Dyadic Clustering in International Relations

Quantitative empirical inquiry in international relations often relies on dyadic data. Standard analytic techniques do not account for the fact that dyads are not generally independent of one another. That is, when dyads share a constituent member (e.g., a common country), they may be statistically dependent, or "clustered." Recent work has developed dyadic clustering robust standard errors (DCRSEs) that account for this dependence. Using these DCRSEs, we reanalyzed all empirical articles published in International Organization between January 2014 and January 2020 that feature dyadic data. We find that published standard errors for key explanatory variables are, on average, approximately half as large as DCRSEs, suggesting that dyadic clustering is leading researchers to severely underestimate uncertainty. However, most (67% of) statistically significant findings remain statistically significant when using DCRSEs. We conclude that accounting for dyadic clustering is both important and feasible, and offer software in R and Stata to facilitate use of DCRSEs in future research

The Evolution of Natriuretic Peptide Augmentation in Management of Heart Failure and the Role of Sacubitril/valsartan

Heart failure (HF) is one of the leading causes of morbidity, mortality, and health care expenditures in the US and worldwide. For three decades, the pillars of treatment of HF with reduced ejection fraction (HFrEF) were medications that targeted the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the natriuretic peptide system (NPS) for the management of HF failed either due to lack of significant clinical benefit or due to the unacceptable side effect profile. This review article will discuss the NPS, the failure of early drugs which targeted the NPS as therapies for HF, and the sequence of events which led to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). LCZ696 has been shown to be superior to the standard of care available for treatment of HFrEF in several substantial hard endpoints including heart failure hospitalizations, cardiovascular mortality, and all-cause mortality

Operationalizing Counterfactual Metrics: Incentives, Ranking, and Information Asymmetry

From the social sciences to machine learning, it has been well documented that metrics to be optimized are not always aligned with social welfare. In healthcare, Dranove et al. (2003) showed that publishing surgery mortality metrics actually harmed the welfare of sicker patients by increasing provider selection behavior. We analyze the incentive misalignments that arise from such average treated outcome metrics, and show that the incentives driving treatment decisions would align with maximizing total patient welfare if the metrics (i) accounted for counterfactual untreated outcomes and (ii) considered total welfare instead of averaging over treated patients. Operationalizing this, we show how counterfactual metrics can be modified to behave reasonably in patient-facing ranking systems. Extending to realistic settings when providers observe more about patients than the regulatory agencies do, we bound the decay in performance by the degree of information asymmetry between principal and agent. In doing so, our model connects principal-agent information asymmetry with unobserved heterogeneity in causal inference

Correlation Between Electrocardiographic Changes and Coronary Findings in Patients With Acute Myocardial Infarction and Single-Vessel Disease

BACKGROUND: Correlation of ST-segment elevation on the 12-lead electrocardiogram (ECG) with the expected affected coronary territory is established in patients with ST-elevation myocardial infarction (STEMI). In patients with non-ST-elevation myocardial infarction (NSTEMI), correlation of ischemic ECG abnormalities with the affected coronary territory has not been well-established. We sought to investigate the correlation of electrocardiographic abnormalities with the location of 1-vessel obstructive coronary artery disease (CAD) in patients with both STEMI and NSTEMI. METHODS: In this retrospective study, the charts of all patients referred for coronary angiography in 2012 were reviewed. Patients with a single obstructive coronary artery plus angina-equivalent symptoms and an elevated cardiac troponin I was included. Available ECGs were interpreted by an experienced cardiologist (WSA) blinded to the result of angiography. Patients with complete bundle branch block or ventricular pacing were excluded. Ischemic ECG changes were correlated to a coronary territory based on predefined criteria. RESULTS: Of 131 included patients (mean age 64+/-13 years; 74% male), 29 had STEMI and 102 had NSTEMI. Eleven of 11 patients (100%) with anterior STEMI had left anterior descending artery (LAD) obstructive CAD. Of 18 patients with inferior STEMI, 14 (78%) had right coronary artery (RCA) obstructive CAD, 3 (17%) had left circumflex artery (LCX) artery obstructive CAD, and 1 (5%) had LAD obstructive CAD. Of 102 NSTEMI patients, 53 (52%) had definite ECG ischemic abnormalities. Of 31 patients with anterior definite ECG ischemic abnormalities, 30 (97%) had LAD obstructive CAD, and 1 (3%) had RCA obstructive CAD. Of 22 patients with inferior definite ECG ischemic abnormalities, 14 (64%) had RCA obstructive CAD, 5 (23%) had LCX obstructive CAD, and 3 (14%) had LAD obstructive CAD. CONCLUSIONS: Patients with anterior STEMI had LAD obstructive CAD. Patients with inferior STEMI were highly likely to have RCA or LCX obstructive CAD. Only half of NSTEMI patients had definite ischemic ECG abnormalities. When present, anterior ischemic ECG changes in patients with single vessel CAD with NSTEMI were predictive of LAD obstructive CAD

Cardiac sarcoidosis: a comprehensive review

Sarcoidosis is a multisystem granulomatous disease of unknown etiology characterized by noncaseating granulomas in involved organs. Organs involved with sarcoidosis include lymph nodes, skin, lung, central nervous system, and eye. Only 40-50% of patients with cardiac sarcoidosis diagnosed at autopsy have the diagnosis made during their lifetime. Cardiac sarcoidosis can manifest itself as complete heart block, ventricular arrhythmias, congestive heart failure, pericardial effusion, pulmonary hypertension, and ventricular aneurysms. Diagnostic tests such as the electrocardiogram, two-dimensional echocardiography, cardiac magnetic resonance imaging, positron emission tomography scan, radionuclide scan, and endomyocardial biopsy can be helpful in the early detection of cardiac sarcoidosis. Considering the increased risk of sudden death, cardiac sarcoidosis is an indication for early treatment with corticosteroids or other immunosuppressive agents. Other treatments include placement of a pacemaker or implantable defibrillator to prevent sudden death. In refractory cases, cardiac transplantation should be considered

Cardiac Papillary Fibroelastoma: the Need for a Timely Diagnosis

Cardiac papillary fibroelastomas (CPFs) are the second most common primary cardiac tumors and the most common cardiac valvular tumors. Although they are histologically benign and usually asymptomatic, CPFs can lead to serious and life-threatening complications like myocardial infarction, stroke, pulmonary embolus, cardiac arrest etc. CPFs represent a rare entity in clinical medicine and literature regarding their management is limited. We report two cases which illustrate such complications arising from undiagnosed CPFs on the aortic valve. We further stress on the importance of identifying CPFs early so that they can be managed appropriately based on recommendations from the available literature

miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia

Wnt/β-catenin signaling is required for development of the exocrine pancreas

BACKGROUND: β-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of β-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that β-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of β-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of β-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of β-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed β-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis. RESULTS: Pdx1-cre floxed β-catenin animals were viable but demonstrated small body size and shortened median survival. The pancreata from knockout mice were hypoplastic and histologically demonstrated a striking paucity of exocrine pancreas, acinar to duct metaplasia, but generally intact pancreatic islets containing all lineages of endocrine cells. In animals with extensive acinar hypoplasia, putative hepatocyte transdifferention was occasionally observed. Obvious and uniform pancreatic hypoplasia was observed by embryonic day E16.5. Transcriptional profiling of Pdx1-cre floxed β-catenin embryonic pancreata at E14.5, before there was a morphological phenotype, revealed significant decreases in the β-catenin target gene N-myc, and the basic HLH transcription factor PTF1, and an increase of several pancreatic zymogens compared to control animals. By E16.5, there was a dramatic loss of exocrine markers and an increase in Hoxb4, which is normally expressed anterior to the pancreas. CONCLUSION: We conclude that β-catenin expression is required for development of the exocrine pancreas, but is not required for development of the endocrine compartment. In contrast, β-catenin/Wnt signaling appears to be critical for proliferation of PTF1+ nascent acinar cells and may also function, in part, to maintain an undifferentiated state in exocrine/acinar cell precursors. Finally, β-catenin may be required to maintain positional identity of the pancreatic endoderm along the anterior-posterior axis. This data is consistent with the findings of frequent β-catenin mutations in carcinomas of acinar cell lineage seen in humans