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ObjectiveWe report on: (1) the proportion of patients with known atrial fibrillation (AF); and (2) demographic, clinical or radiological differences between patients with known AF (and not treated) and patients with newly diagnosed AF, in a cohort of patients who presented with ischaemic stroke or transient ischaemic attack (TIA) not previously treated with anticoagulation.DesignWe reviewed cross-sectional baseline demographic and clinical data from a prospective observational cohort study, (CROMIS-2).SettingPatients were recruited from 79 hospital stroke centres throughout the UK and one centre in the Netherlands.ParticipantsPatients were eligible if they were adults who presented with ischaemic stroke or TIA and AF and had not been previously treated with oral anticoagulation.Main outcome measuresProportion of patients with known AF before index ischaemic stroke or TIA from a cohort of patients who have not been previously treated with oral anticoagulation. Secondary analysis includes the comparison of CHA2DS2-VASc and HAS-BLED scores and other demographics and risk factors between those with newly diagnosed AF and those with previously known AF.ResultsOf 1470 patients included in the analysis (mean age 76 years (SD 10)), 622 (42%) were female; 999 (68%) patients had newly diagnosed AF and 471 (32%) patients had known AF. Of the 471 patients with known AF, 68% had a strong indication for anticoagulation and 89% should have been considered for anticoagulation based upon CHA2DS2-VASc score. Patients with known AF were more likely to have a prior history of dementia (4% vs 2%, p=0.02) and had higher HAS-BLED scores (median 3 vs 2). CHA2DS2-VASc, other risk factors and demographics were similar.ConclusionsAbout 1/3 of patients who present with stroke and have AF who have not been treated with oral anticoagulation have previously known AF. Of these patients, at least 68% were not adequately treated with oral anticoagulation.Trial registration number NCT02513316.

Background and purposeThe optimal time to start oral anticoagulant (OAC) in patients with ischaemic stroke due to non-valvular atrial fibrillation (AF) is unknown. We reviewed OAC timing in relation to 90-day clinical outcomes as a post hoc analysis from a prospective multicentre observational study.MethodsWe included patients with data on time to initiation of OAC from CROMIS-2 (Clinical Relevence Of Microbleeds In Stroke-2), a prospective observational inception cohort study of 1490 patients with ischaemic stroke or transient ischaemic attack (TIA) and AF treated with OAC. The primary outcome was the composite outcome of TIA, stroke (ischaemic stroke or intracranial haemorrhage) or death within 90 days of the qualifying stroke or TIA. We performed adjusted logistic regression analyses to compare early (0–4 days) and later (≥5 days or never started) OAC initiation.ResultsWe included 1355 patients, mean age 76 (SD 10), 580 (43%) women. OAC was started early in 358 (26%) patients and later (or not at all) in 997 (74%) patients. The event rate within 90 days was 48/997 (5%) in the late-OAC group (2 intracranial haemorrhages, 18 ischaemic strokes or TIAs and 31 deaths (three deaths were as a result of new ischaemic strokes)) versus 7/358 (2%) in the early-OAC group (5 ischaemic strokes or TIAs and 2 deaths). In adjusted analyses, late OAC was not associated with the composite outcome (adjusted OR 1.17, 95% CI 0.48 to 2.84, p=0.736).ConclusionIn adjusted analyses, early OAC after acute ischaemic stroke or TIA associated with AF was not associated with a difference in the rate of the composite outcome of stroke, TIA or death at 90 days, compared with late OAC. However, despite adjustment for important baseline factors, patients selected for early OAC and late OAC might still have differed in important respects; evaluation of OAC timing in adequately powered randomised trials is required.Clinical trial registration NCT02513316.

ObjectiveTo evaluate the influence of intracerebral haemorrhage (ICH) location on stroke outcomes.MethodsWe included patients recruited to a UK hospital-based, multicentre observational study of adults with imaging confirmed spontaneous ICH. The outcomes of interest were occurrence of a cerebral ischaemic event (either stroke or transient ischaemic attack) or a further ICH following study entry. Haematoma location was classified as lobar or non-lobar.ResultsAll 1094 patients recruited to the CROMIS-2 (Clinical Relevance of Microbleeds in Stroke) ICH study were included (mean age 73.3 years; 57.4% male). There were 45 recurrent ICH events (absolute event rate (AER) 1.88 per 100 patient-years); 35 in patients presenting with lobar ICH (n=447, AER 3.77 per 100 patient-years); and 9 in patients presenting with non-lobar ICH (n=580, AER 0.69 per 100 patient-years). Multivariable Cox regression found that lobar ICH was associated with ICH recurrence (HR 8.96, 95% CI 3.36 to 23.87, p<0.0001); similar results were found in multivariable completing risk analyses. There were 70 cerebral ischaemic events (AER 2.93 per 100 patient-years); 29 in patients presenting with lobar ICH (AER 3.12 per 100 patient-years); and 39 in patients with non-lobar ICH (AER 2.97 per 100 patient-years). Multivariable Cox regression found no association with ICH location (HR 1.13, 95% CI 0.66 to 1.92, p = 0.659). Similar results were seen in completing risk analyses.ConclusionsIn ICH survivors, lobar ICH location was associated with a higher risk of recurrent ICH events than non-lobar ICH; ICH location did not influence risk of subsequent ischaemic events.Trial registration number NCT02513316.

Post-stroke dementia is common but has heterogenous mechanisms that are not fully understood, particularly in patients with atrial fibrillation (AF)-related ischaemic stroke or TIA. We investigated the relationship between MRI small-vessel disease markers (including a composite cerebral amyloid angiopathy, CAA, score) and cognitive trajectory over 12 months. We included patients from the CROMIS-2 AF study without pre-existing cognitive impairment and with Montreal Cognitive Assessment (MoCA) data. Cognitive impairment was defined as MoCA < 26. We defined “reverters” as patients with an “acute” MoCA (immediately after the index event) score < 26, who then improved by ≥ 2 points at 12 months. In our cohort (n = 114), 12-month MoCA improved overall relative to acute performance (mean difference 1.69 points, 95% CI 1.03–2.36, p < 0.00001). 12-month cognitive impairment was associated with increasing CAA score (per-point increase, adjusted OR 4.09, 95% CI 1.36–12.33, p = 0.012). Of those with abnormal acute MoCA score (n = 66), 59.1% (n = 39) were “reverters”. Non-reversion was associated with centrum semi-ovale perivascular spaces (per-grade increase, unadjusted OR 1.83, 95% CI 1.06–3.15, p = 0.03), cerebral microbleeds (unadjusted OR 10.86, 95% CI 1.22–96.34, p = 0.03), and (negatively) with multiple ischaemic lesions at baseline (unadjusted OR 0.11, 95% CI 0.02–0.90, p = 0.04), as well as composite small-vessel disease (per-point increase, unadjusted OR 2.91, 95% CI 1.23–6.88, p = 0.015) and CAA (per-point increase, unadjusted OR 6.71, 95% CI 2.10–21.50, p = 0.001) scores. In AF-related acute ischaemic stroke or TIA, cerebral small-vessel disease is associated both with cognitive performance at 12 months and failure to improve over this period.

Unearthing the effects of surface water and groundwater interactions on subsurface biogeochemical reactions is crucial for developing a more mechanistic understanding of carbon and energy flow in aquifer ecosystems. To examine physiological characteristics across groundwater microbial communities that experience varying degrees of interaction with surface waters, we investigated 10 springs and a river sink and rise system in north central Florida that discharge from and/or mix with the karstic upper Floridan aquifer (UFA). Groundwater with longer residence times in the aquifer had lower concentrations of dissolved oxygen, dissolved and particulate organic carbon, and microbial biomass, as well as the lowest rates of respiration (0.102 to 0.189 mgO2L-1d-1) and heterotrophic production (198 to 576 µgCL-1d-1). Despite these features, oligotrophic UFA groundwater (< 0.5 mg C L−1) contained bioavailable organic matter that supported doubling times (14 to 62 h) and cell-specific production rates (0.0485 to 0.261 pmol C per cell per hour) comparable to those observed for surface waters (17 to 20 h; 0.105 to 0.124 pmol C per cell per hour). The relatively high specific rates of dissimilatory and assimilatory metabolism indicate a subsurface source of labile carbon to the groundwater (e.g., secondary production and/or chemoautotrophy). Our results link variations in UFA hydrobiogeochemistry to the physiology of its groundwater communities, providing a basis to develop new hypotheses related to microbial carbon cycling, trophic hierarchy, and processes generating bioavailable organic matter in karstic aquifer ecosystems.

The Upper Floridan Aquifer is one of the largest and most productive karstic aquifers in the world. However, few research efforts have characterized its microbiology and the links between microbial processes and the aquifer’s geology, geochemistry and hydrology, including their involvement in producing the greenhouse gas N2O, which previous studies have observed to be emitted from this aquifer. Besides, understanding how life thrives in subsurface oligotrophic environments is valuable to guide astrobiology missions in similar settings beyond Earth. One of the particularities of the UFA is the variable degree of interaction with surficial waters, which allows evaluations of mixing effects between DO and organic rich surface waters with oligotrophic subsurface waters. The aim of the present dissertation is to describe those effects on microbial taxa in the UFA and to understand their effects on microbial ecophysiology.Our results show significantly lower biomass (518 ± 83 ng C L-1) and cell numbers (106 -107 cells L-1) in UFA waters than surface waters. In contrast, diversity is high in all locations, with Shannon indexes above 5.5. Taxonomical studies revealed presence of phyla that commonly occur in other karstic subsurface environments as well, and a clear separation between planktonic and surface-attached communities, reflecting the heterogenicity of these habitats.While bulk heterotrophic carbon incorporation rates were two orders of magnitude higher in surface water, comparable doubling times with those of the subsurface indicates that organic carbon quality, rather than just bulk concentration, is key for microbial communities to thrive in conditions of oligotrophy. High DOC quality, together with anoxia, also determine the areas where N2O is consumed by heterotrophic denitrification, which explains previous observations of lower N2O concentrations in low oxygen, long residence time waters.In summary, this dissertation not only provides information that contributes to the global understanding of the microbiology of karstic aquifers, but also represents a foundational stone about microbiological research in the UFA. Data provided here will be very useful to construct several hypotheses to expand the characterization of carbon and nitrogen cycling in the UFA as well as to implicate the public into the aquifer’s protection through outreach projects.

The suggestion in 1996 that the Martian meteorite ALH84001 could contain proof of possible biologic activity in the past have generated a huge controversy that last until today. One of the most discussed evidence is the presence of magnetite crystals that resemble those produced by a particular group of bacteria, the so called magnetotactic bacteria (MTB). These microorganisms are the only known example of biologically controlled biomineralization among the prokaryotes and exert an exquisite control over the biomineralization process of intracellular magnetite that result in crystals with very unique features that, so far, cannot be replicated by inorganic means. These unique features have been used to recognize the biological origin of natural terrestrial magnetites, but the problem arises when those same biogenecity criteria are applied to extraterrestrial magnetites. Most of the problems are caused by the fact that it is not clear whether or not some of those characteristics can be reproduced inorganically. Magnetosome protein mediated magnetite synthesis seems to be the best approach to obtain magnetosome-like magnetites, and such strategy may help clarify what is the specific biosignature of magnetotactic bacteria.

This thesis examines the provision of housing in England in the 1990s against the context of the land use planning system of the time, with its re-emphasis on the plan-led approach. House building is responsible for the single largest change of use class in the English land use planning system, and house-building companies as a whole are thus the largest users of the system. The work samples longitudinally the data source of the published annual accounts of house building companies each year from 1990 to 1999 inclusive. The data produced is treated in two separate ways. The first novel methodology used is the extraction from the statements section of these accounts, of expressions of concern about the land use planning system. These qualitative data are tabulated, analysed and sorted into categories. The categories in turn are matched to a simple model of the land use planning process in the form of a flow chart. These data are further evaluated to establish some conclusions about the connections between the categories and the steps in the flow chart. Further consideration is given to the same data by a simple typology scoring procedure so that the information can be qualitatively treated for greater understanding. The distribution and intensity of the expressions of planning concern are then plotted to provide information about their changing patterns across the 1990s. Secondly, the same data source is utilised to provide quantitative data about the claimed land stocks of house building companies over the same period. However, a secondary, commercially-produced product - based on the same sources, augments the primary source. This permits a useful degree of augmentation and crosschecking of the primary source. The land types are divided into those that are claimed to have a valid planning consent - termed land bank, and land controlled without a viable consent. House builders think these sites are worth the cost of promotion through the land use planning system to a successful approval. The profile of the areas of these two land categories is totalled each year of the decade to establish an overall trend. The data was compared with the total English national dwelling output for each corresponding year of the decade. By 1999, the dwelling output total of the sampled house builders rose to be a significant proportion of the English national output. This, it is argued, makes it reasonable to scale up the sample land stocks to provide a quantitative appreciation of the whole amount of English land stocks controlled by the house building industry, especially towards the end of the decade. Having considered the findings in their context, conclusions are drawn about the performance of the 1990s planning system and the related pattern of house builders' land acquisition policies.

The suggestion in 1996 that the Martian meteorite ALH84001 could contain proof of possible biologic activity in the past have generated a huge controversy that last until today. One of the most discussed evidence is the presence of magnetite crystals that resemble those produced by a particular group of bacteria, the so called magnetotactic bacteria (MTB). These microorganisms are the only known example of biologically controlled biomineralization among the prokaryotes and exert an exquisite control over the biomineralization process of intracellular magnetite that result in crystals with very unique features that, so far, cannot be replicated by inorganic means. These unique features have been used to recognize the biological origin of natural terrestrial magnetites, but the problem arises when those same biogenecity criteria are applied to extraterrestrial magnetites. Most of the problems are caused by the fact that it is not clear whether or not some of those characteristics can be reproduced inorganically. Magnetosome protein mediated magnetite synthesis seems to be the best approach to obtain magnetosome-like magnetites, and such strategy may help clarify what is the specific biosignature of magnetotactic bacteria.