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BACKGROUND: Prescription opioid use places a considerable economic burden on health care systems. Older patients undergoing surgical procedures for painful conditions commonly receive opioids pre- and postoperatively, and are susceptible to adverse reactions. This study explores predictors of prolonged postoperative opioid use among older patients after lumbar spine surgery and the consequences in terms of health care utilization and costs. METHODS: We conducted a retrospective population-based cohort study using Ontario administrative data from older adults undergoing spine surgery between 2006 and 2017. Data were analyzed from 90 days preoperatively to 1 year after hospital discharge, with last postoperative opioid prescriptions stratified into 90-day increments. We used multivariable ordinal logistic regression to identify predictors of long-term opioid use and generalized linear modelling to examine resource utilization and health care costs (2021 Canadian dollars). RESULTS: Of 15 109 patients included, 40.8% received preoperative opioid prescriptions. Preoperative opioid use strongly predicted prolonged postoperative use (odds ratio [OR] 4.47, 95% confidence interval [CI] 4.16-4.79), with 48.3% of patients who received preoperative opioids continuing to use opioids for longer than 9 months, relative to 12.7% of those without preoperative use. Several other risk factors for prolonged use were identified. Patients receiving long-term postoperative opioids incurred greater health care costs relative to those with opioids prescribed for fewer than 90 days (OR 1.49, 95% CI 1.44-1.54). CONCLUSION: Among older adults undergoing spine surgery, preoperative opioid use was a strong predictor of prolonged postoperative use, which was associated with increased health care costs. These results form an important baseline for future studies evaluating strategies to reduce opioid use targeting older surgical populations.
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Analgésicos Opioides , Vértebras Lombares , Dor Pós-Operatória , Humanos , Ontário , Analgésicos Opioides/uso terapêutico , Idoso , Masculino , Feminino , Dor Pós-Operatória/tratamento farmacológico , Estudos Retrospectivos , Vértebras Lombares/cirurgia , Idoso de 80 Anos ou mais , Alta do Paciente/estatística & dados numéricos , Estudos de CoortesRESUMO
BACKGROUND: Upper extremity musculoskeletal injuries are common with active-duty Army Soldiers and result in increased limited duty days. Patient satisfaction and surgery rates improve with direct access to occupational therapy in the civilian community. PURPOSE: Examine the amount of time from initial evaluation following an upper extremity musculoskeletal injury (MSKI) to return to full duty plus occupational therapy (OT) utilization in Army Soldiers. STUDY DESIGN: Retrospective observational. METHODS: Electronic health records and profiles from 18,206 US active-duty Army soldiers with MSKI and OT evaluation between 2017-2018 were examined. Repeated measures generalized estimating equations provided the rate ratios (RRs) for OT healthcare utilization (total number of OT evaluations and treatment visits) by days to first OT evaluation and limited duty profile (total days on profile). RESULTS: Soldiers were on average 32.0 (SD = 8.9) y/o, predominantly senior enlisted (45.7%), white (58.0%), male (81.4%), 10.0 (SD = 8.4) years of service, and high school or less educated (51.3%). There were 22,617 UE MSKIs with an OT evaluation and 4936 UE MSKIs with profiles. Compared with UE MSKIs with an OT evaluation on the same day, there was a significant increase in rates of OT utilization for 1-7 days (RR: 1.4, 95% CI: 1.3, 1.5), 8-14 days (RR: 1.3, 95% CI: 1.2, 1.4), 15-30 days (RR: 1.4, 95% CI: 1.3, 1.5), 31-60 days (RR: 1.5, 95% CI: 1.4, 1.6), and +60 days later (RR: 1.6, 95% CI: 1.5, 1.7). Similar differences in rates for limited duty profiles were found. CONCLUSION: A greater number of days between diagnosis of UE MSKI and OT evaluation results in greater rates of OT utilization and longer temporary profile. Results suggest that earlier intervention by OT may decrease recovery and healthcare utilization of soldiers.
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BACKGROUND: As healthcare systems strive for efficiency, hospital "length of stay outliers" have the potential to significantly impact a hospital's overall utilization. There is a tendency to exclude such "outlier" stays in local quality improvement and data reporting due to their assumed rare occurrence and disproportionate ability to skew mean and other summary data. This study sought to assess the influence of length of stay (LOS) outliers on inpatient length of stay and hospital capacity over a 5-year period at a large urban academic medical center. METHODS: From January 2014 through December 2019, 169,645 consecutive inpatient cases were analyzed and assigned an expected LOS based on national academic center benchmarks. Cases in the top 1% of national sample LOS by diagnosis were flagged as length of stay outliers. RESULTS: From 2014 to 2019, mean outlier LOS increased (40.98 to 45.11 days), as did inpatient LOS with outliers excluded (5.63 to 6.19 days). Outlier cases increased both in number (from 297 to 412) and as a percent of total discharges (0.98 to 1.56%), and outlier patient days increased from 6.7 to 9.8% of total inpatient plus observation days over the study period. CONCLUSIONS: Outlier cases utilize a disproportionate and increasing share of hospital resources and available beds. The current tendency to exclude such outlier stays in data reporting due to assumed rare occurrence may need to be revisited. Outlier stays require distinct and targeted interventions to appropriately reduce length of stay to both improve patient care and maintain hospital capacity.
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Hospitais Urbanos , Melhoria de Qualidade , Humanos , Tempo de Internação , Estudos RetrospectivosRESUMO
Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and mediate several non-image-forming visual functions, including circadian photoentrainment and the pupillary light reflex (PLR). ipRGCs act as autonomous photoreceptors via the intrinsic melanopsin-based phototransduction pathway and as a relay for rod/cone input via synaptically driven responses. Under low light intensities, where only synaptically driven rod/cone input activates ipRGCs, the duration of the ipRGC response will be determined by the termination kinetics of the rod/cone circuits. Little is known, however, about the termination kinetics of the intrinsic melanopsin-based phototransduction pathway and its contribution to several melanopsin-mediated behaviors. Here, we show that C-terminal phosphorylation of melanopsin determines the recovery kinetics of the intrinsic melanopsin-based photoresponse in ipRGCs, the duration of the PLR, and the speed of reentrainment. In contrast, circadian phase alignment and direct effects of light on activity (masking) are not influenced by C-terminal phosphorylation of melanopsin. Electrophysiological measurements demonstrate that expression of a virally encoded melanopsin lacking all C-terminal phosphorylation sites (C terminus phosphonull) leads to a prolonged intrinsic light response. In addition, mice expressing the C terminus phosphonull in ipRGCs reentrain faster to a delayed light/dark cycle compared with mice expressing virally encoded WT melanopsin; however, the phase angle of entrainment and masking were indistinguishable. Importantly, a sustained PLR in the phosphonull animals is only observed at brighter light intensities that activate melanopsin phototransduction, but not at dimmer light intensities that activate only the rod/cone pathway. Taken together, our results highlight how the kinetics of the melanopsin photoresponse differentially regulate distinct light-mediated behaviors.
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Comportamento Animal , Transdução de Sinal Luminoso/genética , Células Ganglionares da Retina/metabolismo , Opsinas de Bastonetes/metabolismo , Animais , Ritmo Circadiano/genética , Cinética , Luz , Transdução de Sinal Luminoso/fisiologia , Camundongos , Técnicas de Patch-Clamp , Fosforilação/genética , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/fisiologia , Reflexo Pupilar/genética , Reflexo Pupilar/fisiologia , Retina/metabolismo , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/química , Opsinas de Bastonetes/genética , Sinapses/genética , Sinapses/metabolismo , Visão Ocular/genética , Visão Ocular/fisiologiaRESUMO
BACKGROUND: Patients frequently experience suboptimal transitions from the hospital to the community, which can increase the likelihood of readmission. It is not known which care coordination services can lead to improvements in readmission rates. OBJECTIVE: To evaluate the effects of two care coordination interventions on 30-day readmission rates. DESIGN: Prospective multicenter observational study of hospitalized patients eligible for two care coordination services between January 1, 2013, and October 31, 2015. Readmission rates were compared for patients who received each care coordination intervention versus those who did not using multivariable generalized estimating equation logistic regression models. PARTICIPANTS: A total of 25,628 patients hospitalized in medicine, neurosciences, or surgical sciences units. INTERVENTIONS: Patients discharged home and deemed to be at high risk for readmission were assigned a nurse Transition Guide (TG) for 30 days post-discharge. All other patients were assigned the Patient Access Line (PAL) intervention, which provided a post-discharge phone call from a registered nurse. SETTING: Two large academic hospitals in Baltimore, MD. MAIN MEASURES: Thirty-day all-cause readmission to any Maryland hospital. KEY RESULTS: Among all patients, 14.2% (2409/16,993) of those referred for the PAL intervention and 22.8% (1973/8635) of those referred for the TG intervention were readmitted. PAL-referred patients who did not receive the intervention had an adjusted odds ratio (aOR) for readmission of 1.27 (95% confidence interval [95% CI] 1.12-1.44, p < 0.001) compared with patients who did. TG-referred patients who did not receive the TG intervention had an aOR of 1.83 (95% CI 1.60-2.10, p < 0.001) compared with patients who received the intervention. Younger age, male sex, having more comorbidities, and being discharged from a medicine unit were associated with not receiving an assigned intervention. These characteristics were also associated with higher readmission rates. CONCLUSIONS: PAL and TG care coordination interventions were associated with lower rates of 30-day readmission. Our findings underscore the importance of determining the appropriate intervention for the hardest-to-reach patients, who are also at the highest risk of being readmitted.
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Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Alta do Paciente/normas , Readmissão do Paciente/estatística & dados numéricos , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Maryland , Pessoa de Meia-Idade , Estudos Prospectivos , Indicadores de Qualidade em Assistência à Saúde , Medição de RiscoRESUMO
Circadian rhythms are regulated by molecular clockwork and drive 24-h behaviors such as locomotor activity, which can be rendered non-functional through genetic knockouts of clock genes. Circadian rhythms are robust in constant darkness (DD) but are modulated to become exactly 24 h by the external day-night cycle. Whether ill-timed light and dark exposure can render circadian behaviors non-functional to the extent of genetic knockouts is less clear. In this study, we discovered an environmental approach that led to a reduction or lack in rhythmic 24-h-circadian wheel-running locomotor behavior in mice (referred to as arrhythmicity). We first observed behavioral circadian arrhythmicity when mice were gradually exposed to a previously published disruptive environment called the fragmented day-night cycle (FDN-G), while maintaining activity alignment with the four dispersed fragments of darkness. Remarkably, upon exposure to constant darkness (DD) or constant light (LL), FDN-G mice lost any resemblance to the FDN-G-only phenotype and instead, exhibited sporadic activity bursts. Circadian rhythms are maintained in control mice with sudden FDN exposure (FDN-S) and fully restored in FDN-G mice either spontaneously in DD or after 12 h:12 h light-dark exposure. This is the first study to generate a light-dark environment that induces reversible suppression of circadian locomotor rhythms in mice.
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Ritmo Circadiano , Locomoção , Animais , Camundongos , Ritmo Circadiano/fisiologia , Técnicas de Inativação de Genes , Locomoção/fisiologia , Fenótipo , Proteínas CLOCK/genéticaRESUMO
INTRODUCTION: Less than half of service members with a behavioral health (BH) problem seek care. Soldiers may avoid seeking needed care because of concerns related to being placed on a duty-limiting profile and the related medical disclosures that follow. MATERIALS AND METHODS: This study used a retrospective population-based design to identify all new BH diagnoses across the U.S. Army. The relationship between diagnostic category, risk of being issued a duty limitation (profile), and time until return to full duty was also examined. Data were collected from a comprehensive data repository that includes medical and administrative records. Soldiers with a new BH diagnosis were identified from 2017 to 2018. All duty limitation profiles within 12 months of initial diagnosis were identified. RESULTS: Records for 614,107 unique service members were reviewed. This cohort was mostly male, enlisted, unmarried, and White. The mean age was 27.13 years (SD = 8.05). Soldiers with a new BH diagnosis accounted for 16.7% (n = 102,440) of the population. The most common diagnostic category was adjustment disorder (55.7%). About a quarter (23.6%) of soldiers with a new diagnosis were issued a related profile. The mean length of these profiles was 98.55 days (SD = 56.91). Of those with a new diagnosis, sex and race failed to have an effect on the odds of being placed on a profile. Overall, enlisted, unmarried, or younger soldiers had greater odds of being placed on a profile. CONCLUSION: These data provide relevant information for both the service member who seeks care and command teams seeking readiness projections.
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Transtornos Mentais , Militares , Humanos , Masculino , Estados Unidos , Adulto , Feminino , Estudos Retrospectivos , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Fatores de TempoRESUMO
INTRODUCTION: When warfighters are unable to fight, they are formally removed from battle through temporary or permanent duty limitation profiles. This study uses a population-based data repository to characterize permanent behavioral health (BH)-related profiles across the army for an identified 2-year period. The absolute risk of a permanent duty limitation for specific BH categories was also examined. MATERIALS AND METHODS: This study utilized a retrospective population-based design to identify all new BH diagnoses across the U.S. Army. Service members identified as having a new BH diagnosis were tracked for 12 months following the diagnosis to determine the recommendation of a permanent duty limitation profile. RESULTS: From 2017 to 2018, 16% (n = 102,440) of service members received a "new" BH diagnosis. Less than 10% (9.5%; n = 9,752) of soldiers diagnosed with a BH disorder were issued a permanent BH-related duty profile within 12 months of the initial diagnosis. The absolute risk of a permanent profile was highest for soldiers diagnosed with a psychotic or delusional disorder (42%; n = 324) followed by dissociative or somatoform disorders (26%; n = 178) and eating disorders (23%; n = 108). CONCLUSIONS: Military regulations dictating medical readiness and retention standards reflect both the standards required for mission readiness and a layer of medical protection for the service member. This study provides important information on the relationship between a new BH diagnosis and the likelihood that a service member will be referred for a retirement evaluation.
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Transtornos Mentais , Militares , Humanos , Estados Unidos , Estudos Retrospectivos , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologiaRESUMO
Fragmented day-night (FDN) cycles are environments in which multiple periods of light and dark alternate across a 24 h period. Exposure to FDN cycles disrupts circadian rhythms, resulting in period lengthening and alterations to mood in mice. A constant light environment, which also induces period lengthening, is linked to mood and metabolic disturbances and disruption to the development of the circadian clock. This study aims to determine how exposure to the FDN cycle impacts development in mice, with the hypothesis that there would be similar and adverse effects as observed in constant light conditions. Our study used CD-1 mice reared under the FDN cycle compared to the commonly used 12 h light: 12 h dark consolidated day-night cycle. During the first week of development, mouse pups reared under the FDN cycle gained bodyweight at a faster rate and did not avoid aberrant light exposure in comparison to 12:12 LD reared mouse pups. Developmental exposure to the FDN cycle lasted two weeks, and then mice were transferred to the 12:12 LD cycle, where after 2 weeks, bodyweight was similar between FDN reared and 12:12 LD reared mice at 1-month and 2-months old. When re-exposed to the FDN cycle during adulthood, FDN reared pups exhibited binge-like eating behaviors and reduced light avoidance. This study shows that the unnatural distribution of light and dark across the 24 h day can cause disruptions during early development that can reappear during adulthood when placed in the same stressful light-dark environment as adults.
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Transtorno da Compulsão Alimentar , Ritmo Circadiano , Animais , Peso Corporal , Comportamento Alimentar , Camundongos , Fotoperíodo , Aumento de PesoRESUMO
INTRODUCTION: Neuromusculoskeletal injuries (NMSKIs) are the primary cause of ambulatory visits, lost duty days, and disability discharges in the U.S. Military. Methods for accurately grouping injury diagnoses are required to allow for surveillance and research identifying risk factors and prevention strategies. The CDC method of grouping these diagnoses includes only the S and T codes (Injury, poisoning, and certain other consequences of external causes) from the ICD-10-CM. However, this does not include the majority of the NMSKI depleting soldier readiness; the M (Disease of the musculoskeletal system and connective tissue) and G (Diseases of the nervous system) codes should be included as these also contain injuries. The goal was to develop a new matrix that would comprehensively capture all NMSKIs experienced by military personnel. This paper details the development of the Occupational Military Neuromusculoskeletal Injury (OMNI) Matrix and characterizes the number and rates of active duty U.S. Army injuries as measured by the OMNI compared to other matrices. MATERIALS AND METHODS: A team of researchers including physical therapists, physician assistants, occupational therapists, physicians, and epidemiologists developed the OMNI. The OMNI utilizes the commonly accepted injury definition inclusive of any anatomical complaint resulting in pain or dysfunction and categorizes injuries from the G, M, S, and T codes. The OMNI follows the CDC's matrix structure with three body region levels, each becoming more specific, and adds two levels called Description of the Injury. Additionally, the OMNI categorizes injuries as Injury Type (Acute, Overuse, Either, or Not Applicable), NMSKI-Type (NMSKI, NMSKI that could be caused by occupational/training tasks, and not an NMSKI), and a miscellaneous category that demarks injuries as Superficial, Blood Vessels, and/or Internal Organs. The different grouping methods in the OMNI provide standardization for many possible injury case definitions. The OMNI allows these injury categories to be included/excluded in a standardized fashion to meet the researchers' scientific questions. To enumerate the number of NMSKI that would be captured by the available matrices, the OMNI, the CDC's matrix, and the U.S. Army Public Health Center's (APHC) Taxonomy of Injuries were applied to active duty Army outpatient population data and all incident NMSKI diagnostic codes entered in electronic medical provider encounters for calendar years 2017 and 2018. RESULTS: Using the OMNI resulted in the capture of over 800,000 more injuries than the CDC's matrix and over 200,000 more than the APHC Taxonomy. The NMSKI rate utilizing the OMNI was 193 per 100 soldier-years in 2017 (892,780 NMSKI) compared to 23 per 100 soldier-years for the CDC's matrix, and 141 per 100 soldier-years for the APHC Taxonomy. CONCLUSION: The OMNI provides an updated standardized method of assessing injuries, particularly in occupational military injury research, that can be utilized for Military Performance Division of injury across many countries and still allow for replication of methods and comparison of results. Additionally, the OMNI has the capacity to capture a greater burden of injury beyond what is captured by other available matrices.
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Militares , Sistema Musculoesquelético , Traumatismos Ocupacionais , Humanos , Classificação Internacional de Doenças , Sistema Musculoesquelético/lesões , Traumatismos Ocupacionais/epidemiologia , Traumatismos Ocupacionais/etiologia , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Neuromusculoskeletal injuries (MSKI) are the leading cause of medical encounters, lost or limited duty days, medical evacuations, and disability in the U.S. Army. In the U.S. Army, objective MSKI incidence rate metrics can be determined through medical encounter data (M2SKIs) with International Classification of Diseases (ICD) 9 and ICD 10 codes or through documented limited duty profiles (LDPs) documenting time-loss MSKI (TLMSKI). The purpose of the current study was to characterize the population incidence of TLMSKIs among U.S. Army soldiers. MATERIALS AND METHODS: This study was approved by the Medical Research and Development Command's Institutional Review Board. This was a retrospective population-level study. The U.S. Army's eProfile system was utilized to characterize all LDPs issued during 2017-2018 and to describe the body regions injured and activities associated with these TLMSKIs. RESULTS: The incidence rate of TLMSKIs was found to be 44 and 40 TLMSKI/100 soldier-years for 2017 and 2018, respectively, which is lower than previously published incidence rates using MSKI receiving medical care. Approximately one quarter of the total active duty Army population in 2017 and 2018 recorded limited duty injuries, where those to the ankle/foot region resulted in the most LDPs and those to the knee resulted in the most lost duty days. The majority of all TLMSKIs were associated with fitness training-related activities. CONCLUSION: This descriptive study is the first to present the U.S. Army population rates for MSKIs that result in LDPs, representing key time losses when soldiers cannot participate in their military occupational and physical training tasks. This study utilizes the LDP system to calculate limited duty days instead of attempting to estimate this information from other means. The eProfile system is limited in that it combines body regions such as ankle/foot and does not allow isolation of ankle or foot independently. It is recommended that research and training programs target the identification, development, and validation of effective and scaleable strategies to maximize performance without severely reducing combat effectiveness because of training TLMSKIs.
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Militares , Exercício Físico , Humanos , Incidência , Classificação Internacional de Doenças , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
Light exposure at night disrupts circadian-regulated biological functions, including mood. However, the consequence of fragmenting the night period and distributing it across the 24-hr period is less understood. Here we show that fragmenting an 8 -h and 6 -h night into equally distributed 2 -h periods throughout the 24-hr day results in period lengthening of the circadian rhythm in mice. Furthermore, mice exhibited less anxiety, which indicates increased risk-taking behavior, and a lack of pleasure-seeking, known as anhedonia. The successive alley and open field tests were used to assess anxiety, while the sucrose preference test was used to assess anhedonia. Analysis of depressive-like behaviors with the forced swim and tail suspension tests were not observed. After two weeks in 12 h light - 12 h dark, mice exposed to the fragmented night recovered and exhibited normal behaviors for both anxiety and anhedonia. Our results are congruent with published studies that describe the detrimental effects of constant light conditions on circadian rhythms and mood. These findings unveil the negative impact that fragmenting the day-night cycle has on circadian rhythms and mood.
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Anedonia/fisiologia , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Ritmo Circadiano/fisiologia , Fotoperíodo , Assunção de Riscos , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Post-hospitalization transition interventions remain a priority in preventing rehospitalization. However, not all patients referred for readmission prevention interventions receive them. We sought to 1) define patient characteristics associated with non-receipt of readmission prevention interventions (among those eligible for them), and 2) determine whether these same patient characteristics are associated with hospital readmission at the state level. METHODS: We used state-wide data from the Maryland Health Services Cost Review Commission to determine patient-level factors associated with state-wide readmissions. Concurrently, we conducted a retrospective analysis of discharged patients referred to receive 1 of 3 post-discharge interventions between January 2013 and July 2019-a nurse transition guide, post-discharge phone call, or follow-up appointment in our post-discharge clinic-to determine patient-level factors associated with not receiving the intervention. Multivariable generalized estimating equation logistic regression models were used to calculate the odds of not accepting or not receiving the interventions. RESULTS: Older age, male gender, black race, higher expected readmission rate, and lower socioeconomic status were significantly associated with 30-day readmission in hospitalized Maryland patients. Most of these variables (age, sex, race, payer type [Medicaid or non-Medicaid], and socioeconomic status) were also associated with non-receipt of intervention. CONCLUSIONS: We found that many of the same patient-level characteristics associated with the highest readmission risk are also associated with non-receipt of readmission reduction interventions. This highlights the paradox that patients at high risk of readmission are least likely to accept or receive interventions for preventing readmission. Identifying strategies to engage hard-to-reach high-risk patients continues to be an unmet challenge in readmission prevention.
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Assistência ao Convalescente , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Transferência de Pacientes , Serviços Preventivos de Saúde/métodos , Assistência ao Convalescente/métodos , Assistência ao Convalescente/organização & administração , Assistência ao Convalescente/estatística & dados numéricos , Idoso , Continuidade da Assistência ao Paciente , Feminino , Humanos , Masculino , Maryland/epidemiologia , Alta do Paciente , Transferência de Pacientes/métodos , Transferência de Pacientes/estatística & dados numéricos , Medição de Risco , Fatores Sexuais , Fatores SocioeconômicosRESUMO
The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory, and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.
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Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Proteínas de Ciclo Celular/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas Cromossômicas não Histona/metabolismo , Elementos Facilitadores Genéticos , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos Endogâmicos NOD , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Fatores do Domínio POU/genética , Fatores do Domínio POU/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra/genética , CoesinasRESUMO
Jet lag is a circadian disruption that affects millions of people, resulting, among other things, in extreme sleepiness and memory loss. The hazardous implications of such effects are evident in situations in which focus and attention are required. Remarkably, there is a limited understanding of how jet lag recovery and associated memory loss vary year round under different photoperiods. Here we show, using different cycles representing winter, summer, and equinox in male mice, that jet lag recovery and memory vary significantly with photoperiod changes. We uncover a positive correlation of acute light effects on circadian-driven locomotion (known as negative masking) with photoentrainment speed and memory enhancement during jet lag. Specifically, we show that enhancing or reducing negative masking is correlated with better or worse memory performance, respectively. This study indicates that in addition to timed-light exposure for phase shifting, the negative masking response could also be biologically relevant when designing effective treatments of jet lag.
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Ritmo Circadiano/efeitos da radiação , Síndrome do Jet Lag , Locomoção/efeitos da radiação , Memória/efeitos da radiação , Fotoperíodo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
To be physiologically relevant, the period of the central circadian pacemaker, located in the suprachiasmatic nucleus (SCN), has to match the solar day in a process known as circadian photoentrainment. However, little is known about the spatiotemporal molecular changes that occur in the SCN in response to light. In this study, we sought to systematically characterize the circadian and light effects on activity-dependent markers of transcriptional (cFos), translational (pS6), and epigenetic (pH3) activities in the mouse SCN. To investigate circadian versus light influences on these molecular responses, we harvested brains from adult wild-type mice in darkness at different circadian times (CT) or from mice exposed to a 15-min light pulse at the middle of the subjective day (CT6, no phase shifts), early subjective night (CT14, large phase delays), or late subjective night (CT22, small phase advances). We found that cFos and pS6 exhibited rhythmic circadian expression in the SCN with distinct spatial rhythms, whereas pH3 expression was undetectable at all circadian phases. cFos rhythms were largely limited to the SCN shell, whereas pS6 rhythms encompassed the entire SCN. pH3, pS6, and cFos showed gating in response to light; however, we were surprised to find that the expression levels of these markers were not higher at phases when larger phase shifts are observed behaviorally (CT14 versus CT22). We then used animals lacking melanopsin (melanopsin knockout [MKO]), which show deficits in phase delays, to further investigate whether changes in these molecular markers correspond to behavioral phase shifts. Surprisingly, only pS6 showed deficits in MKOs at CT14. Therefore, our previous understanding of the molecular pathways that lead to circadian photoentrainment needs to be revised.
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Luz , Núcleo Supraquiasmático/efeitos da radiação , Animais , Ritmo Circadiano/efeitos da radiação , Escuridão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Opsinas de Bastonetes/deficiência , Opsinas de Bastonetes/genética , Opsinas de Bastonetes/metabolismoRESUMO
The light environment greatly impacts human alertness, mood, and cognition by both acute regulation of physiology and indirect alignment of circadian rhythms. These processes require the melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), but the relevant downstream brain areas involved remain elusive. ipRGCs project widely in the brain, including to the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Here we show that body temperature and sleep responses to acute light exposure are absent after genetic ablation of all ipRGCs except a subpopulation that projects to the SCN. Furthermore, by chemogenetic activation of the ipRGCs that avoid the SCN, we show that these cells are sufficient for acute changes in body temperature. Our results challenge the idea that the SCN is a major relay for the acute effects of light on non-image forming behaviors and identify the sensory cells that initiate light's profound effects on body temperature and sleep.
Assuntos
Ritmo Circadiano/genética , Células Ganglionares da Retina/metabolismo , Opsinas de Bastonetes/genética , Núcleo Supraquiasmático/metabolismo , Animais , Temperatura Corporal/genética , Encéfalo/metabolismo , Encéfalo/fisiologia , Humanos , Camundongos , Células Fotorreceptoras/metabolismo , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/metabolismo , Sono/genética , Sono/fisiologia , Vias Visuais/metabolismoRESUMO
OBJECTIVES: To describe the etiologic distribution of all injuries among U.S. Army Active Duty soldiers by causal energy categories. DESIGN: Retrospective cohort, descriptive analysis. METHODS: Injury was defined as the interruption of tissue function caused by an external energy transfer (mechanical, thermal, radiant, nuclear, chemical, or electrical energy). A comprehensive injury matrix standardized categories by causal energies, body locations, and injury types. Categories differentiated acute (ACT) from cumulative micro-traumatic (CMT) overuse injuries, and musculoskeletal injuries (MSKI) from those affecting other or multiple body systems (non-MSKI). International Classification of Diseases (ICD) diagnoses codes were organized into established categories. The matrix was applied to electronic health records for U.S. Army soldiers in 2017. RESULTS: Mechanical energy transfers caused most injuries (97%, n = 809,914): 76% were CMT overuse and the remaining were ACT (<21%). The majority (83%) were MSKI (71% CMT, 12% ACT). While almost one-half (47%) were to lower extremities (38% CMT, 9% ACT) the most frequently injured anatomical sites were the knee and lower back (16% each, primarily CMT). CONCLUSIONS: For the first time all soldiers' injuries have been presented in the same context for consistent comparisons. Findings confirm the vast majority of injuries in this physically-active population are MSKI, and most are CMT MSKI. A very small portion are non-MSKI or injuries caused by non-mechanical energy (e.g., heat- or cold-weather). Most Army injuries are to the lower extremities as a grouped body region, but additional matrix specificity indicates the most injured anatomical locations are the knee, lower back, and shoulder.
Assuntos
Transtornos Traumáticos Cumulativos/epidemiologia , Militares , Sistema Musculoesquelético/lesões , Ferimentos e Lesões/epidemiologia , Transtornos Traumáticos Cumulativos/classificação , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Estudos Retrospectivos , Estados Unidos , Ferimentos e Lesões/classificaçãoRESUMO
Chronic venous leg ulcers are responsible for significant morbidity and health care costs worldwide. This pilot study evaluated the effectiveness 2 biologically active grafts, TheraSkin and Apligraf, in conjunction with compression therapy. The study, not industry-sponsored, was designed and conducted as a prospective, head-to-head, single-site, randomized clinical trial to assess differences in healing rates, adverse outcomes, and treatment costs. The healing rates were different but not statistically significant, there were no adverse outcomes, and TheraSkin averaged $2495.33 and Apligraf averaged $4316.67 per subject. This suggests that TheraSkin may provide equivalent or superior outcomes to Apligraf while reducing costs.
Assuntos
Colágeno/uso terapêutico , Úlcera da Perna/cirurgia , Transplante de Pele/métodos , Pele Artificial , Idoso , Idoso de 80 Anos ou mais , Criopreservação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , CicatrizaçãoRESUMO
Purpose Academic healthcare systems face great challenges in coordinating services across a continuum of care that spans hospital, community providers, home and chronic care facilities. The Johns Hopkins Community Health Partnership (J-CHiP) was created to improve coordination of acute, sub-acute and ambulatory care for patients, and improve the health of high-risk patients in surrounding neighborhoods. The paper aims to discuss this issue. Design/methodology/approach J-CHiP targeted adults admitted to the Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center, patients discharged to participating skilled nursing facilities (SNFs), and high-risk Medicare and Medicaid patients receiving primary care in eight nearby outpatient sites. The primary drivers of the program were redesigned acute care delivery, seamless transitions of care and deployment of community care teams. Findings Acute care interventions included risk screening, multidisciplinary care planning, pharmacist-driven medication management, patient/family education, communication with next provider and care coordination protocols for common conditions. Transition interventions included post-discharge health plans, hand-offs and follow-up with primary care providers, Transition Guides, a patient access line and collaboration with SNFs. Community interventions involved forming multidisciplinary care coordination teams, integrated behavioral care and new partnerships with community-based organizations. Originality/value This paper offers a detailed description of the design and implementation of a complex program to improve care coordination for high-risk patients in an urban setting. The case studies feature findings from each intervention that promoted patient engagement, strengthened collaboration with community-based organizations and improved coordination of care.