Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer’s and other neurodegenerative diseases? Protocol for an observational cohort study in the UK Clinical Practice Research Datalink

INTRODUCTION: Current treatments for Alzheimer's and other neurodegenerative diseases have only limited effectiveness meaning that there is an urgent need for new medications that could influence disease incidence and progression. We will investigate the potential of a selection of commonly prescribed drugs, as a more efficient and cost-effective method of identifying new drugs for the prevention or treatment of Alzheimer's disease, non-Alzheimer's disease dementias, Parkinson's disease and amyotrophic lateral sclerosis. Our research will focus on drugs used for the treatment of hypertension, hypercholesterolaemia and type 2 diabetes, all of which have previously been identified as potentially cerebroprotective and have variable levels of preclinical evidence that suggest they may have beneficial effects for various aspects of dementia pathology. METHODS AND ANALYSIS: We will conduct a hypothesis testing observational cohort study using data from the Clinical Practice Research Datalink (CPRD). Our analysis will consider four statistical methods, which have different approaches for modelling confounding. These are multivariable adjusted Cox regression; propensity matched regression; instrumental variable analysis and marginal structural models. We will also use an intention-to-treat analysis, whereby we will define all exposures based on the first prescription observed in the database so that the target parameter is comparable to that estimated by a randomised controlled trial. ETHICS AND DISSEMINATION: This protocol has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will publish the results of the study as open-access peer-reviewed publications and disseminate findings through national and international conferences as are appropriate

Reply to comment on the paper by Davies et al. “Resolving MISS conceptions and misconceptions: A geological approach to sedimentary surface textures generated by microbial and abiotic processes”

We thank Noffke (2017) for her comment and for providing an opportunity to clarify our classification of “sedimentary surface textures”. We accord great credit to Dr. Noffke and other dedicated researchers whose detailed work has brought microbially induced sedimentary structures (MISS) to the widespread attention of geoscientists. However, we stand by our assertion that attributing structures observed in practical field and laboratory studies to processes of formation is much more problematic than Noffke (2017) indicates. Indeed, points in the Comment confirm the need for a classification system that categorises the degree of certainty attributed to a given interpretation. We stress that our paper was not designed as a critique of previous studies of MISS but rather was designed to encourage a reasonable assessment of uncertainty in assigning sedimentary surface textures to physical processes or to MISS

Resolving MISS conceptions and misconceptions: A geological approach to sedimentary surface textures generated by microbial and abiotic processes

The rock record contains a rich variety of sedimentary surface textures on siliciclastic sandstone, siltstone and mudstone bedding planes. In recent years, an increasing number of these textures have been attributed to surficial microbial mats at the time of deposition, resulting in their classification as microbially induced sedimentary structures, or MISS. Research into MISS has developed at a rapid rate, resulting in a number of misconceptions in the literature. Here, we attempt to rectify these MISS misunderstandings. The first part of this paper surveys the stratigraphic and environmental range of reported MISS, revealing that contrary to popular belief there are more reported MISS-bearing rock units of Phanerozoic than Precambrian age. Furthermore, MISS exhibit a pan-environmental and almost continuous record since the Archean. Claims for the stratigraphic restriction of MISS to intervals prior to the evolution of grazing organisms or after mass extinction events, as well as claims for the environmental restriction of MISS, appear to result from sampling bias. In the second part of the paper we suggest that raised awareness of MISS has come at the cost of a decreasing appreciation of abiotic processes that may create morphologically similar features. By introducing the umbrella term ‘sedimentary surface textures’, of which MISS are one subset, we suggest a practical methodology for classifying such structures in the geological record. We illustrate how elucidating the formative mechanisms of ancient sedimentary surface textures usually requires consideration of a suite of sedimentological evidence from surrounding strata. Resultant interpretations, microbial or non-microbial, should be couched within a reasonable degree of uncertainty. This approach recognizes that morphological similarity alone does not constitute scientific proof of a common origin, and reinstates a passive descriptive terminology for sedimentary surface textures that cannot be achieved with the current MISS lexicon. It is hoped that this new terminology will reduce the number of overly sensational and misleading claims of MISS occurrence, and permit the means to practically separate initial observation from interpretation. Furthermore, this methodology offers a scientific approach that appreciates the low likelihood of conclusively identifying microbial structures from visual appearance alone, informing the search for true MISS in Earth's geological record and potentially on other planetary bodies such as Mars

Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants

OBJECTIVES: To investigate whether physicians' prescribing preferences were valid instrumental variables for the antidepressant prescriptions they issued to their patients. STUDY DESIGN AND SETTING: We investigated whether physicians' previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom. RESULTS: Prior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.7 percentage points (95% CI, 26.7, 28.8) more likely to prescribe paroxetine, to their next patient. Physicians' previous prescriptions were less strongly associated with patients' baseline characteristics than actual prescriptions. We found no evidence that the estimated association of TCAs with self-harm/suicide using instrumental variable regression differed from conventional regression estimates (P-value = 0.45). CONCLUSION: The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants

What is the impact of regulatory guidance and expiry of drug patents on dementia drug prescriptions in England? A trend analysis in the Clinical Practice Research Datalink

Abstract Background Drugs for dementia have been available in England since 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for Health and Care Excellence (NICE) guidance, several government dementia strategies, the addition of dementia to the Quality and Outcomes Framework (QOF), and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the U.K. Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016. Methods We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer’s disease, receiving their first prescription for each drug class—namely, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-methyl-d-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest. Results The overall trend was for increasing prescriptions in each drug class over the period in which they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI, − 6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI, − 77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister’s Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials. Conclusions Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations, or patent expiry, and when it does, not necessarily in a predictable way. This suggests that communication with clinicians may need to be improved to use drugs for dementia more cost-effectively