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We read with great interest the article "Artificial Intelligence: its Future and Impact on Acute Medicine". Regarding the historical perspective on artificial intelligence (AI) origins, we believe the role of John von Neumann (1903-1957) also deserves emphasis.
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Inteligencia Artificial , Medicina , Humanos , PredicciónRESUMEN
BACKGROUND AND METHODS: A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of donor for allogeneic haematopoietic cell transplantation (HCT) was performed to create a network of best evidence that allows us to identify new potential indirect comparisons for the strategic development of future studies that connect to the existing evidence network. RESULTS: A total of 19 eligible RCTs (2589 total patients) were identified. Nine studies (1566 patients) compared clinical outcomes following the use of peripheral blood progenitor cells (PBPCs) with bone marrow (BM) from matched related donors (eight studies) or matched unrelated donors (one study). The remaining studies compared BM or PBPCs with various methods of BM stimulation or manipulation (six studies), compared different methods of surface molecule-based selection and/or depletion of grafts (two studies) or compared the optimal number of units for paediatric cord blood transplantation (two studies). No published RCTs compared different types of donors. The geometry of the evidence network was analysed to identify opportunities for potential novel indirect comparisons and to identify opportunities to expand the network. Few indirect comparisons are currently feasible due to small sample size and heterogeneity in patient diagnoses and demographics between treatment nodes in the network. CONCLUSION: More RCTs that enrol greater numbers of similar patients are needed to leverage the current evidence network concerning donor choice and source of cells used in allogeneic HCT.
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Selección de Donante/métodos , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Donante no Emparentado , Aloinjertos , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Ultrasound contrast agents have unique acoustic properties that enable them to enhance the cardiac blood flow and thus are used broadly in modern echocardiography laboratories for salvage of nondiagnostic studies, improving accuracy and reducing variability even in the presence of adequate image quality. Contrast echocardiography is also used as an adjunctive technique when unenhanced echocardiography falls short in the differentiation of cardiac structural abnormalities such as cardiac masses. Ultrasound contrast agents are pure intravascular tracers. Development of innovative ultrasound imaging techniques has led to myocardial perfusion imaging with contrast echocardiography. Although currently an off-label indication, it has been shown that perfusion imaging with contrast echocardiography adds incremental value to stress echocardiography in the detection of coronary artery disease. Moreover, it can be used for assessment of myocardial viability. In this paper we briefly discuss the basics of contrast echocardiography and its use in daily clinical practice.
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Medios de Contraste , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Ecocardiografía/métodos , Aumento de la Imagen/métodos , Imagen de Perfusión Miocárdica/métodos , Volumen Sistólico , Disfunción Ventricular Izquierda/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/complicaciones , Medicina Basada en la Evidencia , Humanos , Pautas de la Práctica en Medicina , Disfunción Ventricular Izquierda/etiologíaRESUMEN
PURPOSE: Reconstructed human epidermis (RHE) is standardly used for the risk assessment of chemical compounds. However, analysis is dependent on invasive methods such as histological processing or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining. METHODS: As an alternative, we have developed a non-destructive technology to analyze the integrity of epidermal equivalents based on impedance spectroscopy. RHEs were generated and impedance spectra were recorded. from these spectra, we extrapolated electrical characteristics such as the capacitance and the ohmic resistance. Furthermore, the measurable electrical parameters were used to quantify the effects of mechanical and chemical disruption of the epidermal integrity. RESULTS: A fully matured RHE exhibits typical impedance spectra in a frequency ranging between 1 Hz and 100 kHz, which is comparable to the spectra of freshly isolated human epidermal biopsies. We could show that, during RHE maturation, these characteristics change significantly. Thus, capacitance and ohmic resistance can be employed as a criterion for the quality control of skin equivalents. Additionally, our application of impedance spectroscopy reveals sufficient sensitivity to detect a transient decreased ohmic resistance caused by 2-propanol, which is classified as a non-irritant by MTT assays. CONCLUSION: These results indicate that impedance spectroscopy can be employed as a non-destructive complementary method to assess mild irritative effects, which is currently not possible.
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Espectroscopía Dieléctrica/métodos , Epidermis/química , 2-Propanol/farmacología , Fenómenos Biomecánicos , Células Cultivadas , Impedancia Eléctrica , Epidermis/efectos de los fármacos , Epidermis/patología , Humanos , Estrés MecánicoRESUMEN
Mosquitoes of the Anopheles maculipennis Meigen (Diptera: Culicidae) group are of public health concern: five of the 11 morphologically indistinct species have been historically considered as vectors of malaria in Europe. Three members of the An. maculipennis group have been reported in the U.K.: Anopheles atroparvus van Thiel; Anopheles messeae Falleroni, and Anopheles daciae Linton, Nicolescu & Harbach. To study the distribution of the three U.K. species, particularly that of An. daciae, we developed a polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) assay using the nuclear ribosomal internal transcribed spacer 2 (ITS-2) gene. Anopheles daciae was found to be widespread, occurring in four of the five counties surveyed in southern England and on the Welsh island of Anglesey, often in sympatry with the closely related species An. messeae. The host preferences of 237 blood-fed females were determined using either direct sequencing or PCR-based fragment analysis of the mitochondrial cytochrome oxidase b gene with DNA from females' abdomens. All three species were found to be opportunistic, having fed on at least three different hosts. Seventeen individuals contained multiple bloodmeals, including two An. daciae that had fed on humans and birds. Our results show that An. daciae is widespread in England and Wales, occurs in sympatry with other members of the An. maculipennis group, and feeds on humans, which suggests it is a potential vector of disease in the U.K.
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Distribución Animal , Anopheles/fisiología , Interacciones Huésped-Parásitos/fisiología , Insectos Vectores/fisiología , Animales , Anopheles/genética , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Inglaterra , Conducta Alimentaria , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Insectos Vectores/genética , Malaria/transmisión , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , GalesRESUMEN
The emergence of SARS-CoV-2 virus has resulted in a worldwide pandemic, but effective antiviral therapies are not widely available. To improve treatment options, we conducted a high-throughput screen to uncover compounds that block SARS-CoV-2 infection. A minimally pathogenic human betacoronavirus (OC43) was used to infect physiologically-relevant human pulmonary fibroblasts (MRC5) to facilitate rapid antiviral discovery in a preclinical model. Comprehensive profiling was conducted on more than 600 compounds, with each compound arrayed across 10 dose points. Our screening revealed several FDA-approved agents that can attenuate both OC43 and SARS-CoV-2 viral replication, including lapatinib, doramapimod, and 17-AAG. Importantly, lapatinib inhibited SARS-CoV-2 RNA replication by over 50,000-fold. Further, both lapatinib and doramapimod could be combined with remdesivir to improve antiviral activity in cells. These findings reveal novel therapeutic avenues that could limit SARS-CoV-2 infection.
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Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Lapatinib/farmacología , SARS-CoV-2/efectos de los fármacos , Adenosina Monofosfato/farmacología , Alanina/farmacología , Animales , Benzoquinonas/farmacología , COVID-19/virología , Línea Celular , Chlorocebus aethiops , Combinación de Medicamentos , Descubrimiento de Drogas , Sinergismo Farmacológico , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactamas Macrocíclicas/farmacología , Naftalenos/farmacología , Compuestos de Fenilurea/farmacología , Pirazoles/farmacología , ARN Viral/metabolismo , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND AND STUDY AIM: Chronic radiation coloproctopathy (CRCP) is a well-recognized complication of radiotherapy, with rectal bleeding the most common presentation. It is frequently refractory to conservative management, but the optimal endoscopic treatment of bleeding secondary to CRCP is still controversial. The efficacy and safety of bipolar eletrocoagulation (BEC) and argon plasma coagulation (APC) in the management of bleeding from CRCP were evaluated and compared. PATIENTS AND METHODS: 30 patients (mean age 67.4 years) with active and chronic bleeding from telangiectasias, were randomly allocated to BEC or APC and stratified by severity of CRCP according to clinical severity and endoscopic findings (Saunders score). Success was defined as eradication of all telangiectasias, and therapeutic failure as need for more than seven sessions or for other treatment. Complications were categorized as minor (e.g. fever, anal or abdominal pain) or major (hemorrhagic). RESULTS: Both treatments were equally effective for the treatment of CRCP rectal bleeding. Only one failure was observed in each group (P = 1.000). There was no significant difference between the two groups regarding number of sessions, minor or major complications, or relapse. However, overall complication rate was significantly higher in the BEC group (P = 0.003). CONCLUSIONS: BEC and APC are both effective for the therapy of bleeding telangiectasias from CRCP. There are probably no major differences between them. Although APC seemed safer than BEC in this investigation, further studies, involving a much larger population, are needed to assess the complication rates and determine the best management option.
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Electrocoagulación/métodos , Hemorragia Gastrointestinal/cirugía , Traumatismos por Radiación/cirugía , Radioterapia/efectos adversos , Enfermedades del Recto/cirugía , Enfermedades del Sigmoide/cirugía , Telangiectasia/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Coagulación con Plasma de Argón/efectos adversos , Enfermedad Crónica , Colon Sigmoide/efectos de la radiación , Electrocoagulación/efectos adversos , Neoplasias Endometriales/radioterapia , Femenino , Hemorragia Gastrointestinal/etiología , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/complicaciones , Enfermedades del Recto/etiología , Recto/efectos de la radiación , Índice de Severidad de la Enfermedad , Enfermedades del Sigmoide/etiología , Telangiectasia/complicaciones , Resultado del Tratamiento , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
AIM: Argon plasma coagulation (APC) is considered a safe treatment for haemorrhagic chronic radiation proctocolitis (CRPC), but bacteraemia is a rare complication. The study aimed to evaluate the frequency of bacteraemia after APC. METHOD: A prospective study of 21 patients who underwent APC (30 procedures) for CRPC was carried out. Blood cultures (Bactec(®) ) were obtained before and 30 min after the procedure (60 samples total). Patients were monitored for 48 h after the procedure to detect signs of infection. RESULTS: None of the 21 patients had fever or any sign suggestive of infection after any of the 30 sessions. All baseline blood cultures were negative and two (7%) of the 30-min blood cultures were positive (Staphylococcus hominis n = 1; Streptococcus bovis and Rhodotorula sp n = 1). The first was likely to be a contaminant and the second patient had no evidence of any other colonic disease (neoplasia or polyps) beside CRPC. CONCLUSION: APC is a low-risk procedure regarding bacteraemia and does not warrant prophylactic antibiotic administration.
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Coagulación con Plasma de Argón , Bacteriemia/etiología , Proctocolitis/cirugía , Traumatismos por Radiación/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proctocolitis/etiología , Estudios Prospectivos , Traumatismos por Radiación/etiología , Radioterapia/efectos adversosRESUMEN
BACKGROUND: Parents of young children with type 1 diabetes (T1D) are responsible for executing a complex daily management regimen and are at risk for elevated levels of stress. Normative misbehaviour during the preschool years can complicate T1D management, and interpretation of behavioural concerns may vary because of child health status and parent stress. Within a paediatric transactional model framework, child characteristics (e.g. behaviour problems, metabolic control) and parent functioning (e.g. parenting stress, anxiety) likely impact one another. METHODS: Parents of 2- to 6-year-old children with T1D completed self-report measures, including the Pediatric Inventory for Parents (PIP), State-Trait Anxiety Inventory (STAI), Eyberg Child Behavior Inventory (ECBI), and 24-h Recall Interviews. Medical data were obtained by parent report and medical record review. It was hypothesized that greater parent stress and child blood glucose variability would be significantly associated with greater parent-reported child behaviour concerns. RESULTS: Moderate levels of parent stress and child behaviour problems were endorsed; however, parents perceived children's misbehaviour as problematic, particularly with relation to tasks relevant to diabetes management (e.g. bedtimes and mealtimes). Structural equation modelling indicated that greater general anxiety and paediatric parenting stress was associated with parent report of more problematic child behaviour. Blood glucose variability did not significantly contribute to this relationship. CONCLUSIONS: The stress experienced by parents of young children with chronic illness appears to relate to their perception of their children's behaviour problems. Parents' experiences with developmentally normative misbehaviour may interfere with disease management and exacerbate parents' stress and the subsequent impact on well-being. Implications for supporting parents and children with T1D are discussed.
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Trastornos de la Conducta Infantil/etiología , Diabetes Mellitus Tipo 1/psicología , Padres/psicología , Estrés Psicológico/etiología , Ansiedad/psicología , Glucemia/metabolismo , Niño , Trastornos de la Conducta Infantil/psicología , Hijo de Padres Discapacitados/psicología , Preescolar , Diabetes Mellitus Tipo 1/sangre , Femenino , Humanos , Masculino , Modelos Psicológicos , Relaciones Padres-Hijo , PsicometríaRESUMEN
Measurements of cesium-134 and cesium-137 in Greenland snow together with models of long-range transport have been used to assess radionuclide deposition in the Arctic after the Chernobyl accident. The results suggest that a well-defined layer of radioactive cesium is now present in polar glaciers, providing a new reference for estimating snow accumulation rates and dating ice core samples.
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Accidentes , Radioisótopos de Cesio , Reactores Nucleares , Ceniza Radiactiva , Groenlandia , Modelos Teóricos , Nieve , UcraniaRESUMEN
The performance of indwelling medical devices that depend on an interface with soft tissue is plagued by complex, unpredictable foreign body responses. Such devices-including breast implants, biosensors, and drug delivery devices-are often subject to a collection of biological host responses, including fibrosis, which can impair device functionality. This work describes a milliscale dynamic soft reservoir (DSR) that actively modulates the biomechanics of the biotic-abiotic interface by altering strain, fluid flow, and cellular activity in the peri-implant tissue. We performed cyclical actuation of the DSR in a preclinical rodent model. Evaluation of the resulting host response showed a significant reduction in fibrous capsule thickness (P = 0.0005) in the actuated DSR compared with non-actuated controls, whereas the collagen density and orientation were not changed. We also show a significant reduction in myofibroblasts (P = 0.0036) in the actuated group and propose that actuation-mediated strain reduces differentiation and proliferation of myofibroblasts and therefore extracellular matrix production. Computational models quantified the effect of actuation on the reservoir and surrounding fluid. By adding a porous membrane and a therapy reservoir to the DSR, we demonstrate that, with actuation, we could (i) increase transport of a therapy analog and (ii) enhance pharmacokinetics and time to functional effect of an inotropic agent. The dynamic reservoirs presented here may act as a versatile tool to further understand, and ultimately to ameliorate, the host response to implantable biomaterials.
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Altered ion channel expression and/or function may contribute to the development of certain human epilepsies. In rats, systemic administration of pilocarpine induces a model of human temporal lobe epilepsy, wherein a brief period of status epilepticus (SE) triggers development of spontaneous recurrent seizures that appear after a latency of 2-3 weeks. Here we investigate changes in expression of A-type voltage-gated potassium (Kv) channels, which control neuronal excitability and regulate action potential propagation and neurotransmitter release, in the pilocarpine model of epilepsy. Using immunohistochemistry, we examined the expression of component subunits of somatodendritic (Kv4.2, Kv4.3, KChIPl and KChIP2) and axonal (Kv1.4) A-type Kv channels in hippocampi of pilocarpine-treated rats that entered SE. We found that Kv4.2, Kv4.3 and KChIP2 staining in the molecular layer of the dentate gyrus changes from being uniformly distributed across the molecular layer to concentrated in just the outer two-thirds. We also observed a loss of KChIP1 immunoreactive interneurons, and a reduction of Kv4.2 and KChIP2 staining in stratum radiatum of CA1. These changes begin to appear 1 week after pilocarpine treatment and persist or are enhanced at 4 and 12 weeks. As such, these changes in Kv channel distribution parallel the acquisition of recurrent spontaneous seizures as observed in this model. We also found temporal changes in Kv1.4 immunoreactivity matching those in Timm's stain, being expanded in stratum lucidum of CA3 and in the inner third of the dentate molecular layer. Among pilocarpine-treated rats, changes were only observed in those that entered SE. These changes in A-type Kv channel expression may contribute to hyperexcitability of dendrites in the associated hippocampal circuits as observed in previous studies of the effects of pilocarpine-induced SE.
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Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/patología , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Pilocarpina , Canales de Potasio con Entrada de Voltaje/metabolismo , Animales , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large , Hipocampo/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Interacción con los Canales Kv/metabolismo , Canal de Potasio Kv1.4/metabolismo , Proteínas de la Membrana/metabolismo , Neuronas/clasificación , Neuronas/citología , Neuronas/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Ratas , Ratas Sprague-Dawley , Canales de Potasio Shal/metabolismo , Factores de TiempoRESUMEN
AIMS: Real-time 3D echocardiography (RT3DE) and 2D low mechanical index (LMI), contrast specific, myocardial perfusion imaging are now both accepted techniques. We evaluated the feasibility of an RT3DE LMI implementation in unselected patients. METHODS AND RESULTS: Forty-six patients undergoing contrast enhanced dobutamine stress echo were imaged with novel 3D LMI power modulation software. All patients underwent contrast enhanced 2D and RT3DE acquisitions, in left ventricular opacification (LVO), and LMI perfusion modes. The data sets were evaluated segmentally for wall motion (WM) and myocardial contrast enhancement. Of the 736 evaluated segments, WM could be assessed in 726 (98.6%) of the 2D and 708 (96.2%) 3D segments (P = 0.007). Perfusion could be assessed in 721 (98%) of 2D and 701 (95.2%) of 3D segments (P = 0.006). Six hundred and sixty-one segments had normal WM and thickening in 2D and of these RT3DE demonstrated normal myocardial opacification in 77.2% of basal, 85% of mid, and 91.8% of apical segments. Thirty-four segments were akinetic, with no evidence of perfusion in 2D, and of these RT3DE revealed a perfusion defect in 31 (91%, P = NS). CONCLUSION: LMI RT3DE evaluation of myocardial perfusion is feasible in most segments. It has the potential to accurately locate and possibly quantify perfusion defects.
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Ecocardiografía de Estrés , Ecocardiografía Tridimensional/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Aumento de la Imagen/métodos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
Background: The mitral valve orifice area (MVOA) is difficult to assess accurately by 2D echocardiography because of geometric assumptions; therefore, 3D planimetry may offer advantages. We studied the differences in MVOA measurements between the most frequently used methods, to determine if 3D planimetry would result in the re-grading of severity in any cases, and whether it was a more accurate predictor of clinical outcomes. Methods: This was a head-to-head comparison of the three most commonly used techniques to grade mitral stenosis (MS) by orifice area and to assess their impact on clinical outcomes. 2D measurements (pressure half-time (PHT), planimetry) and 3D planimetry were performed retrospectively on patients with at least mild MS. The clinical primary endpoint was defined as a composite of MV balloon valvotomy, mitral valve repair or replacement (MVR) and/or acute heart failure (HF) admissions. Results: Forty-one consecutive patients were included; the majority were female (35; 85.4%), average age 55 (17) years. Mean and peak MV gradients were 9.4 (4) mmHg and 19 (6) mmHg, respectively. 2D and 3D measures of MVOA differed significantly; mean 2D planimetry MVOA was 1.28 (0.40) cm2, mean 3D planimetry MVOA 1.15 (0.29) cm2 (P = 0.003). Mean PHT MVOA was 1.43 (0.44) cm2 (P = 0.046 and P < 0.001 in comparison to 2D and 3D planimetry methods, respectively). 3D planimetry reclassified 7 (17%) patients from mild-to-moderate MS, and 1 (2.4%) from moderate to severe. Overall, differences between the two methods were significant (X2, P < 0.001). Only cases graded as severe by 3D predicted the primary outcome measure compared with mild or moderate cases (odds ratio 5.7). Conclusion: 3D planimetry in MS returns significantly smaller measurements, which in some cases results in the reclassification of severity. Routine use of 3D may significantly influence the management of MS, with a degree of prediction of clinical outcomes.
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The 2012 World Heart Federation (WHF) criteria for echocardiographic diagnosis of rheumatic heart disease (RHD) identify that the finding of 'pathological' mitral regurgitation (MR) in a screened individual increases the likelihood of detecting underlying RHD. Cases of isolated "pathological MR are thus identified as 'borderline RHD'. A large-scale echocardiographic screening program (Echo in Africa) in South Africa has identified that inter-scallop separations of the posterior mitral valve leaflet (PMVL) can give rise to 'pathological' MR. The authors propose that this finding when associated with isolated 'pathological' MR is unrelated to the rheumatic disease process. In this case report, we present two examples of 'pathological' MR related to inter-scallop separation from the Echo in Africa image database. We provide additional screening tips to accurately identify this entity.
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This focused review presents a critical appraisal of the World Heart Federation criteria for the echocardiographic diagnosis of rheumatic heart disease (RHD) and its performance in African RHD screening programmes. It identifies various logistical and methodological problems that negatively influence the current guideline's performance. The authors explore novel RHD screening methodology that could address some of these shortcomings and if proven to be of merit, would require a paradigm shift in the approach to the echocardiographic diagnosis of subclinical RHD.
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OBJECTIVE: The present study evaluated the impact on psychosocial outcome of parallel clinician and peer-led information programmes for people with a diagnosis of schizophrenia and bipolar disorder and for family members within an Irish context. METHODS: A sequential mixed method design was used. Quantitative data were collected using pre- and post-programme questionnaires followed by an integrated qualitative component involving semi-structured interviews after the programme. The questionnaires assessed knowledge, attitudes towards recovery, hope, support, advocacy and well-being. Interviews with participants, facilitators and project workers explored their experiences and views of the programme. Findings While a number of the questionnaires did not show a statistically significant change, findings from the interviews suggest that the1 programmes had a number of positive outcomes, including increases in perceived knowledge, empowerment and support. Participants in both programmes valued the opportunity to meet people in similar circumstances, share their experiences, learn from each other and provide mutual support. CONCLUSION: The EOLAS programmes offer a novel template for communication and information sharing in a way that embodies the principles of collaboration and offers users and families a meaningful opportunity to become involved in service design, delivery and evaluation.
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BACKGROUND: Left ventricular (LV) mechanical dyssynchrony (LVMD) has emerged as a therapeutic target using cardiac resynchronization therapy (CRT) in selected patients with chronic heart failure. Current methods used to evaluate LVMD are technically difficult and do not assess LVMD of the whole LV simultaneously. We developed and validated real-time 3D echocardiography (RT3DE) as a novel method to assess global LVMD. METHODS AND RESULTS: Eighty-nine healthy volunteers and 174 unselected patients referred for routine echocardiography underwent 2D echocardiography and RT3DE. RT3DE data sets provided time-volume analysis for global and segmental LV volumes. A systolic dyssynchrony index (SDI) was derived from the dispersion of time to minimum regional volume for all 16 LV segments. Healthy subjects and patients with normal LV systolic function had highly synchronized segmental function (SDI, 3.5+/-1.8% and 4.5+/-2.4%; P=0.7). SDI increased with worsening LV systolic function regardless of QRS duration (mild, 5.4+/-0.83%; moderate, 10.0+/-2%; severe LV dysfunction, 15.6+/-1%; P for trend <0.001). We found that 37% of patients with moderate to severe LV systolic dysfunction had significant dyssynchrony with normal QRS durations (SDI, 14.7+/-1.2%). Twenty-six patients underwent CRT. At long-term follow-up, responders demonstrated reverse remodeling after CRT with a significant reduction in SDI (16.9+/-1.1% to 6.9+/-1%; P<0.0001) and end-diastolic volume (196.6+/-17.3 to 132.1+/-13.5 mL; P<0.0001) associated with an increase in LV ejection fraction (17+/-2.2% to 31.6+/-2.9%; P<0.0001). CONCLUSIONS: RT3DE can quantify global LVMD in patients with and without QRS prolongation. RT3DE represents a novel technique to identify chronic heart failure patients who may otherwise not be considered for CRT.
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Ecocardiografía Tridimensional/métodos , Sistemas de Computación , Ecocardiografía , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/epidemiología , Humanos , Procesamiento de Imagen Asistido por Computador , Valores de Referencia , Estados Unidos/epidemiología , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
UNLABELLED: Essentials Factor VIIIa (FVIIIa) is unstable due to loss of A2; D666 and Y1792 contribute to its stability. We conducted a study to identify the interactions made at these residues at the A2-A3 interface. We present evidence for stabilizing interactions between D666-S1787 and T657-Y1792 in FVIIIa. A D666C/S1788C variant with a disulfide A2-A3 linkage has a FVIIIa decay rate that is 1% of wild-type. SUMMARY: Background Factor (F)VIIIa activity and stability depends on the non-covalent association of the A2 subunit with the A1/A3C1C2 dimer, but the interactions that contribute to A2 association are not well defined. Previous work had shown that D666A and Y1792F mutations at the A2-A3 interface resulted in increased FVIIIa decay, suggesting that the residues were involved in bonding interactions important for FVIIIa stability. Objectives Several potential hydrogen bonding partners of D666 and Y1792 across the A2-A3 interface were selected from the low-resolution FVIII crystal structure, and we used mutagenesis and biochemical analysis to examine the bonding interactions occurring at D666 and Y1792. Methods Using a series of stability and functional analyses, we analyzed FVIII variants in which D666 and Y1792 were each swapped with the residues of potential bonding partners. Results and conclusions We present evidence for hydrogen bonds between D666 and S1787 and between Y1792 and T657 that are important for FVIIIa stability. D666S/S1787D and T657Y/Y1792T variants each displayed wild-type (WT)-like FVIIIa stability and performed like WT FVIII in a series of functional analyses, whereas D666S, S1787D, and Y1792T single variants showed increased FVIIIa decay and a T657Y variant had little FVIIIa activity. These results suggest that WT hydrogen bonds are disrupted with the single mutations but maintained in the swap variants. Furthermore, mutation of D666 and S1788 to cysteine resulted in disulfide bond formation across the A2-A3 interface, confirming the close proximity of D666 and S1787, and this covalent attachment of the A2 subunit significantly increased FVIIIa stability.
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Coagulación Sanguínea , Factor VIIIa/química , Mutación , Cisteína/química , Disulfuros , Factor VIII/genética , Factor Xa/química , Variación Genética , Hemofilia A/sangre , Hemofilia A/inmunología , Humanos , Enlace de Hidrógeno , Mutagénesis , Unión Proteica , Multimerización de Proteína , Trombina/química , Trombosis/genéticaRESUMEN
OBJECTIVE: To assess the impact of mitral geometry, left ventricular (LV) remodelling and global LV afterload on mitral regurgitation (MR) after trans-catheter aortic valve implantation (TAVI). METHODS: In this study, 60 patients who underwent TAVI were evaluated by 3D echocardiography at baseline, 1 month and 6 months after procedure. The proportional change in MR following TAVI was determined by examining the percentage change in vena contracta (VC) at 6 months. Patients having a significant reduction of at least 30% in VC were defined as good responders (GR) and the remaining patients were defined as poor responders (PR). RESULTS: After 6 months of TAVI, 27 (45%) patients were GR and 33 (55%) were PR. There was a significant decrease in 3DE-derived mitral annular diameter and area (P = 0.001), mitral valve tenting area (TA) (P = 0.05), and mitral papillary muscle dyssynchrony index (DSI) (P = 0.05) in the GR group. 3DE-derived LVESV (P = 0.016), LV mass (P = 0.001) and LV DSI, (P = 0.001) were also improved 6 months after TAVI. In addition, valvulo-arterial impedance (ZVA) was significantly higher at baseline in patients with PR (P = 0.028). 3DE-derived mitral annular area (ß: 0.47, P = 0.04), mitral papillary DSI (ß: -0.65, P = 0.012) and ZVA (ß: 0.45, P = 0.028) were the strongest independent parameters that could predict the reduction of functional MR after TAVI. CONCLUSION: GR patients demonstrate more regression in mitral annulus area and diameter after significant decrease in high LVEDP and trans-aortic gradients with TAVI. PR patients appear to have increased baseline ZVA, mitral valve tenting and restriction in mitral valve coaptation. These factors are important for predicting the impact of TAVI on pre-existing MR.