Robotic-assisted laparoscopic "salvage" rectopexy for recurrent ileoanal J-pouch prolapse.

Total restorative proctocolectomy with ileal pouch-anal anastomosis (RP/IPAA) has become the standard of care for the surgical treatment of ulcerative colitis. Despite its correlation with an excellent quality of life and favorable long-term outcomes, RP/IPAA has been associated with several complications. Prolapse of the ileoanal pouch is a rare and debilitating complication that should be considered in the differential diagnosis of pouch failure. Limited data exist regarding the prevalence and treatment of pouch prolapse. We present the case of a recurrent J-pouch prolapse treated with a novel minimally invasive "salvage" approach involving a robotic-assisted laparoscopic rectopexy with mesh.

Combining Enzalutamide with Abiraterone, Prednisone, and Androgen Deprivation Therapy in the STAMPEDE Trial.

There are compelling reasons to study the addition of both enzalutamide and abiraterone, in combination, to standard-of-care for hormone-naïve prostate cancer. Through a protocol amendment, this will be assessed in the STAMPEDE trial, with overall survival as primary outcome measure.

Protease inhibitors to treat hepatitis C in the Swiss HIV Cohort Study: high efficacy but low treatment uptake

OBJECTIVES Direct-acting antiviral agents (DAAs) have become the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. We aimed to assess treatment uptake and efficacy in routine clinical settings among HIV/HCV coinfected patients after the introduction of the first generation DAAs. METHODS Data on all Swiss HIV Cohort Study (SHCS) participants starting HCV protease inhibitor (PI) treatment between September 2011 and August 2013 were collected prospectively. The uptake and efficacy of HCV therapy were compared with those in the time period before the availability of PIs. RESULTS Upon approval of PI treatment in Switzerland in September 2011, 516 SHCS participants had chronic HCV genotype 1 infection. Of these, 57 (11%) started HCV treatment during the following 2 years with either telaprevir, faldaprevir or boceprevir. Twenty-seven (47%) patients were treatment-naïve, nine (16%) were patients with relapse and 21 (37%) were partial or null responders. Twenty-nine (57%) had advanced fibrosis and 15 (29%) had cirrhosis. End-of-treatment virological response was 84% in treatment-naïve patients, 88% in patients with relapse and 62% in previous nonresponders. Sustained virological response was 78%, 86% and 40% in treatment-naïve patients, patients with relapse and nonresponders, respectively. Treatment uptake was similar before (3.8 per 100 patient-years) and after (6.1 per 100 patient-years) the introduction of PIs, while treatment efficacy increased considerably after the introduction of PIs. CONCLUSIONS The introduction of PI-based HCV treatment in HIV/HCV-coinfected patients improved virological response rates, while treatment uptake remained low. Therefore, the introduction of PIs into the clinical routine was beneficial at the individual level, but had only a modest effect on the burden of HCV infection at the population level.

Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

BACKGROUND Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). METHODS We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). RESULTS SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype. CONCLUSION In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.

Do Instructional Videos on Sputum Submission Result in Increased Tuberculosis Case Detection? A Randomized Controlled Trial.

OBJECTIVE We examined the effect of an instructional video about the production of diagnostic sputum on case detection of tuberculosis (TB), and evaluated the acceptance of the video. TRIAL DESIGN Randomized controlled trial. METHODS We prepared a culturally adapted instructional video for sputum submission. We analyzed 200 presumptive TB cases coughing for more than two weeks who attended the outpatient department of the governmental Municipal Hospital in Mwananyamala (Dar es Salaam, Tanzania). They were randomly assigned to either receive instructions on sputum submission using the video before submission (intervention group, n = 100) or standard of care (control group, n = 100). Sputum samples were examined for volume, quality and presence of acid-fast bacilli by experienced laboratory technicians blinded to study groups. RESULTS Median age was 39.1 years (interquartile range 37.0-50.0); 94 (47%) were females, 106 (53%) were males, and 49 (24.5%) were HIV-infected. We found that the instructional video intervention was associated with detection of a higher proportion of microscopically confirmed cases (56%, 95% confidence interval [95% CI] 45.7-65.9%, sputum smear positive patients in the intervention group versus 23%, 95% CI 15.2-32.5%, in the control group, p <0.0001), an increase in volume of specimen defined as a volume ≥3ml (78%, 95% CI 68.6-85.7%, versus 45%, 95% CI 35.0-55.3%, p <0.0001), and specimens less likely to be salivary (14%, 95% CI 7.9-22.4%, versus 39%, 95% CI 29.4-49.3%, p = 0.0001). Older age, but not the HIV status or sex, modified the effectiveness of the intervention by improving it positively. When asked how well the video instructions were understood, the majority of patients in the intervention group reported to have understood the video instructions well (97%). Most of the patients thought the video would be useful in the cultural setting of Tanzania (92%). CONCLUSIONS Sputum submission instructional videos increased the yield of tuberculosis cases through better quality of sputum samples. If confirmed in larger studies, instructional videos may have a substantial effect on the case yield using sputum microscopy and also molecular tests. This low-cost strategy should be considered as part of the efforts to control TB in resource-limited settings. TRIAL REGISTRATION Pan African Clinical Trials Registry PACTR201504001098231.

Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial.

BACKGROUND Anticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting. OBJECTIVES The goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR. METHODS A total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding. RESULTS Anticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: -1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant. CONCLUSIONS In this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780).

Stable coronary artery disease: revascularisation and invasive strategies

Stable coronary artery disease is the most common clinical manifestation of ischaemic heart disease and a leading cause of mortality worldwide. Myocardial revascularisation is a mainstay in the treatment of symptomatic patients or those with ischaemia-producing coronary lesions, and reduces ischaemia to a greater extent than medical treatment. Documentation of ischaemia and plaque burden is fundamental in the risk stratification of patients with stable coronary artery disease, and several invasive and non-invasive techniques are available (eg, fractional flow reserve or intravascular ultrasound) or being validated (eg, instantaneous wave-free ratio and optical coherence tomography). The use of new-generation drug-eluting stents and arterial conduits greatly improve clinical outcome in patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). PCI is feasible, safe, and effective in many patients with stable coronary artery disease who remain symptomatic despite medical treatment. In patients with multivessel and left main coronary artery disease, the decision between PCI or CABG is guided by the local Heart Team (team of different cardiovascular specialists, including non-invasive and invasive cardiologists, and cardiac surgeons), who carefully judge the possible benefits and risks inherent to PCI and CABG. In specific subsets, such as patients with diabetes and advanced, multivessel coronary artery disease, CABG remains the standard of care in view of improved protection against recurrent ischaemic adverse events.

Thrombus formation in the left ventricle after large myocardial infarction – assessment with cardiac magnetic resonance imaging

INTRODUCTION Left ventricular thrombus (LVT) formation may worsen the post-infarct outcome as a result of thromboembolic events. It also complicates the use of modern antiplatelet regimens, which are not compatible with long-term oral anticoagulation. The knowledge of the incidence of LVT may therefore be of importance to guide antiplatelet and antithrombotic therapy after acute myocardial infarction (AMI). METHODS In 177 patients with large, mainly anterior AMI, standard cardiac magnetic resonance imaging (CMR) including cine and late gadolinium enhancement (LGE) imaging was performed shortly after AMI as per protocol. CMR images were analysed at an independent core laboratory blinded to the clinical data. Transthoracic echocardiography (TTE) was not mandatory for the trial, but was performed in 64% of the cases following standard of care. In a logistic model, 3 out of 61 parameters were used in a multivariable model to predict LVT. RESULTS LVT was detected by use of CMR in 6.2% (95% confidence interval [CI] 3.1%-10.8%). LGE sequences were best to detect LVT, which may be missed in cine sequences. We identified body mass index (odds ratio 1.18; p = 0.01), baseline platelet count (odds ratio 1.01, p = 0.01) and infarct size as assessed by use of CMR (odds ratio 1.03, p = 0.02) as best predictors for LVT. The agreement between TTE and CMR for the detection of LVT is substantial (kappa = 0.70). DISCUSSION In the current analysis, the incidence of LVT shortly after AMI is relatively low, even in a patient population at high risk. An optimal modality for LVT detection is LGE-CMR but TTE has an acceptable accuracy when LGE-CMR is not available.

Developing drugs for use before, during and soon after percutaneous coronary intervention.

INTRODUCTION Percutaneous coronary intervention (PCI) is a milestone for treating coronary artery disease (CAD). Antithrombotic therapy is essential to prevent ischemic complications, including the microvascular no-reflow, while minimizing bleeding events. Areas covered: This overview discusses available and developing drugs for PCI including anticoagulants, antiplatelets and treatment of no-reflow. Expert opinion: For years unfractionated heparin (UFH) has been the unique anticoagulant to be used before and during PCI. Enoxaparin showed similar efficacy and safety, yet, based on recent trials, bivalirudin has been shown to have some benefits, particularly for patients with ST-segment elevation myocardial infarction (STEMI). The evidence concerning new anticoagulants is still preliminary, except for new oral anticoagulants, particularly rivaroxaban that showed intriguing findings and is currently under investigation. Dual antiplatelet therapy (DAPT) is the standard of care after PCI, but new developments have recently emerged. Indeed, ticagrelor and prasugrel are currently recommended over clopidogrel due to their significant reduction of ischemic events in acute coronary syndrome (ACS) whereas clopidogrel remains the choice in stable CAD. Among new agents, vorapaxar and cangrelor showed positive but limited evidence and might be considered at least in selected patients. Conversely, evidence on effective treatments for no-reflow remains limited and would require future dedicated research.

On Negligence Rules and Self-Selection

Economic models of negligence ordinarily involve a single standard of care that all injurers must meet to avoid liability. When injurers differ in their costs of care, however, this leads to distortions in their care choices. This paper derives the characteristics of a generalized negligence rule that induces injurers to self-select their optimal care levels. The principal features of the rule are (1) the due standard of care is maximal, and (2) liability increases gradually as injurers depart further from this standard. The results are broadly consistent with the gradation in liability under certain causation rules and under comparative negligence.

An interactive intervention to impact adherence to antiretroviral treatment among treatment-naive HIV-infected adults in Thailand: A pilot randomized controlled study

Background. Consistent adherence to antiretroviral treatment is necessary for a treatment success. Improving and maintaining adherence rate >95% are challenging for health care professionals. This pilot randomized controlled study aimed to evaluate the impact of the interactive intervention on adherence to GPO-VIR, to describe the feasibility of the interactive intervention in Thailand, and to illustrate the adherence self-efficacy concept among HIV treatment-naïve patients in Thailand who were starting antiretroviral treatment. ^ Methods. The study took place at three HIV clinics located in Phayao, Thailand. Twenty-three patients were randomly assigned into the experimental (n=11) and the control groups (n=12). Each participant in the experimental group and a significant person to the patient received 5 educational sessions with a nurse at the clinics and at their homes. They also received 3 follow-up evaluations during the 6-month period of the study. The participants in the control group received the standard of care provided by HIV clinical personnel plus three follow-up evaluations at the clinic. ^ Results. Seventeen patients (7 in the experimental and 10 in the control group) completed the study. The 4-day recall on the Thai ACTG Adherence Scale demonstrated adherence rate >95% for most participants from both groups. After the first measurement, no experimental group patients reporting missing ART, while one control group participant continuously skipped ART. Participants from both groups had significantly increased CD4 cell counts after the study (F(1, 15) = 29.30, p = .000), but no differences were found between two groups (F(1, 15) = .001, p = .98). Examination of the intervention showed limitations and possibilities to implement it in Thailand. Qualitative data demonstrated self-efficacy expectations, resignation and acceptance as related concepts to improve adherence outcomes. ^ Conclusions. This interactive intervention, after appropriate modifications, is feasible to apply for Thai HIV-treatment naïve patients. Because of limitations the study could not demonstrate whether the interactive intervention improved adherence to ART among HIV-treatment naïve in Thailand. A longitudinal study in a larger sample would be required to test the impact of the intervention. ^ Keyword: antiretroviral treatment, adherence, treatment-naïve, Thailand, randomized controlled study ^

Bayesian adaptive designs for drug combinations in early phase clinical trials

Treating patients with combined agents is a growing trend in cancer clinical trials. Evaluating the synergism of multiple drugs is often the primary motivation for such drug-combination studies. Focusing on the drug combination study in the early phase clinical trials, our research is composed of three parts: (1) We conduct a comprehensive comparison of four dose-finding designs in the two-dimensional toxicity probability space and propose using the Bayesian model averaging method to overcome the arbitrariness of the model specification and enhance the robustness of the design; (2) Motivated by a recent drug-combination trial at MD Anderson Cancer Center with a continuous-dose standard of care agent and a discrete-dose investigational agent, we propose a two-stage Bayesian adaptive dose-finding design based on an extended continual reassessment method; (3) By combining phase I and phase II clinical trials, we propose an extension of a single agent dose-finding design. We model the time-to-event toxicity and efficacy to direct dose finding in two-dimensional drug-combination studies. We conduct extensive simulation studies to examine the operating characteristics of the aforementioned designs and demonstrate the designs' good performances in various practical scenarios.^

Volumetric Modulated Arc Therapy Evaluation with the Radiological Physics Center Head and Neck Phantom

Validation of treatment plan quality and dose calculation accuracy is essential for new radiotherapy techniques, including volumetric modulated arc therapy (VMAT). VMAT delivers intensity modulated radiotherapy treatments while simultaneously rotating the gantry, adding an additional level of complexity to both the dose calculation and delivery of VMAT treatments compared to static gantry IMRT. The purpose of this project was to compare two VMAT systems, Elekta VMAT and Varian RapidArc, to the current standard of care, IMRT, in terms of both treatment plan quality and dosimetric delivery accuracy using the Radiological Physics Center (RPC) head and neck (H&N) phantom. Clinically relevant treatment plans were created for the phantom using typical prescription and dose constraints for Elekta VMAT (planned with Pinnacle3 Smart Arc) and RapidArc and IMRT (both planned with Eclipse). The treatment plans were evaluated to determine if they were clinically comparable using several dosimetric criteria, including ability to meet dose objectives, hot spots, conformity index, and homogeneity index. The planned treatments were delivered to the phantom and absolute doses and relative dose distributions were measured with thermoluminescent dosimeters (TLDs) and radiochromic film, respectively. The measured and calculated doses of each treatment were compared to determine if they were clinically acceptable based upon RPC criteria of ±7% dose difference and 4 mm distance-to-agreement. Gamma analysis was used to assess dosimetric accuracy, as well. All treatment plans were able to meet the dosimetric objectives set by the RPC and had similar hot spots in the normal tissue. The Elekta VMAT plan was more homogenous but less conformal than the RapidArc and IMRT plans. When comparing the measured and calculated doses, all plans met the RPC ±7%/4 mm criteria. The percent of points passing the gamma analysis for each treatment delivery was acceptable. Treatment plan quality of the Elekta VMAT, RapidArc and IMRT treatments were comparable for consistent dose prescriptions and constraints. Additionally, the dosimetric accuracy of the Elekta VMAT and RapidArc treatments was verified to be within acceptable tolerances.

Desfechos tardios de sobreviventes de ensaio clínico randomizado controlado (protocolo ARDSnet vs. Open Lung Approach para o manejo ventilatório da síndrome do desconforto respiratório agudo moderado-grave)

Apesar da utilização da ventilação mecânica protetora como estratégia para o tratamento da síndrome do desconforto respiratório agudo, ao menos um quarto dos pacientes com essa síndrome ainda apresentam redução na função pulmonar após 6 meses de seguimento. Não se sabe se esta redução está relacionada com a gravidade da síndrome ou associada com a forma de ventilar o paciente. Nosso objetivo neste trabalho foi avaliar a associação entre alterações funcionais e estruturais do pulmão com parâmetros de gravidade clínica e de ventilação mecânica. Foi realizada uma análise secundária dos dados obtidos em estudo randomizado e controlado que incluiu pacientes com síndrome do desconforto respiratório agudo moderada/grave, internados em seis unidades de terapia intensiva em um hospital terciário da cidade de São Paulo. Foram analisados dados de pacientes que tinham ao menos um teste de função pulmonar no seguimento. O teste funcional incluiu a medida da capacidade vital forçada, volumes pulmonares e a capacidade de difusão do monóxido de carbono após 1, 2 e 6 meses de seguimento. Foram considerados variáveis independentes o volume corrente, a pressão de distensão e a pressão positiva ao final da expiração (todos medidos após 24 horas da randomização) e um sistema de classificação de prognóstico (APACHE II), a relação PaO2/FIO2 e a complacência respiratória estática (todos medidos antes da randomização). Também foi realizada tomografia de alta resolução do tórax juntamente com os testes de função pulmonar, e posterior análise quantitativa das imagens. Na avaliação de 6 meses também foi realizado teste de caminhada de 6 minutos e um questionário de qualidade de vida (SF-36). Um total de 21 pacientes realizaram o teste de função pulmonar após 1 mês e 15 pacientes realizaram após 2 e 6 meses de seguimento. A capacidade vital forçada foi relacionada inversamente com a pressão de distensão na avaliação de 1, 2 e 6 meses (p < 0,01). A capacidade de difusão do monóxido de carbono relacionou-se inversamente com a pressão de distensão e com o APACHE II (ambos p < 0,01) na avaliação de 1 e 2 meses. Após 6 meses de seguimento, houve correlação inversa entre a pressão de distensão e a capacidade vital forçada independente do volume corrente, da pressão de platô e da complacência estática respiratória após ajustes (R2 = 0,51, p = 0,02). A pressão de distensão também se relacionou com o volume pulmonar total, a densidade pulmonar media e a porcentagem de volume pulmonar não aerado ou pobremente aerado medidos através da análise quantitativa da tomografia computadorizada de tórax realizada na avaliação de 6 meses. Também foi observada relação entre a qualidade de vida após 6 meses de seguimento e a pressão de distensão considerando o domínio estado geral de saúde. Nós concluímos que mesmo em pacientes ventilados com reduzido volume corrente e pressão de platô limitada, maiores valores de pressão de distensão relacionaram-se com menores valores de função pulmonar no seguimento de longo prazo

Tratamento do vírus da hepatite C : uma evolução para a cura?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014