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Effective management of heart failure is complex, and ensuring evidence-based practice presents a major challenge to health services worldwide. Over the past decade, the United Kingdom introduced a series of national initiatives to improve evidence-based heart failure management, including a landmark pay-for-performance scheme in primary care and a national audit in secondary care started in 2004 and 2007, respectively. Quality improvement efforts have been evaluated within individual clinical settings, but patterns of care across its continuum, although a critical component of chronic disease management, have not been studied. We have designed this study to investigate patients' trajectories of care around the time of diagnosis and their variation over time by age, sex, and socioeconomic status. For this retrospective population-based study, we used linked primary and secondary health records from a representative sample of the UK population provided by the Clinical Practice Research Datalink (CPRD). We identified 93,074 individuals newly diagnosed with heart failure between 2002 and 2014, with a mean age of 76.7 years and of which 49% were women. We examined five indicators of care: (i) diagnosis care setting (inpatient or outpatient), (ii) posthospitalisation follow-up in primary care, (iii) diagnostic investigations, (iv) prescription of essential drugs, and (v) drug treatment dose. We used Poisson and linear regression models to calculate category-specific risk ratios (RRs) or adjusted differences and 95% confidence intervals (CIs), adjusting for year of diagnosis, age, sex, region, and socioeconomic status. From 2002 to 2014, indicators of care presented diverging trends. Outpatient diagnoses and follow-up after hospital discharge in primary care declined substantially (ranging from 56% in 2002 to 36% in 2014, RR 0.64 [0.62, 0.67] and 20% to 14%, RR 0.73 [0.65, 0.82], respectively). Primary care referral for diagnostic investigations and appropriate initiation of beta blockers and angiotensin-converting-enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) both increased significantly (37% versus 82%, RR 2.24 [2.15, 2.34] and 18% versus 63%, RR 3.48 [2.72, 4.43], respectively). Yet, the average daily dose prescribed remained below guideline recommendations (42% for ACE-Is or ARBs, 29% for beta blockers in 2014) and was largely unchanged beyond the first 30 days after diagnosis. Despite increasing rates of treatment initiation, the overall dose prescribed to patients in the 12 months following diagnosis improved little over the period of study (adjusted difference for the combined dose of beta blocker and ACE-I or ARB: +6% [+2%, +10%]). Women and patients aged over 75 years presented significant gaps across all five indicators of care. Our study was limited by the available clinical information, which did not include exact left ventricular ejection fraction values, investigations performed during hospital admissions, or information about follow-up in community heart failure clinics. Management of heart failure patients in the UK presents important shortcomings that affect screening, continuity of care, and medication titration and disproportionally impact women and older people. National reporting and incentive schemes confined to individual clinical settings have been insufficient to identify these gaps and address patients' long-term care needs.

ObjectiveThe impact of heart failure (HF) on perceived and objectively measured levels of physical activity (PA) can inform risk stratification and treatment recommendation. We aimed to compare self-reported and objectively measured PA levels in a large sample of participants with and without HF.MethodsA validated PA questionnaire was used to estimate self-reported weekly PA among 1600 participants with HF and 387 580 participants without HF. Accelerometer data were studied in 596 participants with HF and 96 105 participants without HF for a period of 7 days. Using multivariable linear regression models, we compared the PA levels between participants with HF and without HF, focusing on both the average daily PA levels and the intensity of PAs throughout the day.ResultsPA levels were significantly lower in participants with HF using both self-report (excess metabolic equivalent of task hours per week of 26.5 (95% CI 24.7 to 28.4) vs 34.7 (95% CI 34.5 to 34.9), respectively (p<0.001)) and accelerometer measures (mean accelerations of 23.7 milligravity (95% CI 23.1 to 24.4) vs 28.1 milligravity (95% CI 28.0 to 28.1), respectively (p<0.001)). Findings were consistent across different PA intensities. Hour-by-hour comparisons showed that accelerometer-derived PA levels of patients with HF were reduced throughout the day.ConclusionPerceived and objectively recorded PA levels of patients with chronic HF are significantly lower than those of individuals without HF. This difference is continuous throughout the different hours of the day, with individuals with HF being on average 16% less active than individuals without HF. In patients with HF, increases in everyday activity may be a potential alternative to structured exercise programmes.

SUPPORT-HF 2 tests the hypothesis that home monitoring with information technology–supported specialist management is more effective in optimizing medical therapy than is home monitoring alone for patients with heart failure. The study was designed as a 2-armed partially blinded parallel randomized controlled trial. Seven sites in the United Kingdom (UK) recruited a total of 202 adults with heart failure at high risk of adverse outcomes and with potential to benefit from remote management (mean age 73 years, 28% female, median left ventricular ejection fraction 37%). Both arms are given a home monitoring and communication kit (Internet-enabled tablet computer, Bluetooth-enabled blood pressure and heart rate monitor, and weighing scale). For each participant, an individualized plan for treatment of heart failure and major comorbidities is developed before randomization. Participants randomized to intervention receive regular feedback to support self-management, and their physicians receive advice on blood investigations and pharmacological treatment from a central specialist heart failure team. Participants in the control arm use the same monitoring system but with no central medical management support. The primary outcome is the use of recommended medical therapy, defined as treatment consistent with the guidelines for management of patients with chronic heart failure, and will be measured as a composite opportunity score. The trial data collection ended in October 2017, and results will be reported in 2019. Trial registration: ISRCTN86212709. Preliminary experience suggests that central provision of tailored specialist management using commercially available low-cost monitoring and computing devices, enhanced by customized applications, is feasible.

Chronic heart failure (HF) is a condition that affects more than 900,000 people in the UK. Mortality rates associated with the condition are high, with nearly 20% of patients dying within one year of diagnosis. Continuous monitoring and risk stratification can help identify patients at risk of deterioration and may consequently improve patients' likelihood of survival. Current repeated-measure risk stratification techniques for HF patients often rely on subjective perception of symptoms, such as breathlessness, and markers of fluid retention in the body (e.g. weight). Despite the common use of such markers, studies have shown that they offer limited effectiveness in predicting HF-related events. This thesis set out to identify and evaluate new markers for repeated-measure risk stratification of HF patients. It started with an exploration of traditional HF measurements, including weight, blood pressure, heart rate and symptom scores, and aimed to improve the performance of these measurements using a data-driven approach. A multi-variate model was developed from data acquired during a randomised controlled trial of remotely-monitored HF patients. The rare occurrence of HF-related adverse events during the trial required the developement of a careful methodology. This methodology helped identify the markers with most predictive ability, which achieved moderate performance at identifying patients at risk of HF-related adverse events, clearly outperforming commonly-used thresholds. Subsequently, this thesis explored the potential value of additional, accelerometer-derived physical activity (PA) and sleep markers. For this purpose, the ability of accelerometer-derived markers to differentiate between individuals with and without HF was evaluated. It was found that markers that summarise the frequency and duration of different PA intensities performed best at differentiating between the two groups and may therefore be most suitable for future use in repeated-measure applications. As part of the analysis of accelerometer-derived HF markers, a gap in the methodology of automated accelerometer processing was identified, namely the need for self-reported sleep-onset and wake-up information. As a result, Chapter 5 of this thesis describes the development and evaluation of a data-driven solution for this problem. In summary, this thesis explored both traditional and new, accelerometer-derived markers for the early detection of HF deterioration. It utilised sound methodology to overcome limitations faced by sparse and unbalanced datasets and filled a methodological gap in the processing of signals from wrist-worn accelerometers.

Objective: Current polysomnography-validated measures of sleep status from wrist-worn accelerometers cannot be used in fully automated analysis as they rely on self-reported sleep-onset and -end (sleep-boundary) information. We set out to develop an automated, data-driven approach to sleep-boundary detection from wrist-worn accelerometer data. Methods: On three separate occasions, participants were asked to wear a GENEActiv wrist-worn accelerometer for nine days and concurrently complete sleep diaries with lights-off, asleep and wake-up information. We developed and evaluated three data-driven methods for sleep-boundary detection: a change-point detection based method, a thresholding method and a random forest classifier based method. Mean absolute errors between automatically-derived and self-reported sleep-onset and wake-up times were recorded in addition to kappa statistics for the minute-by-minute performance of each of the methods. Results: 46 participants provided 972 days of accelerometer recordings with corresponding self-reported sleep information. The three sleep-boundary detection methods resulted in mean absolute errors in sleep-onset and wake-up times per individual of 36 min, 34 min and 33 min and kappa statistics of 0.87, 0.89 and 0.89, respectively. Conclusion: Our methods provide a data-driven approach to detect sleep-onset and -end times without the need for self-reported sleep-boundary information. The methods are likely to be of particular use for large-scale studies where the collection of self-reported sleep diaries is impractical. Significance: Objective measures of sleep are needed to reliably detect associations with health outcomes. This work lays the foundation for studies of objectively measured sleep duration and its health consequences in large studies.

The bacterial endosymbiont Wolbachia is a biocontrol tool that inhibits the ability of the Aedes aegypti mosquito to transmit positive-sense RNA viruses such as dengue and Zika. Growing evidence indicates that when Wolbachia strains wMel or wAlbB are introduced into local mosquito populations, human dengue incidence is reduced. Despite the success of this novel intervention, we still do not fully understand how Wolbachia protects mosquitoes from viral infection. Here, we demonstrate that the Wolbachia strain wPip does not inhibit virus infection in Ae. aegypti. We have leveraged this novel finding, and a panel of Ae. aegypti lines carrying virus-inhibitory (wMel and wAlbB) and non-inhibitory (wPip) strains in a common genetic background, to rigorously test a number of hypotheses about the mechanism of Wolbachia-mediated virus inhibition. We demonstrate that, contrary to previous suggestions, there is no association between a strain's ability to inhibit dengue infection in the mosquito and either its typical density in the midgut or salivary glands, or the degree to which it elevates innate immune response pathways in the mosquito. These findings, and the experimental platform provided by this panel of genetically comparable mosquito lines, clear the way for future investigations to define how Wolbachia prevents Ae. aegypti from transmitting viruses.

This study was conducted to determine the species identity and mycotoxin potential of 158 Fusarium strains originally archived in the South African Medical Research Council's Mycotoxigenic Fungal Collection (MRC) that were reported to comprise 17 morphologically distinct species in the classic 1984 compilation by Marasas et al., Toxigenic Fusarium Species: Identity and Mycotoxicology. Maximum likelihood and maximum parsimony molecular phylogenetic analyses of single and multilocus DNA sequence data indicated that the strains represented 46 genealogically exclusive phylogenetically distinct species distributed among eight species complexes. Moreover, the phylogenetic data revealed that 80/158 strains were received under a name that is not accepted today (ex F. moniliforme) or classified under a different species name. In addition, gas chromatography-mass spectrometry (GC-MS) and/or high-performance liquid chromatography-mass spectrometry (HPLC-MS)-based mycotoxin analyses were conducted to determine which toxins the strains could produce in liquid and/or solid cultures. All of the trichothecene toxin-producing fusaria were nested within the F. sambucinum (FSAMSC) or F. incarnatum-equiseti (FIESC) species complexes. Consistent with this finding, GC-MS analyses detected trichothecenes in agmatine-containing broth or rice culture extracts of all 13 FSAMSC and 10/12 FIESC species tested. Species in six and seven of the eight species complexes were able to produce moniliformin and beauvericin, respectively, whereas B-type fumonisins were only detected in extracts of cracked maize kernel cultures of three species in the F. fujikuroi (FFSC) species complex.

Coral exhibits substantial variation in pelagic larval duration, dispersal range, and population connectivity. In this study, we used reduced representation genotyping to compare the genetic structure of Caribbean reef-building species along the southeastern Dominican Republic coastline to assess connectivity within the likely dispersal kernel. Despite relatively small geographic distance between reefs, species-specific differences in genetic structure were observed. The broadcasting coral Orbicella faveolata had high levels of genetic connectivity. Between the two brooding species, Agaricia agaricites showed strong genetic subdivision, while Porites astreoides exhibited high levels of gene flow . These results suggest that multiple factors outside of life history characteristics influence genetic differentiation among populations, with species-level variability underscoring the importance of restoration and management strategies tailored to individual species, considering regional genetic and environmental variability.

The bacterial endosymbiont Wolbachia is a biocontrol tool that inhibits the ability of the Aedes aegypti mosquito to transmit positive-sense RNA viruses such as dengue and Zika. Growing evidence indicates that when Wolbachia strains wMel or wAlbB are introduced into local mosquito populations, human dengue incidence is reduced. Despite the success of this novel intervention, we still do not fully understand how Wolbachia protects mosquitoes from viral infection. Here, we demonstrate that the Wolbachia strain wPip does not inhibit virus infection in Ae. aegypti. We have leveraged this novel finding, and a panel of Ae. aegypti lines carrying virus-inhibitory (wMel and wAlbB) and non-inhibitory (wPip) strains in a common genetic background, to rigorously test a number of hypotheses about the mechanism of Wolbachia-mediated virus inhibition. We demonstrate that, contrary to previous suggestions, there is no association between a strain’s ability to inhibit dengue infection in the mosquito and either its typical density in the midgut or salivary glands, or the degree to which it elevates innate immune response pathways in the mosquito. These findings, and the experimental platform provided by this panel of genetically comparable mosquito lines, clear the way for future investigations to define how Wolbachia prevents Ae. aegypti from transmitting viruses.

Cuticular chemistry variation communicates several types of information about individuals in insect colonies, including caste membership. Independent-founding eusocial paper wasps are useful models for testing hypotheses about the associations of cuticular chemical variation with social roles because caste status can be partly decoupled from reproductive physiology: there is typically a single egg-laying female (queen) in each colony, but several females with ovary development can co-occur with the queen in mature worker-producing colonies. We asked whether the relative concentrations of non-polar cuticular compounds were most reliably associated with individuals’ ovary development (representing putative fertility cues) or with queen status (representing putative caste cues) in the paper wasp Mischocyttarus pallidipectus. In this Neotropical species several females with ovary development can occupy nests with a single laying queen, along with additional females with undeveloped (filamentous) ovaries. Discriminant function analyses of individuals differences in cuticular chemistry suggested a set of seven variable compounds predicted female caste membership (queen versus non-queen); cuticular chemistry variation was more strongly associated with the queen/non-queen distinction than with ovary status (females with developed versus filamentous ovaries). Colony identity was partly predicted by cuticular chemistry, and most of the significant colony-discriminating cuticular compounds were distinct from the significant caste-discriminating compounds. We discuss the implications of these findings for possible mechanisms of queen/non-queen differences in cuticular chemistry.