The impacts of climate change on surface water, waterborne disease, and human health remain a growing area of concern, particularly in Africa, where diarrheal disease is one of the most important ...health threats to children under 5 years of age. Little is known about the role of surface water and annual flood dynamics (flood pulse) on waterborne disease and human health nor about the expected impact of climate change on surface-water-dependent populations.
Using the Chobe River in northern Botswana, a flood pulse river-floodplain system, we applied multimodel inference approaches assessing the influence of river height, water quality (bimonthly counts of Escherichia coli and total suspended solids TSS, 2011-2017), and meteorological variability on weekly diarrheal case reports among children under 5 presenting to health facilities (n = 10 health facilities, January 2007-June 2017). We assessed diarrheal cases by clinical characteristics and season across age groups using monthly outpatient data (January 1998-June 2017). A strong seasonal pattern was identified, with 2 outbreaks occurring regularly in the wet and dry seasons. The timing of outbreaks diverged from that at the level of the country, where surface water is largely absent. Across age groups, the number of diarrheal cases was greater, on average, during the dry season. Demographic and clinical characteristics varied by season, underscoring the importance of environmental drivers. In the wet season, rainfall (8-week lag) had a significant influence on under-5 diarrhea, with a 10-mm increase in rainfall associated with an estimated 6.5% rise in the number of cases. Rainfall, minimum temperature, and river height were predictive of E. coli concentration, and increases in E. coli in the river were positively associated with diarrheal cases. In the dry season, river height (1-week lag) and maximum temperature (1- and 4-week lag) were significantly associated with diarrheal cases. During this period, a 1-meter drop in river height corresponded to an estimated 16.7% and 16.1% increase in reported diarrhea with a 1- and 4-week lag, respectively. In this region, as floodwaters receded from the surrounding floodplains, TSS levels increased and were positively associated with diarrheal cases (0- and 3-week lag). Populations living in this region utilized improved water sources, suggesting that hydrological variability and rapid water quality shifts in surface waters may compromise water treatment processes. Limitations include the potential influence of health beliefs and health seeking behaviors on data obtained through passive surveillance.
In flood pulse river-floodplain systems, hydrology and water quality dynamics can be highly variable, potentially impacting conventional water treatment facilities and the production of safe drinking water. In Southern Africa, climate change is predicted to intensify hydrological variability and the frequency of extreme weather events, amplifying the public health threat of waterborne disease in surface-water-dependent populations. Water sector development should be prioritized with urgency, incorporating technologies that are robust to local environmental conditions and expected climate-driven impacts. In populations with high HIV burdens, expansion of diarrheal disease surveillance and intervention strategies may also be needed. As annual flood pulse processes are predominantly influenced by climate controls in distant regions, country-level data may be inadequate to refine predictions of climate-health interactions in these systems.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An Ebola outbreak of unprecedented scope emerged in West Africa in December 2013 and presently continues unabated in the countries of Guinea, Sierra Leone, and Liberia. Ebola is not new to Africa, ...and outbreaks have been confirmed as far back as 1976. The current West African Ebola outbreak is the largest ever recorded and differs dramatically from prior outbreaks in its duration, number of people affected, and geographic extent. The emergence of this deadly disease in West Africa invites many questions, foremost among these: why now, and why in West Africa? Here, we review the sociological, ecological, and environmental drivers that might have influenced the emergence of Ebola in this region of Africa and its spread throughout the region. Containment of the West African Ebola outbreak is the most pressing, immediate need. A comprehensive assessment of the drivers of Ebola emergence and sustained human-to-human transmission is also needed in order to prepare other countries for importation or emergence of this disease. Such assessment includes identification of country-level protocols and interagency policies for outbreak detection and rapid response, increased understanding of cultural and traditional risk factors within and between nations, delivery of culturally embedded public health education, and regional coordination and collaboration, particularly with governments and health ministries throughout Africa. Public health education is also urgently needed in countries outside of Africa in order to ensure that risk is properly understood and public concerns do not escalate unnecessarily. To prevent future outbreaks, coordinated, multiscale, early warning systems should be developed that make full use of these integrated assessments, partner with local communities in high-risk areas, and provide clearly defined response recommendations specific to the needs of each community.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral ...sclerosis ALS and frontotemporal dementia), muscle, and bone. Here we provide a unified structural view of hnRNPA2 self-assembly, aggregation, and interaction and the distinct effects of small chemical changes—disease mutations and arginine methylation—on these assemblies. The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer, retaining predominant disorder in a liquid-liquid phase-separated form. Disease mutations D290V and P298L induce aggregation by enhancing and extending, respectively, the aggregation-prone region. Co-aggregating in disease inclusions, hnRNPA2 LC directly interacts with and induces phase separation of TDP-43. Conversely, arginine methylation reduces hnRNPA2 phase separation, disrupting arginine-mediated contacts. These results highlight the mechanistic role of specific LC domain interactions and modifications conserved across many hnRNP family members but altered by aggregation-causing pathological mutations.
Display omitted
•hnRNPA2 LC monomer is disordered but compact and undergoes LLPS•hnRNPA2 LC remains predominantly disordered in a phase-separated state•P298L and D290V mutations enhance aggregation, and Arg methylation decreases LLPS•hnRNPA2 LC and TDP-43 CTD co-phase separate and induce co-aggregation
The RNA-binding protein hnRNPA2 is mutated in disease and found in membraneless organelles, but the mechanistic details of phase separation are unknown. Using NMR, simulation, and microscopy, Ryan et al. show how molecular alterations and interactions, common to a large family of disease-associated hnRNPs, alter phase separation and aggregation.
Infectious disease emergence has increased significantly over the last 30 years, with mass mortality events (MMEs) associated with epizootics becoming increasingly common. Factors influencing these ...events have been widely studied in terrestrial systems, but remain relatively unexplored in marine mammals. Infectious disease‐induced MMEs (ID MMEs) have not been reported ubiquitously among marine mammal species, indicating that intrinsic (host) and/or extrinsic (environmental) ecological factors may influence this heterogeneity. We assess the occurrence of ID MMEs (1955–2018) across extant marine mammals (n = 129) in relation to key life‐history characteristics (sociality, trophic level, habitat breadth) and environmental variables (season, sea surface temperature SST anomalies, El Niño occurrence). Our results show that ID MMEs have been reported in 14% of marine mammal species (95% CI 9%–21%), with 72% (n = 36; 95% CI 56%–84%) of these events caused predominantly by viruses, primarily morbillivirus and influenza A. Bacterial pathogens caused 25% (95% CI 14%–41%) of MMEs, with only one being the result of a protozoan pathogen. Overall, virus‐induced MMEs involved a greater number of fatalities per event compared to other pathogens. No association was detected between the occurrence of ID MMEs and host characteristics, such as sociality or trophic level, but ID MMEs did occur more frequently in semiaquatic species (pinnipeds) compared to obligate ocean dwellers (cetaceans; χ2 = 9.6, p = .002). In contrast, extrinsic factors significantly influenced ID MMEs, with seasonality linked to frequency (χ2 = 19.85, p = .0002) and severity of these events, and global yearly SST anomalies positively correlated with their temporal occurrence (Z = 3.43, p = 2.7e‐04). No significant association was identified between El Niño and ID MME occurrence (Z = 0.28, p = .81). With climate change forecasted to increase SSTs and the frequency of extreme seasonal weather events, epizootics causing MMEs are likely to intensify with significant consequences for marine mammal survival.
Infectious disease‐driven mass mortality events (ID MMEs; 1955–2018) were assessed across extant marine mammals (n = 129) in relation to key host characteristics (sociality, trophic level, habitat breadth) and environmental variables (season, sea surface temperature SST anomalies, El Niño occurrence). Climate factors, rather than host characteristics, significantly influenced the occurrence of ID MMEs, with seasonality determining the frequency and severity of these events, and SST anomalies being positively correlated with their temporal occurrence. With global climate change forecasted to increase SSTs and the frequency of extreme seasonal weather events, ID MMEs are likely to intensify with significant consequences for marine mammal survival.
Radiation therapy (RT) activates an in situ vaccine effect when combined with immune checkpoint blockade (ICB), yet this effect may be limited because RT does not fully optimize tumor antigen ...presentation or fully overcome suppressive mechanisms in the tumor-immune microenvironment. To overcome this, we develop a multifunctional nanoparticle composed of polylysine, iron oxide, and CpG (PIC) to increase tumor antigen presentation, increase the ratio of M1:M2 tumor-associated macrophages, and enhance stimulation of a type I interferon response in conjunction with RT. In syngeneic immunologically "cold" murine tumor models, the combination of RT, PIC, and ICB significantly improves tumor response and overall survival resulting in cure of many mice and consistent activation of tumor-specific immune memory. Combining RT with PIC to elicit a robust in situ vaccine effect presents a simple and readily translatable strategy to potentiate adaptive anti-tumor immunity and augment response to ICB or potentially other immunotherapies.
Inadequate health-care provider performance is a major challenge to the delivery of high-quality health care in low-income and middle-income countries (LMICs). The Health Care Provider Performance ...Review (HCPPR) is a comprehensive systematic review of strategies to improve health-care provider performance in LMICs.
For this systematic review we searched 52 electronic databases for published studies and 58 document inventories for unpublished studies from the 1960s to 2016. Eligible study designs were controlled trials and interrupted time series. We only included strategy-versus-control group comparisons. We present results of improving health-care provider practice outcomes expressed as percentages (eg, percentage of patients treated correctly) or as continuous measures (eg, number of medicines prescribed per patient). Effect sizes were calculated as absolute percentage-point changes. The summary measure for each comparison was the median effect size (MES) for all primary outcomes. Strategy effectiveness was described with weighted medians of MES. This study is registered with PROSPERO, number CRD42016046154.
We screened 216 477 citations and selected 670 reports from 337 studies of 118 strategies. Most strategies had multiple intervention components. For professional health-care providers (generally, facility-based health workers), the effects were near zero for only implementing a technology-based strategy (median MES 1·0 percentage points, IQR −2·8 to 9·9) or only providing printed information for health-care providers (1·4 percentage points, −4·8 to 6·2). For percentage outcomes, training or supervision alone typically had moderate effects (10·3–15·9 percentage points), whereas combining training and supervision had somewhat larger effects than use of either strategy alone (18·0–18·8 percentage points). Group problem solving alone showed large improvements in percentage outcomes (28·0–37·5 percentage points), but, when the strategy definition was broadened to include group problem solving alone or other strategy components, moderate effects were more typical (12·1 percentage points). Several multifaceted strategies had large effects, but multifaceted strategies were not always more effective than simpler ones. For lay health-care providers (generally, community health workers), the effect of training alone was small (2·4 percentage points). Strategies with larger effect sizes included community support plus health-care provider training (8·2–125·0 percentage points). Contextual and methodological heterogeneity made comparisons difficult, and most strategies had low quality evidence.
The impact of strategies to improve health-care provider practices varied substantially, although some approaches were more consistently effective than others. The breadth of the HCPPR makes its results valuable to decision makers for informing the selection of strategies to improve health-care provider practices in LMICs. These results also emphasise the need for researchers to use better methods to study the effectiveness of interventions.
Bill & Melinda Gates Foundation, CDC Foundation.
Resource partitioning promotes coexistence among guild members, and carnivores reduce interference competition through behavioral mechanisms that promote spatio-temporal separation. We analyzed ...sympatric lion and spotted hyena movements and activity patterns to ascertain the mechanisms facilitating their coexistence within semi-arid and wetland ecosystems. We identified recurrent high-use (revisitation) and extended stay (duration) areas within home ranges, as well as correlated movement-derived measures of inter- and intraspecific interactions with environmental variables. Spatial overlaps among lions and hyenas expanded during the wet season, and occurred at edges of home ranges, around water-points, along pathways between patches of high-use areas. Lions shared more of their home ranges with spotted hyenas in arid ecosystems, but shared more of their ranges with conspecifics in mesic environments. Despite shared space use, we found evidence for subtle temporal differences in the nocturnal movement and activity patterns between the two predators, suggesting a fine localized-scale avoidance strategy. Revisitation frequency and duration within home ranges were influenced by interspecific interactions, after land cover categories and diel cycles. Intraspecific interactions were also important for lions and, important for hyenas were moon illumination and ungulates attracted to former anthrax carcass sites in Etosha, with distance to water in Chobe/Linyanti. Recursion and duration according to locales of competitor probabilities were similar among female lions and both sexes of hyenas, but different for male lions. Our results suggest that lions and spotted hyenas mediate the potential for interference competition through subtle differences in temporal activity, fine-scale habitat use differentiation, and localized reactive-avoidance behaviors. These findings enhance our understanding of the potential effects of interspecific interactions among large carnivore space-use patterns within an apex predator system and show adaptability across heterogeneous and homogeneous environments. Future conservation plans should emphasize the importance of inter- and intraspecific competition within large carnivore communities, particularly moderating such effects within increasingly fragmented landscapes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and ...secular trends are lacking. Methods. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. Results. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. Conclusions. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) ...patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.
Neuronal inclusions of aggregated RNA‐binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation‐prone, yeast ...prion‐like, low sequence‐complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in‐cell phosphorylation sites across FUS LC. We show that both phosphorylation and phosphomimetic variants reduce its aggregation‐prone/prion‐like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self‐interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS‐associated cytotoxicity. Hence, post‐translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.
Synopsis
Self‐association of the ALS and FTD neurodegenerative disease‐linked RNA‐binding protein FUS is regulated by phosphorylation of its low complexity domain.
FUS low complexity (LC) domain can be phosphorylated at several sites: by DNA‐PK at 12 sites in vitro, and in human cells after DNA damage at additional sites.
FUS LC phosphorylation and phosphomimetic substitution discourages phase separation and aggregation.
FUS LC phosphomimetic substitution decreases FUS aggregation in yeast and human cell models.
FUS LC phosphomimetic substitution reduces FUS toxicity in the yeast model.
Post‐translational modification emerges as a cellular mechanism for controlling physiological assembly of the ALS and FTD neurodegenerative disease‐linked RNA‐binding protein FUS.
PDF
