Cost-effectiveness analysis of empagliflozin treatment in people with Type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME trial.

AIM: In the EMPA-REG OUTCOME trial, empagliflozin therapy reduced cardiovascular death by 38% compared with placebo when added to standard of care. Using the trial results, we created a discrete-event simulation model to assess lifetime health economic outcomes in people with Type 2 diabetes and established cardiovascular disease. METHODS: Time-dependent survival regression analysis was performed on data from EMPA-REG OUTCOME for 10 cardiovascular and renal events (e.g. stroke, heart failure hospitalization, macroalbuminuria, cardiovascular mortality) to capture event rates over time, and interaction between events. Model performance was assessed by comparing predicted and observed outcomes at 3 years. Costs in the United Kingdom (UK) and health utilities were obtained from published literature. Outcomes included cumulative event rates, life-years, costs and quality-adjusted life-years (QALYs). RESULTS: The model predicted an 18% relative increase (by 2.1 life-years) in survival for empagliflozin (14.0 life-years) vs. standard of care (11.9 life-years), attributable to direct treatment effect on cardiovascular mortality, and to indirect effect via reductions in other events. Participants treated with empagliflozin may experience improved quality of life (1.0 QALY) and higher costs (£3737/participant), yielding an incremental cost-effectiveness ratio (ICER) of £4083/QALY. Sensitivity analyses confirmed the robustness of these results to changes in input parameters. CONCLUSIONS: Based on extrapolation of EMPA-REG OUTCOME trial data using a participant-level simulation model, empagliflozin in addition to standard of care is projected to be highly cost-effective using UK healthcare costs. The impact in other countries will vary due to differences in drug pricing and accrual of other costs. (Clinical Trial Registry No: NCT01131676).

[Comparison of the cost-utility of direct oral anticoagulants for the prevention of stroke in patients with atrial fibrillation in Spain]. / Comparacion del coste-utilidad de los anticoagulantes orales de accion directa en la prevencion de ictus en la fibrilacion auricular no valvular en España.

INTRODUCTION: Apixaban, dabigatran and rivaroxaban are three new direct oral anticoagulants (DOACs) used in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) in Spain. AIM: To assess the relative cost-utility of the three DOACs compared with vitamin K antagonists. PATIENTS AND METHODS: A Markov model with 3-month cycles was used to simulate NVAF patients starting with treatment and followed up for their lifetime from the perspective of the National Health System. The model included 36 health states including treatment combinations, disability and events history and considered a hypothetical cohort of 10,000 NVAF patients. Relative efficacy was calculated from a formal indirect treatment comparison using data from the pivotal trials of each DOAC. RESULTS: Dabigatran was associated with the highest number of quality-adjusted life years (QALY) (8.40 QALY), followed by apixaban (8.33 QALY), rivaroxaban (8.15 QALY) and acenocoumarol (8.03 QALY). Patients taking acenocoumarol had the lowest total costs (€22,230), followed by dabigatran (€24,564), apixaban (€24,655) and rivaroxaban (€25,900). Incremental cost-utility ratios compared to vitamin K antagonists, were €6,397, €8,039 and €29,957/QALY for dabigatran, apixaban and rivaroxaban, respectively. If compared together, dabigatran dominated apixaban and rivaroxaban. Sensitivity analyses confirmed the robustness of the baseline case. CONCLUSIONS: All three direct anticoagulants are cost-effective against acenocoumarol. Dabigatran is economically dominant over rivaroxaban and apixaban in the Spanish setting, as it is more effective and cheaper.

TITLE: Comparacion del coste-utilidad de los anticoagulantes orales de accion directa en la prevencion de ictus en la fibrilacion auricular no valvular en España.Introduccion. El apixaban, el dabigatran y el rivaroxaban son tres anticoagulantes orales de accion directa (ACOD) indicados para la prevencion del ictus y la embolia sistemica en pacientes con fibrilacion auricular no valvular (FANV) en España. Objetivo. Comparar el coste-utilidad de los tres ACOD frente a los antivitamina K. Pacientes y metodos. Se utilizo un modelo Markov con ciclos trimestrales para simular pacientes con FANV desde que inician su tratamiento hasta el resto de su vida desde la perspectiva del Sistema Nacional de Salud. El modelo incorporo 36 estados de salud, incluyendo combinaciones de tratamientos, discapacidad y antecedentes de eventos, y considero una cohorte hipotetica de 10.000 pacientes con FANV. La eficacia relativa se calculo a partir de una comparacion indirecta formal de los tratamientos segun los datos de los ensayos pivotales de cada ACOD. Resultados. El dabigatran se asocio al valor maximo de años de vida ajustados por calidad (AVAC) (8,40 AVAC), seguido del apixaban (8,33 AVAC), el rivaroxaban (8,15 AVAC) y el acenocumarol (8,03 AVAC). Los costes totales fueron menores con el acenocumarol (22.230 €), seguido del dabigatran (24.564 €), el apixaban (24.655 €) y el rivaroxaban (25.900 €). La ratio coste-utilidad incremental frente a los antivitamina K fue de 6.397, 8.039 y 29.957 €/AVAC para el dabigatran, el apixaban y el rivaroxaban, respectivamente. Comparados entre ellos, el dabigatran domino al apixaban y al rivaroxaban. Los analisis de sensibilidad confirmaron la robustez del caso base. Conclusiones. Los tres ACOD son coste-efectivos frente al acenocumarol. El dabigatran es economicamente dominante frente al rivaroxaban y al apixaban en España, al ser mas efectivo y menos costoso.

Intestinal pseudo-obstruction associated with biliary tract dilatation in a patient with systemic lupus erythematosus.

Intestinal pseudo-obstruction (IpsO) is an uncommon and severe complication of systemic lupus erythematosus (SLE). We report a patient with SLE who presented with IpsO and biliary dilatation (megacholedochus). The co-manifestation of these two conditions in SLE is unusual and has been reported only twice previously. The patient responded well to immunosuppressive treatment. IpsO is a rare but recognized manifestation of SLE that may be the presenting manifestation of the systemic disease or occur more commonly during disease course. Early recognition of IpsO is necessary to institute appropriate medical treatment and to avoid inappropriate surgical intervention.

Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective.

Oral dabigatran etexilate is indicated for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in whom anticoagulation is appropriate. Based on the RE-LY study we investigated the cost-effectiveness of Health Canada approved dabigatran etexilate dosing (150 mg bid for patients <80 years, 110 mg bid for patients ≥80 years) versus warfarin and "real-world" prescribing (i.e. warfarin, aspirin, or no treatment in a cohort of warfarin-eligible patients) from a Canadian payer perspective. A Markov model simulated AF patients at moderate to high risk of stroke while tracking clinical events [primary and recurrent ischaemic strokes, systemic embolism, transient ischaemic attack, haemorrhage (intracranial, extracranial, and minor), acute myocardial infarction and death] and resulting functional disability. Acute event costs and resulting long-term follow-up costs incurred by disabled stroke survivors were based on a Canadian prospective study, published literature, and national statistics. Clinical events, summarized as events per 100 patient-years, quality-adjusted life years (QALYs), total costs, and incremental cost effectiveness ratios (ICER) were calculated. Over a lifetime, dabigatran etexilate treated patients experienced fewer intracranial haemorrhages (0.49 dabigatran etexilate vs. 1.13 warfarin vs. 1.05 "real-world" prescribing) and fewer ischaemic strokes (4.40 dabigatran etexilate vs. 4.66 warfarin vs. 5.16 "real-world" prescribing) per 100 patient-years. The ICER of dabigatran etexilate was $10,440/QALY versus warfarin and $3,962/QALY versus "real-world" prescribing. This study demonstrates that dabigatran etexilate is a highly cost-effective alternative to current care for the prevention of stroke and systemic embolism among Canadian AF patients.

Right-sided diaphragmatic eventration: A rare entity.

Eventration of the diaphragm is an abnormal elevation of the dome of diaphragm. It is a condition in which all or part of the diaphragm is largely composed of fibrous tissue with only a few or no interspersed muscle fibers. It can be complete or partial. Complete eventration of the right diaphragm, as seen in this adult patient, is relatively rare.

Fat embolism syndrome.

Fat embolism syndrome is a rare complication occurring in 0.5 to 2% of patients following a long bone fracture. It is believed to be caused by the toxic effects of free fatty acids. Diagnosis is clinical, based on respiratory, cerebral and dermal manifestations. Treatment is only supportive, directed mainly at maintaining respiratory functions.

Tubercular hepatic abscess--a rare presentation.

Hepatic tuberculosis is one of the rare forms of extra-pulmonary tuberculosis. The focal or nodular form presenting as tuberculoma or abscess is uncommon. Hepatic tuberculosis without involvement of lungs or other organs is even rarer. We report a rare case of primary tubercular liver abscess without involvement of any other organ of body.

Hypoplastic thumb in Gorlin's syndrome.

Gorlin's syndrome or naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. This condition is due to mutations in the Patched (PTCH) gene which maps to chromosome 9q22 and acts as a tumour suppressor gene. Gorlin's syndrome is characterized by the development of multiple jaw keratocysts and/or basal carcinomas. There is a distinctive coarse facial appearance with macrocephaly, frontal bossing and prognathism. Most individuals have skeletal anomalies such as bifid ribs or wedge-shaped vertebrae. We present a case in which the patient presented with bilateral thumb hypoplasia. Various hand deformities have been reported in patients with Gorlin's syndrome including short metacarpals, cutaneous syndactyly of the second and third fingers, and pre- or post-axial polydactyly, but hypoplasia of the thumb has not been reported previously. These features of Gorlin's syndrome may be helpful diagnostically. The thumbs should be examined carefully in Gorlin's syndrome patients as minor degrees of hypoplasia are easy to miss. However, they still needs a specialist input to give the patient an optimum function of the thumb and the hand.

Application of predictive biosimulation within pharmaceutical clinical development: examples of significance for translational medicine and clinical trial design.

The challenge of accurately predicting human clinical outcome based on preclinical data has led to a high failure rate of compounds in human clinical trials. A series of methods are described by which biosimulation can address these challenges and guide the design and evaluation of experimental and clinical protocols. Early compound development often proceeds on the basis of preclinical data from animal models. The systematic evaluation possible in a simulation can assist in the critical step of translating the preclinical outcomes to human physiology. Later in the process, clinical trials definitively establish a therapy's beneficial effects, as well as any adverse side effects. Biosimulation allows for the optimal design of clinical trials to ensure that key issues are addressed effectively and efficiently, and in doing so, improves the success rate of the trials.

Randomised trial of intravenous infusion of ephedrine or mephentermine for management of hypotension during spinal anaesthesia for Caesarean section.

This study compared the effects of intravenous infusions of ephedrine and mephentermine for maintenance of maternal arterial pressure and neonatal outcome in pregnant women receiving subarachnoid block for lower segment Caesarean section. Sixty patients who developed hypotension following subarachnoid block for Caesarean section were randomly divided into two groups of 30 each to receive an intravenous infusion of ephedrine or mephentermine. Hypotension was defined as a decrease in systolic blood pressure of > or = 20% from the baseline value or an absolute value of <100 mmHg, whichever was higher. The vasopressor infusion was titrated to maintain systolic blood pressure between 'hypotension' and baseline values. Baseline haemodynamic parameters, haemodynamic changes subsequent to the start of vasopressor infusion, duration of hypotension and amount of vasopressor required were statistically similar for both groups. Neonatal APGAR scores and acid-base profiles were also comparable. To conclude, mephentermine can be used as safely and effectively as ephedrine for the management of hypotension during spinal anaesthesia in patients undergoing elective Caesarean section.

Pattern of self-organization in tumour systems: complex growth dynamics in a novel brain tumour spheroid model.

We propose that a highly malignant brain tumour is an opportunistic, self-organizing and adaptive complex dynamic biosystem rather than an unorganized cell mass. To test the hypothesis of related key behaviour such as cell proliferation and invasion, we have developed a new in vitro assay capable of displaying several of the dynamic features of this multiparameter system in the same experimental setting. This assay investigates the development of multicellular U87MGmEGFR spheroids in a specific extracellular matrix gel over time. The results show that key features such as volumetric growth and cell invasion can be analysed in the same setting over 144 h without continuously supplementing additional nutrition. Moreover, tumour proliferation and invasion are closely correlated and both key features establish a distinct ratio over time to achieve maximum cell velocity and to maintain the system's temporo-spatial expansion dynamics. Single cell invasion follows a chain-like pattern leading to the new concept of a intrabranch homotype attraction. Since preliminary studies demonstrate that heterotype attraction can specifically direct and accelerate the emerging invasive network, we further introduce the concept of least resistance, most permission and highest attraction as an essential principle for tumour invasion. Together, these results support the hypothesis of a self-organizing adaptive biosystem.

Emergence of a subpopulation in a computational model of tumor growth.

Malignant brain tumors consist of a number of distinct subclonal populations. Each of these subpopulations may be characterized by its own behaviors and properties. These subpopulations arise from the constant genetic and epigenetic alteration of existing cells in the rapidly growing tumor. However, since each single-cell mutation only leads to a small number of offspring initially, very few newly arisen subpopulations survive more than a short time. The present work quantifies "emergence", i.e. the likelihood of an isolated subpopulation surviving for an extended period of time. Only competition between clones is considered; there are no cooperative effects included. The probability that a subpopulation emerges under these conditions is found to be a sigmoidal function of the degree of change in cell division rates. This function has a non-zero value for mutations which confer no advantage in growth rate, which represents the emergence of a distinct subpopulation with an advantage that has yet to be selected for, such as hypoxia tolerance or treatment resistance. A logarithmic dependence on the size of the mutated population is also observed. A significant probability of emergence is observed for subpopulations with any growth advantage that comprise even 0.1% of the proliferative cells in a tumor. The impact of even two clonal populations within a tumor is shown to be sufficient such that a prognosis based on the assumption of a monoclonal tumor can be markedly inaccurate.

Cellular automaton of idealized brain tumor growth dynamics.

A novel cellular automaton model of proliferative brain tumor growth has been developed. This model is able to simulate Gompertzian tumor growth over nearly three orders of magnitude in radius using only four microscopic parameters. The predicted composition and growth rates are in agreement with a test case pooled from the available medical literature. The model incorporates several new features, improving previous models, and also allows ready extension to study other important properties of tumor growth, such as clonal competition.

Simulated brain tumor growth dynamics using a three-dimensional cellular automaton.

We have developed a novel and versatile three-dimensional cellular automaton model of brain tumor growth. We show that macroscopic tumor behavior can be realistically modeled using microscopic parameters. Using only four parameters, this model simulates Gompertzian growth for a tumor growing over nearly three orders of magnitude in radius. It also predicts the composition and dynamics of the tumor at selected time points in agreement with medical literature. We also demonstrate the flexibility of the model by showing the emergence, and eventual dominance, of a second tumor clone with a different genotype. The model incorporates several important and novel features, both in the rules governing the model and in the underlying structure of the model. Among these are a new definition of how to model proliferative and non-proliferative cells, an isotropic lattice, and an adaptive grid lattice.

Recruitment of the putative transcription-repair coupling factor CSB/ERCC6 to RNA polymerase II elongation complexes.

Cockayne's syndrome (CS) is a disease characterized by developmental and growth defects, sunlight sensitivity, and a defect in transcription-coupled nucleotide excision repair. The two principle proteins involved in CS, CSA and CSB/ERCC6, have been hypothesized to bind RNA polymerase II (Pol II) and link transcription to DNA repair. We have tested CSA and CSB in assays designed to determine their role in transcription-coupled repair. Using a unique oligo(dC)-tailed DNA template, we provide biochemical evidence that CSB/ERCC6 interacts with Pol II molecules engaged in ternary complexes containing DNA and nascent RNA. CSB is a DNA-activated ATPase, and hydrolysis of the ATP beta-gamma phosphoanhydride bond is required for the formation of a stable Pol II-CSB-DNA-RNA complex. Unlike CSB, CSA does not directly bind Pol II.