Effectiveness of an intervention to reduce sedentary behaviour as a personalised secondary prevention strategy for patients with coronary artery disease: main outcomes of the SIT LESS randomised clinical trial.

BACKGROUND: A high sedentary time is associated with increased mortality risk. Previous studies indicate that replacement of sedentary time with light- and moderate-to-vigorous physical activity attenuates the risk for adverse outcomes and improves cardiovascular risk factors. Patients with cardiovascular disease are more sedentary compared to the general population, while daily time spent sedentary remains high following contemporary cardiac rehabilitation programmes. This clinical trial investigated the effectiveness of a sedentary behaviour intervention as a personalised secondary prevention strategy (SIT LESS) on changes in sedentary time among patients with coronary artery disease participating in cardiac rehabilitation. METHODS: Patients were randomised to usual care (n = 104) or SIT LESS (n = 108). Both groups received a comprehensive 12-week centre-based cardiac rehabilitation programme with face-to-face consultations and supervised exercise sessions, whereas SIT LESS participants additionally received a 12-week, nurse-delivered, hybrid behaviour change intervention in combination with a pocket-worn activity tracker connected to a smartphone application to continuously monitor sedentary time. Primary outcome was the change in device-based sedentary time between pre- to post-rehabilitation. Changes in sedentary time characteristics (prevalence of prolonged sedentary bouts and proportion of patients with sedentary time ≥ 9.5 h/day); time spent in light-intensity and moderate-to-vigorous physical activity; step count; quality of life; competencies for self-management; and cardiovascular risk score were assessed as secondary outcomes. RESULTS: Patients (77% male) were 63 ± 10 years and primarily diagnosed with myocardial infarction (78%). Sedentary time decreased in SIT LESS (- 1.6 [- 2.1 to - 1.1] hours/day) and controls (- 1.2 [ ─1.7 to - 0.8]), but between group differences did not reach statistical significance (─0.4 [─1.0 to 0.3]) hours/day). The post-rehabilitation proportion of patients with a sedentary time above the upper limit of normal (≥ 9.5 h/day) was significantly lower in SIT LESS versus controls (48% versus 72%, baseline-adjusted odds-ratio 0.4 (0.2-0.8)). No differences were observed in the other predefined secondary outcomes. CONCLUSIONS: Among patients with coronary artery disease participating in cardiac rehabilitation, SIT LESS did not induce significantly greater reductions in sedentary time compared to controls, but delivery was feasible and a reduced odds of a sedentary time ≥ 9.5 h/day was observed. TRIAL REGISTRATION: Netherlands Trial Register: NL9263. Outcomes of the SIT LESS trial: changes in device-based sedentary time from pre-to post-cardiac rehabilitation (control group) and cardiac rehabilitation + SIT LESS (intervention group). SIT LESS reduced the odds of patients having a sedentary time >9.5 hours/day (upper limit of normal), although the absolute decrease in sedentary time did not significantly differ from controls. SIT LESS appears to be feasible, acceptable and potentially beneficial, but a larger cluster randomised trial is warranted to provide a more accurate estimate of its effects on sedentary time and clinical outcomes. CR: cardiac rehabilitation.

Sedentary Behaviour Intervention as a Personalised Secondary Prevention Strategy (SIT LESS) for patients with coronary artery disease participating in cardiac rehabilitation: rationale and design of the SIT LESS randomised clinical trial.

Patients with coronary artery disease (CAD) are more sedentary compared with the general population, but contemporary cardiac rehabilitation (CR) programmes do not specifically target sedentary behaviour (SB). We developed a 12-week, hybrid (centre-based+home-based) Sedentary behaviour IntervenTion as a personaLisEd Secondary prevention Strategy (SIT LESS). The SIT LESS programme is tailored to the needs of patients with CAD, using evidence-based behavioural change methods and an activity tracker connected to an online dashboard to enable self-monitoring and remote coaching. Following the intervention mapping principles, we first identified determinants of SB from literature to adapt theory-based methods and practical applications to target SB and then evaluated the intervention in advisory board meetings with patients and nurse specialists. This resulted in four core components of SIT LESS: (1) patient education, (2) goal setting, (3) motivational interviewing with coping planning, and (4) (tele)monitoring using a pocket-worn activity tracker connected to a smartphone application and providing vibrotactile feedback after prolonged sedentary bouts. We hypothesise that adding SIT LESS to contemporary CR will reduce SB in patients with CAD to a greater extent compared with usual care. Therefore, 212 patients with CAD will be recruited from two Dutch hospitals and randomised to CR (control) or CR+SIT LESS (intervention). Patients will be assessed prior to, immediately after and 3 months after CR. The primary comparison relates to the pre-CR versus post-CR difference in SB (objectively assessed in min/day) between the control and intervention groups. Secondary outcomes include between-group differences in SB characteristics (eg, number of sedentary bouts); change in SB 3 months after CR; changes in light-intensity and moderate-to-vigorous-intensity physical activity; quality of life; and patients' competencies for self-management. Outcomes of the SIT LESS randomised clinical trial will provide novel insight into the effectiveness of a structured, hybrid and personalised behaviour change intervention to attenuate SB in patients with CAD participating in CR. Trial registration number NL9263.

PrEP Use, Sexual Behaviour, and PrEP Adherence Among Men who have Sex with Men Living in Wales Prior to and During the COVID-19 Pandemic.

We examined PrEP use, condomless anal sex (CAS), and PrEP adherence among men who have sex with men (MSM) attending sexual health clinics in Wales, UK. In addition, we explored the association between the introduction of measures to control transmission of SARS-CoV-2 on these outcomes. We conducted an ecological momentary assessment study of individuals in receipt of PrEP in Wales. Participants used an electronic medication cap to record PrEP use and completed weekly sexual behaviour surveys. We defined adherence to daily PrEP as the percentage of CAS episodes covered by daily PrEP (preceded by ≥ 3 days of PrEP and followed by ≥ 2 days). Sixty participants were recruited between September 2019 and January 2020. PrEP use data prior to the introduction of control measures were available over 5785 person-days (88%) and following their introduction 7537 person-days (80%). Data on CAS episodes were available for 5559 (85%) and 7354 (78%) person-days prior to and following control measures respectively. Prior to the introduction of control measures, PrEP was taken on 3791/5785 (66%) days, there were CAS episodes on 506/5559 (9%) days, and 207/406 (51%) of CAS episodes were covered by an adequate amount of daily PrEP. The introduction of pandemic-related control measures was associated with a reduction in PrEP use (OR 0.44, 95%CI 0.20-0.95), CAS (OR 0.35, 95%CI 0.17-0.69), and PrEP adherence (RR = 0.55, 95%CI 0.34-0.89) and this may have implications for the health and wellbeing of PrEP users and, in addition to disruption across sexual health services, may contribute to wider threats across the HIV prevention cascade.

Adherence to Direct Oral Anticoagulants in Patients With Non-Valvular Atrial Fibrillation: A Cross-National Comparison in Six European Countries (2008-2015).

Aims: To describe and compare the adherence to different direct oral anticoagulants (DOACs) in eight European databases representing six countries. Methods: Longitudinal drug utilization study of new users (≥18 years) of DOACs (dabigatran, rivaroxaban, apixaban) with a diagnosis of non-valvular atrial fibrillation (2008-2015). Adherence was examined by estimating persistence, switching, and discontinuation rates at 12 months. Primary non-adherence was estimated in BIFAP and SIDIAP databases. Results: The highest persistence rate was seen for apixaban in the CPRD database (81%) and the lowest for dabigatran in the Mondriaan database (22%). The switching rate for all DOACs ranged from 2.4 to 13.1% (Mondriaan and EGB databases, respectively). Dabigatran had the highest switching rate from 5.0 to 20.0% (Mondriaan and EGB databases, respectively). The discontinuation rate for all DOACs ranged from 16.0 to 63.9% (CPRD and Bavarian CD databases, respectively). Dabigatran had the highest rate of discontinuers, except in the Bavarian CD and AOK NORDWEST databases, ranging from 23.2 to 64.6% (CPRD and Mondriaan databases, respectively). Combined primary non-adherence for examined DOACs was 11.1% in BIFAP and 14.0% in SIDIAP. There were differences in population coverage and in the type of drug data source among the databases. Conclusion: Despite the differences in the characteristics of the databases and in demographic and baseline characteristics of the included population that could explain some of the observed discrepancies, we can observe a similar pattern throughout the databases. Apixaban was the DOAC with the highest persistence. Dabigatran had the highest proportion of discontinuers and switchers at 12 months in most databases (EMA/2015/27/PH).

Cost-effectiveness of bariatric surgery and non-surgical weight management programmes for adults with severe obesity: a decision analysis model.

OBJECTIVES: To determine the most cost-effective weight management programmes (WMPs) for adults, in England with severe obesity (BMI ≥ 35 kg/m2), who are more at risk of obesity related diseases. METHODS: An economic evaluation of five different WMPs: 1) low intensity (WMP1); 2) very low calorie diets (VLCD) added to WMP1; 3) moderate intensity (WMP2); 4) high intensity (Look AHEAD); and 5) Roux-en-Y gastric bypass (RYGB) surgery, all compared to a baseline scenario representing no WMP. We also compare a VLCD added to WMP1 vs. WMP1 alone. A microsimulation decision analysis model was used to extrapolate the impact of changes in BMI, obtained from a systematic review and meta-analysis of randomised controlled trials (RCTs) of WMPs and bariatric surgery, on long-term risks of obesity related disease, costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) measured as incremental cost per QALY gained over a 30-year time horizon from a UK National Health Service (NHS) perspective. Sensitivity analyses explored the impact of long-term weight regain assumptions on results. RESULTS: RYGB was the most costly intervention but also generated the lowest incidence of obesity related disease and hence the highest QALY gains. Base case ICERs for WMP1, a VLCD added to WMP1, WMP2, Look AHEAD, and RYGB compared to no WMP were £557, £6628, £1540, £23,725 and £10,126 per QALY gained respectively. Adding a VLCD to WMP1 generated an ICER of over £121,000 per QALY compared to WMP1 alone. Sensitivity analysis found that all ICERs were sensitive to the modelled base case, five year post intervention cessation, weight regain assumption. CONCLUSIONS: RYGB surgery was the most effective and cost-effective use of scarce NHS funding resources. However, where fixed healthcare budgets or patient preferences exclude surgery as an option, a standard 12 week behavioural WMP (WMP1) was the next most cost-effective intervention.

The relationship between core stability and athletic performance in female university athletes.

Background: Questions remain as to whether core stability represents single or multiple components, how to assess core stability, and if a relationship exists with athletic performance in different sporting codes. Objectives: To investigate the relationship between core stability and athletic performance in female university athletes. Methods: Eighty-three female athletes (hockey, netball, running, soccer and tennis) participated in this quantitative, cross-sectional study. The isometric back extension (IBE), lateral flexion (LF) and abdominal flexion (AF) tests were used to measure core strength and endurance. The core stability grading system using a pressure biofeedback unit was applied to measure core neuromuscular control (NMC). Athletic performance was assessed using the 40 m sprint, T-test, vertical jump (VJ) and the medicine ball chest throw (MBCT). Correlations between the core stability tests and the athletic performance tests were determined overall and separately by sport. The effect of core stability on athletic performance was analysed using ANCOVA. Results: Overall for all sports, most correlations were weak (r=0.10-0.39), although there was a very strong correlation between LF (strength) and VJ (r=0.90). When the sports were considered separately, there were moderate correlations (r=0.40-0.69) between core strength, endurance and motor control with certain athletic performance tests in all five sport codes. In runners, strong correlations (r=0.70-0.89) were observed between AF (endurance) and VJ, and in tennis players between IBE (strength) and the sprint. Conclusion: Correlations were found between core stability and athletic performance, although most correlations were negligible or weak. Athletic performance in different sport codes is associated with different components of core stability.

A systematic review of UK-based long-term nonsurgical interventions for people with severe obesity (BMI ≥35 kg m-2 ).

INTRODUCTION: The aim of this project was to systematically review UK evidence on the effectiveness of long-term (≥12 months) weight management services (WMSs) for weight loss and weight maintenance for adults (≥16 years) with severe obesity (body mass index ≥35 kg m-2 ), who would generally be eligible for Tier 3 services. METHODS: Four data sources were searched from 1999 to October 2018. RESULTS: Our searches identified 20 studies, mostly noncomparative studies: 10 primary care interventions, nine in secondary care specialist weight management clinics and one commercial setting intervention. A programme including a phase of low energy formula diet (810-833 kcal day-1 ) showed the largest mean (SD) weight change at 12 months of -12.4 (11.4) kg for complete cases, with 25.3% dropout. Limitations or differences in evaluation and reporting (particularly for denominators), unclear dropout rates, and differences between participant groups in terms of comorbidities and psychological characteristics, made comparisons between WMSs and inferences challenging. CONCLUSIONS: There is a persistent and clear need for guidance on long-term weight data collection and reporting methods to allow comparisons across studies and services for participants with severe obesity. Data could also include quality of life, clinical outcomes, adverse events, costs and economic outcomes. A randomised trial comparison of National Health Service Tier 3 services with commercial WMSs would be of value.

Do pharmacy intervention reports adequately describe their interventions? A template for intervention description and replication analysis of reports included in a systematic review.

INTRODUCTION: Scientific progress and translation of evidence into practice is impeded by poorly described interventions. The Template for Intervention Description and Replication (TIDieR) was developed to specify the minimal intervention elements that should be reported. OBJECTIVES: (1) To assess the extent to which outpatient pharmacy interventions were adequately reported. (2) To examine the dimension(s) across which reporting quality varies. (3) To examine trial characteristics that predict better reporting. METHODS: The sample comprised 86 randomised controlled trials identified in a Cochrane review of the effectiveness of pharmacist interventions on patient health outcomes. Duplicate, independent application of a modified 15-item TIDieR checklist was undertaken to assess the intervention reporting. The reporting/non-reporting of TIDieR items was analysed with principal component analysis to evaluate the dimensionality of reporting quality and regression analyses to assess predictors of reporting quality RESULTS: In total, 422 (40%) TIDieR items were fully reported, 395 (38%) were partially reported and 231 (22%) were not reported. A further 242 items were deemed not applicable to the specific trials. Reporting quality loaded on one component which accounted for 26% of the variance in TIDieR scores. More recent trials reported a slightly greater number of TIDieR items (0.07 (95% CI 0.02 to 0.13) additional TIDieR items per year of publication). Trials reported an 0.09 (95% CI 0.04 to 0.14) additional TIDieR items per unit increase in impact factor (IF) of the journal in which the main report was published. CONCLUSIONS: Most trials lacked adequate intervention reporting. This diminished the applied and scientific value of their research. The standard of intervention reporting is, however, gradually increasing and appears somewhat better in journals with higher IFs. The use of the TIDieR checklist to improve reporting could enhance the utility and replicability of trials, and reduce research waste.

Acceptability and feasibility of weight management programmes for adults with severe obesity: a qualitative systematic review.

OBJECTIVES: To improve our understanding of the acceptability of behavioural weight management programmes (WMPs) for adults with severe obesity. DESIGN: A systematic review of qualitative evidence. DATA SOURCES: Medline, Embase, PsycINFO, CINAHL, SCI, SSCI and CAB abstracts were searched from 1964 to May 2017. ELIGIBILITY CRITERIA: Papers that contained qualitative data from adults with body mass index (BMI) ≥35 kg/m2 (and/or the views of providers involved in their care) and considered issues about weight management. DATA EXTRACTION AND SYNTHESIS: Two reviewers read and systematically extracted data from the included papers which were compared, and contrasted according to emerging issues and themes. Papers were appraised for methodological rigour and theoretical relevance using Toye's proposed criteria for quality in relation to meta-ethnography. RESULTS: 33 papers met our inclusion criteria from seven countries published 2007-2017. Findings were presented from a total of 644 participants and 153 programme providers. Participants described being attracted to programmes that were perceived to be novel or exciting, as well as being endorsed by their healthcare provider. The sense of belonging to a group who shared similar issues, and who had similar physiques and personalities, was particularly important and seemed to foster a strong group identity and related accountability. Group-based activities were enjoyed by many and participants preferred WMPs with more intensive support. However, some described struggling with physical activities (due to a range of physical comorbidities) and not everyone enjoyed group interaction with others (sometimes due to various mental health comorbidities). Although the mean BMI reported across the papers ranged from 36.8 to 44.7 kg/m2, no quotes from participants in any of the included papers were linked to specific detail regarding BMI status. CONCLUSIONS: Although group-based interventions were favoured, people with severe obesity might be especially vulnerable to physical and mental comorbidities which could inhibit engagement with certain intervention components.

The EU regulatory landscape of non-biological complex drugs (NBCDs) follow-on products: Observations and recommendations.

"Non-biological complex drugs" (NBCDs), such as liposomal formulations, iron-carbohydrate complexes and glatiramoids, gained increased interest from a regulatory perspective in recent years. Similar to biologics, the quality of NBCD products is highly dependent on a robust and well-controlled manufacturing process. This provides challenges for generic drug developers to replicate NBCD products once market exclusivity of the originator product is expired. However, unlike biologics for which a consistent regulatory framework was established with the biosimilars pathway, NBCDs are not recognised as a distinct category of medicines and hence no formal regulatory pathway for their approval is defined. Currently, a "case-by-case" approach is applied for regulating NBCD follow-on products in the EU. Furthermore, NBCDs can follow a non-centralised authorisation procedure, leaving regulatory approvals to national competent authorities. This can lead to heterogeneity in the regulatory approach and outcomes when assessing NBCD follow-on products throughout the EU, which for some product classes has already resulted in some safety and efficacy implications. Here, we explore the regulatory landscape of NBCDs and their follow on products. This study shows that almost all of the 85 NBCD follow-on products available in the EU in 2018 have been approved via various non-centralised procedures. Although most NBCD follow-on products followed an Article 10(1) procedure, we clearly see a recent increase of the use of the hybrid pathway via Article 10(3). This study shows the heterogeneity in the regulatory approach taken for many NBCD follow on products. To what extent this may have consequences for their safety and efficacy evaluations is unknown and needs to be further investigated. The present study should stimulate the rethinking to design prudent regulatory pathways for NBCD follow-on products.

Beliefs about back pain and pain management behaviours, and their associations in the general population: A systematic review.

Previous mass media campaigns have aimed to influence how people manage back pain, with mixed success. Campaigns should target beliefs which are related to the behaviours they aim to change. This systematic review brings together research that has measured the prevalence of beliefs about back pain in the general population and factors associated with these beliefs, including future pain-related outcomes. Five databases were searched up until April 2017. Quantitative studies which reported a measure of agreement with a belief about back pain, cross-sectional associations, or associations between beliefs and future outcomes were eligible. Eligibility was assessed and data extracted independently by two authors. Results were tabulated and narratively synthesized. Nineteen studies from 10 countries were eligible (median study n [IQR] = 990.5 [524.75-2387.5]). Beliefs were measured using eight questionnaires and 57 stand-alone items. Beliefs about back pain's negative consequences were common across countries and populations, whereas most samples did not hold fear-avoidance beliefs. Beliefs about back pain's consequences were associated with pain and disability, but only one study investigated this specific relationship prospectively. No studies investigated whether beliefs are associated with future pain management behaviours. Agreement with certain beliefs (e.g. about negative consequences) was associated with sociodemographic characteristics (e.g. older age) and poorer self-rated health. Interventions may benefit from targeting beliefs about the perceived negative consequences of back pain in these populations. However, future research should explore how beliefs prospectively influence the management of back pain. SIGNIFICANCE: This review brings together studies which have assessed the prevalence of beliefs about back pain, and factors associated with holding them. It highlights that whether or not these beliefs represent important determinants of how people manage pain remains unknown.

A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects.

177Lu has sprung as a promising radionuclide for targeted therapy. The low soft tissue penetration of its ß- emission results in very efficient energy deposition in small-size tumours. Because of this, 177Lu is used in the treatment of neuroendocrine tumours and is also clinically approved for prostate cancer therapy. In this work, we report a separation method that achieves the challenging separation of the physically and chemically identical nuclear isomers, 177mLu and 177Lu. The separation method combines the nuclear after-effects of the nuclear decay, the use of a very stable chemical complex and a chromatographic separation. Based on this separation concept, a new type of radionuclide generator has been devised, in which the parent and the daughter radionuclides are the same elements. The 177mLu/177Lu radionuclide generator provides a new production route for the therapeutic radionuclide 177Lu and can bring significant growth in the research and development of 177Lu based pharmaceuticals.

Environmental interventions for altering eating behaviours of employees in the workplace: a systematic review.

Environmental, or 'choice-architecture', interventions aim to change behaviour by changing properties/contents of the environment and are commonly used in the workplace to promote healthy behaviours in employees. The present review aimed to evaluate and synthesize the evidence surrounding the effectiveness of environmental interventions targeting eating behaviour in the workplace. A systematic search identified 8157 articles, of which 22 were included in the current review. All included studies were coded according to risk of bias and reporting quality and were classified according to the emergent typology of choice-architecture interventions. More than half of included studies (13/22) reported significant changes in primary measures of eating behaviour (increased fruit/veg consumption, increased sales of healthy options and reduction in calories purchased). However, only one study produced a small significant improvement in weight/body mass index. Many studies had a high or unknown risk of bias; reporting of interventions was suboptimal; and the only trial to measure compensatory behaviours found that intervention participants who ate less during the intervention ate more out with the workplace later in the day. Hence, we conclude that more rigorous, well-reported studies that account for compensatory behaviours are needed to fully understand the impact of environmental interventions on diet and importantly on weight/body mass index outcomes.

Detoxification in medication-overuse headache, a retrospective controlled follow-up study: Does care by a headache nurse lead to cure?

AIM: J.A.P. and M.A.L. contributed equally to this manuscript.The aim of this article is to determine whether support by a headache nurse in the treatment of medication-overuse headache (MOH) increases successful withdrawal, and to study determinants of response to withdrawal therapy. METHODS: A retrospective, controlled follow-up study was performed with 416 MOH patients. All patients were treated with outpatient withdrawal therapy, with two treatment arms: with or without the support of a specialised headache nurse. The outcome measures were: i) successful withdrawal, defined as discontinuation of all headache medication according to the study protocol; and ii) the responder rate, defined as the percentage of patients with ≥ 50% reduction in headache days after successful withdrawal and iii) relative reduction in headache days after successful withdrawal. RESULTS: Successful withdrawal percentages were significantly higher in the group supported by the headache nurse than in the group without support (73.1% vs. 60.7%; p = 0.008), which was confirmed in multivariate analysis (OR 1.73, 95% CI 1.11-2.71, p = 0.016). Support by a headache nurse was not associated with response. The underlying primary headache diagnosis, determined after withdrawal, was significantly correlated with response. CONCLUSION: The support by a headache nurse results in an increased adherence to detoxification.

Use of incretin agents and risk of pancreatic cancer: a population-based cohort study.

AIM: To investigate the association between the use of incretin agents and the risk of pancreatic cancer. METHODS: A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink, 2007-2012, was conducted. Patients (n = 182 428) with at least one non-insulin antidiabetic drug (NIAD) prescription and aged ≥18 years during data collection, were matched one-to-one to control patients without diabetes. Multivariable Cox proportional hazards models and a new user design were used to estimate the hazard ratio (HR) of pancreatic cancer in incretin users (n = 28 370) compared with control subjects without diabetes and other NIAD-treated patients. Time-dependent adjustments were made for age, sex, lifestyle, comorbidities and drug use. RESULTS: The mean duration of follow-up was 4.1 years for incretin users. Current NIAD use was associated with a fourfold increased risk of pancreatic cancer [HR 4.28, 95% confidence interval (CI) 3.49-5.24]. This risk was almost doubled among current incretin users as compared with control subjects. Incretin use was not associated with pancreatic cancer when compared with control subjects with diabetes (HR 1.36, 95% CI 0.94-1.96); however, the 'new user' design did show an association between incretin use and pancreatic cancer when compared with control subjects with diabetes. In both cohorts with prevalent and incident users of antidiabetic drugs, the risk of pancreatic cancer almost doubled in those who had recently initiated incretin therapy (up to seven prescriptions), whereas this elevated risk dropped to baseline levels with prolonged use. CONCLUSIONS: We found that incretin use was not associated with pancreatic cancer after adjustment for the severity of the underlying Type 2 Diabetes Mellitus (T2DM). The elevated risk of pancreatic cancer in those recently initiating incretin agents is likely to be caused by protopathic bias or other types of unknown distortion. The presence of considerable confounding by disease severity and the lack of a duration-of-use relationship do not support a causal explanation for the association between incretin agents and pancreatic cancer.

Drug-induced progressive multifocal leukoencephalopathy: Lessons learned from contrasting natalizumab and rituximab.

Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were received sooner after occurrence. This study serves as an important reminder that spontaneous reports should only be used with great caution to quantify and compare safety profiles across products over time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety.

Strategy in Regulatory Decision-Making for Management of Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been observed after the use of several medicines, including monoclonal antibodies. As these drugs play important roles in the therapeutic armamentarium, it is important to address the challenges that this severe adverse reaction poses to the safe use of medicines. Considering the need for consistent outcomes of regulatory decisions, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) used PML as an example to develop a systematic approach to labeling and risk minimization.