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BACKGROUND: The gaps in healthy life expectancy (HLE) between Indigenous and non-Indigenous Australians are significant. Detailed and accurate information is required to develop strategies that will close these health disparities. This paper aims to quantify and compare the causes and their relative contributions to the life expectancy (LE) gaps between the Indigenous and non-Indigenous population in the Northern Territory (NT), Australia. METHODS: The age-cause decomposition was used to analyse the differences in HLE and unhealthy life expectancy (ULE), where LE = HLE + ULE. The data was sourced from the burden of disease and injury study in the NT between 2014 and 2018. RESULTS: In 2014-2018, the HLE at birth in the NT Indigenous population was estimated at 43.3 years in males and 41.4 years in females, 26.5 and 33.5 years shorter than the non-Indigenous population. This gap approximately doubled the LE gap (14.0 years in males, 16.6 years in females) at birth. In contrast to LE and HLE, ULE at birth was longer in the Indigenous than non-Indigenous population. The leading causes of the ULE gap at birth were endocrine conditions (explaining 2.9-4.4 years, 23-26%), followed by mental conditions in males and musculoskeletal conditions in females (1.92 and 1.94 years, 15% and 12% respectively), markedly different from the causes of the LE gap (cardiovascular disease, cancers and unintentional injury). CONCLUSIONS: The ULE estimates offer valuable insights into the patterns of morbidity particularly useful in terms of primary and secondary prevention.
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Disparidades en el Estado de Salud , Esperanza de Vida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Adulto Joven , Australia , Pueblos Indígenas , Northern Territory/epidemiologíaRESUMEN
OBJECTIVES: To assess the adequacy of the Northern Territory health workforce with respect to population size and burden of disease, overall and by selected health specialties; to assess its sustainability by investigating changes in workforce numbers. STUDY DESIGN: Analysis of Australian Health Practitioner Regulation Agency (AHPRA) health workforce data (2013-2021) and burden of disease data (disability-adjusted life-years, DALYs) drawn from national and NT burden of disease studies (and projected for 2019-2021). SETTING, PARTICIPANTS: NT and Australian health workforces, 2009-2021. MAIN OUTCOME MEASURES: Adequacy of the NT health workforce, assessed as the ratio of the mean annual numbers of NT health workers per 1000 population or health workers per 1000 DALYs (2009-2013 and 2014-2018) to those of the Australian workforce (2013 and 2018); sustainability of the NT health workforce, defined as the number of health workers per 1000 population or per 1000 DALYs increasing between 2013 and 2021. RESULTS: The number of health workers per 1000 population was slightly higher in the NT than for Australia in both time periods (2009-2013 v 2013: 23.30 v 21.79 per 1000 population, 6.9% larger; 2014-2018 v 2018: 25.79 v 23.47 per 1000 population, 9.9% larger); however, it was smaller with respect to burden of disease (2009-2013 v 2013: 82.6 v 107.4 health workers per 1000 DALYs, 23.1% fewer; 2014-2018 v 2018: 91.5 v 117.1 per 1000 DALYs, 21.8% fewer). In particular, 464 more nurses and midwives (11.4% more than the mean for 2013-2021), 196 more physiotherapists (115%), 189 more psychologists (102%), 152 more pharmacists (79%), and 144 more dentists (106%) are needed in the NT to match the corresponding numbers of health workers by disease burden for Australia as a whole. The number of Aboriginal health practitioners per 100 000 DALYs fell during the study period. CONCLUSION: Health worker population density alone does not reliably assess health workforce needs; burden of disease information is important for workforce planning that meets population health needs. The NT health workforce needs to be increased by about 28% to reflect the population burden of disease and injury. Shortages in the NT health workforce must be eliminated to close health gaps between Indigenous and non-Indigenous Australians.
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BACKGROUND: Hemodialysis is a life-saving technology used during periods of acute or chronic kidney failure to remove toxins, and maintain fluid, electrolyte and metabolic balance. While this technology plays an important role for pediatric patients with kidney dysfunction, it can alter the pharmacokinetic behavior of medications placing patients at risk for suboptimal dosing and drug toxicity. The ability to directly translate pharmacokinetic alterations into dosing recommendations has thus far been limited and dosing guidance specific to pediatric hemodialysis patients is rare. Despite differences in dialysis prescription and patient populations, intermittent (iHD) and continuous kidney replacement therapy (CKRT) patients are often pooled together. In order to develop evidence-based dosing guidelines, it is important to first prioritize drugs for study in each modality. METHODS: Here we aim to identify priority drugs in two hemodialysis modalities, through: 1) Identification of hospitalized, pediatric patients who received CKRT or intermittent hemodialysis (iHD) using a machine learning-based predictive model based on medications; 2) Identification of medication administration patterns in these patient cohorts; and 3) Identification of the most commonly prescribed drugs that lack published dosing guidance. RESULTS: Notable differences were found in the pattern of medications and drug dosing guidance between iHD and CKRT patients. Antibiotics, diuretics and sedatives were more common in CKRT patients. Out of the 50 most commonly administered medications in the two modalities, only 34% and 28% had dosing guidance present for iHD and CKRT, respectively. CONCLUSIONS: Our results add to the understanding of the differences between iHD and CKRT patient populations by identifying commonly used medications that lack dosing guidance for each hemodialysis modality, helping to pinpoint priority medications for further study. Overall, this study provides an overview of the current limitations in medication use in this at-risk population, and provides a framework for future studies by identifying commonly used medications in pediatric CKRT and iHD patients.
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Lesión Renal Aguda , Terapia de Reemplazo Renal Continuo , Fallo Renal Crónico , Niño , Humanos , Lesión Renal Aguda/epidemiología , Antibacterianos/uso terapéutico , Fallo Renal Crónico/terapia , Fallo Renal Crónico/metabolismo , Preparaciones Farmacéuticas , Diálisis Renal/métodos , Terapia de Reemplazo RenalRESUMEN
Continuous renal replacement therapy (CRRT) is a lifesaving therapy for critically ill patients with acute renal failure. Some patients supported with CRRT suffer from cardiac arrhythmias, which are often treated with amiodarone. While amiodarone is a very effective antiarrhythmic, it has a relatively narrow therapeutic window and a long half-life, making it challenging to dose safely. This is especially true in patients supported with CRRT, where drug pharmacokinetics are likely altered. This ex vivo study measured the extent of amiodarone extraction by the CRRT circuit. Amiodarone was administered to a closed-loop CRRT circuit. Drug was dosed to achieve therapeutic concentrations. Circuits were primed with a human blood-plasma mixture and maintained at physiologic temperature and pH. Serial blood samples were collected over time and drug concentrations were quantified. Amiodarone was heavily extracted by the ex vivo CRRT circuit with only 23% amiodarone remaining in the plasma at 6 h. The relative concentration was significantly greater in the controls than in the CRRT circuits within 2 h (n = 3; p = 0.0059). Amiodarone is heavily adsorbed by CRRT circuit components, suggesting that clinical dosing adjustments are likely required to achieve therapeutic targets.
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OBJECTIVE: To assess timeliness, efficiency, health outcomes and cost-effectiveness of the 2018 redesigned Central Australian aeromedical retrieval model. DESIGN: Pre- and postimplementation observational study of all patients receiving telehealth consultations from remote medical practitioners (RMPs) or Medical Retrieval and Consultation Centre (MRaCC) physicians between 1/1/2015 and 29/2/2020. Descriptive and inferential statistics measuring system efficiency, timeliness, health outcomes and incremental cost-effectiveness. FINDINGS: There were 9%-10% reductions in rates of total aeromedical retrievals, emergency department admissions and hospitalisations postimplementation, all p-values < 0.001. Usage rates for total hospital bed days and ICU hours were 17% lower (both p < 0.001). After adjusting for periodicity (12% fewer retrievals on weekends), each postimplementation year, there were 0.7 fewer retrievals/day (p = 0.002). The mean time from initial consultation to aeromedical departure declined by 18 minutes post-implementation (115 vs. 97 min, p = 0.007). The hazard of death within 365 days was nonsignificant (0.912, 95% CI 0.743-1.120). Postimplementation, it cost $302 more per hospital admission and $3051 more per year of life saved, with a 75% probability of cost-effectiveness. These costs excluded estimated savings of $744,528/year in reduced hospitalisations and the substantial social and out-of-pocket costs to patients and their families associated with temporary relocation to Alice Springs. CONCLUSION: Central Australia's new critical care consultant-led aeromedical retrieval model is more efficient, is dispatched faster and is more cost-effective. These findings are highly relevant to other remote regions in Australia and internationally that have comparable GP-led retrieval services.
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Ambulancias Aéreas , Humanos , Australia , Análisis Costo-Beneficio , Derivación y Consulta , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND: Ceftazidime and clindamycin are commonly prescribed to critically ill patients who require extracorporeal life support such as ECMO and CRRT. The effect of ECMO and CRRT on the disposition of ceftazidime and clindamycin is currently unknown. METHODS: Ceftazidime and clindamycin extraction were studied with ex vivo ECMO and CRRT circuits primed with human blood. The percent recovery of these drugs over time was calculated to determine the degree of interaction between these drugs and circuit components. RESULTS: Neither ceftazidime nor clindamycin exhibited measurable interactions with the ECMO circuit. In contrast, CRRT cleared 100% of ceftazidime from the experimental circuit within the first 2 h. Clearance of clindamycin from the CRRT circuit was slower, with about 20% removed after 6 h. CONCLUSION: Clindamycin and ceftazidime dosing adjustments are likely required in patients who are supported with CRRT, and future studies to quantify these adjustments should consider the pathophysiology of the patient in combination with the clearance due to CRRT. Dosing adjustments to account for adsorption to ECMO circuit components are likely unnecessary and should focus instead on the pathophysiology of the patient and changes in volume of distribution. These results will help improve the safety and efficacy of ceftazidime and clindamycin in patients requiring ECMO and CRRT.
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Oxigenación por Membrana Extracorpórea , Terapia de Reemplazo Renal , Humanos , Terapia de Reemplazo Renal/métodos , Oxigenación por Membrana Extracorpórea/métodos , Ceftazidima/uso terapéutico , Clindamicina/uso terapéutico , Enfermedad CríticaRESUMEN
BACKGROUND: Meropenem is a broad-spectrum carbapenem-type antibiotic commonly used to treat critically ill patients infected with extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. As many of these patients require extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), it is important to understand how these extracorporeal life support circuits impact meropenem pharmacokinetics. Based on the physicochemical properties of meropenem, it is expected that ECMO circuits will minimally extract meropenem, while CRRT circuits will rapidly clear meropenem. The present study seeks to determine the extraction of meropenem from ex vivo ECMO and CRRT circuits and elucidate the contribution of different ECMO circuit components to extraction. METHODS: Standard doses of meropenem were administered to three different configurations (n = 3 per configuration) of blood-primed ex vivo ECMO circuits and serial sampling was conducted over 24 h. Similarly, standard doses of meropenem were administered to CRRT circuits (n = 4) and serial sampling was conducted over 4 h. Meropenem was administered to separate tubes primed with circuit blood to serve as controls to account for drug degradation. Meropenem concentrations were quantified, and percent recovery was calculated for each sample. RESULTS: Meropenem was cleared at a similar rate in ECMO circuits of different configurations (n = 3) and controls (n = 6), with mean (standard deviation) recovery at 24 h of 15.6% (12.9) in Complete circuits, 37.9% (8.3) in Oxygenator circuits, 47.1% (8.2) in Pump circuits, and 20.6% (20.6) in controls. In CRRT circuits (n = 4) meropenem was cleared rapidly compared with controls (n = 6) with a mean recovery at 2 h of 2.36% (1.44) in circuits and 93.0% (7.1) in controls. CONCLUSION: Meropenem is rapidly cleared by hemodiafiltration during CRRT. There is minimal adsorption of meropenem to ECMO circuit components; however, meropenem undergoes significant degradation and/or plasma metabolism at physiological conditions. These ex vivo findings will advise pharmacists and physicians on the appropriate dosing of meropenem.
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Oxigenación por Membrana Extracorpórea , Humanos , Meropenem , Antibacterianos/farmacocinética , CarbapenémicosRESUMEN
INTRODUCTION: In February 2018 the Remote Medical Practitioner (RMP)-led telehealth model for providing both primary care advice and aeromedical retrievals in Central Australia was replaced by the Medical Retrieval and Consultation Centre (MRaCC) and Remote Outreach Consultation Centre (ROCC). In this new model, specialists with advanced critical care skills provide telehealth consultations for emergencies 24/7 and afterhours primary care advice (MRaCC) while RMPs (general practitioners) provide primary care telehealth advice in business hours via the separate ROCC. OBJECTIVE: To evaluate changes in clinicians' perceptions of efficiency and timeliness of the new (MRaCC) and (ROCC) model in Central Australia. DESIGN: There were 103 and 72 respondents, respectively, to pre- and post-implementation surveys of remote clinicians and specialist staff. FINDINGS: Both emergency and primary care aspects of telehealth support were perceived as being significantly more timely and efficient under the newly introduced MRaCC/ROCC model. Importantly, health professionals in remote community were more likely to feel that their access to clinical support during emergencies was consistent and immediately available. DISCUSSION: Respondents consistently perceived the new MRaCC/ROCC model more favourably than the previous RMP-led model, suggesting that there are benefits to having separate referral streams for telehealth advice for primary health care and emergencies, and staffing the emergency stream with specialists with advanced critical care skills. CONCLUSION: Given the paucity of literature about optimal models for providing pre-hospital medical care to remote residents, the findings have substantial local, national and international relevance and implications, particularly in similar geographically large countries, with low population density.
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Consulta Remota , Telemedicina , Humanos , Australia , Urgencias Médicas , Atención Primaria de Salud , Encuestas y CuestionariosRESUMEN
The purpose of this study is to assess efficacy of 4-factor prothrombin complex concentrates (4F-PCC) for direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) as compared to its use in warfarin-associated ICH. A retrospective cohort study was performed to compare the efficacy of 4F-PCC for reversal of apixaban and rivaroxaban versus warfarin for ICH at Cooper University Health Care from January 2015 to December 2019. Patients included were ≥ 18 years of age who developed an ICH while on apixaban, rivaroxaban, or warfarin. The primary outcome was to compare the percentage of patients with Excellent or Good hemostatic efficacy after 4F-PCC administration. Secondary outcomes were to describe functional outcomes at discharge, in-hospital mortality, and thrombotic complications after 4F-PCC administration. A total of 159 patients were included; 115 patients received warfarin and 44 patients received a DOAC (apixaban, n = 22; rivaroxaban, n = 22). 70 patients were evaluable for the primary endpoint. Thirty-four (66.7%) patients in the warfarin group versus 14 (73.7%) patients in the DOAC group were determined to have excellent or good hemostatic efficacy (p = 0.57). In-hospital mortality (30.4% vs. 40.9%, p = 0.21) and thrombotic complications (9.6% vs. 11.4%, p = 0.67) were comparable between the warfarin vs. DOAC groups, respectively. This small, retrospective study found no difference in patients with excellent/good hemostatic efficacy after reversal with 4F-PCC for DOAC-associated ICH compared to warfarin-associated ICH. This study is limited by its retrospective nature and sample size. Larger, prospective studies are needed to further determine the efficacy of 4F-PCC in reversing DOAC-associated ICH.
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Hemostáticos , Warfarina , Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea , Factor IX , Humanos , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/tratamiento farmacológico , Pirazoles , Piridonas , Estudios Retrospectivos , Rivaroxabán/efectos adversos , Warfarina/efectos adversosRESUMEN
Extracorporeal life support (ECLS) devices are lifesaving for critically ill patients with multi-organ dysfunction. Despite this, patients supported with ECLS are at high risk for ECLS-related complications, including nosocomial infections, and mortality rates are high in this patient population. The high mortality rates are suspected to be, in part, a result of significantly altered drug disposition by the ECLS circuit, resulting in suboptimal antimicrobial dosing. Cefepime is commonly used in critically ill patients with serious infections. Cefepime dosing is not routinely guided by therapeutic drug monitoring and treatment success is dependent upon the percentage of time of the dosing interval that the drug concentration remains above the minimum inhibitory concentration of the organism. This ex vivo study measured the extraction of cefepime by continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) circuits. Cefepime was studied in four closed-loop CRRT circuit configurations and a single closed-loop ECMO circuit configuration. Circuits were primed with a physiologic human blood-plasma mixture and the drug was dosed to achieve therapeutic concentrations. Serial blood samples were collected over time and concentrations were quantified using validated assays. In ex vivo CRRT experiments, cefepime was rapidly cleared by dialysis, hemofiltration, and hemodiafiltration, with greater than 96% cefepime eliminated from the circuit by 2 hours. In the ECMO circuits, the mean recovery of cefepime was similar in both circuit and standard control. Mean (standard deviation) recovery of cefepime in the ECMO circuits (n = 6) was 39.2% (8.0) at 24 hours. Mean recovery in the standard control (n = 3) at 24 hours was 52.2% (1.5). Cefepime is rapidly cleared by dialysis, hemofiltration, and hemodiafiltration in the CRRT circuit but minimally adsorbed by either the CRRT or ECMO circuits. Dosing adjustments are needed for patients supported with CRRT.
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Oxigenación por Membrana Extracorpórea , Hemofiltración , Humanos , Cefepima , Oxigenación por Membrana Extracorpórea/métodos , Enfermedad Crítica/terapia , Diálisis RenalRESUMEN
OBJECTIVE: Retrospectively apply criteria from Center to Advance Palliative Care to a cohort of children treated in a cardiac ICU and compare children who received a palliative care consultation to those who were eligible for but did not receive one. METHODS: Medical records of children admitted to a cardiac ICU between January 2014 and June 2017 were reviewed. Selected criteria include cardiac ICU length of stay >14 days and/or ≥ 3 hospitalisations within a 6-month period. MEASUREMENTS AND RESULTS: A consultation occurred in 17% (n = 48) of 288 eligible children. Children who received a consult had longer cardiac ICU (27 days versus 17 days; p < 0.001) and hospital (91 days versus 35 days; p < 0.001) lengths of stay, more complex chronic conditions at the end of first hospitalisation (3 versus1; p < 0.001) and the end of the study (4 vs.2; p < 0.001), and higher mortality (42% versus 7%; p < 0.001) when compared with the non-consulted group. Of the 142 pre-natally diagnosed children, only one received a pre-natal consult and 23 received it post-natally. Children who received a consultation (n = 48) were almost 2 months of age at the time of the consult. CONCLUSIONS: Less than a quarter of eligible children received a consultation. The consultation usually occurred in the context of medical complexity, high risk of mortality, and at an older age, suggesting potential opportunities for more and earlier paediatric palliative care involvement in the cardiac ICU. Screening criteria to identify patients for a consultation may increase the use of palliative care services in the cardiac ICU.
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Unidades de Cuidados Intensivos , Cuidados Paliativos , Anciano , Niño , Humanos , Unidades de Cuidado Intensivo Pediátrico , Tiempo de Internación , Prevalencia , Derivación y Consulta , Estudios RetrospectivosRESUMEN
OBJECTIVES: Describe pediatric palliative care consult in children with heart disease; retrospectively apply Center to Advance Palliative Care criteria for pediatric palliative care consults; determine the impact of pediatric palliative care on end of life. DESIGN: A retrospective single-center study. SETTING: A 16-bed cardiac ICU in a university-affiliated tertiary care children's hospital. PATIENTS: Children (0-21 yr old) with heart disease admitted to the cardiac ICU from January 2014 to June 2017. MEASUREMENTS AND MAIN RESULTS: Over 1,000 patients (n = 1, 389) were admitted to the cardiac ICU with 112 (8%) receiving a pediatric palliative care consultation. Patients who received a consult were different from those who did not. Patients who received pediatric palliative care were younger at first hospital admission (median 63 vs 239 d; p = 0.003), had a higher median number of complex chronic conditions at the end of first hospitalization (3 vs 1; p < 0.001), longer cumulative length of stay in the cardiac ICU (11 vs 2 d; p < 0.001) and hospital (60 vs 7 d; p < 0.001), and higher mortality rates (38% vs 3%; p < 0.001). When comparing location and modes of death, patients who received pediatric palliative care were more likely to die at home (24% vs 2%; p = 0.02) and had more comfort care at the end of life (36% vs 2%; p = 0.002) compared to those who did not. The Center to Advance Palliative Care guidelines identified 158 patients who were eligible for pediatric palliative care consultation; however, only 30 patients (19%) in our sample received a consult. CONCLUSIONS: Pediatric palliative care consult rarely occurred in the cardiac ICU. Patients who received a consult were medically complex and experienced high mortality. Comfort care at the end of life and death at home was more common when pediatric palliative care was consulted. Missed referrals were apparent when Center to Advance Palliative Care criteria were retrospectively applied.
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Cardiopatías , Cuidado Terminal , Niño , Cardiopatías/terapia , Humanos , Unidades de Cuidados Intensivos , Tiempo de Internación , Cuidados Paliativos , Estudios RetrospectivosRESUMEN
BACKGROUND: Experience and application of recruitment packages can be critical in leadership efforts of surgical chairpersons in promoting research, although attrition of these efforts can happen over time due to lack of new resources. We aimed to examine the impact of experience of surgical chairpersons on departmental National Institutes of Health (NIH) funding. METHODS: Experience as a chairperson defined as the number of years spent as an interim or permanent chair was abstracted from the department Web site (US medical schools only). The NIH funding (US dollars) of the departments were obtained from the Blue Ridge Medical Institute (www.brimr.org). The change in NIH funding from the immediate previous financial year (2010-2009 and 2011-2010) was used to classify chairpersons into four groups: group 1 (-/-), group 2 (-/+), group 3 (+/+), and group 4 (+/-) for analysis. RESULTS: Median NIH funding were $1.9 (0.7-6) million, $1.8 (0.6-5) million, and $1.7 (0.7-5) million for 2009, 2010, and 2011, respectively, and the median experience as a surgical chairperson was 6 y (3-10). Recent chairpersons (<1 y) inherited departments that usually lost NIH funding (62%) and were frequently unable to develop a positive trend for growth over the next fiscal year ([-/-] n = 4 and [+/-] n = 2, 75%). Chairpersons who held their positions for 4-6 y were most likely to be associated with trends of positive funding growth, whereas chairpersons >10 y were most likely to have lost funding (66%, P = 0.07). CONCLUSIONS: Provision of new development dollars later in their tenure and retention of chairpersons might lead to more positive trends in increase in NIH funding.
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Investigación Biomédica/economía , Docentes Médicos , National Institutes of Health (U.S.) , Ejecutivos Médicos/economía , Apoyo a la Investigación como Asunto/economía , Facultades de Medicina/economía , Centros Médicos Académicos/economía , Centros Médicos Académicos/organización & administración , Investigación Biomédica/organización & administración , Eficiencia Organizacional , Humanos , Ejecutivos Médicos/organización & administración , Edición , Apoyo a la Investigación como Asunto/organización & administración , Facultades de Medicina/organización & administración , Cirujanos/economía , Cirujanos/organización & administración , Estados UnidosRESUMEN
Infective endocarditis (IE) poses a diagnostic challenge due to its diverse clinical presentations, especially among high-risk groups. Diagnosis relies on integrating clinical presentation, blood cultures and imaging findings. Advanced imaging techniques enhance diagnostic accuracy, particularly in complex cases. Treatment involves antimicrobial therapy and surgery in complicated cases, with early intervention crucial for optimal outcomes. Coordinated care by an Endocarditis Team ensures tailored treatment plans, prompt complication management and long-term monitoring after discharge. The authors present a case of subacute IE presenting initially with back pain in a patient with a complex medical history, highlighting diagnostic and management approaches.
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Dolor de Espalda , Endocarditis Bacteriana Subaguda , Humanos , Dolor de Espalda/etiología , Endocarditis Bacteriana Subaguda/diagnóstico , Endocarditis Bacteriana Subaguda/complicaciones , Endocarditis Bacteriana Subaguda/tratamiento farmacológico , Masculino , Antibacterianos/uso terapéutico , Endocarditis Bacteriana/diagnóstico , Endocarditis Bacteriana/complicaciones , Endocarditis Bacteriana/microbiología , Persona de Mediana Edad , Diagnóstico DiferencialRESUMEN
Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device commonly used to treat cardiac arrest in children. The American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend using amiodarone as a first-line agent to treat ventricular arrhythmias in children with cardiac arrest. However, there are no dosing recommendations for amiodarone to treat ventricular arrhythmias in pediatric patients on ECMO. Amiodarone has a high propensity for adsorption to the ECMO components due to its physicochemical properties leading to altered pharmacokinetics (PK) in ECMO patients. The change in amiodarone PK due to interaction with ECMO components may result in a difference in optimal dosing in patients on ECMO when compared with non-ECMO patients. To address this clinical knowledge gap, a physiologically-based pharmacokinetic model of amiodarone was developed in adults and scaled to children, followed by the addition of an ECMO compartment. The pediatric model included ontogeny functions of cytochrome P450 (CYP450) enzyme maturation across various age groups. The ECMO compartment was parameterized using the adsorption data of amiodarone obtained from ex vivo studies. Model predictions captured observed concentrations of amiodarone in pediatric patients with ECMO well with an average fold error between 0.5 and 2. Model simulations support an amiodarone intravenous (i.v) bolus dose of 22 mg/kg (neonates), 13 mg/kg (infants), 8 mg/kg (children), and 6 mg/kg (adolescents). This PBPK modeling approach can be applied to explore the dosing of other drugs used in children on ECMO.
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Amiodarona , Antiarrítmicos , Oxigenación por Membrana Extracorpórea , Modelos Biológicos , Amiodarona/farmacocinética , Amiodarona/administración & dosificación , Humanos , Niño , Preescolar , Lactante , Antiarrítmicos/farmacocinética , Antiarrítmicos/administración & dosificación , Adolescente , Recién Nacido , Adulto , Masculino , Relación Dosis-Respuesta a Droga , Femenino , Sistema Enzimático del Citocromo P-450/metabolismo , Factores de EdadRESUMEN
BACKGROUND: Patients supported with extracorporeal life support (ECLS) circuits such as ECMO and CRRT often require high doses of sedatives and analgesics, including ketamine and dexmedetomidine. Concentrations of many medications are affected by ECLS circuits through adsorption to the circuit components, dialysis, as well as the large volume of blood used to prime the circuits. However, the impact of ECLS circuits on ketamine and dexmedetomidine pharmacokinetics has not been well described. This study determined ketamine and dexmedetomidine extraction by extracorporeal circuits in an ex-vivo system. METHODS: Medication was administered at therapeutic concentration to blood-primed, closed-loop ex-vivo ECMO and CRRT circuits. Drug concentrations were measured in plasma, hemofiltrate, and control samples at multiple time points throughout the experiments. At each sample time point, the percentage of drug recovery was calculated. RESULTS: Ketamine plasma concentration in the ECMO and CRRT circuits decreased rapidly, with 43.8% recovery (SD = 0.6%) from ECMO circuits after 8 h and 3.3% (SD = 1.8%) recovery from CRRT circuits after 6 h. Dexmedetomidine was also cleared from CRRT circuits, with 20.3% recovery (SD = 1.8%) after 6 h. Concentrations of both medications were very stable in the control experiments, with approximately 100% drug recovery of both ketamine and dexmedetomidine after 6 h. CONCLUSION: Ketamine and dexmedetomidine concentrations are significantly affected by ECLS circuits, indicating that dosing adjustments are needed for patients supported with ECMO and CRRT.
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Dexmedetomidina , Oxigenación por Membrana Extracorpórea , Ketamina , Ketamina/administración & dosificación , Ketamina/farmacocinética , Ketamina/sangre , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacocinética , Oxigenación por Membrana Extracorpórea/métodos , Humanos , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/sangreRESUMEN
Deterioration of the immune and skeletal systems, each of which parallel obesity, reflects a fragile interrelationship between adiposity and osteoimmunology. Using a murine model of diet-induced obesity, this study investigated the ability of mechanical signals to protect the skeletal-immune systems at the tissue, cellular, and molecular level. A long-term (7 mo) high-fat diet increased total adiposity (+62%), accelerated age-related loss of trabecular bone (-61%), and markedly reduced B-cell number in the marrow (-52%) and blood (-36%) compared to mice fed a regular diet. In the final 4 mo of the protocol, the application of low-magnitude mechanical signals (0.2 g at 90 Hz, 15 min/d, 5 d/wk) restored both bone structure and B cells to those levels measured in control mice fed a regular diet. These phenotypic outcomes were achieved, in part, by reductions in osteoclastic activity and a biasing of hematopoietic stem cell differentiation toward the lymphoid B-cell lineage and away from a myeloid fate. These results emphasize that obesity undermines both the skeletal and immune systems, yet brief exposure to mechanical signals, perhaps as a surrogate to the salutary influence of exercise, diminishes the consequences of diabetes and obesity, restoring bone structure and normalizing B-cell populations by biasing of the fate of stem cells through mechanosensitive pathways.
Asunto(s)
Linfocitos B/metabolismo , Huesos/metabolismo , Obesidad/fisiopatología , Condicionamiento Físico Animal/fisiología , Fosfatasa Ácida/genética , Fosfatasa Ácida/metabolismo , Tejido Adiposo/metabolismo , Animales , Peso Corporal/fisiología , Células de la Médula Ósea/metabolismo , Resorción Ósea/etiología , Resorción Ósea/metabolismo , Huesos/patología , Dieta Alta en Grasa/efectos adversos , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Expresión Génica , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Obesidad/etiología , Obesidad/metabolismo , Factor de Transcripción PAX5/genética , PPAR gamma/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Fosfatasa Ácida Tartratorresistente , Microtomografía por Rayos XRESUMEN
BACKGROUND: Chairpersons of surgery departments are key stakeholders and role models and leaders of research in academic medical institutions. However, the characteristics of surgical chairpersons are understudied. This study aimed to investigate the association between the personal academic achievement of a surgical chairperson and the National Institutes of Health (NIH) funding of the department. METHODS: We calculated the Hirsch index (H-index), a measure of research productivity, for chairpersons of surgery of the top 90 research medical schools that were ranked by U.S. News & World Report. Specialty training, y as chairperson, location, and NIH institutional and department funding were analyzed. Nonparametric tests and linear regression methods were used to compare the different groups. RESULTS: Of the 90 chairpersons, 20 positions for chairs (22%) are either recent (<1 y) or unfilled (n = 6). Only 3% of all chairpersons are women, and the median H-index for the chairpersons is 20 (Interquartile range 14-27) with a median 101 publications with 14 cites per publication. Median surgery-specific NIH funding in 2011 was $1.7 million (Interquartile range $721,042-5,085,305). The chairperson's H-index was exponentially associated with department funding in multivariate models adjusting for institution rank, except when the H-index was extreme (<4 or >49) (coefficient 0.32, P = 0.02). CONCLUSIONS: The research productivity of a chairperson is the only personal attribute of those studied that is associated with the departmental NIH funding. This suggests the important role an academically productive surgical leader may play as a champion for the academic success of the department.