Feasibility and safety of mass drug coadministration with azithromycin and ivermectin for the control of neglected tropical diseases: a single-arm intervention trial.

BACKGROUND: Mass drug administration has made a major contribution to the public health control of several important neglected tropical diseases. For settings with more than one endemic disease, combined mass drug administration has potential practical advantages compared with separate programmes but needs confirmation of feasibility and safety. We undertook a study of mass drug administration in the Solomon Islands for trachoma and scabies control using ivermectin and azithromycin, key drugs in the control of neglected tropical diseases worldwide. METHODS: The entire population of Choiseul province, Solomon Islands, was eligible to participate. An azithromycin-based mass drug administration regimen was offered in line with standard recommendations for trachoma elimination (oral azithromycin or topical tetracycline). An ivermectin-based mass drug administration regimen was offered at the same time (oral ivermectin or topical permethrin), with a further dose 7-14 days later, using a modified version of a regimen demonstrated to be effective for scabies control. All participants underwent safety assessments 7-14 days later. Participants in ten randomly selected sentinel villages underwent a more detailed safety assessment. Routine health system reports of hospital or clinic admissions and deaths were also obtained to compare health outcomes in the 12 month period before and after the mass drug administration. FINDINGS: The study enrolled 26 188 participants, 99·3% of the estimated resident population as determined at the 2009 census. Of those enrolled, 25 717 (98·2%) received the trachoma regimen and 25 819 (98·6%) received the first dose of the scabies regimen between Sept 1, and Oct 2, 2015. A second dose of the scabies regimen was received by 21 931 (83·7%) of participants. Adverse events, all mild and transient, were recorded in 571 (2·6%) of the entire study population and 58 (4·1%) of participants in the ten sentinel villages. In the 12 months before and after the mass drug administration the numbers of hospital admissions (1530 vs 1602) and deaths (73 vs 83) were similar. In the month after the mass drug administration, 84 individuals were admitted to hospital and two died, compared with a monthly median of 116 admissions (IQR 106-159) and six deaths (IQR 4-7) in the 12 months before and after the mass drug administration. INTERPRETATION: In the largest trial so far involving coadministration of regimens based on ivermectin and azithromycin, the combination was safe and feasible in a population of more than 26 000 people. Coadministration of mass drug administration based on these two drugs opens up new potential for the control of neglected tropical diseases. FUNDING: International Trachoma Initiative, Murdoch Children's Research Institute, Scobie and Claire Mackinnon Trust, Wellcome Trust

IDENTIFYING NOVEL PSYCHOLOGICAL AND PHARMACOLOGICAL TREATMENT TARGETS IN ANOREXIA NERVOSA

Fear and anxiety regarding food, eating, weight and body shape are at the core of anorexia nervosa (AN) psychopathology. Weight restoration constitutes the primary goal of treatment and typically elicits significant patient distress. For a significant proportion of individuals with AN, fear and anxiety persist despite weight gain, cognitive symptoms prove difficult to shift, and prognosis remains poor. Innovative treatment adjuncts that target cognitive and biological pathways contributing to fear and anxiety in AN are urgently required. This thesis consists of two streams of research that aim to translate novel cognitive and neurobiological treatment targets implicated in the pathogenesis of fear and anxiety to the study of AN. In Chapter 2, I reviewed the literature identifying Intolerance of Uncertainty (IU) as a novel cognitive mechanism underpinning anxiety. Further, I proposed that IU may be implicated in anxiety, ritualised behaviour, and cognitive rigidity in AN. In Chapter 3, I tested these concepts in a pilot study and found that IU contributed to eating disorder psychopathology and predicted eating-related anxiety and dietary restriction in relation to a meal exposure task. In Chapter 4, I demonstrated that improvement in IU predicted reductions in ritualised behaviour and cognitive rigidity, and mediated treatment-related improvements in AN symptoms. Further, in anticipation of consuming a high-calorie meal, higher IU predicted greater anxiety regarding re-feeding. Finally, in Chapter 5, I examined data from a large randomised controlled trial investigating the efficacy of a novel neurobiological agent, Oxytocin (OT), in improving core psychopathology and re-feeding anxiety in AN. OT proved to be safe and well-tolerated, but did not confer any additional benefit to inpatient treatment. Findings suggest that IU may represent a cognitive bias contributing to eating-related anxiety, perseverative behaviour, and inflexible thinking in AN, and indicate that controlled intervention trials targeting IU are warranted. On the other hand, the application OT as an adjunct to inpatient re-feeding does not appear to hold future therapeutic promise in AN. Combined, these two streams of research represent a meaningful contribution to the search for novel treatment adjuncts that aim to lessen the divide between physical and psychological symptom remission in AN

Estimating carbon stock in lowland Papua New Guinean forest – low density of large trees results in lower than global average carbon stock

Papua New Guinean forests (PNG), sequestering up to 3% of global forest carbon, are a focus of climate change mitigation initiatives yet few field-based studies have quantified forest biomass and carbon for lowland PNG forest. We provide an estimate for the 10,770 hectare Wanang Conservation Area (WCA) to investigate effect of calculation methodology and choice of allometric equation on estimates of above ground live biomass (AGLB) and carbon. We estimated AGLB and carbon from 43 nested plots at the WCA. Our biomass estimate of 292.2 Mg AGLB ha-1 (95% CI 233.4-350.6) and carbon at 137.3 MgCha-1 (95% CI 109.8-164.8) is higher than most estimates for PNG but lower than mean global estimates for tropical forest. Calculation method and choice of allometric model do not significantly influence mean biomass estimates, however the most recently calibrated allometric equation generates estimates 13% higher for lower 95% confidence intervals of mean biomass than previous allometric models – a value often used as a conservative estimate of biomass. Although large trees at WCA (>70 cm DBH) accounted for 1/5 total biomass their density was lower than that seen in SE Asian and Australia forests. Lower density of large trees accounts for lower above-ground live biomass than in neighbouring forests - as large trees contribute disproportionately to forest biomass. Reduced frequency of larger trees at WCA is explained by the lack of diversity of large dipterocarp species common to neighboring SE Asian forests and, potentially, higher rates of local disturbance dynamics. PNG is susceptible to the El Niño Southern Oscillation (ENSO) extreme drought events to which large trees are particularly sensitive and, with still over 20% carbon in large trees, differential mortality under increasing ENSO drought stress raises the risk of PNG forest switching from carbon sink to source with reduced long term carbon storage capacity

Land-use simplification weakens the association between terrestrial producer and consumer diversity in Europe

Land-use change is one of the primary drivers of species loss, yet little is known about its effect on other components of biodiversity that may be at risk, such as local associations between trophic levels. Here, we ask whether, and to what extent, landscape simplification, measured as the percentage of arable land in the landscape, disrupts the functional and phylogenetic association between plants and primary consumers. Across seven European regions, we inferred the potential associations (functional and phylogenetic) between host plants and butterflies in 561 semi-natural grasslands. Local plant diversity showed a strong bottom-up effect on butterfly diversity in the most complex landscapes, but this effect disappeared in simple landscapes. The functional associations between plant and butterflies are, therefore, the results of processes that act not only locally but are also dependent on the surrounding landscape context. Similarly, landscape simplification reduced the phylogenetic congruence among host plants and butterflies indicating that closely related butterfly species are more generalist in the potential resource lineages used. These processes occurred without any detectable change in species richness of plants or butterflies along the gradient of arable land. The structural properties of ecosystems are experiencing substantial erosion, with potentially pervasive effects on ecosystem functions and future evolutionary trajectories. Loss of interacting species might trigger cascading extinction events and reduce the stability of trophic interactions, as well as influence the longer-term resilience of ecosystem functions. This underscores a growing realization that species richness is a crude and insensitive metric and that both functional and phylogenetic associations, measured across multiple trophic levels, are likely to provide far deeper insights into the resilience of ecosystems, and the functions they provide

The unseen invaders : introduced earthworms as drivers of change in plant communities in North American forests (a meta-analysis)

Globally, biological invasions can have strong impacts on biodiversity as well as ecosystem functioning. While less conspicuous than introduced aboveground organisms, introduced belowground organisms may have similarly strong effects. Here, we synthesize for the first time the impacts of introduced earthworms on plant diversity and community composition in North American forests. We conducted a meta-analysis using a total of 645 observations to quantify mean effect sizes of associations between introduced earthworm communities and plant diversity, cover of plant functional groups, and cover of native and non-native plants. We found that plant diversity significantly declined with increasing richness of introduced earthworm ecological groups. While plant species richness or evenness did not change with earthworm invasion, our results indicate clear changes in plant community composition: cover of graminoids and non-native plant species significantly increased, and cover of native plant species (of all functional groups) tended to decrease, with increasing earthworm biomass. Overall, these findings support the hypothesis that introduced earthworms facilitate particular plant species adapted to the abiotic conditions of earthworm-invaded forests. Further, our study provides evidence that introduced earthworms are associated with declines in plant diversity in North American forests. Changing plant functional composition in these forests may have long-lasting effects on ecosystem functioning.Peer reviewe

A phylogenetic classification of the world’s tropical forests

Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition and dynamics. Such understanding will enable anticipation of region specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present the first classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (1) Indo-Pacific, (2) Subtropical, (3) African, (4) American, and (5) Dry forests. Our results do not support the traditional Neo- versus Palaeo-tropical forest division, but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar and India. Additionally, a northern hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern hemisphere forests

The global burden of scabies:a cross-sectional analysis from the Global Burden of Disease Study 2015

Background: Numerous population-based studies have documented high prevalence of scabies in overcrowded settings, particularly among children and in tropical regions. We provide an estimate of the global burden of scabies using data from the Global Burden of Disease (GBD) Study 2015. Methods: We identified scabies epidemiological data sources from an extensive literature search and hospital insurance data and analysed data sources with a Bayesian meta-regression modelling tool, DisMod-MR 2·1, to yield prevalence estimates. We combined prevalence estimates with a disability weight, measuring disfigurement, itch, and pain caused by scabies, to produce years lived with disability (YLDs). With an assumed zero mortality from scabies, YLDs were equivalent to disability-adjusted life-years (DALYs). We estimated DALYs for 195 countries divided into 21 world regions, in both sexes and 20 age groups, between 1990 and 2015. Findings: Scabies was responsible for 0·21% of DALYs from all conditions studied by GBD 2015 worldwide. The world regions of east Asia (age-standardised DALYs 136·32), southeast Asia (134·57), Oceania (120·34), tropical Latin America (99·94), and south Asia (69·41) had the greatest burden of DALYs from scabies. Mean percent change of DALY rate from 1990 to 2015 was less than 8% in all world regions, except North America, which had a 23·9% increase. The five individual countries with greatest scabies burden were Indonesia (age-standardised DALYs 153·86), China (138·25), Timor-Leste (136·67), Vanuatu (131·59), and Fiji (130·91). The largest standard deviations of age-standardised DALYs between the 20 age groups were observed in southeast Asia (60·1), Oceania (58·3), and east Asia (56·5), with the greatest DALY burdens in children, adolescents, and the elderly. Interpretation: The burden of scabies is greater in tropical regions, especially in children, adolescents, and elderly people. As a worldwide epidemiological assessment, GBD 2015 provides broad and frequently updated measures of scabies burden in terms of skin effects. These global data might help guide research protocols and prioritisation efforts and focus scabies treatment and control measures. Funding: Bill & Melinda Gates Foundation

The global burden of scabies: a cross-sectional analysis from the Global Burden of Disease Study 2015.

Background Numerous population-based studies have documented high prevalence of scabies in overcrowded settings, particularly among children and in tropical regions. We provide an estimate of the global burden of scabies using data from the Global Burden of Disease (GBD) Study 2015. Methods We identified scabies epidemiological data sources from an extensive literature search and hospital insurance data and analysed data sources with a Bayesian meta-regression modelling tool, DisMod-MR 2·1, to yield prevalence estimates. We combined prevalence estimates with a disability weight, measuring disfigurement, itch, and pain caused by scabies, to produce years lived with disability (YLDs). With an assumed zero mortality from scabies, YLDs were equivalent to disability-adjusted life-years (DALYs). We estimated DALYs for 195 countries divided into 21 world regions, in both sexes and 20 age groups, between 1990 and 2015. Findings Scabies was responsible for 0·21% of DALYs from all conditions studied by GBD 2015 worldwide. The world regions of east Asia (age-standardised DALYs 136·32), southeast Asia (134·57), Oceania (120·34), tropical Latin America (99·94), and south Asia (69·41) had the greatest burden of DALYs from scabies. Mean percent change of DALY rate from 1990 to 2015 was less than 8% in all world regions, except North America, which had a 23·9% increase. The five individual countries with greatest scabies burden were Indonesia (age-standardised DALYs 153·86), China (138·25), Timor-Leste (136·67), Vanuatu (131·59), and Fiji (130·91). The largest standard deviations of age-standardised DALYs between the 20 age groups were observed in southeast Asia (60·1), Oceania (58·3), and east Asia (56·5), with the greatest DALY burdens in children, adolescents, and the elderly. Interpretation The burden of scabies is greater in tropical regions, especially in children, adolescents, and elderly people. As a worldwide epidemiological assessment, GBD 2015 provides broad and frequently updated measures of scabies burden in terms of skin effects. These global data might help guide research protocols and prioritisation efforts and focus scabies treatment and control measures. Funding Bill & Melinda Gates Foundation