Many-to-one comparisons after safety selection in multi-arm clinical trials.

In phase II platform trials, 'many-to-one' comparisons are performed when K experimental treatments are compared with a common control to identify the most promising treatment(s) to be selected for Phase III trials. However, when sample sizes are limited, such as when the disease of interest is rare, only a single Phase II/III trial addressing both treatment selection and confirmatory efficacy testing may be feasible. In this paper, we suggest a two-step safety selection and testing procedure for such seamless trials. At the end of the study, treatments are first screened on the basis of safety, and those deemed to be sufficiently safe are then taken forwards for efficacy testing against a common control. All safety and efficacy evaluations are therefore performed at the end of the study, when for each patient all safety and efficacy data are available. If confirmatory conclusions are to be drawn from the trial, strict control of the family-wise error rate (FWER) is essential. However, to avoid unnecessary losses in power, no type I error rate should be "wasted" on comparisons which are no longer of interest because treatments have been dropped due to safety concerns. We investigate the impact on power and FWER control of multiplicity adjustments which correct efficacy tests only for the number of safe selected treatments instead of adjusting for all K null hypotheses the trial begins testing. We derive conditions under which strict control of the FWER can be achieved. Procedures using the estimated association between safety and efficacy outcomes are developed for the case when the correlation between endpoints is unknown. The operating characteristics of the proposed procedures are assessed via simulation.

Evidence, eminence and extrapolation.

A full independent drug development programme to demonstrate efficacy may not be ethical and/or feasible in small populations such as paediatric populations or orphan indications. Different levels of extrapolation from a larger population to smaller target populations are widely used for supporting decisions in this situation. There are guidance documents in drug regulation, where a weakening of the statistical rigour for trials in the target population is mentioned to be an option for dealing with this problem. To this end, we propose clinical trials designs, which make use of prior knowledge on efficacy for inference. We formulate a framework based on prior beliefs in order to investigate when the significance level for the test of the primary endpoint in confirmatory trials can be relaxed (and thus the sample size can be reduced) in the target population while controlling a certain posterior belief in effectiveness after rejection of the null hypothesis in the corresponding confirmatory statistical test. We show that point-priors may be used in the argumentation because under certain constraints, they have favourable limiting properties among other types of priors. The crucial quantity to be elicited is the prior belief in the possibility of extrapolation from a larger population to the target population. We try to illustrate an existing decision tree for extrapolation to paediatric populations within our framework. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Surgical specimens, haemodynamics and long-term outcomes after pulmonary endarterectomy.

BACKGROUND: Chronic thromboembolic pulmonary hypertension is surgically curable by pulmonary endarterectomy (PEA). It is unclear whether PEA impacts primarily steady state right ventricular afterload (ie, pulmonary vascular resistance (PVR)) or pulsatile right ventricular afterload (ie, pulmonary arterial compliance (C(PA))). Our objectives were to (1) quantify PEA specimens and measure the impact of PEA on PVR and C(PA) in a structure/function study and (2) analyse the effects of haemodynamic changes on long-term survival/freedom of lung transplantation in an outcome study. METHODS: Thrombi were laid out, weighed, photographed and measured. PVR, C(PA) and resistance times compliance (RC-time) were assessed at baseline, within 4 days after PEA ('immediately postoperative') and 1 year after PEA, in 110 consecutive patients who were followed for 34.5 (11.9; 78.3) months. RESULTS: Lengths and numbers of PEA specimen tails were inversely correlated with immediate postoperative PVR (p<0.0001, r=-0.566; p<0.0001, r=-0.580). PVR and C(PA) normalised immediately postoperatively while RC-time remained unchanged. Immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation (p<0.0001). Patients with immediate postoperative PVR<590 dynes.s.cm(-5) had better long-term outcomes than patients with PVR≥590 dynes.s.cm(-5) (p<0.0001, respectively). CONCLUSIONS: PEA immediately decreased PVR and increased C(PA) under a constant RC-time. However, immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation. Our study confirms the importance of a complete, bilateral surgical endarterectomy. Low PVR measured immediately postoperative predicts excellent long-term outcome.

Lithium in the public water supply and suicide mortality in Texas.

There is increasing evidence from ecological studies that lithium levels in drinking water are inversely associated with suicide mortality. Previous studies of this association were criticized for using inadequate statistical methods and neglecting socioeconomic confounders. This study evaluated the association between lithium levels in the public water supply and county-based suicide rates in Texas. A state-wide sample of 3123 lithium measurements in the public water supply was examined relative to suicide rates in 226 Texas counties. Linear and Poisson regression models were adjusted for socioeconomic factors in estimating the association. Lithium levels in the public water supply were negatively associated with suicide rates in most statistical analyses. The findings provide confirmatory evidence that higher lithium levels in the public drinking water are associated with lower suicide rates. This association needs clarification through examination of possible neurobiological effects of low natural lithium doses.

Out of hospital cardiac arrest in Vienna: incidence and outcome.

AIM OF THE STUDY: To determine the incidence of out-of-hospital cardiac arrest and the survival rate of those patients who received CPR in the city of Vienna. METHODS: A cohort of patients with out-of-hospital cardiac arrests and who were treated by the Vienna Ambulance Service between January 1, 2009, and December 31, 2010, were followed up until either death or hospital discharge. The associations of survival and neurological outcome with their potential predictors were analysed using simple logistic regression models. Odds ratios were estimated for each factor. RESULTS: During the observation period, a total of 7030 (206.8/100,000 inhabitants/year) patients without signs of circulation were assessed by teams of the Vienna Ambulance Service, and 1448 adult patients were resuscitated by emergency medical service personnel. A sustained return of spontaneous circulation was reported in 361 (24.9%) of the treated patients, and in all 479 (33.0%) of the patients were taken to the emergency department. A total of 164 (11.3%) of the patients were discharged from the hospital alive, and 126 (8.7%) of the patients showed cerebral performance categories of 1 or 2 at the time of discharge. Younger age, an arrest in a public area, a witnessed arrest and a shockable rhythm were associated with a higher probability of survival to hospital discharge. CONCLUSION: Survival rates for out-of-hospital cardiac arrests remain low. Efforts should be focused on rapidly initiating basic life support, early defibrillation, and high-quality CPR by emergency medical services and state-of-the art post-resuscitation care.

Modified solid-phase alloantibody detection for improved crossmatch prediction.

Virtual crossmatching based on single-antigen bead (SAB) assays for the detection of donor-specific antibodies (DSA) has limited accuracy of predicting complement-dependent cytotoxicity crossmatch (CDCXM) results. In this study, 672 crossmatch combinations (32 allosensitized patients tested against cells from 21 high resolution-typed individuals) were analyzed to assess the potential of modified SAB tests in predicting T- or B-cell-CDCXM outcomes. Test modifications included measurement of C4d-fixation to detect complement-activating DSA ([C4d]DSA), or addition of dithiotreitol to abrogate the prozone effect ([IgG/DTT]DSA). Receiver operating characteristic (ROC) analysis revealed superior predictive accuracy of [C4d]DSA detection. Computing the mean fluorescence intensity (MFI) sum value of HLA class I [C4d]DSA in relation to T-cell-CDCXM revealed an area under the ROC curve (AUC) of 0.81. Other parameters, including DSA MFI maximum or number, were less predictive. Computing MFI sum values, AUC levels were lower for [IgG/DTT] (0.77) or [IgG]DSA detection (0.72), and did not considerably increase upon combining classifiers ([C4d] plus [IgG/DTT]: 0.82). ROC analysis revealed that [C4d]DSA detection (HLA class II) was also better at predicting B-cell-CDCXM results, even though, at very low MFI thresholds, the assay was found to provide comparably lower levels of specificity. Overall, B-cell-CDXM prediction was less precise, but could be enhanced by adjusting CDCXM thresholds to higher levels. Our data suggest particular efficiency of solid-phase complement detection as a tool for virtual crossmatching.

Correlation of serum procalcitonin with the severity of skin and skin structure infections - a pilot study.

BACKGROUND: Procalcitonin (PCT) is a specific biomarker for early detection of bacterial infections. While the usefulness of procalcitonin in severe conditions such as sepsis is well established, its relevance in the diagnosis and prognosis of localized cutaneous bacterial infections is unknown. Our aim was to initially evaluate if PCT is a useful parameter for predicting the severity of skin and skin structure infections (SSSI). Furthermore, the correlation of PCT levels with C-reactive protein (CRP), leukocyte counts, erythrocyte sedimentation rate (ESR), and body temperature was investigated. PATIENTS AND METHODS: Serum PCT, routine laboratory parameters, and body temperature were regularly examined in 50 consecutive patients with SSSI requiring inpatient intravenous antibiotic treatment. Patients were classified into 2 groups according to the guidelines developed by the FDA (U.S. Food and Drug Administration) as having either an uncomplicated (SSSI) or a complicated skin and skin structure infection (cSSSI). RESULTS: No significant correlation could be detected between the length of inpatient antibiotic treatment and PCT on days 1, 2, 3, and the maximum value on these days. The same result was found when uncomplicated SSSI and complicated SSSI (cSSSI) were evaluated separately. However, PCT levels were significantly higher in the latter. Furthermore, PCT levels showed a significant correlation with CRP, leukocyte count, ESR, and body temperature. CONCLUSION: PCT might be a useful additional tool for initial diagnosis and monitoring of patients with SSSI.

Rapid induction of hypothermia with a small volume aortic flush during cardiac arrest in pigs.

PURPOSE: The induction of deep cerebral hypothermia (15°C) via large-volume cold (4°C) saline aortic flush during cardiac arrest and resuscitation with cardiopulmonary bypass improves neurologic outcome in pigs. We hypothesized that induction of mild cerebral hypothermia (33°C) via smaller volume and resuscitation without bypass will improve survival and neurologic outcome after 15 minutes of cardiac arrest as compared with conventional resuscitation attempts. BASIC PROCEDURES: Twenty-four pigs (29-38 kg) underwent ventricular fibrillation cardiac arrest for 15 minutes. Conventional resuscitation (n=8) was compared with hypothermic (4°C, n=8) and normothermic (38.5°C, n=8) aortic flush (30 mL/kg) at the beginning of resuscitation efforts, with defibrillation attempts 2 minutes later. Outcomes after 9 days were compared. MAIN FINDINGS: In the hypothermic flush group, brain temperature decreased from 38.3°C±0.5°C to 33°C±0.5°C within 277±112 seconds. We observed considerably higher mean coronary perfusion pressures in the normothermic and hypothermic flush groups (hypothermic vs conventional, P=.023; normothermic vs conventional, P=.041). Three animals of each flush group, compared with none of the conventional group, achieved restoration of spontaneous circulation (P=.2); and 3 pigs of the hypothermic flush group and 2 pigs of the normothermic flush group survived to 9 days without differences in neurologic outcome. PRINCIPAL CONCLUSION: A smaller volume, cold saline aortic flush during prolonged cardiac arrest rapidly induces mild cerebral hypothermia to 33°C and improves coronary perfusion pressure but does not result in a significant improvement in outcome as compared with conventional resuscitation attempts.

Anti-alpha-Gal antibody titres remain unaffected by the consumption of fermented milk containing Lactobacillus casei in healthy adults.

Alpha-Gal is a glycoconjugate present on cell membranes of non-primate mammals and bacteria, but not in humans, who display anti-Gal antibodies (ABs) in high titres. Probiotics contain bacterial strains which colonize the intestinal tract. In the present study, we investigated whether intake of fermented milk containing Lactobacillus casei (FML) affects anti-Gal AB titres. Serum was drawn from healthy probands (n = 19) for 6 weeks. After the second week, the probands consumed 125 ml of FML per day. Anti-Gal ABs of all isotypes and cytokines were measured. Bacterial cultures were bred from FML and bacteria were stained for alpha-Gal. Concentration of bacteria in FML was manifold higher than in conventional yoghurt (2 × 10(5)/g yoghurt vs. 1.1 × 10(7)/g FML). Both stained highly positive for Alpha-Gal. Alpha-Gal-specific ABs and cytokines remained unaffected by FML intake. Our results indicated that the consumption of FML does not elicit a humoral immune response in healthy adults.

Total body skin examination for skin cancer screening in patients with focused symptoms.

BACKGROUND: The value of total body skin examination (TBSE) for skin cancer screening is controversial. OBJECTIVE: We sought to determine whether TBSE could be helpful in patients with focused skin symptoms who would not otherwise have undergone TBSE. METHODS: In a prospective, multicenter, cross-sectional study consecutive adult patients were recruited during a period of 18 months. Physicians first inspected problem areas and uncovered areas and then performed TBSE. Equivocal lesions detected in both steps were excised or biopsied. Primary outcomes were the absolute and relative risks of missing skin cancer and the number of patients needed to examine to detect melanoma or another malignancy. A secondary outcome was the proportion of false-positive results obtained by TBSE. RESULTS: We examined 14,381 patients and detected 40 (0.3%) patients with melanoma and 299 (2.1%) with at least one nonmelanoma skin cancer by TBSE. In 195 (1.3%) patients equivocal lesions found by TBSE turned out to be benign. We calculated that 47 patients need to be examined by TBSE to find one skin malignancy and 400 patients to detect one melanoma. The risk of missing one malignancy if not performing TBSE was 2.17% (95% confidence interval 1.25-3.74). Factors significantly increasing the chance to find a skin cancer were age, male gender, previous nonmelanoma skin cancer, fair skin type, skin tumor as the reason for consultation, and presence of an equivocal lesion on problem/uncovered areas. LIMITATIONS: The impact of TBSE on skin cancer mortality was not evaluated. CONCLUSIONS: TBSE improves skin cancer detection in patients with focused skin symptoms and shows a low rate of false-positive results.

Lithium in drinking water and suicide mortality.

BACKGROUND: There is some evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality. AIMS: To evaluate the association between local lithium levels in drinking water and suicide mortality at district level in Austria. METHOD: A nationwide sample of 6460 lithium measurements was examined for association with suicide rates per 100,000 population and suicide standardised mortality ratios across all 99 Austrian districts. Multivariate regression models were adjusted for well-known socioeconomic factors known to influence suicide mortality in Austria (population density, per capita income, proportion of Roman Catholics, as well as the availability of mental health service providers). Sensitivity analyses and weighted least squares regression were used to challenge the robustness of the results. RESULTS: The overall suicide rate (R(2) = 0.15, ß = -0.39, t = -4.14, P = 0.000073) as well as the suicide mortality ratio (R(2) = 0.17, ß = -0.41, t = -4.38, P = 0.000030) were inversely associated with lithium levels in drinking water and remained significant after sensitivity analyses and adjustment for socioeconomic factors. CONCLUSIONS: In replicating and extending previous results, this study provides strong evidence that geographic regions with higher natural lithium concentrations in drinking water are associated with lower suicide mortality rates.