CRISPR-Cas12a is a promising genome editing system for targeting AT-rich genomic regions. Comprehensive genome engineering requires simultaneous targeting of multiple genes at defined locations. ...Here, to expand the targeting scope of Cas12a, we screen nine Cas12a orthologs that have not been demonstrated in plants, and identify six, ErCas12a, Lb5Cas12a, BsCas12a, Mb2Cas12a, TsCas12a and MbCas12a, that possess high editing activity in rice. Among them, Mb2Cas12a stands out with high editing efficiency and tolerance to low temperature. An engineered Mb2Cas12a-RVRR variant enables editing with more relaxed PAM requirements in rice, yielding two times higher genome coverage than the wild type SpCas9. To enable large-scale genome engineering, we compare 12 multiplexed Cas12a systems and identify a potent system that exhibits nearly 100% biallelic editing efficiency with the ability to target as many as 16 sites in rice. This is the highest level of multiplex edits in plants to date using Cas12a. Two compact single transcript unit CRISPR-Cas12a interference systems are also developed for multi-gene repression in rice and Arabidopsis. This study greatly expands the targeting scope of Cas12a for crop genome engineering.
By revisiting Thomas Jefferson's understanding of executive power this book offers a new understanding of the origins of presidential power. Before Jefferson was elected president, he arrived at a ...way to resolve the tension between constitutionalism and executive power. Because his solution would preserve a strict interpretation of the Constitution as well as transform the precedents left by his Federalist predecessors, it provided an alternative to Alexander Hamilton's understanding of executive power. In fact, a more thorough account of Jefferson's political career suggests that Jefferson envisioned an executive that was powerful, or 'energetic', because it would be more explicitly attached to the majority will. Jefferson's Revolution of 1800, often portrayed as a reversal of the strong presidency, was itself premised on energy in the executive and was part of Jefferson's project to enable the Constitution to survive and even flourish in a world governed by necessity.
We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the ...Sustainable Development Goals of the United Nations.
In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses.
A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval CI, 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing.
Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .).
Does the president represent the entire nation? Or does he speak for core partisans and narrow constituencies? TheFederalist Papers, the electoral college, history and circumstance from the founders' ...time to our own: all factor in theories of presidential representation, again and again lending themselves to different interpretations. This back-and-forth, Jeremy D. Bailey contends, is a critical feature, not a flaw, in American politics. Arriving at a moment of great debate over the nature and exercise of executive power, Bailey's history offers an invaluable, remarkably relevant analysis of the intellectual underpinnings, political usefulness, and practical merits of contending ideas of presidential representation over time. Among scholars, a common reading of political history holds that the founders, aware of the dangers of demagogy, created a singularly powerful presidency that would serve as a check on the people's representatives in Congress; then, this theory goes, the Progressives, impatient with such a counter-majoritarian approach, reformed the presidency to better reflect the people's will-and, they reasoned, advance the public good.The Idea of Presidential Representation challenges this consensus, offering a more nuanced view of the shifting relationship between the president and the American people. Implicit in this pattern, Bailey tells us, is another equivocal relationship-that between law and public opinion as the basis for executive power in republican constitutionalism. Tracing these contending ideas from the framers time to our own, his book provides both a history and a much-needed context for our understanding of presidential representation in light of the modern presidency. InThe Idea of Presidential Representation Bailey gives us a new and useful sense of an enduring and necessary feature of our politics.
Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine ...whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malaria.
In a cluster-randomized trial conducted from 23 November 2014 until 31 July 2017, 30 rural communities in Niger were randomized to 2 years of biannual mass distributions of either azithromycin (20 mg/kg oral suspension) or placebo to children aged 1 to 59 months. Participants, field staff, and investigators were masked to treatment allocation. The primary malaria outcome was the community prevalence of parasitemia on thick blood smear, assessed in a random sample of children from each community at study visits 12 and 24 months after randomization. Analyses were performed in an intention-to-treat fashion. At the baseline visit, a total of 1,695 children were enumerated in the 15 azithromycin communities, and 3,029 children were enumerated in the 15 placebo communities. No communities were lost to follow-up. The mean prevalence of malaria parasitemia at baseline was 8.9% (95% CI 5.1%-15.7%; 52 of 552 children across all communities) in the azithromycin-treated group and 6.7% (95% CI 4.0%-12.6%; 36 of 542 children across all communities) in the placebo-treated group. In the prespecified primary analysis, parasitemia was lower in the azithromycin-treated group at month 12 (mean prevalence 8.8%, 95% CI 5.1%-14.3%; 51 of 551 children across all communities) and month 24 (mean 3.5%, 95% CI 1.9%-5.5%; 21 of 567 children across all communities) than it was in the placebo-treated group at month 12 (mean 15.3%, 95% CI 10.8%-20.6%; 81 of 548 children across all communities) and month 24 (mean 4.8%, 95% CI 3.3%-6.4%; 28 of 592 children across all communities) (P = 0.02). Communities treated with azithromycin had approximately half the odds of parasitemia compared to those treated with placebo (odds ratio OR 0.54, 95% CI 0.30 to 0.97). Parasite density was lower in the azithromycin group than the placebo group at 12 and 24 months (square root-transformed outcome; density estimates were 7,540 parasites/μl lower 95% CI -350 to -12,550 parasites/μl; P = 0.02 at a mean parasite density of 17,000, as was observed in the placebo arm). No significant difference in hemoglobin was observed between the 2 treatment groups at 12 and 24 months (mean 0.34 g/dL higher in the azithromycin arm, 95% CI -0.06 to 0.75 g/dL; P = 0.10). No serious adverse events were reported in either group, and among children aged 1 to 5 months, the most commonly reported nonserious adverse events (i.e., diarrhea, vomiting, and rash) were less common in the azithromycin-treated communities. Limitations of the trial include the timing of the treatments and monitoring visits, both of which took place before the peak malaria season, as well as the uncertain generalizability to areas with different malaria transmission dynamics.
Mass azithromycin distributions were associated with a reduced prevalence of malaria parasitemia in this trial, suggesting one possible mechanism for the mortality benefit observed with this intervention.
The trial was registered on ClinicalTrials.gov (NCT02048007).
Malnourished children are at increased risk of mortality from infectious diseases such as diarrhea and respiratory tract infections 6. ...the relationship between malnutrition and infection is ...complex, with undernutrition suppressing the immune system and increasing the risk of infection, and infection causing a reduction in appetite, malabsorption of nutrients, and competition for nutrients 7,8, Provision of antibiotics to malnourished children could lead to clearance of both overt and subclinical infections associated with mortality. Outcomes The outcome for this analysis is mortality, defined as community mortality rate (deaths per 1,000 person-years at risk). Given the fixed design, the prevalence of moderate to severe and severe underweight, and the mortality rates within subgroups, this subgroup analysis had 80% power to detect additive interaction effects of the following sizes, interpreted as the mortality rate among underweight children receiving placebo in excess of the individual effects of underweight or placebo on mortality: 17 deaths per 1,000 person-years for the moderate to severe subgroup and 25 deaths per 1,000 person-years for the severe subgroup 22. Analyses were conducted in R. Participant characteristics, WAZ, and outcomes were summarized by arm using frequency and percentage for categorical variables, mean and standard deviation for continuous variables, and incidence rate (deaths per 1,000 person-years, hereafter referred to as “mortality rate”) and 95% confidence interval for outcomes.
Recent evidence indicates mass drug administration with azithromycin may reduce child mortality. This study uses verbal autopsy (VA) to investigate the causes of individual deaths during the ...Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Malawi. Cluster randomization was performed as part of MORDOR. Biannual household visits were conducted to distribute azithromycin or placebo to children aged 1-59 months and update the census to identify deaths for VA. MORDOR was not powered to investigate mortality effects at individual sites, but the available evidence is presented here for hypothesis generation regarding the mechanism through which azithromycin may reduce child mortality. Automated VA analysis was performed to infer the likely cause of death using two major analysis programs, InterVA and SmartVA. A total of 334 communities were randomized to azithromycin or placebo, with more than 130,000 person-years of follow-up. During the study, there were 1,184 deaths, of which 1,131 were followed up with VA. Mortality was 9% lower in azithromycin-treated communities than in placebo communities (rate ratio 0.91 95% CI: 0.79-1.05;
= 0.20). The intention-to-treat analysis by cause using InterVA suggested fewer HIV/AIDS deaths in azithromycin-treated communities (rate ratio 0.70 95% CI: 0.50-0.97;
= 0.03) and fewer pneumonia deaths (rate ratio 0.82 95% CI: 0.60-1.12;
= 0.22). The use of the SmartVA algorithm suggested fewer diarrhea deaths (rate ratio 0.71 95% CI: 0.51-1.00;
= 0.05) and fewer pneumonia deaths (rate ratio 0.58 95% CI: 0.33-1.00;
= 0.05). Although this study is not able to provide strong evidence, the data suggest that the mortality reduction during MORDOR in Malawi may have been due to effects on pneumonia and diarrhea or HIV/AIDS mortality.
Populism raises questions about the extent to which public opinion should be a legitimate foundation for executive power. In the United States, it is often thought, such a foundation was established ...at the beginning of the twentieth century through the creation of a newly "representative" modern presidency (one that enabled the president to represent the popular will). This new presidency, it is held, acts as an agent of populist majorities to undermine constitutional and legal norms. In fact, however, the argument for presidential representation is a long-standing element of politics in the United States. It is appealed to, recurrently, by what might be called the party of opinion against its natural opponent, the party of law.
To investigate radiation necrosis in patients treated for glioma in terms of incidence, outcomes, predictive and prognostic factors.
Records were reviewed for 426 patients followed up until death or ...for at least 3 years. Logistic regression analysis was performed to identify predictive and prognostic factors. Multivariate survival analysis was conducted using Cox proportional hazards regression. Separate analyses were performed for the subset of 352 patients who received a biologically effective dose (BED) > or =85.5 Gy2 (> or =45 Gy/25 fractions) who were at highest risk for radionecrosis.
Twenty-one patients developed radionecrosis (4.9%). Actuarial incidence plateaued at 13.3% after 3 years. In the high-risk subset, radiation parameters confirmed as risk factors included total dose (p < 0.001), BED (p < 0.005), neuret (p < 0.001), fraction size (p = 0.028), and the product of total dose and fraction size (p = 0.001). No patient receiving a BED <96 Gy2 developed radionecrosis. Subsequent chemotherapy significantly increased the risk of cerebral necrosis (p = 0.001) even when adjusted for BED (odds ratio OR, 5.8; 95% confidence interval CI, 1.6-20.3) or length of follow-up (OR, 5.4; 95% CI, 1.5-19.3). Concurrent use of valproate appeared to delay the onset of necrosis (p = 0.013). The development of radionecrosis did not affect survival (p = 0.09).
Cerebral necrosis is unlikely at doses below 50 Gy in 25 fractions. The risk increases significantly with increasing radiation dose, fraction size, and the subsequent administration of chemotherapy.
Mass azithromycin distribution reduces under-5 child mortality. Trachoma control programs currently treat infants aged 6 months and older. Here, we report findings from an infant adverse event survey ...in 1-5 month olds who received azithromycin as part of a large community-randomized trial in Niger.
Active surveillance of infants aged 1-5 months at the time of treatment was conducted in 30 randomly selected communities from within a large cluster randomized trial of biannual mass azithromycin distribution compared to placebo to assess the potential impact on child mortality. We compared the distribution of adverse events reported after treatment among azithromycin-treated versus placebo-treated infants. From January 2015 to February 2018, the caregivers of 1,712 infants were surveyed. Approximately one-third of caregivers reported at least one adverse event (azithromycin: 29.6%, placebo: 34.3%, risk ratio RR 0.86, 95% confidence interval CI 0.68 to 1.10, P = 0.23). The most commonly reported adverse events included diarrhea (azithromycin: 19.3%, placebo: 28.1%, RR 0.68, 95% CI 0.49 to 0.96, P = 0.03), vomiting (azithromycin: 15.9%, placebo: 21.0%, RR 0.76, 95% CI 0.56 to 1.02, P = 0.07), and skin rash (azithromycin: 12.3%, placebo: 13.6%, RR 0.90, 95% CI 0.59 to 1.37, P = 0.63). No cases of infantile hypertrophic pyloric stenosis were reported.
Azithromycin given to infants aged 1-5 months appeared to be safe. Inclusion of younger infants in larger azithromycin-based child mortality or trachoma control programs could be considered if deemed effective.
ClinicalTrials.gov NCT02048007.
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