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Several patients with heart failure and reduced ejection fraction (HFrEF) do not receive renin-angiotensin-aldosterone system (RAAS) inhibitors at the recommended dose or at all, frequently due to actual or feared hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is an orally administered non-absorbed intestinal potassium binder proven to lower serum potassium concentrations.PRIORITIZE-HF was an international, multicentre, parallel-group, randomized, double-blind, placebo-controlled study to evaluate the benefits and risks of using SZC to intensify RAAS inhibitor therapy. Patients with symptomatic HFrEF were eligible and randomly assigned to receive SZC 5 g or placebo once daily for 12 weeks. Doses of study medication and RAAS inhibitors were titrated during the treatment period. The primary endpoint was the proportion of patients at 12 weeks in the following categories: (i) any RAAS inhibitor at less than target dose, and no MRA; (ii) any RAAS inhibitor at target dose and no MRA; (ii) MRA at less than target dose; and (iv) MRA at target dose. Due to challenges in participant management related to the COVID-19 pandemic, the study was prematurely terminated with 182 randomized patients. There was no statistically significant difference in the distribution of patients by RAAS inhibitor treatment categories at 3 months (P = 0.43). The proportion of patients at target MRA dose was numerically higher in the SZC group (56.4%) compared with the placebo group (47.0%). Overall, SZC was well tolerated.PRIORITIZE-HF was terminated prematurely due to COVID-19 and did not demonstrate a statistically significant increase in the intensity of RAAS inhibitor therapies with the potassium-reducing agent SZC compared with placebo.

Background Sodium zirconium cyclosilicate (SZC) is an oral, highly selective potassium binder approved for the treatment of hyperkalaemia in adults. SZC may change the absorption of co-administered drugs that exhibit pH-dependent bioavailability. This study evaluated whether the pharmacokinetic (PK) profiles of tacrolimus and cyclosporin were altered by concomitant SZC administration in healthy participants. Methods This was an open-label, randomised sequence, two-cohort crossover, single-centre study. Healthy adults were assigned to one of two cohorts: Cohort 1 (tacrolimus) received a single dose of tacrolimus 5 mg and tacrolimus 5 mg + SZC 15 g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100 mg and cyclosporin 100 mg + SZC 15 g in a random order. Primary PK endpoints were maximum observed blood concentration (Cmax) and area under the concentration–time curve (AUC) from time zero to infinity (AUCinf). Differences in mean Cmax and AUCinf were analysed using a mixed effects model. Results Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus + SZC versus tacrolimus alone: Cmax geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44–77.24], AUCinf 62.91% (55.64–71.13). Cyclosporin exposure was similar with cyclosporin + SZC compared with cyclosporin alone: Cmax GMR 102.9% (90% CI 96.11–110.10), AUCinf 97.23% (92.93–101.70). Conclusions Tacrolimus exposure was lower when co-administered with SZC 15 g and should be administered ≥2 h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.

Naturalistic driving studies (NDS) generate tremendous amounts of traffic data and constitute an important component of modern traffic safety research. However, analysis of the entire NDS database is rarely feasible, as it often requires expensive and time-consuming annotations of video sequences. We describe how automatic measurements, readily available in an NDS database, may be utilised for selection of time segments for annotation that are most informative with regards to detection of potential associations between driving behaviour and a consecutive safety critical event. The methodology is illustrated and evaluated on data from a large naturalistic driving study, showing that the use of optimised instance selection may reduce the number of segments that need to be annotated by as much as 50%, compared to simple random sampling.

IntroductionPatients with kidney failure receiving chronic haemodialysis have elevated risk of arrhythmias potentially increasing the likelihood of sudden cardiac death, stroke and hospitalisation. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an efficacious and well-tolerated treatment for predialysis hyperkalaemia in patients undergoing haemodialysis. The DIALIZE-Outcomes study evaluates the effect of SZC on sudden cardiac death and arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with recurrent hyperkalaemia.Methods and analysisInternational, multicentre, randomised, double-blind, placebo-controlled study conducted at 357 study sites across 25 countries. Adults (≥18 years) receiving chronic haemodialysis three times per week with recurrent predialysis serum potassium (K+) ≥5.5 mmol/L post long interdialytic interval (LIDI) are eligible. Patients (~2800) will be randomised 1:1 to SZC or placebo, starting at 5 g orally once daily on non-dialysis days and titrated weekly in 5 g increments (maximum 15 g) to target predialysis serum K+4.0–5.0 mmol/L post LIDI. The primary objective is to evaluate efficacy of SZC versus placebo in reducing occurrence of the primary composite endpoint of sudden cardiac death, stroke or arrhythmia-related hospitalisation, intervention or emergency department visit. Secondary endpoints include efficacy of SZC versus placebo in maintaining normokalaemia (serum K+4.0–5.5 mmol/L post LIDI) at the 12-month visit, preventing severe hyperkalaemia (serum K+≥6.5 mmol/L post LIDI) at the 12-month visit and reducing the incidence of individual cardiovascular outcomes. Safety of SZC will be evaluated. The study is event driven, with participants remaining in the study until 770 primary endpoint events have occurred. Average time in the study is expected to be ~25 months.Ethics and disseminationApproval was obtained from the relevant institutional review board/independent ethics committee from each participating site (approving bodies in supplementary information). The results will be submitted to a peer-reviewed journal.Trial registration numbersEudraCT 2020-005561-14 and clinicaltrials.gov identifierNCT04847232.

BACKGROUND AND AIMS Sodium zirconium cyclosilicate (SZC) is a novel, oral, highly selective potassium binder approved for the treatment of hyperkalaemia (HK) in adults. As well as binding potassium, SZC binds hydrogen ions in the acidic environment of the stomach, causing a transient increase in gastric pH which may alter absorption of oral drugs with gastric pH-dependent bioavailability. HK is a recognized issue for renal transplant patients. Tacrolimus and cyclosporin are important drugs in transplant patients, but it is unknown if co-administration of SZC affects their pharmacokinetic (PK) profiles. The aim of this study was to evaluate if the PK profiles of tacrolimus and cyclosporin are altered by SZC co-administration in healthy subjects. METHOD This was an open-label, randomized-sequence, 2-cohort crossover study conducted at a site in Germany (NCT04788641). Healthy adults aged 18–50 years were assigned to either cohort 1 (tacrolimus) or cohort 2 (cyclosporin). Subjects in cohort 1 (tacrolimus) received a single dose of tacrolimus 5 mg and tacrolimus 5 mg + SZC 15 g in a random order. Subjects in cohort 2 (cyclosporin) received a single dose of cyclosporin 100 mg and cyclosporin 100 mg + SZC 15 g in a random order. Drug administrations were planned to occur after a 12-h overnight fast and a ≥14-day washout period between treatment periods. Blood samples were collected pre-dose and post-dose up to 72 h. The primary PK endpoints for tacrolimus and cyclosporin were maximum observed blood concentration (Cmax) and area under the concentration-time curve (AUC) from time zero to infinity (AUCinf). Secondary endpoints for tacrolimus and cyclosporin were AUC from time zero to the time of the last quantifiable concentration (AUClast), half-life associated with terminal λz of a semi-logarithmic concentration-time curve (t½λz), and time to reach maximum observed concentration (tmax). The difference in mean PK parameters was analysed using a mixed effects model following a natural logarithmic transformation, with period, treatment and sequence as fixed effects, and subject nested within sequence as random effects. Safety and tolerability evaluation included assessment of adverse events (AEs). RESULTS Overall, 31 subjects were enrolled in each cohort; 30 subjects in cohort 1 (tacrolimus) and 29 in cohort 2 (cyclosporin) completed the study. Tacrolimus exposure was lower with tacrolimus + SZC compared with tacrolimus alone (Figure 1); Cmax geometric mean ratio (GMR): 71.1% (90% confidence interval [CI] 65.4–77.2), AUCinf: 62.9% (55.6–71.1), AUClast: 65.6% (58.7–73.2). t½λz of tacrolimus was similar between tacrolimus + SZC and tacrolimus alone (GMR: 98.4%; 90% CI 94.6–102.4). Median tmax of tacrolimus was earlier with tacrolimus + SZC (1.50 h) compared with tacrolimus alone (1.75 h; GMR: 83.9%; 90% CI 73.4–95.8). Cyclosporin exposure was similar with cyclosporin + SZC compared with cyclosporin alone (Figure 2); Cmax GMR: 102.9% (90% CI 96.1–110.1), AUCinf: 97.2% (92.9–101.7), AUClast: 97.0% (92.7–101.6). t½λz of cyclosporin was comparable with cyclosporin + SZC and cyclosporin alone (GMR: 94.1%; 90% CI 85.7–103.3). Median tmax of cyclosporin was 1.25 h with cyclosporin + SZC and 1.50 h with cyclosporin alone (GMR: 97.6; 90% CI 87.2–109.2). A total of 15 AEs were reported in 13 subjects with tacrolimus + SZC, 12 AEs in 7 subjects with tacrolimus, 9 AEs in 7 subjects with cyclosporin + SZC and 8 AEs in 8 subjects with cyclosporin. AEs were generally mild in intensity in all groups. There were no serious AEs and no systematic pattern in preferred terms. CONCLUSION Tacrolimus exposure was lower when co-administered with SZC 15 g, which has the potential to reduce its immunosuppressive efficacy. As for other oral drugs with drug–drug interactions with SZC, tacrolimus should be administered ≥ 2 h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.

Background Sodium zirconium cyclosilicate (SZC) is an effective and well-tolerated treatment for hyperkalemia in maintenance hemodialysis patients. In post-hoc analyses of the phase 3b DIALIZE study, we examined the spectrum of potassium responses to SZC. Methods Post-hoc analyses with SZC and placebo included: the number of long interdialytic interval (LIDI) visits during the 4-week evaluation period where patients attained pre-dialysis serum potassium (sK+) concentrations of 4.0–5.0 and 4.0–5.5 mmol/L; potassium gradient (the difference between pre-dialysis sK+ and dialysate potassium) at days 36, 43, 50, and 57, and change from baseline to the end of treatment (EOT) using categories of potassium gradient (1 to Results A greater proportion of patients achieved the ranges of pre-dialysis sK+ concentration with SZC versus placebo for ≥1, ≥ 2, ≥ 3, and 4 LIDI visits over 4 weeks; 23.7 and 48.5% of patients in the SZC group achieved pre-dialysis sK+ concentrations of 4.0–5.0 and 4.0–5.5 mmol/L, respectively, at all 4 LIDI visits. Baseline mean potassium gradient was similar with SZC and placebo. At day 57, mean (standard deviation) potassium gradient was 2.78 (0.08) mmol/L with SZC and 3.52 (0.08) mmol/L with placebo; mean difference (95% confidence interval) was − 0.74 mmol/L (− 0.97 to − 0.52). A greater reduction in potassium gradient category from baseline towards lower-risk categories at EOT was observed with SZC versus placebo. Conclusions These analyses expand our knowledge of the spectrum of potassium responses with SZC in hyperkalemic hemodialysis patients. Trial registration NCT03303521.

Separate collection and recycling of used batteries is required in the EU member states and other countries, as a measure for environmentally sound management of batteries. Monitoring of collection rate of the separate battery stream is important for decision making, in particular for implementing interventions to improve the separate collection and evaluating their results. Limitations of the currently applied method for the estimation of battery collection rate are discussed and a new method, which improves the estimation, is suggested. The method utilizes a more accurate way of estimating the total battery waste generation. This estimation is based on batteries historical consumption estimated with material flow analysis method and distributions of batteries lifespan obtained from empirical data. Empirical data from two decades of battery consumption and disposal in Sweden were analyzed and lifespan distributions have been found for eight different types of batteries by dating over 5000 disposed batteries. The lifespans stretched from 1 to 28 years, with a median lifespan of 3–8 years. It is shown how the use of lifespan distributions in the suggested method could considerably improve the estimation of the collection rate. Consequently, the intervention potentials can be identified more accurately and the decision making for investments in the collection system can be improved. The observed lifespans are also useful for understanding batteries fate in households as well as trends in battery consumption and disposal.

BACKGROUND: Patients with ESRD have minimal renal potassium excretion and, despite hemodialysis, often have persistent predialysis hyperkalemia. The DIALIZE study (NCT03303521) evaluated sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in hemodialysis patients. METHODS: In the DIALIZE study, a double-blind, placebo-controlled, phase 3b multicenter study, we randomized adults with ESRD who were managed by three-times weekly hemodialysis and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on non-dialysis days, and titrated towards maintaining normokalemia over 4 weeks, in 5 g increments to a maximum of 15 g. The primary efficacy outcome was proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0–5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval and did not require urgent rescue therapy to reduce serum potassium. RESULTS: In total, 196 patients (mean [standard deviation (SD)] age =58.1 [13.7] years old) were randomized to sodium zirconium cyclosilicate or placebo. Of 97 patients receiving sodium zirconium cyclosilicate, 41.2% met the primary end point and were deemed treatment responders compared with 1.0% of 99 patients receiving placebo (P

We simultaneously examined 14 patients with OTS and dynamic radiostereometric analysis (RSA) to evaluate the accuracy of both skin- and a cluster-marker models. The mean differences between the OTS and RSA system in hip flexion, abduction, and rotation varied up to 9.5° for the skin-marker and up to 11.3° for the cluster-marker models, respectively. Both models tended to underestimate the amount of flexion and abduction, but a significant systematic difference between the marker and RSA evaluations could only be established for recordings of hip abduction using cluster markers (p = 0.04). The intra-class correlation coefficient (ICC) was 0.7 or higher during flexion for both models and during abduction using skin markers, but decreased to 0.5-0.6 when abduction motion was studied with cluster markers. During active hip rotation, the two marker models tended to deviate from the RSA recordings in different ways with poor correlations at the end of the motion (ICC ≤0.4). During active hip motions soft tissue displacements occasionally induced considerable differences when compared to skeletal motions. The best correlation between RSA recordings and the skin- and cluster-marker model was found for studies of hip flexion and abduction with the skin-marker model. Studies of hip abduction with use of cluster markers were associated with a constant underestimation of the motion. Recordings of skeletal motions with use of skin or cluster markers during hip rotation were associated with high mean errors amounting up to about 10° at certain positions. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1515-1522, 2017.

As naturalistic driving data become increasingly available, new analyses are revealing the significance of drivers’ glance behavior in traffic crashes. Due to the rarity of crashes, even in the largest naturalistic datasets, near-crashes are often included in the analyses and used as surrogates for crashes. However, to date we lack a method to assess the extent to which driver glance behavior influences crash and injury risk across both crashes and near-crashes. This paper presents a novel method for estimating crash and injury risk from off-road glance behavior for crashes and near-crashes alike; this method can also be used to evaluate the safety impact of secondary tasks (such as tuning the radio). We apply a ‘what-if’ (counterfactual) simulation to 37 lead-vehicle crashes and 186 lead-vehicle near-crashes from lead-vehicle scenarios identified in the SHRP2 naturalistic driving data. The simulation combines the kinematics of the two conflicting vehicles with a model of driver glance behavior to estimate two probabilities: (1) that each event becomes a crash, and (2) that each event causes a specific level of injury. The usefulness of the method is demonstrated by comparing the crash and injury risk of normal driving with the risks of driving while performing one of three secondary tasks: the Rockwell radio-tuning task and two hypothetical tasks. Alternative applications of the method and its metrics are also discussed. The method presented in this paper can guide the design of safer driver–vehicle interfaces by showing the best tradeoff between the percent of glances that are on-road, the distribution of off-road glances, and the total task time for different tasks.

Material flow analysis (MFA) is a tool for research and decision support in environmental policy and management. In order to promote the use of MFA at different spatial scales, a quantification of the uncertainty in nationwide, regional, and urban MFA methodologies is provided. In particular, the impact of the input data quality on the main MFA indicators is analyzed and the sources and extent of uncertainties for different spatial scales are listed. The types, origin, and extent of the errors are described in detail and several imputation methods are explained and evaluated. By introducing a novel approach to account measurement errors in data sets with very few details on the measurement errors, this article aims at contributing to the development of a standardized method to account for the uncertainty in MFA studies. This study uses the time series of MFA data for 1996-2011 at three spatial scalesnationwide (Sweden), regional (the Stockholm Region), and metropolitan (Stockholm, Gothenburg, and Malmo)to determine how propagation of measurement errors affects the MFA results. The following MFA indicators were studied: direct material input; domestic processed output; and domestic material consumption. Generally, availability decreased as the spatial scale was lowered, whereas data errors increased. In the specific case of Sweden, the data on freight transport by rail and on waste produced by economic activities at the regional and metropolitan level should be improved.

Background: Special insoles and shoes designed to prevent foot ulcers caused by repetitive high pressures are recommended for patients with diabetes who have any of the following risk factors: neuropathy; peripheral vascular disease; foot deformities; previous ulcers; amputation; and skin pathologies. However, there is a need for increased knowledge regarding: a) differences in the peak pressure (PP) and pressure time integral (PTI) for different types of insoles; and b) the properties of the pressure distribution for insoles used over a period of several months. We present the results of a randomized trial to compare the plantar pressures of three commonly used insoles. Objectives: The primary objective was to compare the PP and PTI between three types of insoles. The secondary objective was to explore the long-term pattern of peak plantar pressure distribution and variations in specific regions of interest (ROI). The tertiary objective was to investigate the impacts of insole adjustments, how much the insoles were used, and the levels of patient satisfaction. Methods: In a 2-year trial, 114 patients with type 1 (N = 31) or type 2 (N = 83) diabetes (62 men and 52 women; mean age, 57.7 ± 15.4 years; duration of diabetes, 12.3 ± 11.2 years; neuropathy, 38%), were randomized to be supplied with one of three different insoles. The ethylene vinyl acetate (EVA) insoles were used in outdoor walking shoes. The 35 EVA group (N = 39) received soft custom-made insoles composed of EVA of 35 shore A hardness, the 55 EVA group (N = 37) received custom-made insoles composed of EVA of 55 shore hardness, and the control group (N = 38) received prefabricated insoles composed of a hard core with a top layer of soft 12 shore hardness microfiber. Using F-Scan®, the in-shoe plantar pressures were measured at seven ROI (hallux, metatarsal head 1, metatarsal head 2, metatarsal head 4, metatarsal head 5, lateral aspect of the mid-foot, heel) on five occasions during the study period. The plantar-pressure variables used were PP (main outcome) and PTI. The plantar patterns of load were explored, satisfaction and usage of the insoles were rated by the participants, and insole adjustments were recorded. Results: A mixed model analysis estimated lower PP values in the heel regions for the 35 EVA and 55 EVA insoles (171 ± 13 and 161 ± 13 kPa, respectively) than for the prefabricated insoles (234 ± 10 kPa) (p

Background The gait pattern varies within the population and between patient groups with different musculoskeletal diseases. It also varies over time due to various reasons. Three-dimensional gait analysis (3DGA) is frequently used to measure these changes, but the precision of this methodology may vary. Methods We primarily aimed to study the repeatability of hip motion measurements in patients with unilateral osteoarthritis (OA), patients with unilateral total hip arthroplasty (THA) and healthy controls. A secondary aim was to delineate any differences in hip motion during walking between these groups. Ten males and 10 females in each group were recruited. All patients underwent gait assessments using 3DGA recorded by 2 examiners. Data was analysed with comparison of variance and linear regression. Results The variability of the extension-flexion recordings was smallest in healthy controls (SD

This paper focuses on the concept of optimizing a multiple testing procedure (MTP) with respect to a predefined utility function. The class of Bonferroni-based closed testing procedures, which includes, for example, (weighted) Holm, fallback, gatekeeping, and recycling/graphical procedures, is used in this context. Numerical algorithms for calculating expected utility for some MTPs in this class are given. The obtained optimal procedures, as well as the gain resulting from performing an optimization are then examined in a few, but informative, examples.

The proportion of patients with clinically isolated syndrome (CIS) reported to convert to clinically definite multiple sclerosis varied between 30 and 75%. We studied the lifetime probability of remaining in the “CIS only” condition. The study was based on the longitudinally followed Gothenburg 1950–1964 incidence cohort ( n = 306). Survival analysis revealed that 17.8% of 236 attack onset patients remained “CIS only”. Patients with afferent (optic and sensory) symptoms had a better prognosis with approximately 30% of these patients remaining “CIS only”. Patients who had experienced no relapse during the first 25 years remained “CIS only” for the subsequent 25 years of follow-up.

We simultaneously examined 14 patients with OTS and dynamic radiostereometric analysis (RSA) to evaluate the accuracy of both skin- and a cluster-marker models. The mean differences between the OTS and RSA system in hip flexion, abduction, and rotation varied up to 9.5° for the skin-marker and up to 11.3° for the cluster-marker models, respectively. Both models tended to underestimate the amount of flexion and abduction, but a significant systematic difference between the marker and RSA evaluations could only be established for recordings of hip abduction using cluster markers (p = 0.04). The intra-class correlation coefficient (ICC) was 0.7 or higher during flexion for both models and during abduction using skin markers, but decreased to 0.5-0.6 when abduction motion was studied with cluster markers. During active hip rotation, the two marker models tended to deviate from the RSA recordings in different ways with poor correlations at the end of the motion (ICC ≤0.4). During active hip motions soft tissue displacements occasionally induced considerable differences when compared to skeletal motions. The best correlation between RSA recordings and the skin- and cluster-marker model was found for studies of hip flexion and abduction with the skin-marker model. Studies of hip abduction with use of cluster markers were associated with a constant underestimation of the motion. Recordings of skeletal motions with use of skin or cluster markers during hip rotation were associated with high mean errors amounting up to about 10° at certain positions. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1515-1522, 2017.

Background: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). less thanbrgreater than less thanbrgreater thanObjective: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. less thanbrgreater than less thanbrgreater thanMethods: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. less thanbrgreater than less thanbrgreater thanResults: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). less thanbrgreater than less thanbrgreater thanConclusion: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given. Funding Agencies|Swedish||Gothenburg Multiple Sclerosis Societies||Bayer Schering Pharma||Biogen Idec||Novartis||Sanofi-Aventis||BiogenIdec||Merck-Serono||Bayer-Schering||Teva||Swedish Research Council||Gothenburg Societies of the Neurologically Disabled

Many modern adaptive designs apply an analysis where p-values from different stages are weighted together to an overall hypothesis test. One merit of this combination approach is that the design can be made very flexible. However, combination tests violate the sufficiency and conditionality principles. As a consequence, combination tests may lead to absurd conclusions, such as 'proving' a positive effect while the average effect is negative. We explore the possibility of modifying the test so that such illogical conclusions are no longer possible. The dual test requires both the weighted combination test and a naïve test, ignoring the adaptations, to be statistically significant. The result is that the flexibility and type I error level control of the combination test are preserved, while the naïve test adds a safeguard against unconvincing results. The dual test is, by construction, at least as conservative as the combination test. However, many design changes will not lead to any power loss. A typical situation where the combination approach can be used is two-stage sample size reestimation (SSR). For this case, we give a complete specification of all sample size modifications for which the two tests are equally powerful. We also study the overall power loss for some suggested SSR rules. Rules based on conditional power generally lead to ignorable power loss while a decision analytic approach exhibits clear discrepancies between the two tests.

Objective : Foot deformities, neuropathy, and dysfunction in the lower extremities are known risk factors that increase plantar peak pressure (PP) and, as a result, the risk of developing foot ulcers in patients with diabetes. However, knowledge about the prevalence of these factors is still limited. The aim of the present study was to describe the prevalence of risk factors observed in patients with diabetes without foot ulcers and to explore possible connections between the risk factors and high plantar pressure. Patients and methods : Patients diagnosed with type 1 ( n= 27) or type 2 ( n= 47) diabetes (mean age 60.0±15.0 years) were included in this cross-sectional study. Assessments included the registration of foot deformities; test of gross function at the hip, knee, and ankle joints; a stratification of the risk of developing foot ulcers according to the Swedish National Diabetes Register; a walking test; and self-reported questionnaires including the SF-36 health survey. In-shoe PP was measured in seven regions of interests on the sole of the foot using F-Scan ® . An exploratory analysis of the association of risk factors with PP was performed. Results : Neuropathy was present in 28 (38%), and 39 (53%) had callosities in the heel region. Low forefoot arch was present in 57 (77%). Gait-related parameters, such as the ability to walk on the forefoot or heel, were normal in all patients. Eighty percent had normal function at the hip and ankle joints. Gait velocity was 1.2±0.2 m/s. All patients were stratified to risk group 3. Hallux valgus and hallux rigidus were associated with an increase in the PP in the medial forefoot. A higher body mass index (BMI) was found to increase the PP at metatarsal heads 4 and 5. Pes planus was associated with a decrease in PP at metatarsal head 1. Neuropathy did not have a high association with PP. Conclusions : This study identified several potential risk factors for the onset of diabetic foot ulcers (DFU). Hallux valgus and hallux rigidus appeared to increase the PP under the medial forefoot and a high BMI appeared to increase the PP under the lateral forefoot. There is a need to construct a simple, valid, and reliable assessment routine to detect potential risk factors for the onset of DFU. Keywords : diabetic foot; foot deformities; neuropathy; prevention; foot anthropometrics; plantar pressure; risk factors (Published: 17 June 2015) Citation: Diabetic Foot & Ankle 2015, 6: 27593 - http://dx.doi.org/10.3402/dfa.v6.27593

Background: Although clinical reports have suggested a relationship between systemic infections and multiple sclerosis (MS) relapses, MRI evidence supporting an association is conflicting. Here we evaluated the temporal relationship between upper respiratory infections (URIs) and MRI activity in relapsing-remitting (RR) MS. Methods: We combined individual data on URI with data on active lesions in pre-scheduled MRI examinations performed every 4 weeks for 28 weeks in 69 patients. A 4-week at-risk (AR) period started, by definition, 1 week before the onset of a URI. We recorded the relationship between the number of active lesions in each MRI with (1) the number of days of AR time in the immediately preceding 4-week period and (2) the number of days passed since the onset of a preceding URI. Results: Average MRI lesions/day showed no difference between AR (0.0764) and not-AR (0.0774) periods. The number of lesions in 483 pre-scheduled MRI examinations did not correlate with the AR proportion in the prior 4-week period (rho = -0.03), and time from URI onset did not correlate with lesion number on the next MRI examination (rho = 0.003). Conclusion: The occurrence of a URI did not increase the risk of MRI activity evaluated in an adjacent 4-week window in RRMS.

It was not such a long time ago that finding literature on multiplicity procedures was an arduous task. Despite there being several books on the subject, many of them, excellent in their own way, h...

Interest in the long-term natural history of multiple sclerosis (MS) is being revived, as disability endpoints become increasingly important with the advent of highly efficacious long range but potentially harmful drugs. MS had an increasingly benign course, probably due to better assessment and changing diagnostic criteria. Incidence cohorts reduce inclusion bias, capturing both extreme benign and severe cases. We conducted a 50-year follow-up of an incidence cohort of Gothenburg residents with MS onset in 1950-1964 (n = 254; 212 with an initial relapsing-remitting course and 42 with a monophasic course, diagnostic criteria according to Poser). Patients were followed longitudinally until censoring, death, or study termination in 2012 and evaluated using Kaplan-Meier estimates and Cox regression analysis. Median time to secondary progression was 15 years. Median time to EDSS6 and EDSS7 was 26 and 48 years (n = 254), respectively. The cumulative risk of reaching EDSS6 was 50 % at 55 years of age and 80 % at 80 years of age (n = 212). A score based on a cluster of clinical features at onset predicted secondary progression, EDSS6, EDSS7, and EDSS10 (hazard ratio 1.6-2.3 per score unit for women, 0.99-1.49 for men). This score predicted the disease course during five decades indirectly, by predicting time to secondary progression. Age at onset predicted the course in men, with 3-6 % yearly increase in the risk of reaching disability milestones. The present incidence cohort provided hard outcome data in untreated patients over several decades.

Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5–6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) =2 12.17+ (age60.11) + (BMI (kg/m2)60.23) + (D7-lathosterol (mg/100 mg cholesterol)6(20.013)) + (Platelet count (x109/L)6(2 0.018)) + (Prothrombin-INR63.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86– 0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82–0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection. publishedVersion

This paper focuses on the concept of optimizing a multiple testing procedure (MTP) with respect to a predefined utility function. The class of Bonferroni-based closed testing procedures, which includes, for example, (weighted) Holm, fallback, gatekeeping, and recycling/graphical procedures, is used in this context. Numerical algorithms for calculating expected utility for some MTPs in this class are given. The obtained optimal procedures, as well as the gain resulting from performing an optimization are then examined in a few, but informative, examples.

Many potential new medicines fail in phase III clinical trials, because of either insufficient efficacy or intolerability. Such failures may be caused by the absence of an effect and also if a suboptimal dose is being tested. It is thus important to consider how to optimise the choice of dose or doses that continue into the confirmatory phase. For many indications, it is common to test one single active dose in phase III. However, phase IIB dose-finding trials are relatively small and often lack the ability of precisely estimating the dose–response curves for efficacy and tolerability. Because of this uncertainty in dose response, it is reasonable to consider bringing more than one dose into phase III. Using simple but illustrative models, we find the optimal doses and compare the probability of success, for fixed total sample sizes, when one or two active doses are included in phase III.