Preferences about Future Alzheimer's Disease Treatments Elicited through an Online Survey Using the Threshold Technique.

BACKGROUND: Treatments aiming at slowing down the progression of Alzheimer's disease (AD) may soon become available. However, information about the risks that people are willing to accept in order to delay the progression of the disease is limited. OBJECTIVE: To determine the trade-offs that individuals are willing to make between the benefits and risks of hypothetical treatments for AD, and the extent to which these trade-offs depend on individuals' characteristics and beliefs about medicines. DESIGN: Online, cross-sectional survey study. SETTING: Population in the UK. Public link to the survey available at the websites of Alzheimer's Research UK and Join Dementia Research. PARTICIPANTS: Everyone self-reported ≥18 years old was eligible to participate. A total of 4384 people entered the survey and 3658 completed it. MEASUREMENTS: The maximum acceptable risks (MARs) of participants for moderate and severe adverse events in exchange for a 2-year delay in disease progression. The risks were expressed on ordinal scales, from <10% to ≥50%, above a pre-existing risk of 30% for moderate adverse events and 10% for severe adverse events. We obtained the population median MARs using log-normal survival models and quantified the effects of individuals' characteristics and beliefs about medicines in terms of acceleration factors. RESULTS: For the moderate adverse events, 26% of the participants had a MAR ≥50%, followed by 25% of the participants with a MAR of 10 to <20%, giving an estimated median MAR of 25.4% (95% confidence interval [CI] 24.5 to 26.3). For the severe adverse events, 43% of the participants had a MAR <10%, followed by 25% of the participants with a MAR of 10 to <20%, resulting in an estimated median MAR of 12.1% (95%CI 11.6 to 12.5). Factors that were associated with the individuals' MARs for one or both adverse events were age, gender, educational level, living alone, and beliefs about medicines. Whether or not individuals were living with memory problems or had experience as a caregiver had no effect on the MARs for any of the adverse events. CONCLUSION: Trade-offs between benefits and risks of AD treatments are heterogeneous and influenced by individuals' characteristics and beliefs about medicines. This heterogeneity should be acknowledged during the medicinal product decision-making in order to fulfil the needs of the various subpopulations.

The influence of depth of anesthesia and blood pressure on muscle recorded motor evoked potentials in spinal surgery. A prospective observational study protocol.

For high-risk spinal surgeries, intraoperative neurophysiological monitoring (IONM) is used to detect and prevent intraoperative neurological injury. The motor tracts are monitored by recording and analyzing muscle transcranial electrical stimulation motor evoked potentials (mTc-MEPs). A mTc-MEP amplitude decrease of 50-80% is the most common warning criterion for possible neurological injury. However, these warning criteria often result in false positive warnings. False positives may be caused by inadequate depth of anesthesia and blood pressure on mTc-MEP amplitudes. The aim of this paper is to validate the study protocol in which the goal is to investigate the effects of depth of anesthesia (part 1) and blood pressure (part 2) on mTc-MEPs. Per part, 25 patients will be included. In order to investigate the effects of depth of anesthesia, a processed electroencephalogram (pEEG) monitor will be used. At pEEG values of 30, 40 and 50, mTc-MEP measurements will be performed. To examine the effect of blood pressure on mTc-MEPs the mean arterial pressure will be elevated from 60 to 100 mmHg during which mTc-MEP measurements will be performed. We hypothesize that by understanding the effects of depth of anesthesia and blood pressure on mTc-MEPs, the mTc-MEP monitoring can be interpreted more reliably. This may contribute to fewer false positive warnings. By performing this study after induction and prior to incision, this protocol provides a unique opportunity to study the effects of depths of anesthesia and blood pressure on mTc-MEPs alone with as little confounders as possible. Trial registration number NL7772.

Correction to: Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

The values given for copeptin levels in men in quartiles 1 and 2 (Table 1) were incorrect, and should have read.

Individual patient information to select patients for different radiation techniques.

BACKGROUND AND PURPOSE: Proton therapy is an emerging technique in radiotherapy which results in less dose to the normal tissues with similar target dose than photon therapy, the current standard. Patient-level simulation models support better decision making on which patients would benefit most. MATERIALS AND METHODS: A simulation model was developed tracking individual patients' status regarding the primary tumour and multiple complications. As a proof of principle, the model was populated based on information from a cohort of 1013 head and neck cancer patients. Dose-volume parameters for photon and proton radiation treatment plans were then fed into the model to compare outcomes in terms of length and quality of life and select patients that would benefit most. RESULTS: The illustrative model could adequately replicate the outcomes of photon therapy in the cohort. Improvements from proton therapy varied considerably between patients. The model projects medium-term outcomes for specific individuals and determines the benefits of applying proton rather than photon therapy. CONCLUSIONS: While the model needs to be fed with more and especially recent data before being fully ready for use in clinical practice, it could already distinguish between patients with high and low potential benefits from proton therapy. Benefits are highest for patients with both good prognosis and high expected damage to adjacent organs. The model allows for selecting such patients a priori based on patient relevant outcomes.

Incorporating patient preferences into drug development and regulatory decision making: Results from a quantitative pilot study with cancer patients, carers, and regulators.

Currently, patient preference studies are not required to be included in marketing authorization applications to regulatory authorities, and the role and methodology for such studies have not been agreed upon. The European Medicines Agency (EMA) conducted a pilot study to gain experience on how the collection of individual preferences can inform the regulatory review. Using a short online questionnaire, ordinal statements regarding the desirability of different outcomes in the treatment of advanced cancer were elicited from 139 participants (98 regulators, 29 patient or carers, and 12 healthcare professionals). This was followed by face-to-face meetings to gather feedback and validate the individual responses. In this article we summarize the EMA pilot study and discuss the role of patient preference studies within the regulatory review. Based on the results, we conclude that our preference elicitation instrument was easy to implement and sufficiently precise to learn about the distribution of the participants' individual preferences.

Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women.

Former smoking is a risk factor for chronic kidney disease after lung transplantation.

Chronic kidney disease (CKD) is a common complication after lung transplantation (LTx). Smoking is a risk factor for many diseases, including CKD. Smoking cessation for >6 months is required for LTx enlistment. However, the impact of smoking history on CKD development after LTx remains unclear. We investigated the effect of former smoking on CKD and mortality after LTx. CKD was based on glomerular filtration rate (GFR) ((125) I-iothalamate measurements). GFR was measured before and repeatedly after LTx. One hundred thirty-four patients never smoked and 192 patients previously smoked for a median of 17.5 pack years. At 5 years after LTx, overall cumulative incidences of CKD-III, CKD-IV and death were 68.5%, 16.3% and 34.6%, respectively. Compared to never smokers, former smokers had a higher risk for CKD-III (hazard ratio [HR] 95% confidence interval [95%CI]= 1.69 [1.27-2.24]) and IV (HR = 1.90 [1.11-3.27]), but not for mortality (HR = 0.99 [0.71-1.38]). Adjustment for potential confounders did not change results. Thus, despite cessation, smoking history remained a risk factor for CKD in LTx recipients. Considering the increasing acceptance for LTx of older recipients with lower baseline renal function and an extensive smoking history, our data suggest that the problem of post-LTx CKD may increase in the future.

A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus.

AIMS/HYPOTHESIS: Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). METHODS: In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥ 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria < 30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation. RESULTS: The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03). CONCLUSIONS/INTERPRETATION: CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.