Mobile health in adults with congenital heart disease: current use and future needs

ObjectiveMany adults with congenital heart disease (CHD) are affected lifelong by cardiac events, particularly arrhythmias and heart failure. Despite the care provided, the cardiac event rate remains high. Mobile health (mHealth) brings opportunities to enhance daily monitoring and hence timely response in an attempt to improve outcome. However, it is not known if adults with CHD are currently using mHealth and what type of mHealth they may need in the near future.MethodsConsecutive adult patients with CHD who visited the outpatient clinic at the Academic Medical Center in Amsterdam were asked to fill out questionnaires. Exclusion criteria for this study were mental impairment or inability to read and write Dutch.ResultsAll 118 patients participated (median age 40 (range 18–78) years, 40 % male, 49 % symptomatic) and 92 % owned a smartphone. Whereas only a small minority (14 %) of patients used mHealth, the large majority (75 %) were willing to start. Most patients wanted to use mHealth in order to receive more information on physical health, and advice on progression of symptoms or signs of deterioration. Analyses on age, gender and complexity of defect showed significantly less current smartphone usage at older age, but no difference in interest or preferences in type of mHealth application for the near future.ConclusionThe relatively young adult CHD population only rarely uses mHealth, but the majority are motivated to start using mHealth. New mHealth initiatives are required in these patients with a chronic condition who need lifelong surveillance in order to reveal if a reduction in morbidity and mortality and improvement in quality of life can be achieved.     

Polymorphisms in B Cell Co-Stimulatory Genes Are Associated with IgG Antibody Responses against Blood–Stage Proteins of Plasmodium vivax

The development of an effective immune response can help decrease mortality from malaria and its clinical symptoms. However, this mechanism is complex and has significant inter-individual variation, most likely owing to the genetic contribution of the human host. Therefore, this study aimed to investigate the influence of polymorphisms in genes involved in the costimulation of B-lymphocytes in the naturally acquired humoral immune response against proteins of the asexual stage of Plasmodium vivax. A total of 319 individuals living in an area of malaria transmission in the Brazilian Amazon were genotyped for four SNPs in the genes CD40, CD40L, BLYS and CD86. In addition, IgG antibodies against P. vivax apical membrane antigen 1 (PvAMA–1), Duffy binding protein (PvDBP) and merozoite surface protein 1 (PvMSP–1₁₉) were detected by ELISA. The SNP BLYS –871C>T was associated with the frequency of IgG responders to PvAMA–1 and PvMSP–1₁₉. The SNP CD40 –1C>T was associated with the IgG response against PvDBP, whereas IgG antibody titers against PvMSP–1₁₉ were influenced by the polymorphism CD86 +1057G>A. These data may help to elucidate the immunological aspects of vivax malaria and consequently assist in the design of malaria vaccines.     

Microarray-Based Genotyping and Clinical Outcomes of Staphylococcus aureus Bloodstream Infection: An Exploratory Study

The clinical course of Staphylococcus aureus bacteremia varies extensively. We sought to determine the relationship between genetic characteristics of the infecting pathogen and clinical outcomes in an exploratory study. In two study centers, 317 blood culture isolates were analyzed by DNA microarray and spa genotyping. By uni- and multivariate regression analyses associations of genotype data with 30-day all-cause mortality, severe sepsis/septic shock, disseminated disease, endocarditis, and osteoarticular infection were investigated. Univariate analysis showed significant association between S. aureus genes/gene-clusters or clonal complexes and clinical endpoints. For example CC15 was associated with 30-day mortality and CC22 with osteoarticular infection. In multivariate analysis methicillin resistance (mecA, OR 4.8 [1.43–16.06]) and the beta-lactamase-gene (bla, OR 3.12 [1.17–8.30]) remained independently associated with 30-day mortality. The presence of genes for enterotoxins (sed/sej/ser) was associated with endocarditis (OR 5.11 [1.14–18.62]). Host factors such as McCabe classification (OR 4.52 [2.09–9.79] for mortality), age (OR 1.06 [1.03–1.10] per year), and community-acquisition (OR 3.40 [1.31–8.81]) had a major influence on disease severity, dissemination and mortality. Individual genotypes and clonal complexes of S. aureus can only partially explain clinical features and outcomes of S. aureus bacteremia. Genotype-phenotype association studies need to include adjustments for host factors like age, comorbidity and community-acquisition.     

Scaling up diarrhea prevention and treatment interventions: a Lives Saved Tool analysis

Background

Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated.

Methods and Findings

We use the Lives Saved Tool (LiST) to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding) were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions) and universal (assumes near 100% coverage of all interventions) scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions.

Conclusion

Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations'' Millennium Development Goal 4 (MDG4) by 2015. Please see later in the article for the Editors'' Summary     

CRISPR–Cas9-assisted recombineering in Lactobacillus reuteri

Clustered regularly interspaced palindromic repeats (CRISPRs) and the CRISPR-associated (Cas) nuclease protect bacteria and archeae from foreign DNA by site-specific cleavage of incoming DNA. Type-II CRISPR–Cas systems, such as the Streptococcus pyogenes CRISPR–Cas9 system, can be adapted such that Cas9 can be guided to a user-defined site in the chromosome to introduce double-stranded breaks. Here we have developed and optimized CRISPR–Cas9 function in the lactic acid bacterium Lactobacillus reuteri ATCC PTA 6475. We established proof-of-concept showing that CRISPR–Cas9 selection combined with single-stranded DNA (ssDNA) recombineering is a realistic approach to identify at high efficiencies edited cells in a lactic acid bacterium. We show for three independent targets that subtle changes in the bacterial genome can be recovered at efficiencies ranging from 90 to 100%. By combining CRISPR–Cas9 and recombineering, we successfully applied codon saturation mutagenesis in the L. reuteri chromosome. Also, CRISPR–Cas9 selection is critical to identify low-efficiency events such as oligonucleotide-mediated chromosome deletions. This also means that CRISPR–Cas9 selection will allow identification of recombinant cells in bacteria with low recombineering efficiencies, eliminating the need for ssDNA recombineering optimization procedures. We envision that CRISPR–Cas genome editing has the potential to change the landscape of genome editing in lactic acid bacteria, and other Gram-positive bacteria.     

Enhancing antisense efficacy with multimers and multi-targeting oligonucleotides (MTOs) using cleavable linkers

The in vivo potency of antisense oligonucleotides (ASO) has been significantly increased by reducing their length to 8–15 nucleotides and by the incorporation of high affinity RNA binders such as 2′, 4′-bridged nucleic acids (also known as locked nucleic acid or LNA, and 2′,4′-constrained ethyl [cET]). We now report the development of a novel ASO design in which such short ASO monomers to one or more targets are co-synthesized as homo- or heterodimers or multimers via phosphodiester linkers that are stable in plasma, but cleaved inside cells, releasing the active ASO monomers. Compared to current ASOs, these multimers and multi-targeting oligonucleotides (MTOs) provide increased plasma protein binding and biodistribution to liver, and increased in vivo efficacy against single or multiple targets with a single construct. In vivo, MTOs synthesized in both RNase H-activating and steric-blocking oligonucleotide designs provide ≈4–5-fold increased potency and ≈2-fold increased efficacy, suggesting broad therapeutic applications.     

Carbon Sequestration Potential in Stands under the Grain for Green Program in Southwest China

The Grain for Green Program (GGP) is the largest afforestation and reforestation project in China in the early part of this century. To assess carbon sequestration in stands under the GGP in Southwest China, the carbon stocks and their annual changes in the GGP stands in the region were estimated based on the following information: (1) collected data on the annually planted area of each tree species under the GGP in Southwest China from 1999 to 2010; (2) development of empirical growth curves and corresponding carbon estimation models for each species growing in the GPP stands; and (3) parameters associated with the stands such as wood density, biomass expansion factor, carbon fraction and the change rate of soil organic carbon content. Two forest management scenarios were examined: scenario A, with no harvesting, and scenario B, with logging at the customary rotation followed by replanting. The results showed that by the years 2020, 2030, 2040, 2050 and 2060, the expected carbon storage of the GGP stands in Southwest China is 139.58 TgC, 177.50–207.55 TgC, 196.86–259.65 TgC, 240.45–290.62 TgC and 203.22–310.03 TgC (T = 10¹²), respectively. For the same years, the expected annual change in carbon stocks is 7.96 TgCyr⁻¹, −7.95–5.95 TgCyr⁻¹, −0.10–4.67 TgCyr⁻¹, 4.31–2.24 TgCyr⁻¹ and −0.02–1.75 TgCyr⁻¹, respectively. This indicates that the stands significantly contribute to forest carbon sinks in this region. In 2060, the estimated carbon stocks in the seven major species of GGP stands in Southwest China are 4.16–13.01 TgC for Pinus armandii, 6.30–15.01 TgC for Pinus massoniana, 11.51–13.44 TgC for Cryptomeria fortunei, 15.94–24.13 TgC for Cunninghamia lanceolata, 28.05 TgC for Cupressus spp., 5.32–15.63 TgC for Populus deltoides and 5.87–14.09 TgC for Eucalyptus spp. The carbon stocks in these seven species account for 36.8%–41.4% of the total carbon stocks in all GGP stands over the next 50 years.     

Angiopoietin-2 Is Associated with Albuminuria and Microinflammation in Chronic Kidney Disease

Although cardiovascular disease (CVD) is the leading cause of mortality in patients with chronic kidney disease (CKD), the pathophysiology is not thoroughly understood. Given that elevated albuminuria or circulating angiopoietin-2 associates with CVD and mortality in CKD patients, we were intrigued by the relationship between albuminuria and angiopoietin-2. A total of 416 patients with CKD stages 3 to 5 were stratified by urine albumin-creatinine ratio as normoalbuminuria (<30 mg/g), microalbuminuria (30–300 mg/g), or macroalbuminuria (>300 mg/g). The levels of plasma angiopoietin-2 and vascular endothelial growth factor (VEGF) increased, and soluble Tie-2 decreased in the subgroups of albuminuria; whereas angiopoietin-1 did not change. Linear regression showed a positive correlation between urine albumin-creatinine ratio (ACR) and plasma angiopoietin-2 (correlation coefficient r = 0.301, 95% confidence interval 0.211–0.386, P<0.0001), but not between ACR and VEGF or soluble Tie-2. Multivariate linear regression analysis showed that plasma angiopoietin-2 was independently associated with ACR (P = 0.025). Furthermore, plasma angiopoietin-2 was positively correlated with high sensitive C-reactive protein (r = 0.114, 95% confidence interval 0.018–0.208, P = 0.020). In conclusion, plasma angiopoietin-2 was associated with albuminuria and markers of systemic microinflammation in CKD patients. Although previous evidence has shown that angiopoietin-2 destabilizes vasculature and induces inflammation in different scenarios, further study will be required to delineate the role of angiopoietin-2 in albuminuria and microinflammation in CKD patients.     

Confronting Uncertainty in Wildlife Management: Performance of Grizzly Bear Management

Scientific management of wildlife requires confronting the complexities of natural and social systems. Uncertainty poses a central problem. Whereas the importance of considering uncertainty has been widely discussed, studies of the effects of unaddressed uncertainty on real management systems have been rare. We examined the effects of outcome uncertainty and components of biological uncertainty on hunt management performance, illustrated with grizzly bears (Ursus arctos horribilis) in British Columbia, Canada. We found that both forms of uncertainty can have serious impacts on management performance. Outcome uncertainty alone – discrepancy between expected and realized mortality levels – led to excess mortality in 19% of cases (population-years) examined. Accounting for uncertainty around estimated biological parameters (i.e., biological uncertainty) revealed that excess mortality might have occurred in up to 70% of cases. We offer a general method for identifying targets for exploited species that incorporates uncertainty and maintains the probability of exceeding mortality limits below specified thresholds. Setting targets in our focal system using this method at thresholds of 25% and 5% probability of overmortality would require average target mortality reductions of 47% and 81%, respectively. Application of our transparent and generalizable framework to this or other systems could improve management performance in the presence of uncertainty.     

Patterns and Variability of Projected Bioclimatic Habitat for Pinus albicaulis in the Greater Yellowstone Area

Projected climate change at a regional level is expected to shift vegetation habitat distributions over the next century. For the sub-alpine species whitebark pine (Pinus albicaulis), warming temperatures may indirectly result in loss of suitable bioclimatic habitat, reducing its distribution within its historic range. This research focuses on understanding the patterns of spatiotemporal variability for future projected P.albicaulis suitable habitat in the Greater Yellowstone Area (GYA) through a bioclimatic envelope approach. Since intermodel variability from General Circulation Models (GCMs) lead to differing predictions regarding the magnitude and direction of modeled suitable habitat area, nine bias-corrected statistically down-scaled GCMs were utilized to understand the uncertainty associated with modeled projections. P.albicaulis was modeled using a Random Forests algorithm for the 1980–2010 climate period and showed strong presence/absence separations by summer maximum temperatures and springtime snowpack. Patterns of projected habitat change by the end of the century suggested a constant decrease in suitable climate area from the 2010 baseline for both Representative Concentration Pathways (RCPs) 8.5 and 4.5 climate forcing scenarios. Percent suitable climate area estimates ranged from 2–29% and 0.04–10% by 2099 for RCP 8.5 and 4.5 respectively. Habitat projections between GCMs displayed a decrease of variability over the 2010–2099 time period related to consistent warming above the 1910–2010 temperature normal after 2070 for all GCMs. A decreasing pattern of projected P.albicaulis suitable habitat area change was consistent across GCMs, despite strong differences in magnitude. Future ecological research in species distribution modeling should consider a full suite of GCM projections in the analysis to reduce extreme range contractions/expansions predictions. The results suggest that restoration strageties such as planting of seedlings and controlling competing vegetation may be necessary to maintain P.albicaulis in the GYA under the more extreme future climate scenarios.     

Association of Early Repolarization Pattern on ECG with Risk of Cardiac and All-Cause Mortality: A Population-Based Prospective Cohort Study (MONICA/KORA)

Background

Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent.

Methods and Findings

Electrocardiograms of 1,945 participants aged 35–74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05–3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21–5.83, p = 0.015) for men between 35–54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58–6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90–9.61, p<0.001) for men between 35–54 y. HRs for all-cause mortality were weaker but reached significance.

Conclusions

We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors'' Summary     

Aetiology-Specific Estimates of the Global and Regional Incidence and Mortality of Diarrhoeal Diseases Commonly Transmitted through Food

Background

Diarrhoeal diseases are major contributors to the global burden of disease, particularly in children. However, comprehensive estimates of the incidence and mortality due to specific aetiologies of diarrhoeal diseases are not available. The objective of this study is to provide estimates of the global and regional incidence and mortality of diarrhoeal diseases caused by nine pathogens that are commonly transmitted through foods.

Methods and Findings

We abstracted data from systematic reviews and, depending on the overall mortality rates of the country, applied either a national incidence estimate approach or a modified Child Health Epidemiology Reference Group (CHERG) approach to estimate the aetiology-specific incidence and mortality of diarrhoeal diseases, by age and region. The nine diarrhoeal diseases assessed caused an estimated 1.8 billion (95% uncertainty interval [UI] 1.1–3.3 billion) cases and 599,000 (95% UI 472,000–802,000) deaths worldwide in 2010. The largest number of cases were caused by norovirus (677 million; 95% UI 468–1,153 million), enterotoxigenic Escherichia coli (ETEC) (233 million; 95% UI 154–380 million), Shigella spp. (188 million; 95% UI 94–379 million) and Giardia lamblia (179 million; 95% UI 125–263); the largest number of deaths were caused by norovirus (213,515; 95% UI 171,783–266,561), enteropathogenic E. coli (121,455; 95% UI 103,657–143,348), ETEC (73,041; 95% UI 55,474–96,984) and Shigella (64,993; 95% UI 48,966–92,357). There were marked regional differences in incidence and mortality for these nine diseases. Nearly 40% of cases and 43% of deaths caused by these nine diarrhoeal diseases occurred in children under five years of age.

Conclusions

Diarrhoeal diseases caused by these nine pathogens are responsible for a large disease burden, particularly in children. These aetiology-specific burden estimates can inform efforts to reduce diarrhoeal diseases caused by these nine pathogens commonly transmitted through foods.     

Root–root interactions: extending our perspective to be more inclusive of the range of theories in ecology and agriculture using in-vivo analyses

Background

There is a large body of literature on competitive interactions among plants, but many studies have only focused on above-ground interactions and little is known about root–root dynamics between interacting plants. The perspective on possible mechanisms that explain the outcome of root–root interactions has recently been extended to include non-resource-driven mechanisms (as well as resource-driven mechanisms) of root competition and positive interactions such as facilitation. These approaches have often suffered from being static, partly due to the lack of appropriate methodologies for in-situ non-destructive root characterization.

Scope

Recent studies show that interactive effects of plant neighbourhood interactions follow non-linear and non-additive paths that are hard to explain. Common outcomes such as accumulation of roots mainly in the topsoil cannot be explained solely by competition theory but require a more inclusive theoretical, as well as an improved methodological framework. This will include the question of whether we can apply the same conceptual framework to crop versus natural species.

Conclusions

The development of non-invasive methods to dynamically study root–root interactions in vivo will provide the necessary tools to study a more inclusive conceptual framework for root–root interactions. By following the dynamics of root–root interactions through time in a whole range of scenarios and systems, using a wide variety of non-invasive methods, (such as fluorescent protein which now allows us to separately identify the roots of several individuals within soil), we will be much better equipped to answer some of the key questions in root physiology, ecology and agronomy.     

The Impact of Opportunistic Infections on Clinical Outcome and Healthcare Resource Uses for Adult T Cell Leukaemia

We examined the impact of opportunistic infections on in-hospital mortality, hospital length of stay (LOS), and the total cost (TC) among adult T-cell leukaemia (ATL) patients. In this retrospective cohort study, we identified 3712 patients with ATL using national hospital administrative data. Analysed opportunistic infections included Aspergillus spp., Candida spp., cytomegalovirus (CMV), herpes simplex virus (HSV), pneumocystis pneumonia (PCP), tuberculosis, varicella zoster virus (VZV), Cryptococcus spp., nontuberculous mycobacteria, and Strongyloides spp. Multilevel logistic regression analysis for in-hospital mortality and a multilevel linear regression analysis for LOS and TC were employed to determine the impact of opportunistic infections on clinical outcomes and healthcare resources. We found ATL patients infected with CMV had significantly higher in-hospital mortality (adjusted odds ratio (AOR) 2.29 [1.50–3.49] p < 0.001), longer LOS (coefficient (B): 0.13 [0.06–0.20] p < 0.001) and higher TC (B: 0.25 [0.17–0.32] p < 0.001) than those without CMV. Those with CAN and PCP were associated with a lower in-hospital mortality rate (AOR 0.72 [0.53–0.98] p = 0.035 and 0.54[0.41–0.73] p < 0.001, respectively) than their infections. VZV was associated with longer LOS (B: 0.13 [0.06–0.19] p < 0.001), while aspergillosis, HSV, or VZV infections were associated with higher TC (B: 0.16 [0.07–0.24] p < 0.001, 0.12 [0.02–0.23] p = 0.025, and 0.17 [0.10–0.24] p < 0.001, respectively). Our findings reveal that CMV infection is a major determinant of poor prognosis in patients affected by ATL.     

Trends of Tuberculosis Case Notification and Treatment Outcomes in the Sidama Zone,Southern Ethiopia: Ten-Year Retrospective Trend Analysis in Urban-Rural Settings

BackgroundEthiopia is one of the high tuberculosis (TB) burden countries. An analysis of trends and differentials in case notifications and treatment outcomes of TB may help improve our understanding of the performance of TB control services.MethodsA retrospective trend analysis of TB cases was conducted in the Sidama Zone in southern Ethiopia. We registered all TB cases diagnosed and treated during 2003–2012 from all health facilities in the Sidama Zone, and analysed trends of TB case notification rates and treatment outcomes.ResultsThe smear positive (PTB+) case notification rate (CNR) increased from 55 (95% CI 52.5–58.4) to 111 (95% CI 107.4–114.4) per 10⁵ people. The CNRs of PTB+ in people older than 45 years increased by fourfold, while the mortality of cases during treatment declined from 11% to 3% for smear negative (PTB-) (X²_trend, P<0.001) and from 5% to 2% for PTB+ (X²_trend, P<0.001). The treatment success was higher in rural areas (AOR 1.11; CI 95%: 1.03–1.2), less for PTB- (AOR 0.86; CI 95%: 0.80–0.92) and higher for extra-pulmonary TB (AOR 1.10; CI 95%: 1.02–1.19) compared to PTB+. A higher lost-to-follow up was observed in men (AOR 1.15; CI 95%: 1.06–1.24) and among PTB- cases (AOR 1.14; CI 95%: 1.03–1.25). More deaths occurred in PTB-cases (AOR 1.65; 95% CI: 1.44–1.90) and among cases older than 65 years (AOR 3.86; CI 95%: 2.94–5.10). Lastly, retreatment cases had a higher mortality than new cases (6% vs 3%).ConclusionOver the past decade TB CNRs and treatment outcomes improved, whereas the disparities of disease burden by gender and place of residence reduced and mortality declined. Strategies should be devised to address higher risk groups for poor treatment outcomes.     

Genetic Variants in Inflammation-Related Genes Are Associated with Radiation-Induced Toxicity Following Treatment for Non-Small Cell Lung Cancer

Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10–3.39), rs5275 (HR:1.58, 95% CI:1.09–2.27), and rs689470 (HR:3.38, 95% CI:1.09–10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31–0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14–7.63 and HR:3.23, 95% CI:1.03–10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P<0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events.     

Effects of climate change on the distribution of wild Akebia trifoliata

Understanding the impacts and constraints of climate change on the geographical distribution of wild Akebia trifoliata is crucial for its sustainable management and economic development as a medicinal material or fruit. In this study, according to the first‐hand information obtained from field investigation, the distribution and response to climate change of A. trifoliata were studied by the MaxEnt model and ArcGIS. The genetic diversity and population structure of 21 natural populations of A. trifoliata were studied by simple sequence repeat (SSR) markers. The results showed that the most important bioclimatic variable limiting the distribution of A. trifoliata was the Mean Temperature of Coldest Quarter (bio11). Under the scenarios SSP1‐2.6 and SSP2‐4.5, the suitable area of A. trifoliata in the world will remain stable, and the suitable area will increase significantly under the scenarios of SSP3‐7.0 and SSP5‐8.5. Under the current climate scenario, the suitable growth regions of A. trifoliata in China were 79.9–122.7°E and 21.5–37.5°N. Under the four emission scenarios in the future, the geometric center of the suitable distribution regions of Akebia trifoliata in China will move to the north. The clustering results of 21 populations of A. trifoliata analyzed by SSR markers showed that they had a trend of evolution from south to north.     

Programmable cleavage of linear double-stranded DNA by combined action of Argonaute CbAgo from Clostridium butyricum and nuclease deficient RecBC helicase from E. coli

Prokaryotic Argonautes (pAgos) use small nucleic acids as specificity guides to cleave single-stranded DNA at complementary sequences. DNA targeting function of pAgos creates attractive opportunities for DNA manipulations that require programmable DNA cleavage. Currently, the use of mesophilic pAgos as programmable endonucleases is hampered by their limited action on double-stranded DNA (dsDNA). We demonstrate here that efficient cleavage of linear dsDNA by mesophilic Argonaute CbAgo from Clostridium butyricum can be activated in vitro via the DNA strand unwinding activity of nuclease deficient mutant of RecBC DNA helicase from Escherichia coli (referred to as RecB^exo–C). Properties of CbAgo and characteristics of simultaneous cleavage of DNA strands in concurrence with DNA strand unwinding by RecB^exo–C were thoroughly explored using 0.03–25 kb dsDNAs. When combined with RecB^exo–C, CbAgo could cleave targets located 11–12.5 kb from the ends of linear dsDNA at 37°C. Our study demonstrates that CbAgo with RecB^exo–C can be programmed to generate DNA fragments with custom-designed single-stranded overhangs suitable for ligation with compatible DNA fragments. The combination of CbAgo and RecB^exo–C represents the most efficient mesophilic DNA-guided DNA-cleaving programmable endonuclease for in vitro use in diagnostic and synthetic biology methods that require sequence-specific nicking/cleavage of linear dsDNA at any desired location.     

Mechanisms of biodiversity between Campylobacter sequence types in a flock of broiler–breeder chickens

Commercial poultry flocks frequently harbor the dangerous bacterial pathogen Campylobacter. As exclusion efforts frequently fail, there is interest in potential ecologically informed solutions. A long‐term study of Campylobacter sequence types was used to investigate the competitive framework of the Campylobacter metacommunity and understand how multiple sequence types simultaneously co‐occur in a flock of chickens. A combination of matrix and patch‐occupancy models was used to estimate parameters describing the competition, transmission, and mortality of each sequence type. It was found that Campylobacter sequence types form a strong hierarchical framework within a flock of chickens and occupied a broad spectrum of transmission–mortality trade‐offs. Upon further investigation of how biodiversity is thus maintained within the flock, it was found that the demographic capabilities of Campylobacter, such as mortality and transmission, could not explain the broad biodiversity of sequence types seen, suggesting that external factors such as host‐bird health and seasonality are important elements in maintaining biodiversity of Campylobacter sequence types.