RESUMEN
Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of â¼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-D'D3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.
Asunto(s)
Factor VIII/metabolismo , Hemofilia A/terapia , Hemorragia/prevención & control , Proteínas Recombinantes de Fusión/administración & dosificación , Factor de von Willebrand/metabolismo , Animales , Factor VIII/genética , Hemofilia A/metabolismo , Hemofilia A/patología , Hemostasis , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Primates , Factor de von Willebrand/genéticaRESUMEN
There is a growing need for interventions to improve well-being in healthcare workers, particularly since the onset of COVID-19. OBJECTIVES: To synthesise evidence since 2015 on the impact of interventions designed to address well-being and burnout in physicians, nurses and allied healthcare professionals. DESIGN: Systematic literature review. DATA SOURCES: Medline, Embase, Emcare, CINAHL, PsycInfo and Google Scholar were searched in May-October 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies that primarily investigated burnout and/or well-being and reported quantifiable preintervention and postintervention outcomes using validated well-being measures were included. DATA EXTRACTION AND SYNTHESIS: Full-text articles in English were independently screened and quality assessed by two researchers using the Medical Education Research Study Quality Instrument. Results were synthesised and presented in both quantitative and narrative formats. Meta-analysis was not possible due to variations in study designs and outcomes. RESULTS: A total of 1663 articles were screened for eligibility, with 33 meeting inclusion criterium. Thirty studies used individually focused interventions, while three were organisationally focused. Thirty-one studies used secondary level interventions (managed stress in individuals) and two were primary level (eliminated stress causes). Mindfulness-based practices were adopted in 20 studies; the remainder used meditation, yoga and acupuncture. Other interventions promoted a positive mindset (gratitude journaling, choirs, coaching) while organisational interventions centred on workload reduction, job crafting and peer networks. Effective outcomes were reported in 29 studies, with significant improvements in well-being, work engagement, quality of life and resilience, and reductions in burnout, perceived stress, anxiety and depression. CONCLUSION: The review found that interventions benefitted healthcare workers by increasing well-being, engagement and resilience, and reducing burnout. It is noted that the outcomes of numerous studies were impacted by design limitations that is, no control/waitlist control, and/or no post intervention follow-up. Suggestions are made for future research.
Asunto(s)
COVID-19 , Enfermeras y Enfermeros , Médicos , Humanos , Calidad de Vida , Personal de Salud , Lugar de Trabajo , Agotamiento Psicológico , Atención a la SaludRESUMEN
Variants in the CDKN2A tumor suppressor are associated with Familial Melanoma (FM), although for many variants the linkage is weak. The effects of missense variants on protein function and pathogenicity are often unclear. Multiple methods (e.g., laboratory, computational, epidemiological) have been developed to analyze whether a missense variant is pathogenic or not. It is not yet clear how to integrate these data types into a strategy for variant classification. We studied 51 CDKN2A missense variants using a cell cycle arrest assay. There was a continuum of results ranging from full wild-type effect through partial activity to complete loss of arrest. A reproducible decrease of 30% of cell cycle arrest activity correlated with FM association. We analyzed missense CDKN2A germline variants using a Bayesian method to combine multiple data types and derive a probability of pathogenicity. When equal to or more than two data types could be evaluated with this method, 22 of 25 FM-associated variants and 8 of 15 variants of uncertain significance were classified as likely pathogenic with >95% probability. The other 10 variants were classified as uncertain (probability 5-95%). For most variants, there were insufficient data to draw a conclusion. The Bayesian model appears to be a sound method of classifying missense variants in cancer susceptibility genes.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Bioensayo , Ciclo Celular/genética , Línea Celular Tumoral , Biología Computacional , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Bases de Datos Genéticas , Predisposición Genética a la Enfermedad/genética , Humanos , Melanoma/epidemiología , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Valores de ReferenciaRESUMEN
We have used a previously unavailable model of pancreatic development, derived in vitro from human embryonic stem cells, to capture a time-course of gene, miRNA and histone modification levels in pancreatic endocrine cells. We investigated whether it is possible to better understand, and hence control, the biological pathways leading to pancreatic endocrine formation by analysing this information and combining it with the available scientific literature to generate models using a casual reasoning approach. We show that the embryonic stem cell differentiation protocol is highly reproducible in producing endocrine precursor cells and generates cells that recapitulate many aspects of human embryonic pancreas development, including maturation into functional endocrine cells when transplanted into recipient animals. The availability of whole genome gene and miRNA expression data from the early stages of human pancreatic development will be of great benefit to those in the fields of developmental biology and diabetes research. Our causal reasoning algorithm suggested the involvement of novel gene networks, such as NEUROG3/E2F1/KDM5B and SOCS3/STAT3/IL-6, in endocrine cell development We experimentally investigated the role of the top-ranked prediction by showing that addition of exogenous IL-6 could affect the expression of the endocrine progenitor genes NEUROG3 and NKX2.2.
Asunto(s)
Diferenciación Celular/genética , Linaje de la Célula/genética , Redes Reguladoras de Genes , Islotes Pancreáticos/metabolismo , Algoritmos , Animales , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodominio , Humanos , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Islotes Pancreáticos/embriología , Ratones , Proteínas Nucleares , Factores de TranscripciónRESUMEN
Gangrenous cholecystitis is a serious complication of acute cholecystitis and is associated with increased morbidity and mortality rates. We report a case in which the diagnosis was suggested by ultrasound, but cholecystectomy delayed due to atypical clinical presentation and a false negative radionuclide biliary scan.
Asunto(s)
Colecistitis/diagnóstico por imagen , Vesícula Biliar/diagnóstico por imagen , Gangrena/diagnóstico por imagen , Enfermedad Aguda , Adulto , Reacciones Falso Negativas , Femenino , Vesícula Biliar/patología , Humanos , Cintigrafía , UltrasonografíaRESUMEN
Demographic, clinical and laboratory data were retrospectively collected from records of 146 cases of CT fluoroscopy-guided chemical lumbar sympathectomy for the palliation of inoperable peripheral vascular disease (PVD) between January 1997 and August 1999. Of these, 16% had claudication, 39% had rest pain and 44% had ischaemic ulcers or gangrene. Seventy-three percent of elective cases were outpatients. At 3 months, 27 cases were lost to follow up, leaving 119 cases. Within 3 months, improvement, defined as doubling of the walking distance, cessation of rest pain or healing of ulcers, occurred in 30.3% of cases. No change was observed in 45.4% of cases and 24.3% of cases deteriorated. Patients with ulcers or gangrene had significantly poorer results than those without any ischaemic lesions, as only 19% versus 39% of patients improved (P < 0.05). The presence of hypertension, diabetes mellitus, hyperlipidaemia and smoking had no value in predicting clinical outcome (P > 0.05). There were no major complications noted. CT fluoroscopy-guided chemical lumbar sympathectomy is safe and effective, with a complication rate of less than 1%, and efficacy of at least 30% measured within 3 months. It is a simple and minimally invasive procedure, easily performed on an outpatient basis. CT fluoroscopy-guided chemical lumbar sympathectomy should be considered for all patients in the early stages of inoperable PVD.
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Enfermedades Vasculares Periféricas/cirugía , Simpatectomía Química/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluoroscopía , Humanos , Región Lumbosacra/inervación , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Enfermedades Vasculares Periféricas/diagnóstico por imagen , Complicaciones Posoperatorias , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Methotrexate is a well recognised cause of diffuse symmetrical leucoencephalopathy. The widespread use of the drug in chemotherapeutic regimes necessitates awareness of this complication. A case report and a brief literature review is presented.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Encefalopatías/inducido químicamente , Imagen por Resonancia Magnética , Metotrexato/efectos adversos , Tomografía Computarizada por Rayos X , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encefalopatías/diagnóstico , Encefalopatías/diagnóstico por imagen , Femenino , HumanosRESUMEN
We describe four patients who developed severe knee pain within 3 months of renal transplantation. Plain radiographs were normal and inflammatory markers (CRP, ESR) were all within normal ranges. Magnetic resonance imaging (MRI) showed a distinctive pattern in all four cases of bone marrow signal changes, extending from the epiphyseal region into the metaphyseal region in two cases. The appearances were different from those of avascular necrosis (AVN) and reflex sympathetic dystrophy and showed no progression to develop AVN during the follow-up period of 36 months. In all cases the pain resolved over a period of 3 months without specific therapy. Follow-up MRI scans were obtained in all patients after the pain had subsided, which revealed resolution of the MRI changes. We suggest that MRI be the investigation in such patients and that bone marrow edema changes will regress without the need to withdraw cyclosporin.
Asunto(s)
Enfermedades de la Médula Ósea/etiología , Edema/etiología , Trasplante de Riñón , Adulto , Enfermedades de la Médula Ósea/diagnóstico por imagen , Enfermedades de la Médula Ósea/fisiopatología , Edema/diagnóstico por imagen , Edema/fisiopatología , Femenino , Humanos , Rodilla/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Osteonecrosis/etiología , Dolor , Radiografía , Síndrome , Factores de TiempoRESUMEN
PURPOSE: To determine the imaging characteristics of infected aortic aneurysms. MATERIALS AND METHODS: Review of records of patients with surgical and/or microbiologic proof of infected aortic aneurysm obtained over a 25-year period revealed 31 aneurysms in 29 patients. This study included 21 men and eight women (mean age, 70 years). One radiologist reviewed 28 computed tomographic (CT) studies (22 patients underwent CT once and three patients underwent CT twice), 12 arteriograms (12 patients underwent arteriography once), eight nuclear medicine studies (six patients underwent nuclear medicine imaging once and one patient underwent nuclear medicine imaging twice), and three magnetic resonance (MR) studies (three patients underwent MR imaging once). Features evaluated included aneurysm size, shape, and location; branch involvement; aortic wall calcification; gas; radiotracer uptake on nuclear medicine studies; and periaortic and associated findings. The location of infected aortic aneurysms was compared with that of arteriosclerotic aneurysms. RESULTS: Aneurysms were located in the ascending aorta (n = 2, 6%), descending thoracic aorta (n = 7, 23%), thoracoabdominal aorta (n = 6, 19%), paravisceral aorta (n = 2, 6%), juxtarenal aorta (n = 3, 10%), infrarenal aorta (n = 10, 32%), and renal artery (n = 1, 3%). Two patients had two infected aortic aneurysms. CT revealed 25 saccular (93%) and two fusiform (7%) aneurysms with a mean diameter at initial discovery of 5.4 cm (range, 1-11 cm). Paraaortic soft-tissue mass, stranding, and/or fluid was present in 13 (48%) of 27 aneurysms, and early periaortic edema with rapid aneurysm progression and development was present in three (100%) patients with sequential studies. Other findings included adjacent vertebral body destruction with psoas muscle abscess (n = 1, 4%), kidney infarct (n = 1, 4%), absence of calcification in the aortic wall (n = 2, 7%), and periaortic gas (n = 2, 7%). Angiography showed 13 saccular aneurysms with lobulated contour in 10 (77%). Nuclear medicine imaging showed increased activity consistent with infection in six (86%) of seven aneurysms. MR imaging showed three saccular aneurysms. Adjacent abnormal vertebral body marrow signal intensity was seen in one (33%) of three patients. CONCLUSION: Saccular aneurysms (especially those with lobulated contour) with rapid expansion or development and adjacent mass, stranding, and/or fluid in an unusual location are highly suspicious for an infected aneurysm.
Asunto(s)
Aneurisma Infectado/diagnóstico , Aneurisma de la Aorta Abdominal/diagnóstico , Aneurisma de la Aorta Torácica/diagnóstico , Infecciones por Escherichia coli/diagnóstico , Infecciones por Haemophilus/diagnóstico , Listeriosis/diagnóstico , Infecciones por Salmonella/diagnóstico , Infecciones Estafilocócicas/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Aneurisma Infectado/clasificación , Aneurisma Infectado/microbiología , Aneurisma de la Aorta Abdominal/clasificación , Aneurisma de la Aorta Abdominal/microbiología , Aneurisma de la Aorta Torácica/clasificación , Aneurisma de la Aorta Torácica/microbiología , Arteria Celíaca/diagnóstico por imagen , Arteria Celíaca/microbiología , Infecciones por Escherichia coli/clasificación , Infecciones por Escherichia coli/microbiología , Femenino , Infecciones por Haemophilus/clasificación , Infecciones por Haemophilus/microbiología , Humanos , Procesamiento de Imagen Asistido por Computador , Listeriosis/clasificación , Listeriosis/microbiología , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Arterias Mesentéricas/diagnóstico por imagen , Arterias Mesentéricas/microbiología , Persona de Mediana Edad , Minnesota , Arteria Renal/diagnóstico por imagen , Arteria Renal/microbiología , Infecciones por Salmonella/clasificación , Infecciones por Salmonella/microbiología , Infecciones Estafilocócicas/clasificación , Infecciones Estafilocócicas/microbiología , Infecciones Estreptocócicas/clasificación , Infecciones Estreptocócicas/microbiología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Segmental allograft infarction is a poorly characterized complication following renal transplantation. The present study was undertaken with the goal of defining the incidence, clinical characteristics, pathogenesis, and prognosis of this entity. METHODS: A retrospective study was performed, reviewing the renal scans performed on all renal transplant recipients at our institution, from January 1997 to January 2000. Segmental infarction was diagnosed on the basis of a significant elevation in lactate dehydrogenase (>500 U/l) together with a photopenic perfusion defect. In these patients, graft characteristics, operative details, clinical course, and long-term outcomes were evaluated. RESULTS: Segmental infarction was identified in 13 of 277 consecutive renal transplant recipients (4.7%). In nine recipients the onset of infarction occurred within 24 h after transplantation. All received marginal grafts, and in five recipients the transplant operation was complicated by major blood loss. Eight of these recipients exhibited primary non-function, or developed dialysis-dependent renal failure after the onset of infarction. In four patients, the onset of infarction occurred after 24 h (35 h to 10 days). One recipient demonstrated primary non-function, and renal function deteriorated after the onset of infarction in the remaining three. Overall, long-term graft function was impaired. Two allografts never functioned, and six recipients had nadir creatinine clearances below 60 ml/min. CONCLUSIONS: The pathogenesis of segmental infarction appears to be multi-factorial, reflecting the combination of an initiating anatomic lesion and potentiating thrombogenic milieu. Segmental infarction typically occurs in the early postoperative period, and prompt diagnosis is difficult to obtain. In view of this, prophylactic heparin may be warranted for those at highest risk. There was no correlation between the infarct area and the graft function, and the long-term graft function is compromised out of proportion to the extent of parenchymal loss. This finding highlights the role of predisposing factors, particularly marginal graft quality, in determining the functional outcome. Segmental infarction may be more frequently encountered as cadaveric organ shortages encourage greater use of marginal donor kidneys.