BIC extensions for order-constrained model selection.

The Schwarz or Bayesian information criterion (BIC) is one of the most widely used tools for model comparison in social science research. The BIC however is not suitable for evaluating models with order constraints on the parameters of interest. This paper explores two extensions of the BIC for evaluating order constrained models, one where a truncated unit information prior is used under the order-constrained model, and the other where a truncated local unit information prior is used. The first prior is centered around the maximum likelihood estimate and the latter prior is centered around a null value. Several analyses show that the order-constrained BIC based on the local unit information prior works better as an Occam's razor for evaluating order-constrained models and results in lower error probabilities. The methodology based on the local unit information prior is implemented in the R package 'BFpack' which allows researchers to easily apply the method for order-constrained model selection. The usefulness of the methodology is illustrated using data from the European Values Study.

Consistency for the tree bootstrap in respondent-driven sampling.

Respondent-driven sampling is an approach for estimating features of populations that are difficult to access using standard survey tools, e.g., the fraction of injection drug users who are HIV positive. Baraff et al. (2016) introduced an approach to estimating uncertainty in population proportion estimates from respondent-driven sampling using the tree bootstrap method. In this paper we establish the consistency of this tree bootstrap approach in the case of [Formula: see text]-trees.

Dealing with loss: food and eating in women with ovarian cancer on parenteral nutrition.

BACKGROUND: Malignant bowel obstruction is a common complication of ovarian cancer, resulting in limited oral intake. Home parenteral nutrition (HPN) may be offered to patients in this condition to meet nutritional requirements. However, it is not known how they experience being unable to eat. The present study reports how patients related to food when receiving HPN. METHODS: The investigation was a qualitative study underpinned by phenomenology with women with advanced ovarian cancer in bowel obstruction receiving parenteral nutrition. Interview transcripts were analysed thematically guided by the techniques of Van Manen. RESULTS: We recruited 20 women to the study. Participants were interviewed a maximum of four times and a total of 39 in-depth longitudinal interviews were conducted. Participants could tolerate minimal amounts of food, if they had a venting gastrostomy. Not being able to eat engendered a sense of sadness and loss, and most women found it challenging to be in the presence of others eating. They adopted strategies to cope, which included fantasising about food and watching cookery programmes. These approaches were not a long-term solution; either participants came to terms with their loss or the strategies became less effective in providing relief. CONCLUSIONS: Home parenteral nutrition meets the nutritional requirements of patients with malignant bowel obstruction but cannot replace the non-nutritive functions of food. Healthcare professionals can offer a patient-centred approach by acknowledging the difficulties that patients may face and, wherever possible, encourage them to focus on the positive benefits of interacting with people rather than the loss of eating on social occasions.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Predicting relapse prior to transplantation in chronic myeloid leukemia by integrating expert knowledge and expression data.

MOTIVATION: Selecting a small number of signature genes for accurate classification of samples is essential for the development of diagnostic tests. However, many genes are highly correlated in gene expression data, and hence, many possible sets of genes are potential classifiers. Because treatment outcomes are poor in advanced chronic myeloid leukemia (CML), we hypothesized that expression of classifiers of advanced phase CML when detected in early CML [chronic phase (CP) CML], correlates with subsequent poorer therapeutic outcome. RESULTS: We developed a method that integrates gene expression data with expert knowledge and predicted functional relationships using iterative Bayesian model averaging. Applying our integrated method to CML, we identified small sets of signature genes that are highly predictive of disease phases and that are more robust and stable than using expression data alone. The accuracy of our algorithm was evaluated using cross-validation on the gene expression data. We then tested the hypothesis that gene sets associated with advanced phase CML would predict relapse after allogeneic transplantation in 176 independent CP CML cases. Our gene signatures of advanced phase CML are predictive of relapse even after adjustment for known risk factors associated with transplant outcomes.

Linezolid in the treatment of multidrug-resistant tuberculosis.

BACKGROUND: Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and in animal studies. Several small case series suggest that linezolid is poorly tolerated because of the side effects of anemia/thrombocytopenia and peripheral neuropathy. To characterize our clinical experience with linezolid, the California Department of Public Health Tuberculosis Control Branch's Multidrug-Resistant Tuberculosis (MDR-TB) Service reviewed cases in which the MDR-TB treatment regimens included linezolid therapy. METHODS: Record review was performed for 30 patients treated with linezolid as part of an MDR-TB regimen. Data were collected on clinical and microbiological characteristics, linezolid tolerability, and treatment outcomes. The dosage of linezolid was 600 mg daily. Vitamin B6 at a dosage of 50-100 mg daily was used to mitigate hematologic toxicity. RESULTS: During 2003-2007, 30 patients received linezolid for the treatment of MDR-TB. Patients had isolates resistant to a median of 5 drugs (range, 2-13 drugs). Of the 30 cases, 29 (97%) were pulmonary; of these 29, 21 (72%) had positive results of acid-fast bacilli smear, and 16 (55%) were cavitary. Culture conversion occurred in all pulmonary cases at a median of 7 weeks. At data censure (31 December 2008), 22 (73%) of 30 patients had successfully completed treatment. Five continued to receive treatment. There were no deaths. Three patients had a poor outcome, including 2 defaults and 1 treatment failure. Side effects occurred in 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea. However, only 3 patients stopped linezolid treatment because of side effects. CONCLUSIONS: Linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR-TB.

Bayesian melding for estimating uncertainty in national HIV prevalence estimates.

OBJECTIVE: To construct confidence intervals for HIV prevalence in countries with generalised epidemics. METHODS: In the Bayesian melding approach, a sample of country-specific epidemic curves describing HIV prevalence over time is derived based on time series of antenatal clinic prevalence data and general information on the parameters that describe the HIV epidemic. The prevalence trends at antenatal clinics are calibrated to population-based HIV prevalence estimates from national surveys. For countries without population based estimates, a general calibration method is developed. Based on the sample of calibrated epidemic curves, we derive annual 95% confidence intervals for HIV prevalence. The curve that best represents the data at antenatal clinics and population-based surveys, as well as general information about the epidemic, is chosen to represent the best estimates and predictions. RESULTS: We present results for urban areas in Haiti and Namibia to illustrate the estimates and confidence intervals that are derived with the methodology.

Progress and challenges in modelling country-level HIV/AIDS epidemics: the UNAIDS Estimation and Projection Package 2007.

The UNAIDS Estimation and Projection Package (EPP) was developed to aid in country-level estimation and short-term projection of HIV/AIDS epidemics. This paper describes advances reflected in the most recent update of this tool (EPP 2007), and identifies key issues that remain to be addressed in future versions. The major change to EPP 2007 is the addition of uncertainty estimation for generalised epidemics using the technique of Bayesian melding, but many additional changes have been made to improve the user interface and efficiency of the package. This paper describes the interface for uncertainty analysis, changes to the user interface for calibration procedures and other user interface changes to improve EPP's utility in different settings. While formal uncertainty assessment remains an unresolved challenge in low-level and concentrated epidemics, the Bayesian melding approach has been applied to provide analysts in these settings with a visual depiction of the range of models that may be consistent with their data. In fitting the model to countries with longer-running epidemics in sub-Saharan Africa, a number of limitations have been identified in the current model with respect to accommodating behaviour change and accurately replicating certain observed epidemic patterns. This paper discusses these issues along with their implications for future changes to EPP and to the underlying UNAIDS Reference Group model.

Quality of life of living kidney donors: a single-center experience.

Renal transplantation improves the quality of life (QoL) of patients with end-stage renal disease. The preservation of QoL of living kidney donors is paramount. The aim of this study was to assess the QoL pre- and postdonation using Medical Outcome Survey Short Form-36 (SF-36) and to compare with a control group of potential donors who did not proceed with donation. Over a period of 28 years (1978 to 2006), 82 living donor renal transplantations were performed. Of the 78 eligible donors, 66 (85%) participated in the survey. The median postdonation period was 4.6 years (range, 3 months to 27 years). Thirty eight individuals were assessed in the control group. The postdonation SF-36 scores of the donors were not statistically significantly different from those of the control group except in one out of eight dimensions, which was physical role. However, in 44/66 (66%) donors, the postdonation scores were significantly lower compared to their predonation scores because of development of comorbidities such as musculoskeletal pain, migraine, myocardial infarction, diabetes, and peptic ulcers as the time progressed since kidney donation. The age, sex, time since donation, and relationship to recipient did not affect QoL. Eighty three percentage of the donors would have donated again if possible, and 90.9% wished to encourage living kidney donation. We conclude that the QoL of living kidney donors was not different from the healthy controls, although with the passage of time, there was some deterioration of QoL due to development of comorbidities.

The effect of body temperature in a rat model of renal ischemia-reperfusion injury.

BACKGROUND: Renal ischemia-reperfusion injury (IRI) is an unavoidable event in renal transplantation; the effects of IRI can be seen in both the acute and long-term function of the transplanted organ. For this reason, research into the pathophysiology of ischemia-reperfusion is at the forefront of transplantation research. Animal models, particularly in the rat, provide a useful research tool in studying the intricacies of IRI and in evaluating new treatments. We describe a model of right nephrectomy and left renal clamping for 45 minutes and demonstrate the effects of temperature variation during the ischemic period. METHODS: Male Sprague-Dawley rats (under isoflurane anesthesia) underwent bilateral flank incision with removal of the right kidney and clamping of the left renal hilum for 45 minutes. The animals were divided into 3 groups (n=6): group 1 had the procedure performed on a heating mat with no temperature control facilities, group 2 used no heating mat, and group 3 used a rectal temperature-controlled homeothermic blanket system (Harvard Medical, United Kingdom). Temperature was taken every 5 minutes throughout the procedure and blood samples were taken on a daily postoperative basis via tail vein venepuncture. RESULTS: The average temperature at the end of the procedure in group 1 was 39.67 degrees C and the creatinine level at day 3 was 574+/-17.84, in group 2 the temperature was 32.6 degrees C and the creatinine level was 115+/-4.06, and in group 3 the temperature was maintained between 36.5 degrees C-37 degrees C and the serum creatinine level was 329+/-19.18. The temperature of the animal during the ischemia phase of IRI significantly affects the severity of injury. Relative hyperthermia resulted in more severe renal injury and unrecoverable acute renal failure, no source of heat led to a relative hypothermia, and reduction of renal injury. Use of the homeothermic heating blanket led to an increase in creatinine level by day 3, indicating a significant ischemic stimulus; however, by day 10 the creatinine level had returned to normal. CONCLUSION: This illustrates the importance of temperature as a variable in animal models of IRI and thus should be clearly stated in all experimental methods to ensure an appropriate ischemic stimulus and for adequate comparisons between various therapeutic interventions.

FTY720 reduces extracellular matrix expansion associated with ischemia-reperfusion induced injury.

BACKGROUND: Ischemia-reperfusion (IR) is one of the strongest nonimmune factors associated with the development of chronic allograft nephropathy (CAN). This effect is often exacerbated by immunosuppressive medications, most notably cyclosporine. Although traditionally the macrophage was thought to stimulate fibroblast activity in CAN, recent evidence supports a role for lymphocytes. FTY720 is a new immunosuppressant that promotes lymphocyte sequestration into lymph nodes and Peyer's patches. This study investigated the effect of FTY720 on renal fibrosis in the rat following an IR insult (IRI). METHODS: A rat model of IRI was used in which male Sprague-Dawley rats (under isoflurane anaesthesia) underwent bilateral flank incision with removal of the right kidney and clamping of the left renal hilum for 45 minutes. Five groups of animals were studied (n=4): nephrectomy only, IRI only, IRI+FTY720 (1 mg/kg/d), IRI+cyclosporine (15 mg/kg/d), and IRI+FTY 720 (1 mg/kg/d) and cyclosporine (15 mg/kg/d). Animals were humanely killed at 30 days. RESULTS: Serum creatinine (SCr) level was significantly reduced in the FTY720-treated animals. IRI alone produced a significant increase in SCr level compared with neprectomized animals (138 micromol/L vs 55 micromol/L; P<.05). This effect was potentiated by treatment with cyclosporine (173 micromol/L vs 55 micromol/L; P<.05). Treatment with FTY720 significantly reduced SCr level in rats following IRI alone (81 micromol/L vs 138 micromol/L; P<.01) and in rats following IRI + cyclosporine (98 micromol/L vs 173 micromol/L; P<.014). Parallel changes were seen in the levels of proteinuria. Fibrosis was assessed using Masson's trichrome (MT) staining. IRI alone produced a significant increase in MT staining compared with nephrectomized animals (0.92 vs 0.03; P<.05). This effect was potentiated by treatment with cyclosporine (1.12 vs 0.92; P=.022). Treatment with FTY720 reduced the level of MT staining in rats following IRI alone (0.34 vs 0.92; P<.05) and in rats following IRI+cyclosporine (70.34 vs 1.12; P<.05). Levels of TGF-beta1 were considerably reduced in FTY720-treated animals (compared with cyclosporine+IRI and IRI only), either alone (196+/-31 pg/mL vs 1105+/-59 pg/mL and 611+/-38; P<.05) or in conjunction with cyclosporine (423+/-26 pg/mL vs 1105+/-59 pg/mL and 611+/-38; P<.05). CONCLUSION: Our study shows that treatment with FTY720 can reduce renal fibrosis as a result of IRI, both alone and in conjunction with cyclosporine. This provides promising evidence for using FTY720 in a calcineurin-free or reduced-dose immunosuppression protocol in an effort to reduce the incidence of CAN.

Renal transplantation after endovascular repair of abdominal aortic aneurysm.

An increasing number of abdominal aortic aneurysms (AAA) occur in renal failure patients because of strong association between atherosclerosis and chronic kidney disease. Endovascular aneurysm repair (EVAR) has proven to be an effective modality to treat AAA, particularly in patients with renal disease, because of its several advantages over the standard open procedure, including lower morbidity, shorter operative time, and shorter hospital stay. A Medline search showed a single publication on renal transplantation (RT) following EVAR of AAA. In this context, we report our case of successful RT in a patient who had undergone EVAR 2 years prior for a 5.7-cm AAA. No stent-related complications, such as graft occlusion, dislodgement, dissection, or endoleak, were observed in the perioperative period. The transplanted kidney had primary function leading to a stable serum creatinine of 115 micromol/L at 6 months. Although the long-term outcome of RT after endovascular repair of AAA remains unknown, currently available evidence shows favorable outcomes of EVAR in the normal population, in patients with renal diseases, and in RT recipients; hence, RT should not be denied to renal failure patients who have undergone EVAR in the past.

Vacuum-assisted closure (VAC) therapy in the management of wound infection following renal transplantation.

OBJECTIVES: Wound infection in the setting of immunosuppressed state such as renal transplantation (RT) causes significant morbidity from sepsis, prolongs hospital stay and is expensive. Vacuum-assisted closure (VAC) therapy is a new technique of management of wound based on the principle of application of controlled negative pressure. The aim of this study was to assess the efficacy of VAC therapy in the management of wound infection following RT. MATERIALS AND METHODS: This is a prospective study of a cohort of 180 consecutive RTs performed over a period of 4 years, where the data were retrieved from a prospectively maintained computerised database and case-notes. RESULTS: 9 of 180 (5%) patients developed wound infection following RT which led to cavitations and dehiscence with copious discharge, and refused to heal with conventional treatment. All 9 cases were treated with VAC therapy. The VAC system was removed after a median of 9 (range 3-30) days when discharge from the wound ceased. Four patients were discharged home with portable VAC device and managed on an outpatient basis, where the system was removed after a median 5.5 (range 3-7) days. The median hospital stay after initiation of VAC therapy was significantly shorter (5, range 2-12 days) than on conventional treatment prior to VAC therapy (11, range, 5-20 days) (p=0.003). Complete healing was achieved in all cases. CONCLUSIONS: The use of VAC therapy is an effective and safe adjunct to conventional and established treatment modalities for the management of wound infection and dehiscence following RT. Key words: Renal transplantation, wound infection, vacuum-assisted closure therapy.

Variable selection and Bayesian model averaging in case-control studies.

Covariate and confounder selection in case-control studies is often carried out using a statistical variable selection method, such as a two-step method or a stepwise method in logistic regression. Inference is then carried out conditionally on the selected model, but this ignores the model uncertainty implicit in the variable selection process, and so may underestimate uncertainty about relative risks. We report on a simulation study designed to be similar to actual case-control studies. This shows that p-values computed after variable selection can greatly overstate the strength of conclusions. For example, for our simulated case-control studies with 1000 subjects, of variables declared to be 'significant' with p-values between 0.01 and 0.05, only 49 per cent actually were risk factors when stepwise variable selection was used. We propose Bayesian model averaging as a formal way of taking account of model uncertainty in case-control studies. This yields an easily interpreted summary, the posterior probability that a variable is a risk factor, and our simulation study indicates this to be reasonably well calibrated in the situations simulated. The methods are applied and compared in the context of a case-control study of cervical cancer.