Drug prescriptions and dementia incidence: a medication-wide association study of 17000 dementia cases among half a million participants

Previous studies have suggested that some medications may influence dementia risk. We conducted a hypothesis-generating medication-wide association study to investigate systematically the association between all prescription medications and incident dementia. We used a population-based cohort within the Secure Anonymised Information Linkage (SAIL) databank, comprising routinely-collected primary care, hospital admissions and mortality data from Wales, UK. We included all participants born after 1910 and registered with a SAIL general practice at ≤60 years old. Follow-up was from each participant's 60th birthday to the earliest of dementia diagnosis, deregistration from a SAIL general practice, death or the end of 2018. We considered participants exposed to a medication if they received ≥1 prescription for any of 744 medications before or during follow-up. We adjusted for sex, smoking and socioeconomic status. The outcome was any all-cause dementia code in primary care, hospital or mortality data during follow-up. We used Cox regression to calculate hazard ratios and Bonferroni-corrected p values. Of 551 344 participants, 16 998 (3%) developed dementia (median follow-up was 17 years for people who developed dementia, 10 years for those without dementia). Of 744 medications, 221 (30%) were associated with dementia. Of these, 217 (98%) were associated with increased dementia incidence, many clustering around certain indications. Four medications (all vaccines) were associated with a lower dementia incidence. Almost a third of medications were associated with dementia. The clustering of many drugs around certain indications may provide insights into early manifestations of dementia. We encourage further investigation of hypotheses generated by these results. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

The fallacy of enrolling only high-risk subjects in cancer prevention trials: Is there a "free lunch"?

BACKGROUND: There is a common belief that most cancer prevention trials should be restricted to high-risk subjects in order to increase statistical power. This strategy is appropriate if the ultimate target population is subjects at the same high-risk. However if the target population is the general population, three assumptions may underlie the decision to enroll high-risk subject instead of average-risk subjects from the general population: higher statistical power for the same sample size, lower costs for the same power and type I error, and a correct ratio of benefits to harms. We critically investigate the plausibility of these assumptions. METHODS: We considered each assumption in the context of a simple example. We investigated statistical power for fixed sample size when the investigators assume that relative risk is invariant over risk group, but when, in reality, risk difference is invariant over risk groups. We investigated possible costs when a trial of high-risk subjects has the same power and type I error as a larger trial of average-risk subjects from the general population. We investigated the ratios of benefit to harms when extrapolating from high-risk to average-risk subjects. RESULTS: Appearances here are misleading. First, the increase in statistical power with a trial of high-risk subjects rather than the same number of average-risk subjects from the general population assumes that the relative risk is the same for high-risk and average-risk subjects. However, if the absolute risk difference rather than the relative risk were the same, the power can be less with the high-risk subjects. In the analysis of data from a cancer prevention trial, we found that invariance of absolute risk difference over risk groups was nearly as plausible as invariance of relative risk over risk groups. Therefore a priori assumptions of constant relative risk across risk groups are not robust, limiting extrapolation of estimates of benefit to the general population. Second, a trial of high-risk subjects may cost more than a larger trial of average risk subjects with the same power and type I error because of additional recruitment and diagnostic testing to identify high-risk subjects. Third, the ratio of benefits to harms may be more favorable in high-risk persons than in average-risk persons in the general population, which means that extrapolating this ratio to the general population would be misleading. Thus there is no free lunch when using a trial of high-risk subjects to extrapolate results to the general population. CONCLUSION: Unless the intervention is targeted to only high-risk subjects, cancer prevention trials should be implemented in the general population

Control of Mycobacterium bovis infection in two sika deer herds in Ireland

In a number of countries, tuberculosis (due to infection with Mycobacterium bovis) is a significant health problem of captive deer. This paper describes outbreaks of bovine tuberculosis in sika deer (Cervus nippon) on two farms in Ireland and the methods used to control the disease. On Farm A, infection was first detected during 1993. The infection was eradicated using a programme of test and removal, in association with segregation of young animals. A second outbreak (also due to infection with M. bovis, but a different RFLP profile) was detected in 2002. In the latter outbreak, infection was particularly prevalent in two groups of young deer. M. bovis with the same RFLP profile was also isolated in a badger found dead on the farm. Control was achieved by test and removal in association with herd management changes. In Herd B, infection was first detected in 1995, and subsequently eradicated using test and removal alone. In Herd A, re-infection remains an ongoing risk. Control rather than eradication of infection may more realistic in the short-to medium-term

Alcohol consumption and lifetime change in cognitive ability:a gene × environment interaction study

Studies of the effect of alcohol consumption on cognitive ability are often confounded. One approach to avoid confounding is the Mendelian randomization design. Here, we used such a design to test the hypothesis that a genetic score for alcohol processing capacity moderates the association between alcohol consumption and lifetime change in cognitive ability. Members of the Lothian Birth Cohort 1936 completed the same test of intelligence at age 11 and 70 years. They were assessed for recent alcohol consumption in later life and genotyped for a set of four single-nucleotide polymorphisms in three alcohol dehydrogenase genes. These variants were unrelated to late-life cognition or to socioeconomic status. We found a significant gene × alcohol consumption interaction on lifetime cognitive change (p = 0.007). Individuals with higher genetic ability to process alcohol showed relative improvements in cognitive ability with more consumption, whereas those with low processing capacity showed a negative relationship between cognitive change and alcohol consumption with more consumption. The effect of alcohol consumption on cognitive change may thus depend on genetic differences in the ability to metabolize alcohol

Single Cut Integration

We present an analytic technique for evaluating single cuts for one-loop integrands, where exactly one propagator is taken to be on shell. Our method extends the double-cut integration formalism of one-loop amplitudes to the single-cut case. We argue that single cuts give meaningful information about amplitudes when taken at the integrand level. We discuss applications to the computation of tadpole coefficients.Comment: v2: corrected typo in abstrac

The role of ongoing dendritic oscillations in single-neuron dynamics

The dendritic tree contributes significantly to the elementary computations a neuron performs while converting its synaptic inputs into action potential output. Traditionally, these computations have been characterized as temporally local, near-instantaneous mappings from the current input of the cell to its current output, brought about by somatic summation of dendritic contributions that are generated in spatially localized functional compartments. However, recent evidence about the presence of oscillations in dendrites suggests a qualitatively different mode of operation: the instantaneous phase of such oscillations can depend on a long history of inputs, and under appropriate conditions, even dendritic oscillators that are remote may interact through synchronization. Here, we develop a mathematical framework to analyze the interactions of local dendritic oscillations, and the way these interactions influence single cell computations. Combining weakly coupled oscillator methods with cable theoretic arguments, we derive phase-locking states for multiple oscillating dendritic compartments. We characterize how the phase-locking properties depend on key parameters of the oscillating dendrite: the electrotonic properties of the (active) dendritic segment, and the intrinsic properties of the dendritic oscillators. As a direct consequence, we show how input to the dendrites can modulate phase-locking behavior and hence global dendritic coherence. In turn, dendritic coherence is able to gate the integration and propagation of synaptic signals to the soma, ultimately leading to an effective control of somatic spike generation. Our results suggest that dendritic oscillations enable the dendritic tree to operate on more global temporal and spatial scales than previously thought

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

Stem-cell competition

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62534/1/418025a.pd

Balancing the dilution and oddity effects: Decisions depend on body size

Background Grouping behaviour, common across the animal kingdom, is known to reduce an individual's risk of predation; particularly through dilution of individual risk and predator confusion (predator inability to single out an individual for attack). Theory predicts greater risk of predation to individuals more conspicuous to predators by difference in appearance from the group (the ‘oddity’ effect). Thus, animals should choose group mates close in appearance to themselves (eg. similar size), whilst also choosing a large group. Methodology and Principal Findings We used the Trinidadian guppy (Poecilia reticulata), a well known model species of group-living freshwater fish, in a series of binary choice trials investigating the outcome of conflict between preferences for large and phenotypically matched groups along a predation risk gradient. We found body-size dependent differences in the resultant social decisions. Large fish preferred shoaling with size-matched individuals, while small fish demonstrated no preference. There was a trend towards reduced preferences for the matched shoal under increased predation risk. Small fish were more active than large fish, moving between shoals more frequently. Activity levels increased as predation risk decreased. We found no effect of unmatched shoal size on preferences or activity. Conclusions and Significance Our results suggest that predation risk and individual body size act together to influence shoaling decisions. Oddity was more important for large than small fish, reducing in importance at higher predation risks. Dilution was potentially of limited importance at these shoal sizes. Activity levels may relate to how much sampling of each shoal was needed by the test fish during decision making. Predation pressure may select for better decision makers to survive to larger size, or that older, larger fish have learned to make shoaling decisions more efficiently, and this, combined with their size relative to shoal-mates, and attractiveness as prey items influences shoaling decisions

On Population Growth Near Protected Areas

Background: Protected areas are the first, and often only, line of defense in efforts to conserve biodiversity. They might be detrimental or beneficial to rural communities depending on how they alter economic opportunities and access to natural resources. As such, protected areas may attract or repel human settlement. Disproportionate increases in population growth near protected area boundaries may threaten their ability to conserve biodiversity. Methodology/Principal Findings: Using decadal population datasets, we analyze population growth across 45 countries and 304 protected areas. We find no evidence for population growth near protected areas to be greater than growth of rural areas in the same country. Furthermore, we argue that what growth does occur near protected areas likely results from a general expansion of nearby population centers. Conclusions/Significance: Our results contradict those from a recent study by Wittemyer et al., who claim overwhelming evidence for increased human population growth near protected areas. To understand the disagreement, we re-analyzed the protected areas in Wittemyer et al.’s paper. Their results are simply artifacts of mixing two incompatible datasets. Protected areas may experience unusual population pressures near their edges; indeed, individual case studies provid