Developing Augmented Pro-SOFA and Pro-SAPS Models by Integrating Biomarkers PCT, NLR, and CRP with SOFA and SAPS-III Scores.

Background: Sepsis, a life-threatening condition characterized by a dysregulated immune response to infection, remains a significant clinical challenge globally. This study aims to enhance the predictive accuracy of existing sepsis severity scores by developing augmented versions of the SOFA and SAPS-III models, termed Pro-SOFA and Pro-SAPS, through the integration of biomarkers procalcitonin (PCT), neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP). Methods: This prospective observational study was conducted in the medical ICU of a tertiary care hospital in southern India from August 2022 to December 2023. A total of 301 adult patients suspected or confirmed to have sepsis were assessed for eligibility, with 171 patients completing the study. Demographic and clinical data were collected; SOFA and SAPS-III scores were calculated and augmented with PCT, NLR, and CRP to develop Pro-SOFA and Pro-SAPS models. The performance of these models was evaluated using Brier scores, AUC, and net reclassification index (NRI). Results: The augmented Pro-SOFA and Pro-SAPS models demonstrated superior predictive accuracy compared to their original counterparts. The Brier scores for Pro-SOFA and Pro-SAPS were 0.181 and 0.165, respectively, indicating better calibration than the original scores. The Pro-SAPS showed significant improvement over the original SAPS-III score (NRI = 0.50, SE = 0.14, p < 0.01). Similarly, Pro-SOFA outperformed the original SOFA (NRI = 0.49, SE = 0.13, p < 0.01). Conclusion and clinical significance: Integrating PCT, CRP, and NLR with SOFA and SAPS-III scores to develop Pro-SOFA and Pro-SAPS significantly improves the predictive accuracy for sepsis mortality and can thus potentially improve sepsis outcomes. How to cite this article: Nandakumar A, Sudeep S, Sreemohan AC, Vijayakumar S, Sudhakaran GJ, Gutjahr G, et al. Developing Augmented Pro-SOFA and Pro-SAPS Models by Integrating Biomarkers PCT, NLR, and CRP with SOFA and SAPS-III Scores. Indian J Crit Care Med 2024;28(10):935-941.

Survival Outcomes of Breast Cancer Patients in South India Over 20 Years.

OBJECTIVE: The study aimed to investigate the distribution and clinicopathologic features of breast cancer patients in South India, while also examining the overall survival (OS) and identifying predictive factors affecting it. Additionally, we aimed to assess the influence of risk factors on Disease Free Survival (DFS) and Distant Disease-Free Survival (DDFS). METHODS: This retrospective cohort study on breast cancer trends used comprehensive follow-up including regular patient contact, medical record review and collaboration with healthcare providers. Patients without follow-up information for more than 12 months were contacted by telephone, while those with no follow-up after 2 years were labelled as lost to follow-up. RESULTS: A total of 3256 patients were identified from a single cancer institute in India. The median follow-up time was 8.1 years. The 5-year survival rates were 89%, 84%, 85%, 88% and 10-year were 82%, 78%, 79%, 83% for luminal cancers, Triple Negative Breast Cancers, HER2 enriched and luminal with HER2 enriched respectively. CONCLUSION: Poorer survival rates were seen among those with pT3/4 tumors, nodal involvement at diagnosis, Estrogen receptor negative status, high Ki67 proliferative index and higher TNM stage at diagnosis of the disease. Although our patients were younger and had more aggressive types of cancer, their DFS, DDFS and overall survival were comparable to other developed nations.

Predicting COVID 19-Associated Pulmonary Aspergillosis Risk in Low- and Middle-Income Countries: A Matched Case-Control Study.

Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a life-threatening fungal infection. Studies focusing on CAPA in low- and middle-income countries are limited. Methods: This retrospective matched case-control study was conducted at a tertiary care center in South India. Cases of CAPA were classified using the 2020 European Confederation of Medical Mycology/International Society for Human and Animal Mycology consensus criteria. A total of 95 cases were matched 1:1 with COVID-19 patients without CAPA. Matching was done based on age and period of admission. Inverse probability weighting was used to account for imbalances in COVID-19 severity and intensive care unit (ICU) admission. Data on demographics, clinical details, microbiologic and radiologic data, and treatment outcomes were collected. A predictive score for CAPA was developed from baseline risk factors. Results: The predictive score identified lymphopenia, European Organisation for Research and Treatment of Cancer risk factors, and broad-spectrum antibiotic use as the main risk factors for CAPA. Positivity for bacterial pathogens in blood or bronchoalveolar lavage samples reduced the risk of CAPA. The predictive model performed well in cross-validation, with an area under the curve value of 82%. CAPA diagnosis significantly increased mortality and shift to ICU. Conclusions: The predictive model derived from the current study offers a valuable tool for clinicians, especially in high-endemic low- and middle-income countries, for the early identification and treatment of CAPA. With further validation, this risk score could improve patient outcomes.

Distribution and reference values of peripheral perfusion index in neonates from population-wide screening.

BACKGROUND: Peripheral perfusion index (PPI) is useful in a variety of neonatal settings. Currently, available reference values are from small numbers and highly variable. METHODS: We sought to generate reference values of PPI by analysing previously collected data from newborns who underwent mandated universal pulse oximetry and PPI screening from 2018 to 2021 using uniform protocol and equipment. Q-Q plots and boxplots were used to visualise distributions. Kernel density estimation for heaped and rounded data was used to estimate percentiles of the distributions. RESULTS: Data from 388 205 newborns who underwent universal pulse oximetry screening in the first week of life were used for this analysis. Pre and postductal values showed a non-normal distribution and skewed to the left, the former had a thicker tail with more extreme values. Minor, but statistically significant differences were seen in the PPI values from day 1 to 7. Median preductal PPI (2.77, IQR:1.83-3.93) was significantly higher than postductal (2.38 IQR: 1.41-3.55) (p<0.01). PPI values increased with weight and boys had higher PPI. Kernel estimates of the percentiles in the overall sample and subgroups for gender and weight have been provided for preductal and post-ductal values. CONCLUSION: This study, based on the largest available dataset, provides reference values for PPI in newborns. A significant influence of gender and birth weight on PPI values in newborns has been identified. Future research on understanding the influence of age, sex, birth weight, gestational age, ambient temperature and genetic factors on PPI is recommended.

Prolonged indwelling catheter time after RARP does not lead to follow-up surgery.

BACKGROUND: Indwelling catheterization following radical prostatectomy is used to aid healing and urinary drainage. While early removal is well investigated, prolonged catheterization has only been investigated in terms of urinary incontinence. Other complications such as anastomotic strictures are unexplored so far. This study aims to analyze the sequelae of catheterization lasting more than 14 days after robotic-assisted radical prostatectomy (RARP). METHODS: A prospective database of 3087 patients undergoing RARP was analyzed, focusing on 180 patients with catheterization exceeding 14 days (Group A) and 88 matched controls (Group B). Outcome measures included subsequent surgeries, complications, and functional outcomes. RESULTS: Prolonged catheterization did not significantly increase the need for subsequent surgeries (6% in Group A vs. 7% in Group B, p = .95). However, anastomotic strictures were more common in Group A (3%) compared to Group B (0%) after exclusion of risk factors. Incontinence rates were similar between groups, although a subgroup analysis revealed higher incontinence rates in patients with catheterization exceeding 28 days. No significant differences were observed in erectile function or quality of life between the groups. CONCLUSION: Prolonged catheterization after RARP does not independently increase the risk of anastomotic strictures in the general population. However, in patients without risk factors, prolonged catheter dwell time may elevate the risk of strictures and subsequent surgeries. Additionally, patients with catheterization exceeding 28 days may experience higher rates of long-term incontinence. Further studies with larger sample sizes are needed to confirm these findings and elucidate the long-term implications of prolonged catheterization.

Characterization and predictive risk scoring of long COVID in a south indian cohort after breakthrough COVID infection; a prospective single centre study.

BACKGROUND: With the World Health Organization (WHO) declaring an end to the COVID-19 pandemic, the focus has shifted to understanding and managing long-term post-infectious complications. "Long COVID," characterized by persistent or new onset symptoms extending beyond the initial phase of infection, is one such complication. This study aims to describe the incidence, clinical features and risk profile of long COVID among individuals in a South Indian cohort who experienced post-ChAdOx1 n-Cov-2 vaccine breakthrough infections. METHODS: A single-centre hospital-based prospective observational study was conducted from October to December 2021. The study population comprised adult patients (> 18 years) with a confirmed COVID-19 diagnosis who had received at least a single dose of vaccination. Data was collected using a specially tailored questionnaire at week 2, week 6, and week 12 post-negative COVID-19 test. A propensity score based predictive scoring system was developed to assess the risk of long COVID. RESULTS: Among the 414 patients followed up in the study, 164 (39.6%) reported long COVID symptoms persisting beyond 6 week's post-infection. The presence of long COVID was significantly higher among patients above 65 years of age, and those with comorbidities such as Type II Diabetes Mellitus, hypertension, dyslipidemia, coronary artery disease, asthma, and cancer. Using backwards selection, a reduced model was developed, identifying age (OR 1.053, 95% CI 0.097-1.07, p < 0.001), hypertension (OR 2.59, 95% CI 1.46-4.59, p = 0.001), and bronchial asthma (OR 3.7176, 95% CI 1.24-11.12, p = 0.018) as significant predictors of long COVID incidence. A significant positive correlation was observed between the symptomatic burden and the number of individual comorbidities. CONCLUSIONS: The significant presence of long COVID at 12 weeks among non-hospitalised patients underscores the importance of post-recovery follow-up to assess for the presence of long COVID. The predictive risk score proposed in this study may help identify individuals at risk of developing long COVID. Further research is needed to understand the impact of long COVID on patients' quality of life and the potential role of tailored rehabilitation programs in improving patient outcomes.

Ideal timing of indwelling catheter removal after robot-assisted radical prostatectomy with a running barbed suture technique: a prospective analysis of 425 consecutive patients.

OBJECTIVE: To compare prospectively early outcome and complications of catheter removal after robot-assisted radical prostatectomy (RARP) on the 4th or 7th day with a standardized running barbed suture technique. INTRODUCTION: The time point of removing the indwelling catheter after RARP mainly depends on institute's/surgeon's preferences. Removal should be late enough to avoid urinary leakage and complications such as acute urinary retention (AUR) but early enough to avoid unnecessary catheter indwelling. MATERIALS AND METHODS: A consecutive single-institutional series of patients underwent RARP between July 2015 and August 2017 and were entered in a prospectively maintained data base. Between July 2015 and December 2016 a cystogram was performed on 7th postoperative day (group A), thereafter the cystogram was performed on 4th postoperative day (group B). Incidence of acute urinary retention (AUR), urinary tract infections (UTI) and adverse events between the two cohorts was compared. RESULTS: 425 patients were analyzed (group A: n = 231; group B: n = 194). Both cohorts were comparable regarding demographic and oncological parameters. Watertight anastomosis was present in 84.8% in group A and in 82.5% in group B, respectively. AUR within 4 weeks after RARP occurred in 2.2% (n = 3) in A and 9.4% (n = 15) in B (p = 0.001). AUR within 72 h after catheter removal occurred in group A: 1% (n = 2) and in group B: 6.3% (n = 10) (p = 0.005). Symptomatic urinary tract infections occurred in 8.2% (n = 16) in group A and in 6.9% (n = 11) in group B. There were no differences in the rate of secondary anastomosis dehiscence. Age, BMI, prostate size, surgeon, or intraoperative bladder neck reconstruction were not correlated to the occurrence of AUR or UTI. CONCLUSIONS: The removal of indwelling catheter on day 4 after a RARP with a running barbed suture shows similar anastomosis leakage rates as on the 7th postoperative day. However, AUR rates are higher for early removal. Patients scheduled for early removal should be carefully informed about the increased risk for AUR. Catheter indwelling time does not represent a risk factor for UTI.

Waiting for Godot: A cross sectional survey based analysis of the hydroxychloroquine prophylaxis strategy against COVID-19 in India.

Background: India currently has the second largest burden of infections due to COVID-19. Health Care Worker (HCW) shortages are endemic to Indian healthcare. It should therefore be a huge priority to protect this precious resource as a critical component of the systemic response to this pandemic. Advisories from the Indian Council of Medical Research (ICMR) have focused on using hydroxychloroquine prophylaxis against COVID-19 in at risk HCW. This prophylaxis strategy has no evidence. In further jeopardy there appear to insubstantial attempts to build this evidence as well. In this connection, we commissioned a survey within our Institution to estimate the penetration of hydroxychloroquine (HCQ) use and use this to statistically model the impact of current ongoing studies in India. We also briefly review the literature on HCQ prophylaxis for COVID-19. Design and methods: A structured survey designed using RedCAP application was disseminated among healthcare professionals employed at an academic referral tertiary care centre via online social media platforms. The survey was kept open for the entire month of June 2020. The survey was additionally used to statistically model the size of studies required to comprehensively address the efficacy of HCQ in this setting. Results: 522 responses were received, of which 4 were incomplete. The ICMR strategy of 4 or more doses of HCQ was complete only in 15% of HCW in our survey. The majority of respondents were doctors (238, 46%). Amongst all category of responders, only 12% (n=63) received the full course. A majority of those who initiated the chemoprophylaxis with HCQ turned out to be medical professionals (59/63) with neither nurse nor other categories of healthcare workers accessing the medication. The respondents of our institutional survey did not report any life-threatening side effects. Presuming efficacy as per ICMR modelling for new registry trial on the lines of the published case control study, equal allocation between cases and controls and assuming a RR of 1.3.6, the power of such a study would be very low for n=2000 for event rates from 2.5-12.5%. Conclusion: We report the low penetration of HCQ chemoprophylaxis among the healthcare workers of our institution. We highlight the inherent drawbacks in the study design of current national COVID related trial based on the statistical modelling of our survey results and published literature, and thereby emphasis the need of evidence-based strategies contributing to research policy at national level.

Data-Driven Methods for Advancing Precision Oncology.

PURPOSE OF REVIEW: This article discusses the advances, methods, challenges, and future directions of data-driven methods in advancing precision oncology for biomedical research, drug discovery, clinical research, and practice. RECENT FINDINGS: Precision oncology provides individually tailored cancer treatment by considering an individual's genetic makeup, clinical, environmental, social, and lifestyle information. Challenges include voluminous, heterogeneous, and disparate data generated by different technologies with multiple modalities such as Omics, electronic health records, clinical registries and repositories, medical imaging, demographics, wearables, and sensors. Statistical and machine learning methods have been continuously adapting to the ever-increasing size and complexity of data. Precision Oncology supportive analytics have improved turnaround time in biomarker discovery and time-to-application of new and repurposed drugs. Precision oncology additionally seeks to identify target patient populations based on genomic alterations that are sensitive or resistant to conventional or experimental treatments. Predictive models have been developed for cancer progression and survivorship, drug sensitivity and resistance, and identification of the most suitable combination treatments for individual patient scenarios. In the future, clinical decision support systems need to be revamped to better incorporate knowledge from precision oncology, thus enabling clinical practitioners to provide precision cancer care. SUMMARY: Open Omics datasets, machine learning algorithms, and predictive models have enabled the advancement of precision oncology. Clinical decision support systems with integrated electronic health record and Omics data are needed to provide data-driven recommendations to assist clinicians in disease prevention, early identification, and individualized treatment. Additionally, as cancer is a constantly evolving disorder, clinical decision systems will need to be continually updated based on more recent knowledge and datasets.

Likelihood ratio tests for a dose-response effect using multiple nonlinear regression models.

We consider the problem of testing for a dose-related effect based on a candidate set of (typically nonlinear) dose-response models using likelihood-ratio tests. For the considered models this reduces to assessing whether the slope parameter in these nonlinear regression models is zero or not. A technical problem is that the null distribution (when the slope is zero) depends on non-identifiable parameters, so that standard asymptotic results on the distribution of the likelihood-ratio test no longer apply. Asymptotic solutions for this problem have been extensively discussed in the literature. The resulting approximations however are not of simple form and require simulation to calculate the asymptotic distribution. In addition, their appropriateness might be doubtful for the case of a small sample size. Direct simulation to approximate the null distribution is numerically unstable due to the non identifiability of some parameters. In this article, we derive a numerical algorithm to approximate the exact distribution of the likelihood-ratio test under multiple models for normally distributed data. The algorithm uses methods from differential geometry and can be used to evaluate the distribution under the null hypothesis, but also allows for power and sample size calculations. We compare the proposed testing approach to the MCP-Mod methodology and alternative methods for testing for a dose-related trend in a dose-finding example data set and simulations.

10 Years' Plaque Incision and Vein Grafting for Peyronie's Disease: Does Time Matter?

INTRODUCTION: Surgical correction is advocated in patients with stable Peyronie's disease (PD) and severe curvature of the penis. Contemporary series demonstrate favorable outcomes based on relatively short follow-up periods. However, long-term follow-up is rarely reported and there is a paucity of evidence on the influence of patients' age, comorbidities, and natural history on surgical outcomes. AIMS: The present study aims to examine the influence of patient's age, comorbidities, severity of the disease, and natural history of PD on long-term outcomes and satisfaction following plaque incision and vein grafting for PD. METHODS: Patients with follow-up of more than 10 years who underwent plaque incision and grafting (Lue technique) for stable PD were included in the study. MAIN OUTCOME MEASURES: A combination of prospective and retrospective analysis of patients' histories, anatomical, functional, and surgical parameters, development of PD recurrences, improvements of sexual functions, and overall satisfaction were performed between 1992 and 2014. Multiple logistic regression models were applied to calculate adjusted odds ratios for predictors for development of erectile dysfunction (ED) and PD recurrence. RESULTS: Thirty patients with a median age of 57.5 years were eligible for inclusion in the study with a mean follow-up of 13.0 years (range 10.0-17.6). Angle of preoperative penile deviation was 40° to 110° (median 90°). On follow-up, 26 men (86.7%) had a straight erect penis. Eleven men (36.7%) developed ED, of whom 2 (6.7%) had other comorbidities contributing to their ED. Twenty-five men (83.3%) were still sexually active with or without medication. The mean percentage improvement in sexual function was 69.0%, with 17 men (56.7%) reporting 100% improvement and 7 (23.3%) reporting no improvement. Perceived penile shortening occurred in 13 patients (43.3%) and 6 patients (20.0%) experienced penile hyposensitivity. PD/plaque recurrence was found in 7 men (23.3%). The mean overall satisfaction with the procedure was 73.0%, with 18 men (60.0%) still 100% satisfied and 6 (20.0%) reporting satisfaction below 50%. CONCLUSION: Improvement of sexual function and overall satisfaction remain high at 10 years follow-up and make the technique a safe and effective form of treatment in carefully selected patients.

Precision of maximum likelihood estimation in adaptive designs.

There has been increasing interest in trials that allow for design adaptations like sample size reassessment or treatment selection at an interim analysis. Ignoring the adaptive and multiplicity issues in such designs leads to an inflation of the type 1 error rate, and treatment effect estimates based on the maximum likelihood principle become biased. Whereas the methodological issues concerning hypothesis testing are well understood, it is not clear how to deal with parameter estimation in designs were adaptation rules are not fixed in advanced so that, in practice, the maximum likelihood estimate (MLE) is used. It is therefore important to understand the behavior of the MLE in such designs. The investigation of Bias and mean squared error (MSE) is complicated by the fact that the adaptation rules need not be fully specified in advance and, hence, are usually unknown. To investigate Bias and MSE under such circumstances, we search for the sample size reassessment and selection rules that lead to the maximum Bias or maximum MSE. Generally, this leads to an overestimation of Bias and MSE, which can be reduced by imposing realistic constraints on the rules like, for example, a maximum sample size. We consider designs that start with k treatment groups and a common control and where selection of a single treatment and control is performed at the interim analysis with the possibility to reassess each of the sample sizes. We consider the case of unlimited sample size reassessments as well as several realistically restricted sample size reassessment rules.

Adaptive seamless designs with interim treatment selection: a case study in oncology.

The planning of an oncology clinical trial with a seamless phase II/III adaptive design is discussed. Two regimens of an experimental treatment are compared to a control at an interim analysis, and the most-promising regimen is selected to continue, together with control, until the end of the study. Because the primary endpoint is expected to be immature at the interim regimen selection analysis, designs that incorporate primary as well as surrogate endpoints in the regimen selection process are considered. The final testing of efficacy at the end of the study comparing the selected regimen to the control with respect to the primary endpoint uses all relevant data collected both before and after the regimen selection analysis. Several approaches for testing the primary hypothesis are assessed with regard to power and type I error rate. Because the operating characteristics of these designs depend on the specific regimen selection rules considered, benchmark scenarios are proposed in which a perfect surrogate and no surrogate is used at the regimen selection analysis. The operating characteristics of these benchmark scenarios provide a range where those of the actual study design are expected to lie. A discussion on family-wise error rate control for testing primary and key secondary endpoints as well as an assessment of bias in the final treatment effect estimate for the selected regimen are also presented.

A hybrid method to estimate the minimum effective dose for monotone and non-monotone dose-response relationships.

This article proposes a new multiple-testing approach for estimation of the minimum effective dose allowing for non-monotonous dose-response shapes. The presented approach combines the advantages of two commonly used methods. It is shown that the new approach controls the error rate of underestimating the true minimum effective dose. Monte Carlo simulations indicate that the proposed method outperforms alternative methods in many cases and is only marginally worse in the remaining situations.

Pre-implant biopsy predicts outcome of single-kidney transplantation independent of clinical donor variables.

BACKGROUND: Pre-implant biopsy findings account for the discard of many donor kidneys although their clinical value is not fully understood. We retrospectively investigated the predictive value of pre-implant histology, which in our center was obtained for protocol purposes, not for transplant decisions, on long-term allograft and recipient outcome after single-kidney transplantation. METHODS: This single-center study included 628 consecutive adult recipients of 174 Expanded Criteria Donor (ECD) and 454 Standard Criteria Donor kidneys. Chronic donor organ injury was assessed applying a chronic lesion score differentiating between mild, moderate, and severe histologic organ injury based on the integration of glomerular, vascular, tubular, and interstitial lesions. Recipients were followed over a median time of 7.8 years. RESULTS: Donor kidneys exhibiting mild or moderate chronic lesions yielded almost identical graft and recipient survival independent of ECD status or other clinical covariables (HR 1.20, 95% CI 0.83-1.74, P=0.326, and HR 1.27, 95% CI 0.83-1.95, P=0.274, respectively). However, if allograft injury was severe, occurring in 3% of transplanted kidneys, graft and recipient survival was significantly reduced (HR 3.13, 95% CI 1.61-6.07, P<0.001 and HR 2.42, 95% CI 1.16-5.04, P=0.005, respectively). CONCLUSION: The results suggest that donor kidneys displaying moderate chronic injury can safely be transplanted as single kidneys, while organs displaying severe injury should be discarded. Thus, pre-implant biopsy might offer an effective approach to increase the utilization of renal donor organs, especially from ECD and donors with cerebrovascular accident as cause of death, and to improve overall graft outcome.

Outcome of coumarin-therapy in an outpatient setting over a 10-year period: coumarin-therapy in clinical practice.

OBJECTIVES: A retrospective study was conducted on an unselected sample of patients on vitamin K antagonists (VKAs; phenprocoumon, acenocoumarol) in an outpatient setting in Austria. The main objective was to determine whether bleeding and thromboembolic events reported in randomised trials are comparable to the experience in clinical practice. In addition, we focused on differences between the two VKAs and the particular indications for treatment and influences of risk factors. PARTICIPANTS: Total observation time was 10 years, the number of patients was 599 and the patient years-at-risk (pyr) was 1,856. RESULTS: Severe bleeding occurred in 1.1 % pyr and the bleeding-related mortality was 0.1 %. Severe thromboembolic events occurred in 2.8 % pyr, with a rate of fatal events of 0.3 %. A significant increase in risk was found in patients older than 75 years concerning bleeding as well as thromboembolic events. Acenocoumarol showed significantly higher rates in life-threatening and fatal bleeding episodes in comparison to phenprocoumon. CONCLUSIONS: The outcome of patients receiving VKA in an office setting is similar to that reported in the literature and the use of VKAs in this setting appears to be safe.

Is there an association between lower urinary tract symptoms and cardiovascular risk in men? A cross sectional and longitudinal analysis.

OBJECTIVE: To investigate the association between lower urinary tract symptoms (LUTS) and both coronary vascular disease (CVD) and stroke in men in a cross-sectional and longitudinal setting. MATERIAL AND METHODS: Men aged 30-92 years underwent a free health investigation and completed the International Prostate Symptom Score questionnaire. In the cross-sectional part, the 10-year CVD and stroke risks were estimated according to the Framingham risk score. In the follow-up period (mean 6.1 years) the CVD and stroke events were recorded. RESULTS: Two-thousand ninety-two men aged 47.8 years (SD 11.5) were analyzed. No to mild LUTS were present in 1,738 men, 337 men had moderate LUTS, and 17 had severe LUTS. The 10-year risk (cross-sectional design) for CVD or stroke in men with no to mild, moderate, and severe LUTS was 8.8%, 10.6%, and 15.9% (P <.01) and 6.9%, 7.5%, and 11.7% (P <.01), respectively. Adjusted for age, diabetes, total and low-density lipoprotein cholesterol, the odds ratios for CVD and stroke risk were 0.98 (P = .58) and 0.99 (P = .72) for moderate and 1.28 (P = .03) and 1.66 (P <.01) for severe LUTS. During follow-up, 96 events (CVD or stroke) were recorded: Men with no to mild, moderate, and severe LUTS had 76 (4.4%), 15 (4.5%), and 5 (29.4%) events, respectively. The adjusted (see above) hazard ratios were 0.63 (P = .16) for moderate and 3.82 (P = .01) for severe LUTS. CONCLUSION: Although moderate LUTS do not seem to be a risk factor for CVD and stroke, men with severe LUTS were at increased risk for both according to a cross-sectional and longitudinal analysis. Studies with a larger group of men with severe LUTS are warranted to further substantiate these observations.

Familywise error control in multi-armed response-adaptive two-stage designs.

For comparing multiple treatments against a single control with normally distributed observations, we consider two-stage designs of the following form: During the first stage, control and treatments are allocated by response-adaptive randomization; after completion of the first stage, some treatments are selected to proceed to the second stage; during the second stage, control and selected treatments are allocated by block randomization. Tests for such designs that use the data from both stages have been based on simulation under the global null hypothesis. We present an approach that does not rely on simulation and protects the familywise error rate in the strong sense. The main idea is to view the trial as a data-dependent modification of a simpler design, for which we know the distributions of its test statistics. To account for the data-dependent modification, we use the conditional invariance principle (Brannath et al., 2007).

Cost-effectiveness analysis of renal replacement therapy in Austria.

BACKGROUND: Providing renal replacement therapy (RRT) for end-stage renal disease patients is resource intensive. Despite growing financial pressure in health care systems worldwide, cost-effectiveness studies of RRT modalities are scarce. METHODS: We developed a Markov model of costs, quality of life and survival to compare three different assignment strategies to chronic RRT in Europe. RESULTS: Mean annual treatment costs for haemodialysis were €43,600 during the first 12 months, €40,000 between 13 and 24 months and €40,600 beyond 25 months after initiation of treatment. Mean annual treatment costs for peritoneal dialysis were €25,900 during the first 12 months, €15,300 between 13 and 24 months and €20,500 beyond 25 months. Mean annual therapy costs for a kidney transplantation during the first 12 months were €50,900 from a living donor, €51,000 from a deceased donor, €17,200 between 13 and 24 months and €12,900 beyond 25 months after engraftment. Over the next 10 years in Austria with a population of 8 million people, increased assignment to peritoneal dialysis of 20% incident patients saved €26 million with a discount rate of 3% and gained 839 quality-adjusted life years (QALYs); additionally, increasing renal transplants to 10% from live donations saved €38 million discounted and gained 2242 QALYs. CONCLUSIONS: Live donor renal transplantation is cost effective and associated with increase in QALYs. Therefore, preemptive live kidney transplantation should be promoted from a fiscal as well as medical point of view.

An approach to the conditional error rate principle with nuisance parameters.

In the presence of nuisance parameters, the conditional error rate principle is difficult to apply because of the dependency of the conditional error function of the preplanned test on nuisance parameters. To use the conditional error rate principle with nuisance parameters, we propose to search among tests that guarantee overall error control for the test that maximizes a weighted combination of the conditional error rates over possible values of the nuisance parameters. We show that the optimization problem that defines such a test can be solved efficiently by existing algorithms.