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Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.
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Current evidence suggests that early enteral nutrition is a best practice and leads to improved clinical outcomes. An evidence-based practice project was implemented in a busy neurointensive care unit in a midwestern tertiary care facility that was designed to improve care by implementing the early nutrition portion of Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine and the American Society for Enteral and Parenteral Nutrition. The Registered Nurses' Association of Ontario's (RNAO) Toolkit: Implementation of Best Practice Guidelines (BPGs) was selected and followed to guide implementation and achieve optimal results. During a 90-day implementation period, this project resulted in a 100% improvement in early nutrition. Interventions included the use of a series of cards that reminded the team to order enteral nutrition and prepacked bundles of nasogastric tube supplies. The RNAO toolkit served as a structured and effective step-by-step methodology for the implementation of a BPG.
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Nutrición Enteral , Unidades de Cuidados Intensivos , Adulto , Humanos , Nutrición Enteral/métodos , Apoyo Nutricional/métodos , Estado Nutricional , Cuidados Críticos/métodos , Enfermedad Crítica/terapiaAsunto(s)
Edema Encefálico , Fentanilo , Analgésicos Opioides , Cerebelo , Preescolar , Edema , Femenino , HumanosRESUMEN
BACKGROUND: Abnormal restricted diffusion on magnetic resonance imaging is often associated with ischemic stroke or anoxic injury, but other conditions can present similarly. We present six cases of an unusual but consistent pattern of restricted diffusion in bilateral hippocampi and cerebellar cortices. This pattern of injury is distinct from typical imaging findings in ischemic, anoxic, or toxic injury, suggesting it may represent an under-recognized clinicoradiographic syndrome. Despite initial presentation with stupor or coma in the context of obstructive hydrocephalus, patients may have acceptable outcomes if offered early intervention. METHODS: We identified an ad hoc series of patients at our two institutions between years 2014 and 2017 who presented to the neurocritical care unit with severe, otherwise unexplained cerebellar edema and retrospectively identified several commonalities in history, presentation, and imaging. RESULTS: Between two institutions, we identified six patients-ages 33-59 years, four male-with similar presentations of decreased level of consciousness in the context of intoxicant exposure, with acute cytotoxic edema of the cerebellar cortex, hippocampi, and aspects of the basal nuclei. All patients presented with severe cerebellar edema which led to obstructive hydrocephalus requiring aggressive medical and/or surgical management. The five patients who survived to discharge demonstrated variable degrees of physical and memory impairment on discharge and at follow-up. CONCLUSIONS: We present findings of a potentially novel syndrome involving a distinct pattern of cerebellar and hippocampal restricted diffusion, with imaging and clinical characteristics distinct from ischemic stroke, hypoxic injury, and known toxidromes and leukoencephalopathies. Given the potential for favorable outcome despite early obstructive hydrocephalus, early identification and treatment of this syndrome are critical.
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Ganglios Basales/diagnóstico por imagen , Benzodiazepinas/efectos adversos , Edema Encefálico/diagnóstico por imagen , Estimulantes del Sistema Nervioso Central/efectos adversos , Corteza Cerebelosa/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Hidrocefalia/diagnóstico por imagen , Alcaloides Opiáceos/efectos adversos , Adulto , Intoxicación Alcohólica/complicaciones , Anfetaminas/efectos adversos , Edema Encefálico/inducido químicamente , Edema Encefálico/fisiopatología , Edema Encefálico/terapia , Cerebelo/diagnóstico por imagen , Cocaína/efectos adversos , Coma/etiología , Femenino , Heroína/efectos adversos , Humanos , Hidrocefalia/etiología , Hidrocefalia/fisiopatología , Hidrocefalia/terapia , Hidromorfona/efectos adversos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/tratamiento farmacológico , Estupor/etiología , Trastornos Relacionados con Sustancias , SíndromeRESUMEN
INTRODUCTION: The aim of this study is to assess the attractiveness in the smile arch of different vertical positions of the incisal edges of the maxillary lateral incisors. MATERIAL AND METHODS: A frontal photograph of a Caucasian woman's smile was digitally modified to obtain an image with the incisal edges of the maxillary lateral incisors symmetrically tangent to the smile arch. These incisal edges were then moved vertically by 0.5 mm increments. The value was considered positive for an occlusal shift and negative for a gingival shift. Four other images were obtained by moving the incisal edges from +0.5 mm to -1.5 mm. The five images were rated on a visual analog scale by three groups of evaluators: orthodontists, dentists and laypersons. A statistical analysis was performed. RESULTS: Laypersons preferred first lateral incisors tangent to the smile arch, second a +0.5 mm shift, and third a -0.5 mm shift. Orthodontists and dentists preferred first a -0.5 mm shift and second a null shift. CONCLUSIONS: The aesthetic perception of the smile, as regard to the vertical relationships between the incisal edges of the anterior teeth, differs between laypersons and professionals but remains homogenous between orthodontists and dentists. The most consensual aesthetic situation, from both professionals' and laypersons' points of view, is the geometry in which the incisal edges of the maxillary lateral incisors are tangent to the smile arch.
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Estética Dental , Incisivo , Sonrisa , Adulto , Anciano , Actitud del Personal de Salud , Odontólogos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ortodoncistas , Adulto JovenRESUMEN
OBJECTIVES: The objective of this study was to evaluate operational policies that may improve the proportion of eligible stroke patients within a population who would receive intravenous recombinant tissue plasminogen activator (rt-PA) and minimize time to treatment in eligible patients. METHODS: In the context of a regional stroke team, the authors examined the effects of staff location and telemedicine deployment policies on the timeliness of thrombolytic treatment, and estimated the efficacy and cost-effectiveness of six different policies. A process map comprising the steps from recognition of stroke symptoms to intravenous administration of rt-PA was constructed using data from published literature combined with expert opinion. Six scenarios were investigated: telemedicine deployment (none, all, or outer-ring hospitals only) and staff location (center of region or anywhere in region). Physician locations were randomly generated based on their zip codes of residence and work. The outcomes of interest were onset-to-treatment (OTT) time, door-to-needle (DTN) time, and the proportion of patients treated within 3 hours. A Monte Carlo simulation of the stroke team care-delivery system was constructed based on a primary data set of 121 ischemic stroke patients who were potentially eligible for treatment with rt-PA. RESULTS: With the physician located randomly in the region, deploying telemedicine at all hospitals in the region (compared with partial or no telemedicine) would result in the highest rates of treatment within 3 hours (80% vs. 75% vs. 70%) and the shortest OTT (148 vs. 164 vs. 176 minutes) and DTN (45 vs. 61 vs. 73 minutes) times. However, locating the on-call physician centrally coupled with partial telemedicine deployment (five of the 17 hospitals) would be most cost-effective with comparable eligibility and treatment times. CONCLUSIONS: Given the potential societal benefits, continued efforts to deploy telemedicine appear warranted. Aligning the incentives between those who would have to fund the up-front technology investments and those who will benefit over time from reduced ongoing health care expenses will be necessary to fully realize the benefits of telemedicine for stroke care.
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Servicio de Urgencia en Hospital/organización & administración , Programas Médicos Regionales/organización & administración , Accidente Cerebrovascular/terapia , Telemedicina/estadística & datos numéricos , Terapia Trombolítica/estadística & datos numéricos , Isquemia Encefálica/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Humanos , Método de Montecarlo , Accidente Cerebrovascular/diagnóstico , Factores de Tiempo , Activador de Tejido Plasminógeno/uso terapéuticoRESUMEN
INTRODUCTION: Copper-nickel-titanium alloys are supposed to deliver a shape memory effect: when they are brought to a low temperature phase and subjected to a plastic deformation, they should recover their initial shape by simple heating. Nickel-titanium alloys can display different crystallographic phases: martensite, austenite and an inconstant intermediate R-phase. The shape memory effect is generally associated with the transition from martensite to austenite but it could also accompany the transition from R-phase to austenite. Since oral temperatures are not compatible with a fully martensitic alloy, this study aims, for 35° Copper Ni-Ti(®), to assess the R-phase presence at oral temperatures and to verify the possibility of using the R-phase shape memory effect under clinical conditions. MATERIALS AND METHODS: Thirty consecutive 35° Copper Ni-Ti(®) archwires from two different batches were examined by differential scanning calorimetry with partial cycles limited to temperatures encountered within the oral cavity (from 0 °C to 50 °C). The presence of an intermediate crystallographic phase was assessed on the thermograms. The transformation temperatures were determined and the two batches were compared using the Mann-Whitney U Test. RESULTS: Upon heating, all wires transformed directly from martensite to austenite. Af (mean = 33.5 °C, SD = 0.8 °C) was generally below the temperature stated by the manufacturer and a statistically significant difference (p ≤ 0.01) was found between the two batches. CONCLUSIONS: No R-phase was detected and transformation temperatures were not constant. This study questions the supposed shape memory effect displayed by 35° Copper Ni-Ti(®) wires under clinical conditions.
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Rastreo Diferencial de Calorimetría , Cobre , Aleaciones/química , Ensayo de Materiales , Alambres para OrtodonciaRESUMEN
In recent years, there has been a dramatic increase in the number of adults receiving comprehensive orthodontic treatment. In clinical practice, management of adults may be somewhat different than for most adolescents. Adults are more likely than adolescents to have dentitions that have undergone some degree of mutilation over time, which may necessitate alterations in the treatment strategy. Excessive wear, missing and compromised teeth are some of the differences observed. For adult patients who have experienced bone and attachment loss as a consequence of periodontal disease, a new set of biomechanical requirements exists for producing the tooth movements desired during the orthodontic therapy. Proper planning and appliance design for adults presenting with multiple missing teeth may require some degree of creativity to adapt to unique malocclusions and deliver the proper biomechanical force system. In this article, current clinical application of biomechanical principles will be presented with emphasis on clinical orthodontic management of severely mutilated dentitions.
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Maloclusión/complicaciones , Planificación de Atención al Paciente , Enfermedades Periodontales/complicaciones , Técnicas de Movimiento Dental/métodos , Adulto , Pérdida de Hueso Alveolar/complicaciones , Fenómenos Biomecánicos , Implantes Dentales , Humanos , Maloclusión/terapia , Métodos de Anclaje en Ortodoncia/instrumentación , Métodos de Anclaje en Ortodoncia/métodos , Diseño de Aparato Ortodóncico , Pérdida de la Inserción Periodontal/complicaciones , Enfermedades Periodontales/terapia , Estrés Mecánico , Diente/fisiopatología , Pérdida de Diente/complicaciones , Técnicas de Movimiento Dental/instrumentación , Desgaste de los Dientes/complicacionesRESUMEN
BACKGROUND: Mock oral board exams, fashioned after the live patient hour of the American Board of Psychiatry and Neurology exam, are commonly part of resident assessment during residency training. Exams using real patients selected from clinics or hospitals are not standardized and do not allow comparisons of resident performance across the residency program. We sought to create a standardized patient mock oral board exam that would allow comparison of residents' clinical performance. METHODS: Three cases were created and then used for this mock oral boards exercise utilizing trained standardized patients. Residents from the University of Cincinnati and Indiana University participated in the exam. Residents were scored by attending physician examiners who directly observed the encounter with the standardized patient. The standardized patient also assessed each resident. A post-test survey was administered to ascertain participant's satisfaction with the examination process. RESULTS: Resident scores were grouped within one standard deviation of the mean, with the exception of one resident who was also subjectively felt to "fail" the exam. In exams with two faculty "evaluators", scores were highly correlated. The survey showed satisfaction with the examination process in general. CONCLUSION: Standardized patients can be used for mock oral boards in the live patient format. Our initial experience with this examination process was positive. Further testing is needed to determine if this examination format is more reliable and valid than traditional methods of assessing resident competency.
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Psiquiatría Biológica/educación , Evaluación Educacional/métodos , Internado y Residencia/normas , Neurología/educación , Simulación de Paciente , Consejos de Especialidades , Actitud del Personal de Salud , Competencia Clínica , Humanos , Indiana , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/terapia , Ohio , Relaciones Médico-Paciente , Proyectos Piloto , Evaluación de Programas y Proyectos de Salud , Revelación de la VerdadRESUMEN
Delayed cerebral vasospasm after subarachnoid hemorrhage (SAH) remains a significant cause of mortality and morbidity; however, the etiology is, as yet, unknown, despite intensive research efforts. Research in this laboratory indicates that bilirubin and oxidative stress may be responsible by leading to formation of bilirubin oxidation products (BOXes), so we investigated changes in bilirubin concentration and oxidative stress in vitro, and in cerebral spinal fluid (CSF) from SAH patients. Non-SAH CSF, a source of heme oxygenase I (HO-1), and blood were incubated, and in vitro bilirubin production measured. Cerebrospinal fluid from SAH patients was collected, categorized using stimulation of vascular smooth muscle metabolism in vitro, and information obtained regarding occurrence of vasospasm in the patients. Cerebral spinal fluid was analyzed for hemoglobin, total protein and bilirubin, BOXes, malonyldialdehyde and peroxidized lipids (indicators of an oxidizing environment), and HO-1 concentration. The formation of bilirubin in vitro requires that CSF is present, as well as whole, non-anti-coagulated blood. Bilirubin, BOXes, HO-1, and peroxidized lipid content were significantly higher in CSF from SAH patients with vasospasm, compared with nonvasospasm SAH CSF, and correlated with occurrence of vasospasm. We conclude that vasospasm may be more likely in patients with elevated BOXes. The conditions necessary for the formation of BOXes are indeed present in CSF from SAH patients with vasospasm, but not CSF from SAH patients without vasospasm.
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Bilirrubina/líquido cefalorraquídeo , Hemorragia Subaracnoidea/líquido cefalorraquídeo , Vasoespasmo Intracraneal/líquido cefalorraquídeo , Adulto , Anciano , Animales , Bilirrubina/biosíntesis , Lesiones Encefálicas/metabolismo , Femenino , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemoglobinas/metabolismo , Humanos , Peroxidación de Lípido , Masculino , Malondialdehído/metabolismo , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Oxidación-Reducción , Estrés Oxidativo/fisiología , Ratas , Hemorragia Subaracnoidea/metabolismo , Vasoespasmo Intracraneal/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Acute ischemic stroke patients are infrequently treated with rtPA, despite its proven effectiveness. Poor physician reimbursement for acute stroke care is one possible explanation for the low frequency of use. We describe the physician reimbursement for thrombolytic therapy for the stroke team physicians serving the Greater Cincinnati/Northern Kentucky region (GCNK), and the Alberta region. METHODS: GCNK: billing logs were accessed for the study period of 7/01-12/02, and cross-matched to stroke call logs. University of Calgary (UC): treatment records of a single physician were reviewed from 4/02-3/04. A telephone survey of Canadian provinces was conducted regarding billing practices. RESULTS: GCNK: During the study period, 151 patients received rtPA. For treated pts. the average time spent was 2.6 hours, and average reimbursement received was 472 dollars (of those with insurance). The highest reimbursement was received by billing critical care codes. Reimbursement for critical care was similar to or lower than common office procedures for neurologists. UC: during the study period, 131 patients received rtPA. Average reimbursement for rtPA treated patients was 340 dollars US, not including on-call payments. Survey across Canada revealed many provinces with weekend/after hour premium stipends and on-call stipends. CONCLUSIONS: Physician reimbursement for the evaluation and treatment of acute stroke, when compared with other diagnoses commonly treated by neurologists, is relatively low in both the U.S. and Canada. Health policy decision-makers in the US and Canada should be made aware of the importance of providing a more balanced plan to provide medical care to stroke patients.