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Venomous animals have evolved toxins that interfere with specific components of their victim’s core physiological systems, thereby causing biological dysfunction that aids in prey ...capture, defense against predators, or other roles such as intraspecific competition. Many animal lineages evolved venom systems independently, highlighting the success of this strategy. Over the course of evolution, toxins with exceptional specificity and high potency for their intended molecular targets have prevailed, making venoms an invaluable and almost inexhaustible source of bioactive molecules, some of which have found use as pharmacological tools, human therapeutics, and bioinsecticides. Current biomedically-focused research on venoms is directed towards their use in delineating the physiological role of toxin molecular targets such as ion channels and receptors, studying or treating human diseases, targeting vectors of human diseases, and treating microbial and parasitic infections. We provide examples of each of these areas of venom research, highlighting the potential that venom molecules hold for basic research and drug development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Temporal variation of temperature-health associations depends on the combination of two pathways: pure adaptation to increasingly warmer temperatures due to climate change, and other attenuation ...mechanisms due to non-climate factors such as infrastructural changes and improved health care. Disentangling these pathways is critical for assessing climate change impacts and for planning public health and climate policies. We present evidence on this topic by assessing temporal trends in cold- and heat-attributable mortality risks in a multi-country investigation.
Trends in country-specific attributable mortality fractions (AFs) for cold and heat (defined as below/above minimum mortality temperature, respectively) in 305 locations within 10 countries (1985–2012) were estimated using a two-stage time-series design with time-varying distributed lag non-linear models. To separate the contribution of pure adaptation to increasing temperatures and active changes in susceptibility (non-climate driven mechanisms) to heat and cold, we compared observed yearly-AFs with those predicted in two counterfactual scenarios: trends driven by either (1) changes in exposure-response function (assuming a constant temperature distribution), (2) or changes in temperature distribution (assuming constant exposure-response relationships). This comparison provides insights about the potential mechanisms and pace of adaptation in each population.
Heat-related AFs decreased in all countries (ranging from 0.45–1.66% to 0.15–0.93%, in the first and last 5-year periods, respectively) except in Australia, Ireland and UK. Different patterns were found for cold (where AFs ranged from 5.57–15.43% to 2.16–8.91%), showing either decreasing (Brazil, Japan, Spain, Australia and Ireland), increasing (USA), or stable trends (Canada, South Korea and UK). Heat-AF trends were mostly driven by changes in exposure-response associations due to modified susceptibility to temperature, whereas no clear patterns were observed for cold.
Our findings suggest a decrease in heat-mortality impacts over the past decades, well beyond those expected from a pure adaptation to changes in temperature due to the observed warming. This indicates that there is scope for the development of public health strategies to mitigate heat-related climate change impacts. In contrast, no clear conclusions were found for cold. Further investigations should focus on identification of factors defining these changes in susceptibility.
•Evidence on adaptation is crucial for the assessment of climate change impacts.•Most of the studied countries showed a strong reduction in heat vulnerability.•We found more diffuse patterns on cold-mortality trends.•Pace of decrease in heat susceptibility was faster than the observed warming.•There is scope for development of mitigation strategies of climate change impacts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In winter 2013/14 there was widespread flooding in England. Previous studies have described an increased prevalence of psychological morbidity six months after flooding. Disruption to essential ...services may increase morbidity however there have been no studies examining whether those experiencing disruption but not directly flooded are affected. The National Study of Flooding and Health was established in order to investigate the longer-term impact of flooding and related disruptions on mental health and wellbeing.
In year one we conducted a cross sectional analysis of people living in neighbourhoods affected by flooding between 1 December 2013 and 31 March 2014. 8761 households were invited to participate. Participants were categorised according to exposure as flooded, disrupted by flooding or unaffected. We used validated instruments to screen for probable psychological morbidity, the Patient Health Questionnaire (PHQ 2), Generalised Anxiety Disorder scale (GAD-2) and Post Traumatic Stress Disorder (PTSD) checklist (PCL-6). We calculated prevalence and odds ratios for each outcome by exposure group relative to unaffected participants, adjusting for confounders.
2126 people (23%) responded. The prevalence of psychological morbidity was elevated amongst flooded participants (n = 622 depression 20.1%, anxiety 28.3%, PTSD 36.2%) and disrupted participants (n = 1099 depression 9.6%, anxiety 10.7% PTSD 15.2%). Flooding was associated with higher odds of all outcomes (adjusted odds ratios (aORs), 95% CIs for depression 5.91 (3.91-10.99), anxiety 6.50 (3.77-11.24), PTSD 7.19 (4.33-11.93)). Flooded participants who reported domestic utilities disruption had higher odds of all outcomes than other flooded participants, (aORs, depression 6.19 (3.30-11.59), anxiety 6.64 (3.84-11.48), PTSD 7.27 (4.39-12.03) aORs without such disruption, depression, 3.14 (1.17-8.39), anxiety 3.45 (1.45-8.22), PTSD 2.90 (1.25-6.73)). Increased floodwater depth was significantly associated with higher odds of each outcome. Disruption without flooding was associated with borderline higher odds of anxiety (aOR 1.61 (0.94-2.77)) and higher odds of PTSD 2.06 (1.27-3.35)) compared with unaffected participants. Disruption to health/social care and work/education was also associated with higher odds of psychological morbidity.
This study provides an insight into the impact of flooding on mental health, suggesting that the impacts of flooding are large, prolonged and extend beyond just those whose homes are flooded.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Mortality increases with hot weather, although the extent to which lives are shortened is rarely quantified. We compare the extent to which short-term mortality displacement can explain ...heat deaths in Delhi, São Paulo, and London given contrasting demographic and health profiles. Methods: We examined time-series of daily mortality data in relation to daily ambient temperature using Poisson models and adjusting for season, relative humidity, rainfall, particulate air pollution, day of the week, and public holidays. We used unconstrained distributed lag models to identify the extent to which heat-related excesses were followed by deficits (mortality displacement). Results: For each city, an increase in all-cause mortality was observed with same-day (lag 0) and previous day (lag 1) temperatures greater than a threshold of 20°C. At lag 0, the excess risk was greatest in Delhi and smallest in London. In Delhi, an excess was apparent up to 3 weeks after exposure, after which a deficit was observed that offset just part of the overall excess. In London, the heat excess persisted only 2 days and was followed by deficits, such that the sum of effects was 0 by day 11. The pattern in São Paulo was intermediate between these. The risk summed over the course of 28 days was 2.4% (95% confidence interval = 0.1 to 4.7%) per degree greater than the heat threshold in Delhi, 0.8% (-0.4 to 2.1%) in São Paulo and -1.6% (-3.4 to 0.3%) in London. Excess risks were sustained up to 4 weeks for respiratory deaths in São Paulo and London and for children in Delhi. Conclusions: Heat-related short-term mortality displacement was high in London but less in Delhi, where infectious and childhood mortality still predominate.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract
Heat-related mortality has been identified as one of the key climate extremes posing a risk to human health. Current research focuses largely on how heat mortality increases with mean global ...temperature rise, but it is unclear how much climate change will increase the frequency and severity of extreme summer seasons with high impact on human health. In this probabilistic analysis, we combined empirical heat-mortality relationships for 748 locations from 47 countries with climate model large ensemble data to identify probable past and future highly impactful summer seasons. Across most locations, heat mortality counts of a 1-in-100 year season in the climate of 2000 would be expected once every ten to twenty years in the climate of 2020. These return periods are projected to further shorten under warming levels of 1.5 °C and 2 °C, where heat-mortality extremes of the past climate will eventually become commonplace if no adaptation occurs. Our findings highlight the urgent need for strong mitigation and adaptation to reduce impacts on human lives.
The purpose of this study was to determine whether short-term changes in ambient temperature were associated with daily mortality among persons who lived in Montreal, Canada, and who died in the ...urban area between 1984 and 2007. We made use of newly developed distributed lag non-linear Poisson models, constrained to a 30 day lag period, and we adjusted for temporal trends and nitrogen dioxide and ozone. We found a strong non-linear association with high daily maximum temperatures showing an apparent threshold at about 27
°C; this association persisted until about lag 5 days. For example, we found across all lag periods that daily non-accidental mortality increased by 28.4% (95% confidence interval: 13.8–44.9%) when temperatures increased from 22.5 to 31.8
°C (75–99th percentiles). This association was essentially invariant to different smoothers for time. Cold temperatures were not found to be associated with daily mortality over 30 days, although there was some evidence of a modest increased risk from 2 to 5 days. The adverse association with colder temperatures was sensitive to the smoother for time. For cardio-respiratory mortality we found increased risks for higher temperatures of a similar magnitude to that of non-accidental mortality but no effects at cold temperatures.
► Hot weather in Montreal was associated with increases in daily mortality. ► The effects from heat persisted for about six days. ► Cold weather was associated with increased risk only at lags 2–5 days.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Norovirus, the most commonly identified cause of both sporadic cases and outbreaks of infectious diarrhoea in developed countries, exhibits a complex epidemiology and has a strong wintertime ...seasonality. Viral populations are dynamic and evolve under positive selection pressure.
Time series-adapted Poisson regression models were fitted to daily counts of laboratory reports of norovirus in England and Wales from 1993 to 2006.
Inverse linear associations with daily temperature over the previous seven weeks (rate ratio (RR) = 0.85; 95% CI: 0.83 to 0.86 for every 1 degrees C increase) and relative humidity over the previous five weeks (RR = 0.980; 95% CI: 0.973 to 0.987 for every 1% increase) were found, with temperature having a greater overall effect. The emergence of new norovirus variants (RR = 1.16; 95% CI: 1.10 to 1.22) and low population immunity were also associated with heightened norovirus activity. Temperature and humidity, which may be localised, had highly consistent effects in each region of England and Wales.
These results point to a complex interplay between host, viral and climatic factors driving norovirus epidemic patterns. Increases in norovirus are associated with cold, dry temperature, low population immunity and the emergence of novel genogroup 2 type 4 antigenic variants.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Estimates of the effectiveness of influenza vaccines in older adults may be biased because of difficulties identifying and adjusting for confounders of the vaccine-outcome association. We estimated ...vaccine effectiveness for prevention of serious influenza complications among older persons by using methods to account for underlying differences in risk for these complications.
We conducted a retrospective cohort study among Ontario residents aged ≥ 65 years from September 1993 through September 2008. We linked weekly vaccination, hospitalization, and death records for 1.4 million community-dwelling persons aged ≥ 65 years. Vaccine effectiveness was estimated by comparing ratios of outcome rates during weeks of high versus low influenza activity (defined by viral surveillance data) among vaccinated and unvaccinated subjects by using log-linear regression models that accounted for temperature and time trends with natural spline functions. Effectiveness was estimated for three influenza-associated outcomes: all-cause deaths, deaths occurring within 30 days of pneumonia/influenza hospitalizations, and pneumonia/influenza hospitalizations.
During weeks when 5% of respiratory specimens tested positive for influenza A, vaccine effectiveness among persons aged ≥ 65 years was 22% (95% confidence interval CI, -6%-42%) for all influenza-associated deaths, 25% (95% CI, 13%-37%) for deaths occurring within 30 days after an influenza-associated pneumonia/influenza hospitalization, and 19% (95% CI, 4%-31%) for influenza-associated pneumonia/influenza hospitalizations. Because small proportions of deaths, deaths after pneumonia/influenza hospitalizations, and pneumonia/influenza hospitalizations were associated with influenza virus circulation, we estimated that vaccination prevented 1.6%, 4.8%, and 4.1% of these outcomes, respectively.
By using confounding-reducing techniques with 15 years of provincial-level data including vaccination and health outcomes, we estimated that influenza vaccination prevented ~4% of influenza-associated hospitalizations and deaths occurring after hospitalizations among older adults in Ontario.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Several studies have found an effect on mortality of between-city contrasts in long-term exposure to air pollution. The effect of within-city contrasts is still poorly understood. ...Objectives: We studied the association between long-term exposure to traffic-related air pollution and mortality in a Dutch cohort. Methods: We used data from an ongoing cohort study on diet and cancer with 120,852 subjects who were followed from 1987 to 1996. Exposure to black smoke (BS), nitrogen dioxide, sulfur dioxide, and particulate matter ≤ 2.5 microm$({\rm{PM}}_{2.5} ),$as well as various exposure variables related to traffic, were estimated at the home address. We conducted Cox analyses in the full cohort adjusting for age, sex, smoking, and area-level socioeconomic status. Results: Traffic intensity on the nearest road was independently associated with mortality. Relative risks (95% confidence intervals) for a 10-microg/m? increase in BS concentrations (difference between 5th and 95th percentile) were 1.05 (1.00-1.11) for natural cause, 1.04 (0.95-1.13) for cardiovascular, 1.22 (0.99-1.50) for respiratory, 1.03 (0.88-1.20) for lung cancer, and 1.04 (0.97-1.12) for mortality other than cardiovascular, respiratory, or lung cancer. Results were similar for NO2 and${\rm{PM}}_{2.5} ,$but no associations were found for SO2. Conclusions: Traffic-related air pollution and several traffic exposure variables were associated with mortality in the full cohort. Relative risks were generally small. Associations between natural-cause and respiratory mortality were statistically significant for NO2 and BS. These results add to the evidence that long-term exposure to ambient air pollution is associated with increased mortality.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Animal toxins that modulate the activity of voltage-gated sodium (Na
) channels are broadly divided into two categories-pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and ...saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Na
channel Na
PaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSD
and the pore of Na
PaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na
access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Na
channel drugs.
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