new mental health condition after traumatic injury were evaluated using multivariable logistic regression that controlled for confounders. RESULTS: There were 3979 combat-injured servicemember and 3979 matched controls. The majority of combat injured servicemembers (n = 2524, 63%) were diagnosed with a new mental health condition during the course of follow-up, compared to 36% (n = 1415) of controls ( P < 0.001). In the adjusted model, those with combat-related injury were significantly more likely to be diagnosed with a new mental health condition [odds ratio (OR): 3.18, [95% confidence interval (CI): 2.88-3.50]]. Junior (OR: 3.33, 95%CI: 2.66-4.17) and senior enlisted (OR: 2.56, 95%CI: 2.07-3.17) servicemem-bers were also at significantly greater risk. CONCLUSIONS: We found significantly higher rates of new mental health conditions among servicemembers injured in combat compared to service-members sustaining injuries in noncombat settings. This indicates that injury mechanism and environment are important drivers of mental health sequelae after trauma.


Assuntos
Militares , Transtornos de Estresse Pós-Traumáticos , Humanos , Saúde Mental , Ansiedade , Transtornos de Ansiedade , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia
2.
Ann Surg ; 277(1): 159-164, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33651722

RESUMO

OBJECTIVE: We sought to evaluate long-term healthcare requirements of American military servicemembers with combat-related injuries. SUMMARY OF BACKGROUND DATA: US military conflicts since 2001 have produced the most combat casualties since Vietnam. Long-term consequences on healthcare utilization and associated costs remain unknown. METHODS: We identified servicemembers who were treated for combat-related injuries between 2007 and 2011. Controls consisted of active-duty servicemembers injured in the civilian sector, without any history of combat-related trauma, matched (1:1) on year of injury, biologic sex injury severity, and age at time of injury. Surveillance was performed through 2018. Total annual healthcare expenditures were evaluated overall and then as expenditures in the first year after injury and for subsequent years. Negative binomial regression was used to identify the adjusted influence of combat injury on healthcare costs. RESULTS: The combat-injured cohort consisted of 3981 individuals and we identified 3979 controls. Total healthcare utilization during the follow-up period resulted in median costs of $142,214 (IQR $61,428, $323,060) per combat-injured servicemember as compared to $50,741 (IQR $26,669, $104,134) among controls. Median expenditures, adjusted for duration of follow-up, for the combat-injured were $45,211 (IQR $18,698, $105,437). In adjusted analysis, overall costs were 30% higher (1.30; 95% confidence interval: 1.23, 1.37) for combat-injured personnel. CONCLUSION: This investigation represents the longest continuous observation of healthcare utilization among individuals after combat injury and the first to assess costs. Expenditures were 30% higher for individuals injured as a result of combat-related trauma when compared to those injured in the civilian sector.


Assuntos
Custos de Cuidados de Saúde , Militares , Humanos , Estados Unidos , Aceitação pelo Paciente de Cuidados de Saúde , Gastos em Saúde , Campanha Afegã de 2001- , Estudos Retrospectivos
3.
Ann Surg ; 277(1): e204-e211, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33914485

RESUMO

OBJECTIVE: The aim of this study was to critically evaluate whether admission at the beginning versus end of the academic year is associated with increased risk of major adverse outcomes. SUMMARY BACKGROUND DATA: The hypothesis that the arrival of new residents and fellows is associated with increases in adverse patient outcomes has been the subject of numerous research studies since 1989. Methods: We conducted a systematic review and random-effects meta-analysis of July Effect studies published before December 20, 2019, looking for differences in mortality, major morbidity, and readmission. Given a paucity of studies reporting readmission, we further analyzed 7 years of data from the Nationwide Readmissions Database to assess for differences in 30-day readmission for US patients admitted to urban teaching versus nonteach-ing hospitals with 3 common medical (acute myocardial infarction, acute ischemic stroke, and pneumonia) and 4 surgical (elective coronary artery bypass graft surgery, elective colectomy, craniotomy, and hip fracture) conditions using risk-adjusted logistic difference-in-difference regression. RESULTS: A total of 113 studies met inclusion criteria; 92 (81.4%) reported no evidence of a July Effect. Among the remaining studies, results were mixed and commonly pointed toward system-level discrepancies in efficiency. Metaanalyses of mortality [odds ratio (95% confidence interval): 1.01 (0.98-1.05)] and major morbidity [1.01 (0.99-1.04)] demonstrated no evidence of a July Effect, no differences between specialties or countries, and no change in the effect over time. A total of 5.98 million patient encounters were assessed for readmission. No evidence of a July Effect on readmission was found for any of the 7 conditions. CONCLUSION: The preponderance of negative results over the past 30 years suggests that it might be time to reconsider the need for similarly-themed studies and instead focus on system-level factors to improve hospital efficiency and optimize patient outcomes.


Assuntos
AVC Isquêmico , Infarto do Miocárdio , Humanos , Hospitalização , Readmissão do Paciente , Ponte de Artéria Coronária , Fatores de Risco , Estudos Retrospectivos
4.
Ann Surg ; 276(5): e584-e590, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065654

RESUMO

OBJECTIVE: To compare the needs based assessment of trauma systems (NBATS) tool estimates of trauma center need to the existing trauma infrastructure using observed national trauma volume. SUMMARY OF BACKGROUND DATA: Robust trauma systems have improved outcomes for severely injured patients. The NBATS tool was created by the American College of Surgeons to align trauma resource allocation with regional needs. METHODS: Data from the Agency for Healthcare Research and Quality Healthcare Costs and Utilization Project State Inpatient Databases, the Trauma Information Exchange Program, and US Census was used to calculate an NBATS score for each trauma service area (TSA) as defined by the Pittsburgh Atlas. This score was used to estimate the number of trauma centers allocated to each TSA and compared to the number of existing trauma centers. RESULTS: NBATS predicts the need for 117 additional trauma centers across the United States to provide adequate access to trauma care nationwide. At least 1 additional trauma center is needed in 49% of TSAs. CONCLUSIONS: Application of the NBATS tool nationally shows the need for additional trauma infrastructure across a large segment of the United States. We identified some limitations of the NBATS tool, including preferential weighting based on current infrastructure. The NBATS tool provides a good framework to begin the national discussion around investing in the expansion of trauma systems nationally, however, in many instances lacks the granularity to drive change at the local level.


Assuntos
Cirurgiões , Ferimentos e Lesões , Humanos , Bases de Dados Factuais , Avaliação das Necessidades , Centros de Traumatologia , Estados Unidos , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/cirurgia
5.
J Surg Res ; 275: 115-128, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35272088

RESUMO

INTRODUCTION: Geographic variation is an inherent feature of the US health system. Despite efforts to account for geographic variation in trauma system strengthening, it remains unclear how trauma "regions" should be defined. The objective of this study is to evaluate the utility of a novel definition of Trauma Referral Regions (TRR) for assessing geographic variation in inpatient trauma across the age span of hospitalized trauma patients. METHODS: Using 2016-2017 State Inpatient Databases, we assessed the extent of geographic variability in three common metrics of hospital use (localization index, market share index, net patient flow) among TRRs and, as a comparison, trauma regions alternatively defined based on Hospital Referral Regions, Hospital Service Areas, and counties. RESULTS: A total of 860,593 admissions from 102 TRRs, 127 Hospital Referral Regions, 884 Hospital Service Areas, and 583 counties were included. Consistent with expectations for distinct trauma regions, TRR presented with high average localization indices (mean [standard deviation]: 83.4 [11.7%]), low market share indices (mean [standard deviation]: 11.9 [7.0%]), and net patient flows close to 1.00. Similar results were found among stratified pediatric, adult, and older adult patients. Associations between TRRs and variations in important demographic features (e.g., travel time by road to the nearest Level I or II Trauma Center) suggest that while indicative of standalone trauma regions, TRRs are also able to simultaneously capture critical variations in regional trauma care. CONCLUSIONS: TRRs offer a standalone set of geographic regions with minimal variation in common metrics of hospital use, minimal geographic clustering, and preserved associations with important demographic factors. They provide a needed, valid means of assessing geographic variation among trauma systems.


Assuntos
Pacientes Internados , Encaminhamento e Consulta , Idoso , Criança , Hospitalização , Hospitais , Humanos , Centros de Traumatologia
6.
Ann Emerg Med ; 79(6): 518-526, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34952728

RESUMO

STUDY OBJECTIVE: The COVID-19 pandemic in the United States has underscored the need to understand health care in a regional context. However, there are multiple definitions of health care regions available for conducting geospatial analyses. In this study, we compare the novel Pittsburgh Atlas, which defined regions for emergency care, with the existing definitions of regions, counties, and the Dartmouth Atlas, with respect to nonemergent acute medical conditions using pneumonia admissions. METHODS: We identified patients hospitalized with a primary diagnosis of pneumonia or a primary admitting diagnosis of sepsis with a secondary diagnosis of pneumonia in the Agency for Healthcare Research and Quality's State Inpatient Databases. We calculated the percentage of region concordant care, the localization index, and market share for 3 definitions of health care regions (the Pittsburgh Atlas, Dartmouth Atlas, and counties). We used logistic regression identified predictors of region concordant care. RESULTS: We identified 1,582,287 patients who met the inclusion criteria. We found that the Pittsburgh Atlas and Dartmouth Atlas definitions of regions performed similarly with respect to both localization index (92.0 [interquartile range 87.9 to 95.7] versus 90.3 [interquartile range 81.4 to 94.5]) and market share (8.5 [interquartile range 5.1 to 13.6] versus 9.4 [interquartile range 6.7 to 14.1]). Both atlases outperformed the localization index (67.5 [interquartile range 49.9 to 83.9]) and market share (20.0% [interquartile range 11.4 to 31.4]) of the counties. Within a given referral region, the demographic factors, including age, sex, race/ethnicity, insurance status, and the level of severity, affected concordance rates between residential and hospital regions. CONCLUSION: Because the Pittsburgh Atlas also has the benefit of respecting state and county boundaries, the use of this definition may have improved policy applicability without sacrificing accuracy in defining health care regions for acute medical conditions.


Assuntos
COVID-19 , Pneumonia , COVID-19/epidemiologia , Atenção à Saúde , Hospitalização , Humanos , Pandemias , Pneumonia/diagnóstico por imagem , Pneumonia/epidemiologia , Estados Unidos/epidemiologia
7.
J Surg Res ; 257: 486-492, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916501

RESUMO

BACKGROUND: There are well-documented disparities in outcomes for injured Black and Hispanic patients in the United States. However, patient level characteristics cannot fully explain the differences in outcomes and system-level factors, including the trauma center designation of the hospital to which a patient presents, may contribute to their worse outcomes. We aim to determine if Black and Hispanic patients are more likely to be undertriaged, compared with white patients. METHODS: This is a retrospective, cross-sectional, population-based study that uses data from the 2014 Agency for Healthcare Research and Quality Healthcare Costs and Utilization Project State Inpatient Databases. We included data from all states with available State Inpatient Databases data that included both race and hospital characteristics needed for analysis (n = 18). Logistic regression was used to identify predictors of severely injured (Injury Severity Score ≥16) patients being brought to a trauma center. RESULTS: We identified 70,970 severely injured trauma patients with complete data. Non-Hispanic White represented 74.1% of the study population, 9.8% were non-Hispanic Black, and 9.7% were Hispanic. After adjustment for other demographic and injury characteristics, Non-Hispanic Black and Hispanic patients were more likely to be undertriaged, compared with white patients (odds ratio, 1.20; 95% confidence interval, 1.12-1.29 and odds ratio, 1.39; 95% confidence interval, 1.29-1.48, respectively). Male sex and older age were associated with higher odds of undertriage, whereas urban residence, high injury severity, and penetrating injury were associated with lower odds of undertriage. CONCLUSIONS: Severely injured Black and Hispanic trauma patients are more likely to be undertriaged than otherwise similar white patients. The factors that contribute to racial and ethnic disparities in receiving trauma center care need to be identified and addressed to provide equitable trauma care.


Assuntos
População Negra/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Hispânico ou Latino/estatística & dados numéricos , Triagem/estatística & dados numéricos , Ferimentos e Lesões/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
8.
BMC Health Serv Res ; 21(1): 112, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33530994

RESUMO

INTRODUCTION: Bundled payments for spine surgery, which is known for having high overall cost with wide variation, have been previously studied in older adults. However, there has been limited work examining bundled payments in working-age patients. We sought to identify the variation in the cost of spine surgery among working age adults in a large, national insurance claims database. METHODS: We queried the TRICARE claims database for all patients, aged 18-64, undergoing cervical and non-cervical spinal fusion surgery between 2012 and 2014. We calculated the case mix adjusted, price standardized payments for all aspects of care during the 60-, 90-, and 180-day periods post operation. Variation was assessed by stratifying Hospital Referral Regions into quintiles. RESULTS: After adjusting for case mix, there was significant variation in the cost of both cervical ($10,538.23, 60% of first quintile) and non-cervical ($20,155.59, 74%). Relative variation in total cost decreased from 60- to 180-days (63 to 55% and 76 to 69%). Index hospitalization was the primary driver of costs and variation for both cervical (1st-to-5th quintile range: $11,033-$19,960) and non-cervical ($18,565-$36,844) followed by readmissions for cervical ($0-$11,521) and non-cervical ($0-$13,932). Even at the highest quintile, post-acute care remained the lowest contribution to overall cost ($2070 & $2984). CONCLUSIONS: There is wide variation in the cost of spine surgery across the United States for working age adults, driven largely by index procedure and readmissions costs. Our findings suggest that implementing episodes longer than the current 90-day standard would do little to better control cost variation.


Assuntos
Grupos Diagnósticos Relacionados , Cuidados Semi-Intensivos , Adolescente , Adulto , Idoso , Hospitalização , Humanos , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Estados Unidos , Adulto Jovem
10.
J Econ Inequal ; 19(3): 527-550, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456657

RESUMO

This paper examines employment patterns by wage group over the course of the coronavirus pandemic in the United States using microdata from two well-known data sources from the U.S. Bureau of Labor Statistics: the Current Employment Statistics and the Current Population Survey. We find establishments paying the lowest average wages and the lowest wage workers had the steepest decline in employment and experienced the most persistent losses. We disentangle the extent to which the effect observed for low wage workers is due to these workers being concentrated within a few low wage sectors of the economy versus the pandemic affecting low wage workers in a number of sectors across the economy. Our results indicate that the experience of low wage workers is not entirely due to these workers being concentrated in low wage sectors - for many sectors, the lowest wage quintiles in that sector also has had the worst employment outcomes. From April 2020 to May 2021, between 23% and 46% of the decline in employment among the lowest wage establishments was due to within-industry changes. Another important finding is that even for those who remain employed during the pandemic, the probability of becoming part-time for economic reasons increased, especially for low-wage workers. Supplementary Information: The online version contains supplementary material available at 10.1007/s10888-021-09506-6.

11.
J Pharmacol Exp Ther ; 370(2): 148-159, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31113837

RESUMO

Pharmacokinetic studies in rats and dogs were performed to characterize the in vivo performance of a novel prodrug, fosciclopirox. Ciclopirox olamine (CPX-O) is a marketed topical antifungal agent with demonstrated in vitro and in vivo preclinical anticancer activity in several solid tumor and hematologic malignancies. The oral route of administration for CPX-O is not feasible due to low bioavailability and dose-limiting gastrointestinal toxicities. To enable parenteral administration, the phosphoryl-oxymethyl ester of ciclopirox (CPX), fosciclopirox (CPX-POM), was synthesized and formulated as an injectable drug product. In rats and dogs, intravenous CPX-POM is rapidly and completely metabolized to its active metabolite, CPX. The bioavailability of the active metabolite is complete following CPX-POM administration. CPX and its inactive metabolite, ciclopirox glucuronide (CPX-G), are excreted in urine, resulting in delivery of drug to the entire urinary tract. The absolute bioavailability of CPX following subcutaneous administration of CPX-POM is excellent in rats and dogs, demonstrating the feasibility of this route of administration. These studies confirmed the oral bioavailability of CPX-O is quite low in rats and dogs compared with intravenous CPX-POM. Given its broad-spectrum anticancer activity in several solid tumor and hematologic cancers and renal elimination, CPX-POM is being developed for the treatment of urothelial cancer. The safety, dose tolerance, pharmacokinetics, and pharmacodynamics of intravenous CPX-POM are currently being characterized in a United States multicenter first-in-human Phase 1 clinical trial in patients with advanced solid tumors (NCT03348514).


Assuntos
Ciclopirox/metabolismo , Pró-Fármacos/farmacologia , Pró-Fármacos/farmacocinética , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Urotélio/efeitos dos fármacos , Animais , Disponibilidade Biológica , Cães , Masculino , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico , Ratos
12.
J Surg Res ; 233: 403-407, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502277

RESUMO

BACKGROUND: Trauma centers frequently accept patients from other institutions who are being sent due to the need for a higher level of care. We hypothesized that patients with minor traumatic injuries who are transferred from outside institutions would impart a negative financial impact on the receiving trauma center. METHODS: We performed a retrospective review of all trauma patients admitted to our urban level I trauma center from October 1, 2011, through September 30, 2013. Patients were categorized as minor trauma if they did not require operation within 24 h of arrival, did not require ICU admission, did not die, and had a hospital length of stay <24 h. Transferred patients and nontransfers (those received directly from the field) were compared with respect to injury severity, insurance status, and hospital net margin. Student's t-test and z-test for proportions were performed for data analysis. RESULTS: A total of 6951 trauma patients were identified (transfer n = 2228, nontransfer n = 4724). Minor injury transfers (n = 440) were compared to nontransfers (n = 689). Hospital net margin of transferred patients and nontransferred patients were $2227 and $2569, respectively (P = 0.22). Percentages of uninsured/underinsured for transfers and nontransfers were 27.3% and 36.1%, respectively (P = 0.002). CONCLUSIONS: During our study period, 19.7% of transfers and 14.6% of nontransfers can be categorized as having minor trauma. Minor trauma transfer patients are associated with a positive hospital net margin for the trauma center that is similar to that of the nontransfer group. The data also demonstrate a lower percentage of uninsured/underinsured in the transferred group.


Assuntos
Gastos em Saúde/estatística & dados numéricos , Uso Excessivo dos Serviços de Saúde/economia , Transferência de Pacientes/economia , Centros de Traumatologia/economia , Ferimentos e Lesões/economia , Adolescente , Adulto , Feminino , Humanos , Escala de Gravidade do Ferimento , Cobertura do Seguro/economia , Cobertura do Seguro/estatística & dados numéricos , Masculino , Uso Excessivo dos Serviços de Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Transferência de Pacientes/estatística & dados numéricos , Estudos Retrospectivos , Centros de Traumatologia/estatística & dados numéricos , Triagem , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/terapia , Adulto Jovem
13.
J Surg Res ; 218: 92-98, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28985883

RESUMO

BACKGROUND: Although most trauma centers have a regularly scheduled trauma clinic, research demonstrates that trauma patients do not consistently attend follow-up appointments and often use the emergency department (ED) for outpatient care. METHODS: A retrospective review of outpatient follow-up of adult patients admitted to the trauma service (January 2014-December 2014) at an urban level I trauma center was conducted (n = 2134). RESULTS: A total of 219 patients (10%) were evaluated in trauma clinic after discharge from the hospital. Twenty-one percent of patients seen in trauma clinic visited the ED within 30 d compared with 12% of those not seen in clinic (P < 0.001). A total of 104 patients were readmitted within 30 d of discharge; no difference existed in the rate of hospital readmission between patients seen in clinic and those not seen in clinic (P = 0.25). Stepwise logistic regression showed that clinic follow-up was not a significant predictor of decreased ED utilization (adjusted odds ratio [OR] 1.16 [95% confidence interval 0.78-1.72], P = 0.461) and also showed that while ED use was a significant predictor of readmission (adjusted OR 216 [93-500], P < 0.001), clinic visits were not (adjusted OR 0.74 [0.33-1.69], P = 0.48). CONCLUSIONS: Outpatient follow-up in the trauma clinic does not decrease ED utilization or hospital readmissions indicating that interventions aimed at improving access to a conventional outpatient clinic will not impact ED utilization rates. Further study is necessary to determine the best system for providing clinically appropriate and cost-effective outpatient follow-up for trauma patients.


Assuntos
Assistência ao Convalescente/estatística & dados numéricos , Assistência Ambulatorial/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Ferimentos e Lesões/terapia , Adulto , Assistência ao Convalescente/organização & administração , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/organização & administração , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , New Jersey , Readmissão do Paciente/estatística & dados numéricos , Estudos Retrospectivos , Centros de Traumatologia/organização & administração , Centros de Traumatologia/estatística & dados numéricos
14.
bioRxiv ; 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37732203

RESUMO

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here we report a 3.1 Å resolution cryo-EM structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.

15.
Elife ; 122024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38517752

RESUMO

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.


Assuntos
Doença de Huntington , Tetrabenazina , Humanos , Tetrabenazina/metabolismo , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/química , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Prótons , Microscopia Crioeletrônica
16.
Sci Adv ; 10(1): eadi4919, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38181083

RESUMO

Cell-based therapies hold promise for many chronic conditions; however, the continued need for immunosuppression along with challenges in replacing cells to improve durability or retrieving cells for safety are major obstacles. We subcutaneously implanted a device engineered to exploit the innate transcapillary hydrostatic and colloid osmotic pressure generating ultrafiltrate to mimic interstitium. Long-term stable accumulation of ultrafiltrate was achieved in both rodents and nonhuman primates (NHPs) that was chemically similar to serum and achieved capillary blood oxygen concentration. The majority of adult pig islet grafts transplanted in non-immunosuppressed NHPs resulted in xenograft survival >100 days. Stable cytokine levels, normal neutrophil to lymphocyte ratio, and a lack of immune cell infiltration demonstrated successful immunoprotection and averted typical systemic changes related to xenograft transplant, especially inflammation. This approach eliminates the need for immunosuppression and permits percutaneous access for loading, reloading, biopsy, and recovery to de-risk the use of "unlimited" xenogeneic cell sources to realize widespread clinical translation of cell-based therapies.


Assuntos
Terapia de Imunossupressão , Primatas , Adulto , Animais , Humanos , Suínos , Xenoenxertos , Transplante Heterólogo , Biópsia
17.
Lancet ; 380(9837): 157-64, 2012 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-22784534

RESUMO

Relations between demographic change and emissions of the major greenhouse gas carbon dioxide (CO(2)) have been studied from different perspectives, but most projections of future emissions only partly take demographic influences into account. We review two types of evidence for how CO(2) emissions from the use of fossil fuels are affected by demographic factors such as population growth or decline, ageing, urbanisation, and changes in household size. First, empirical analyses of historical trends tend to show that CO(2) emissions from energy use respond almost proportionately to changes in population size and that ageing and urbanisation have less than proportional but statistically significant effects. Second, scenario analyses show that alternative population growth paths could have substantial effects on global emissions of CO(2) several decades from now, and that ageing and urbanisation can have important effects in particular world regions. These results imply that policies that slow population growth would probably also have climate-related benefits.


Assuntos
Dióxido de Carbono/análise , Demografia/tendências , Efeito Estufa/estatística & dados numéricos , Crescimento Demográfico , Adulto , Fatores Etários , Poluentes Ambientais/análise , Combustíveis Fósseis/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Densidade Demográfica , Urbanização/tendências
18.
Proc Natl Acad Sci U S A ; 107(41): 17521-6, 2010 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-20937861

RESUMO

Substantial changes in population size, age structure, and urbanization are expected in many parts of the world this century. Although such changes can affect energy use and greenhouse gas emissions, emissions scenario analyses have either left them out or treated them in a fragmentary or overly simplified manner. We carry out a comprehensive assessment of the implications of demographic change for global emissions of carbon dioxide. Using an energy-economic growth model that accounts for a range of demographic dynamics, we show that slowing population growth could provide 16-29% of the emissions reductions suggested to be necessary by 2050 to avoid dangerous climate change. We also find that aging and urbanization can substantially influence emissions in particular world regions.


Assuntos
Poluição do Ar/estatística & dados numéricos , Dióxido de Carbono/análise , Aquecimento Global/estatística & dados numéricos , Modelos Teóricos , Dinâmica Populacional , Urbanização , Distribuição por Idade , Dióxido de Carbono/economia , Simulação por Computador , Humanos , Fatores Socioeconômicos
19.
J Trauma Acute Care Surg ; 95(6): 899-904, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37381148

RESUMO

INTRODUCTION: In 2015, the United States moved from the International Classification of Diseases, Ninth Revision ( ICD-9 ), to the International Classification of Diseases, Tenth Revision ( ICD-10 ), coding system. The American Association for the Surgery of Trauma Committee on Severity Assessment and Patient Outcomes previously established a list of ICD-9 diagnoses to define the field of emergency general surgery (EGS). This study evaluates the general equivalence mapping (GEM) crosswalk to generate an equivalent list of ICD-10 -coded EGS diagnoses. METHODS: The GEM was used to generate a list of ICD-10 codes corresponding to the American Association for the Surgery of Trauma ICD-9 EGS diagnosis codes. These individual ICD-9 and ICD-10 codes were aggregated by surgical area and diagnosis groups. The volume of patients admitted with these diagnoses in the National Inpatient Sample in the ICD-9 era (2013-2014) was compared with the ICD-10 volumes to generate observed to expected ratios. The crosswalk was manually reviewed to identify the causes of discrepancies between the ICD-9 and ICD-10 lists. RESULTS: There were 485 ICD-9 codes, across 89 diagnosis categories and 11 surgical areas, which mapped to 1,206 unique ICD-10 codes. A total of 196 (40%) ICD-9 codes have an exact one-to-one match with an ICD-10 code. The median observed to expected ratio among the diagnosis groups for a primary diagnosis was 0.98 (interquartile range, 0.82-1.12). There were five key issues identified with the ability of the GEM to crosswalk ICD-9 EGS diagnoses to ICD-10 : (1) changes in admission volumes, (2) loss of necessary modifiers, (3) lack of specific ICD-10 code, (4) mapping to a different condition, and (5) change in coding nomenclature. CONCLUSION: The GEM provides a reasonable crosswalk for researchers and others to use when attempting to identify EGS patients in with ICD-10 diagnosis codes. However, we identify key issues and deficiencies, which must be accounted for to create an accurate patient cohort. This is essential for ensuring the validity of policy, quality improvement, and clinical research work anchored in ICD-10 coded data. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level III.


Assuntos
Pacientes Internados , Classificação Internacional de Doenças , Humanos , Hospitalização , Políticas , Melhoria de Qualidade
20.
J Trauma Acute Care Surg ; 93(5): 664-671, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35687808

RESUMO

BACKGROUND: By providing definitive care for many, and rapid assessment, resuscitation, stabilization, and transfer to Level I/II centers when needed, Level III trauma centers can augment capacity in high resource regions and extend the geographic reach to lower resource regions. We sought to (1) characterize populations served principally by Level III trauma centers, (2) estimate differences in time to care by trauma center level, and (3) update national estimates of trauma center access. METHODS: In a cross-sectional study (United States, 2019), we estimated travel time from census block groups to the nearest Level I/II trauma center and nearest Level III trauma center. Block groups were categorized based on the level of care accessible within 60 minutes, then distributions of population characteristics and differences in time to care were estimated. RESULTS: An estimated 22.8% of the US population (N = 76,119,228) lacked access to any level of trauma center care within 60 minutes, and 8.8% (N = 29,422,523) were principally served by Level III centers. Black and American Indian/Alaska Native (AIAN) populations were disproportionately represented among those principally served by Level III centers (39.1% and 12.2%, respectively). White and AIAN populations were disproportionately represented among those without access to any trauma center care (26.2% and 40.8%, respectively). Time to Level III care was shorter than Level I/II for 27.9% of the population, with a mean reduction in time to care of 28.9 minutes (SD = 31.4). CONCLUSION: Level III trauma centers are a potential source of trauma care for underserved populations. While Black and AIAN disproportionately rely on Level III centers for care, most with access to Level III centers also have access to Level I/II centers. The proportion of the US population with timely access to trauma care has not improved since 2010. LEVEL OF EVIDENCE: Prognostic/Epidemiological; Level IV.


Assuntos
Acessibilidade aos Serviços de Saúde , Centros de Traumatologia , Estados Unidos , Humanos , Estudos Transversais , Populações Vulneráveis , Viagem
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