The authors of this ambitious book address a fundamental political question: why are leaders who produce peace and prosperity turned out of office while those who preside over corruption, war, and ...misery endure? Considering this political puzzle, they also answer the related economic question of why some countries experience successful economic development and others do not. The authors construct a provocative theory on the selection of leaders and present specific formal models from which their central claims can be deduced. They show how political leaders allocate resources and how institutions for selecting leaders create incentives for leaders to pursue good and bad public policy. They also extend the model to explain the consequences of war on political survival. Throughout the book, they provide illustrations from history, ranging from ancient Sparta to Vichy France, and test the model against statistics gathered from cross-national data. The authors explain the political intuition underlying their theory in nontechnical language, reserving formal proofs for chapter appendixes. They conclude by presenting policy prescriptions based on what has been demonstrated theoretically and empirically.
The laws of war seek to regulate conduct during wartime. The record of compliance with these treaties is mixed. I explain compliance as the result of publicly accepted and so legally binding ...agreements that create incentives for the parties to enforce those agreements through reciprocity. Ratification by a democracy is a signal that it intends to abide by the treaty standard; those that ratify are more likely to comply. Ratification does not effect the behavior of nondemocracies, however. Ratification of the relevant treaty by both warring parties strengthens reciprocity. There is a hierarchy of average compliance across issues which matches the scope for violations by individuals on each issue, with greater scope for such violations corresponding to lower levels of compliance.
Kenwick, Vasquez, and Powers contend that defensive alliances provoke conflict; Leeds and Johnson argue that they deter conflict. I use a formal model to deduce conditions under which alliances ...provoke and those under which they deter, allowing us to distinguish the two effects. The model shows that both sets of analyses include cases that should be left out of an analysis of whether alliances are more likely to provoke or deter. I re-analyze both sides’ data and find evidence suggestive that alliances provoke only when the two sides do not have a recent history of conflict or alliances but deter when they do.
The Rh-catalyzed hydroacylative union of aldehydes and o-alkynyl anilines leads to 2-aminophenyl enones, and onward to substituted quinolines. The mild reaction conditions employed in this chemistry ...result in a process that displays broad functional group tolerance, allowing the preparation of diversely substituted quinolines in high yields. Extension to the use of o-alkynyl nitro arenes as substrates leads to 2-nitrochalcones, from which both quinolines and quinoline N-oxides can be accessed.
Aims
The rate of inpatient mortality associated with diabetic ketoacidosis (DKA) has steadily decreased in recent decades. However, there remains a significantly increased outpatient death rate ...following an episode of survived DKA. We undertook this study to investigate the observed increase in mortality following an episode of DKA.
Methods
We completed a retrospective cohort study to investigate rates and causes of death in people admitted to our hospital with DKA between 2013 and 2018. DKA was confirmed by pre-defined biochemical parameters and cause of death data was extracted from multiple sources. Follow-up was for two years after discharge for all participants with one-year mortality being the main time point for analysis.
Results
We identified 818 admissions to hospital with DKA, affecting 284 people. Twenty people died as inpatients and a further 40 people died during the two-year follow-up. Of these 60 participants, cause of death was able to be determined for 41 (68%), with most deaths occurring due to infection or macrovascular disease. Risk factors for death within a year of hospital discharge included older age, vascular complications of diabetes, intellectual impairment and residential care living. Those who survived an episode of DKA had a one-year age-corrected mortality rate 13 times higher than the general population. This was more marked in the younger cohort with those aged 15–39 years being 49 times more likely to die in the year after surviving a DKA admission compared to their general population counterparts.
Conclusion
An episode of diabetic ketoacidosis is associated with a significant outpatient mortality risk with most deaths due to infectious or macrovascular causes. This study should prompt investigation of predictive scoring tools to identify those at increased mortality risk after DKA and encourage the development of targeted interventions to reduce mortality.
States negotiate over the specific terms of multilateral treaties because those terms determine states’ willingness to ratify the treaty. In some cases, a state might decline to ratify a treaty it ...otherwise supports because specific terms are too far from those it prefers. States and inter-governmental organizations negotiating treaties would like to uncover the minimal terms needed to secure the ratification of key states, but under what circumstances will those states candidly reveal those terms? Using a spatial representation of the issues in a treaty negotiation, we use mechanism design to determine what information states will reveal in a treaty negotiation. We find that states are willing to reveal how they would like tradeoffs between different issues to be resolved but not the minimal terms they require for ratification. Further, negotiations cannot always separate types that need concessions to ratify from other types that would like concessions but would ratify the treaty even if they do not receive them. These findings provide insight into how treaty negotiations can succeed or fail, and they lay the theoretical groundwork for a new line of empirical research on how multilateral treaties are negotiated.
Chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 30 to 60% of people who receive neurotoxic chemotherapy. CIPN is associated with impaired quality of life and function and has ...few effective treatments. This 6-site, subject and assessor-blinded randomized clinical trial (RCT) was designed to assess 1) preliminary efficacy (ie, alpha pre-specified at .2) of a wearable, app-controlled, transcutaneous electrical nerve stimulation (TENS) device for chronic CIPN and 2) feasibility of conducting a confirmatory trial within the National Cancer Institute Community Oncology Research Program (NCORP) (NCT04367480). The primary outcome was the EORTC-CIPN20. The main secondary outcomes were individual symptoms assessed daily (via 0-10 numeric rating scales). The primary analysis was an analysis of covariance (outcome: EORTC-CIPN20, fixed effect: arm, covariates: baseline EORTC-CIPN20 and site). Secondary analyses used a similar analysis of covariance models (excluding site) for each symptom on subgroups of subjects with ≥4 out of 10 for that symptom at baseline. 142 eligible subjects were randomized and received a device; 130 (91%) completed the study. The difference between groups in the EORCT-CIPN20 at the endpoint (placebo-active) was 1.05 (95% Confidence Interval: -.56, 2.67; P = .199). The difference between groups for the individual symptoms was as follows: hot/burning pain: 1.37 (-.33, 3.08; P = .112), sharp/shooting pain: 1.21 (-.37, 2.79; P = .128), cramping: 1.35 (-.32, 3.02; P = .110), tingling: .23 (-.61, 1.08; P = .587), numbness: .27 (-.51, 1.05; P = .492). An RCT of an app-controlled TENS device for chronic CIPN with excellent retention is feasible in the NCORP. Preliminary efficacy evidence suggests that TENS is promising for pain and cramping from CIPN. A confirmatory RCT of TENS for painful CIPN is highly warranted. PERSPECTIVE: Daily, home-based TENS therapy demonstrates promising efficacy for painful CIPN symptoms in this proof-of-concept randomized clinical trial. Future confirmatory trial is warranted.
DNA methylation can be affected by systemic exposures, such as cigarette smoking and genetic sequence variation; however, the relative impact of each on the epigenome is unknown. We aimed to assess ...if cigarette smoking and genetic variation are associated with overlapping or distinct sets of DNA methylation marks and pathways. We selected 85 Caucasian current and former smokers with genome-wide single nucleotide polymorphism (SNP) genotyping available from the COPDGene study. Genome-wide methylation was obtained on DNA from whole blood using the Illumina HumanMethylation27 platform. To determine the impact of local sequence variation on DNA methylation (mQTL), we examined the association between methylation and SNPs within 50 kb of each CpG site. To examine the impact of cigarette smoking on DNA methylation, we examined the differences in methylation by current cigarette smoking status. We detected 770 CpG sites annotated to 708 genes associated at an FDR < 0.05 in the cis-mQTL analysis and 1,287 CpG sites annotated to 1,242 genes, which were nominally associated in the smoking-CpG association analysis (P
unadjusted
< 0.05). Forty-three CpG sites annotated to 40 genes were associated with both SNP variation and current smoking; this overlap was not greater than that expected by chance. Our results suggest that cigarette smoking and genetic variants impact distinct sets of DNA methylation marks, the further elucidation of which may partially explain the variable susceptibility to the health effects of cigarette smoking. Ascertaining how genetic variation and systemic exposures differentially impact the human epigenome has relevance for both biomarker identification and therapeutic target development for smoking-related diseases.
Aims/hypothesis
Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile ...and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension.
Methods
This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose- and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (
n
= 6), praliciguat 40 mg once daily for days 1–14 (
n
= 10), or praliciguat 20 mg twice daily for days 1–7 then 40 mg once daily for days 8–14 (
n
= 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment.
Results
Participants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of −0.7 (−1.8, 0.4) mmol/l for fasting plasma glucose, −0.7 (−1.1, −0.2) mmol/l for total cholesterol, −0.5 (−1.0, −0.1) mmol/l for LDL-cholesterol, −23 (−56, 9) for HOMA-IR in those not being treated with insulin, and −5 (−10, 1) mmHg and 3 (−1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients.
Conclusions/interpretation
In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat.
Trial registration
ClinicalTrials.gov
NCT03091920.
Funding
This trial was funded by Cyclerion Therapeutics.
Abstract
Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that ...rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value < 2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value = 0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.
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