Duration of and time to response in oncology clinical trials from the perspective of the estimand framework.

Duration of response (DOR) and time to response (TTR) are typically evaluated as secondary endpoints in early-stage clinical studies in oncology when efficacy is assessed by the best overall response and presented as the overall response rate. Despite common use of DOR and TTR in particular in single-arm studies, the definition of these endpoints and the questions they are intended to answer remain unclear. Motivated by the estimand framework, we present relevant scientific questions of interest for DOR and TTR and propose corresponding estimand definitions. We elaborate on how to deal with relevant intercurrent events which should follow the same considerations as implemented for the primary response estimand. A case study in mantle cell lymphoma illustrates the implementation of relevant estimands of DOR and TTR. We close the paper with practical recommendations to implement DOR and TTR in clinical study protocols.

Modelling the population effectiveness of the national seasonal influenza vaccination programme in Scotland: The impact of targeting all individuals aged 65 years and over.

BACKGROUND: For the last 17 years, the UK has employed a routine influenza vaccination programme with the aim of reducing the spread of seasonal influenza. In mid-2000, the programme moved from a purely risk-based approach to a risk and age group-targeted approach with all those aged 65+ years being included. To date, there has been no assessment of the population effectiveness of this age-targeted policy in Scotland. OBJECTIVES: Statistical modelling techniques were used to determine what impact the routine vaccination of those aged 65+ years has had on influenza-related morbidity and mortality in Scotland. METHODS: Two Poisson regression models were developed using weekly counts of all-cause mortality, cause-specific mortality and emergency hospitalisations for the period 1981-2012, one using week-in-year and the other using temperature to capture the seasonal variability in mortality/hospitalisations. These models were used to determine the number of excess deaths/hospitalisations associated with the introduction of the local risk and age-based vaccination programme in 2000. RESULTS: Routinely vaccinating those aged 65+ years is associated with a reduction in excess all-cause mortality, cardiovascular and COPD-related mortality and COPD-related hospitalisations. Our analysis suggests that using the week-in-year model, on average, 732 (95% CI 66-1398) deaths from all causes, 248 (95% CI 10-486) cardiovascular-related deaths, 123 (95% CI 28-218) COPD-related deaths and 425 (95% CI 258-592) COPD-related hospitalisations have been prevented each flu season among the those aged 65+. Similar results were found using the temperature model. There was no evidence to suggest that the change in policy was associated with reductions in influenza/pneumonia-related mortality or influenza/cardiovascular-related hospitalisations. CONCLUSIONS: Routinely vaccinating those aged 65+ years appears to have reduced influenza-related morbidity and mortality in Scotland. With the childhood vaccination programme well underway, these data provide an importance benchmark which can be used to accurately assess the impact of this new seasonal influenza vaccination programme.

What does it take to stress a word? Digital manipulation of stress markers in ataxic dysarthria.

BACKGROUND: Stress production is important for effective communication, but this skill is frequently impaired in people with motor speech disorders. The literature reports successful treatment of these deficits in this population, thus highlighting the therapeutic potential of this area. However, no specific guidance is currently available to clinicians about whether any of the stress markers are more effective than others, to what degree they have to be manipulated, and whether strategies need to differ according to the underlying symptoms. AIMS: In order to provide detailed information on how stress production problems can be addressed, the study investigated (1) the minimum amount of change in a single stress marker necessary to achieve significant improvement in stress target identification; and (2) whether stress can be signalled more effectively with a combination of stress markers. METHODS & PROCEDURES: Data were sourced from a sentence stress task performed by 10 speakers with ataxic dysarthria and 10 healthy matched control participants. Fifteen utterances perceived as having incorrect stress patterns (no stress, all words stressed or inappropriate word stressed) were selected and digitally manipulated in a stepwise fashion based on typical speaker performance. Manipulations were performed on F0, intensity and duration, either in isolation or in combination with each other. In addition, pitch contours were modified for some utterances. A total of 50 naïve listeners scored which word they perceived as being stressed. OUTCOMES & RESULTS: Results showed that increases in duration and intensity at levels smaller than produced by the control participants resulted in significant improvements in listener accuracy. The effectiveness of F0 increases depended on the underlying error pattern. Overall intensity showed the most stable effects. Modifications of the pitch contour also resulted in significant improvements, but not to the same degree as amplification. Integration of two or more stress markers did not result in better results than manipulation of individual stress markers, unless they were combined with pitch contour modifications. CONCLUSIONS & IMPLICATIONS: The results highlight the potential for improvement of stress production in speakers with motor speech disorders. The fact that individual parameter manipulation is as effective as combining them will facilitate the therapeutic process considerably, as will the result that amplification at lower levels than seen in typical speakers is sufficient. The difference in results across utterance sets highlights the need to investigate the underlying error pattern in order to select the most effective compensatory strategy for clients.

Targeted hepatitis C antibody testing interventions: a systematic review and meta-analysis.

Testing for hepatitis C virus (HCV) infection may reduce the risk of liver-related morbidity, by facilitating earlier access to treatment and care. This review investigated the effectiveness of targeted testing interventions on HCV case detection, treatment uptake, and prevention of liver-related morbidity. A literature search identified studies published up to 2013 that compared a targeted HCV testing intervention (targeting individuals or groups at increased risk of HCV) with no targeted intervention, and results were synthesised using meta-analysis. Exposure to a targeted testing intervention, compared to no targeted intervention, was associated with increased cases detected [number of studies (n) = 14; pooled relative risk (RR) 1.7, 95% CI 1.3, 2.2] and patients commencing therapy (n = 4; RR 3.3, 95% CI 1.1, 10.0). Practitioner-based interventions increased test uptake and cases detected (n = 12; RR 3.5, 95% CI 2.5, 4.8; and n = 10; RR 2.2, 95% CI 1.4, 3.5, respectively), whereas media/information-based interventions were less effective (n = 4; RR 1.5, 95% CI 0.7, 3.0; and n = 4; RR 1.3, 95% CI 1.0, 1.6, respectively). This meta-analysis provides for the first time a quantitative assessment of targeted HCV testing interventions, demonstrating that these strategies were effective in diagnosing cases and increasing treatment uptake. Strategies involving practitioner-based interventions yielded the most favourable outcomes. It is recommended that testing should be targeted at and offered to individuals who are part of a population with high HCV prevalence, or who have a history of HCV risk behaviour.

Treatment of hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis.

BACKGROUND: Although guidelines recommend that people who inject drugs (PWID) should not be excluded from hepatitis C (HCV) treatment, some services remain reluctant to treat PWID. The aim of this review was to investigate sustained virologic response (SVR), adherence, discontinuation, and HCV reinfection among PWID. METHODS: A search of Medline, Embase, and Cochrane databases (between 2002 and January 2012) was conducted for primary articles/conference abstracts examining HCV treatment outcomes in PWID. Meta-analysis was used to obtain pooled estimates of SVR, adherence, discontinuation, and HCV reinfection. RESULTS: Ten primary articles and 1 conference abstract met the inclusion criteria. Across 6 studies (comprising 314 drug users, of whom 141 [45%] were PWID), pooled SVR was 56% (95% confidence interval [CI], 50%-61%) for all genotypes, 37% (95% CI, 26%-48%) for genotypes 1/4, and 67% (95% CI, 56%-78%) for genotypes 2/3. Pooled 80/80/80 adherence was 82% (95% CI, 74%-89%) across 2 studies, and pooled treatment discontinuation was 22% (95% CI, 16%-27%) across 4 studies. Across 5 studies (comprising 131 drug users) examining reinfection, pooled risk was 2.4 (95% CI, .9-6.1) per 100 person-years. CONCLUSIONS: HCV treatment outcomes are acceptable in PWID, supporting treatment guidelines. The pooled estimate of HCV reinfection risk was low, but there was considerable uncertainty around this estimate. Further studies on the risk of reinfection are needed to assess the long-term effectiveness of HCV treatment in PWID.

Modelling the prevalence of HCV amongst people who inject drugs: an investigation into the risks associated with injecting paraphernalia sharing.

BACKGROUND: In order to prevent the spread of the hepatitis C virus (HCV) amongst people who inject drugs (PWID), it is imperative that any injecting risk behaviour which may contribute to the transmission of disease has its role quantified. To inform public health organisations, mathematical modelling techniques were used to explore the risk of HCV infection through the sharing of injecting paraphernalia (including filters, cookers and water). METHODS: A mathematical model was developed for the spread of HCV based on the injecting behaviour of PWID in Scotland, with transmission occurring through the sharing of needles/syringes and other injecting paraphernalia. Numerical simulations were used to estimate the transmission probability for HCV through the sharing of injecting paraphernalia such that the modelled endemic HCV prevalence fitted with that observed amongst PWID in Scotland. RESULTS: The transmission probability of HCV through injecting paraphernalia was modelled to be over 8 times lower than that through needles/syringes (approximately 0.19-0.30% and 2.5%, respectively), assuming transmission occurs through a combination of at least filters and cookers. In the context of reported needle/syringe and paraphernalia sharing rates in Scotland, it is estimated that 38% and 62% of HCV infections are contributed by these practices, respectively. If needle/syringe sharing rates were to be twice those reported, the contributions would be 70% and 30%, respectively. CONCLUSION: Given that the sharing of injecting paraphernalia among PWID is common, HCV transmission through this route could be contributing to the growing healthcare burden associated with this chronic disease. Every effort should therefore be made to establish (a) the contribution that paraphernalia sharing is making to the spread of HCV, and (b) the effectiveness of services providing sterile paraphernalia in preventing infection.

Risk of Hepatitis C virus re-infection following spontaneous viral clearance in injecting drug users: a systematic review.

BACKGROUND: In order to develop new ways to prevent Hepatitis C virus (HCV) transmission amongst injecting drug users (IDUs), it is necessary to fully understand the dynamics of this disease. We reviewed the evidence on three key areas of HCV transmission in this population: the rate of acute HCV infection amongst IDUs who have spontaneously resolved a previous infection, the rate of chronic HCV infection amongst IDUs who have spontaneously resolved a previous infection, and the ability of IDUs to be re-infected with either the same or a different HCV genotype. METHODS: A literature search of PUBMED (January 1950 to January 2009), EMBASE (January 1980 to January 2009) and PsycINFO (January 1967 to January 2009) for English language, primary research papers was undertaken to identify longitudinal studies examining HCV re-infection following spontaneous viral clearance amongst IDUs. RESULTS: The systematic review identified three studies that satisfied the inclusion and exclusion criteria. Regarding the risk of acute HCV infection amongst IDUs, the findings from the three studies were conflicting and thus provided no compelling evidence in support of an increased or decreased risk of acute infection amongst IDUs who have spontaneously resolved compared to those previously uninfected. Limited evidence was found from two studies to support a reduced risk of subsequent chronic HCV infection in those who have previously spontaneously resolved an infection. Further, two studies found IDUs who spontaneously resolved an infection can be re-infected (with comparable proportions) with either the same or a different HCV genotype. CONCLUSION: The limited, and sometimes contradictory, evidence published in the worldwide literature highlights the need for more longitudinal studies of IDUs to fully understand the dynamics of the disease in this population.

The Hydro ThermAblator.

The Hydro ThermAblator system is a unique approach to endometrial ablation, employing constant direct visual control via hysteroscopy combined with a 'no-touch' gravity flow of heated saline that treats the entire endometrial surface regardless of its topography. The automated controller helps to ensure reproducible results without the necessity for high operator skill. The system employs a safety feature that monitors the fluid level constantly within a closed system, so that loss of fluid through unsuspected uterine perforation occurring during dilatation can be diagnosed even though it may not be visually apparent to the operator. Results as judged by patient satisfaction, amenorrhoea rates and/or return to normal menstrual flow are excellent.