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Although several high-fidelity SpCas9 variants have been reported, it has been observed that this increased specificity is associated with reduced on-target activity, limiting the applications of the high-fidelity variants when efficient genome editing is required. Here, we developed an improved version of Sniper–Cas9, Sniper2L, which represents an exception to this trade-off trend as it showed higher specificity with retained high activity. We evaluated Sniper2L activities at a large number of target sequences and developed DeepSniper, a deep learning model that can predict the activity of Sniper2L. We also confirmed that Sniper2L can induce highly efficient and specific editing at a large number of target sequences when it is delivered as a ribonucleoprotein complex. Mechanically, the high specificity of Sniper2L originates from its superior ability to avoid unwinding a target DNA containing even a single mismatch. We envision that Sniper2L will be useful when efficient and specific genome editing is required.

Primary Sjögren’s syndrome (pSS) is an autoimmune disease with increased risk of infections. Here, we assessed whether pSS patients were at higher risk of hospitalization for community and opportunistic infections. We selected newly hospitalized pSS patients between 2011 and 2018, through a nationwide population-based retrospective study using the French Health insurance database. We compared the incidence of hospitalization for several types of infections (according to International Classification for Disease codes, ICD-10) between pSS patients and an age- and sex-matched (1:10) hospitalized control group. We calculated adjusted Hazard Ratios (aHR, 95% CI) adjusted on socio-economic status, past cardiovascular or lung diseases and blood malignancies factors. We compared 25 661 pSS patients with 252 543 matched patients. The incidence of hospitalizations for a first community infection was increased in pSS patients [aHR of 1.29 (1.22–1.31), p < .001]. The incidence of hospitalization for bronchopulmonary infections was increased in pSS patients [aHR of 1.50 (1.34–1.69), p < .001, for pneumonia]. Hospitalizations for pyelonephritis and intestinal infections were increased [aHR of 1.55 (1.29–1.87), p < .001 and 1.18 (1.08–1.29), p < .001, respectively]. Among opportunistic infections, only zoster, and mycobacteria infections (tuberculosis and non-tuberculous) were at increased risk of hospitalization [aHR of 3.32 (1.78–6.18), p < .001; 4.35 (1.41–13.5), p = .011 and 2.54 (1.27–5.06), p = .008, respectively]. pSS patients are at higher risk of hospitalization for infections. The increased risk of hospitalization for mycobacterial infections illustrates the potential bilateral relationship between the two conditions. Vaccination against respiratory pathogens and herpes zoster virus may help prevent some hospitalizations in pSS patients.KEY MESSAGESPrimary Sjögren’s syndrome (pSS) increases hospitalization risk for community infections: bronchopulmonary, skin, dental, ear–nose–throat, intestinal infections and pyelonephritis.Hospitalizations for zoster and mycobacterial infections are also increased in this population.Dedicated preventive measures and vaccination campaigns could decrease the burden of infections in pSS patients. Primary Sjögren’s syndrome (pSS) increases hospitalization risk for community infections: bronchopulmonary, skin, dental, ear–nose–throat, intestinal infections and pyelonephritis. Hospitalizations for zoster and mycobacterial infections are also increased in this population. Dedicated preventive measures and vaccination campaigns could decrease the burden of infections in pSS patients.

This paper investigates the relationship between business cycle synchronization and trade integration in the Latin American region. Using data for 17 Latin American countries and the United States (US) from 1980 to 2018, we document the time-series characteristics of business cycle synchronization and intraand inter-regional trade in the region and empirically test whether trade integration contributed to business cycle synchronization. The data demonstrate that the business cycle synchronization index has been steadily increasing in the region. Regional trade integration increased until the financial crisis in 2008 and decreased slightly thereafter. The results of a system generalized method of moments (GMM) regression indicate that bilateral trade with the US significantly increased business cycle synchronization in the region, except during the 2000s, while regional trade had no significant effect. These results emphasize the importance of the indirect trade channel, especially with the US, as a main channel of business cycle synchronization in Latin America.

Advances in sequencing technologies have facilitated the discovery of previously unknown genetic variants in both inherited and acquired disorders, and tools to correct these pathogenic variants are rapidly evolving. Since the first introduction of CRISPR-Cas9 in 2012, the field of CRISPR-based genome editing has progressed immensely, giving hope to many patients suffering from genetic disorders that lack effective treatment. In this review, we will examine the basic principles of CRISPR-based genome editing, explain the mechanisms of new genome editors, including base editors and prime editors, and evaluate the therapeutic possibilities of CRISPR-based genome editing by focusing on recently published clinical trials and animal studies. Although efficacy and safety issues remain a large concern, we cannot deny that CRISPR-based genome editing will soon be prevalent in clinical practice.

Previous reports have described non-ischaemic cardiomyopathy related to a variety of autoimmune diseases. However, very few case reports describe Sjögren disease as a contributing factor to cardiomyopathy. We report the case of a 69-year-old woman with a history of Sjögren disease who presented with cardiogenic shock. Laboratory testing and cardiac MRI revealing apical septal late gadolinium enhancement were consistent with an autoimmune aetiology. After ruling out ischaemic, infectious and other possible causes, the patient’s clinical presentation was thought to be related to underlying Sjögren disease. She was treated with intravenous steroids and evidence-based heart failure therapy, but she eventually died after having declined heart transplantation. Given the rarity of Sjögren disease, no diagnostic criteria or standard treatment has been established for cardiomyopathy related to this disease. Diagnosis should be considered in patients who show evidence of autoimmune processes after other possible causes are ruled out.

Recent sovereign debt crisis has challenged policy makers to explore the possibility of establishing a …scal-transfer system that could alleviate the negative impact of asymmetric shocks across countries. Using a simple labor-production economy model, we …rst derive an analytically tractable solution for optimal degree of …scal transfers. In this economy, …scal transfers can improve welfare by moving the competitive equilibrium with …scal transfers closer to the social planner’s solution. We then extend the model to a DSGE setting with capital formation

Recent studies suggest that primary percutaneous coronary intervention (PCI) and targeted temperature management (TTM) improve outcome in ST-segment elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA). The objective of this study was to evaluate a contemporary series of patients with STEMI and OHCA to characterize treatment approaches and predictors of neurologic outcome.From January 2009 through November 2012, a total of 239 patients who underwent emergent coronary angiography at 10 medical centers across the United States were enrolled. All patients suffered OHCA with STEMI on either the prehospital or post-resuscitation electrocardiogram. Neurologic outcome was assessed using the cerebral performance category (CPC) score. Predictors of neurologic outcome were determined using multivariate logistic regression analysis. The primary endpoint was in-hospital survival with good neurologic function (CPC score 1 or 2).Mean age was 60 ± 13 years, 72% were male, and the majority of patients had a history of cardiovascular event. Initial rhythm was ventricular fibrillation in 72%. At hospital presentation, 76% of patients were intubated, 37% were in cardiogenic shock, and 33% were receiving vasopressors. Primary PCI was performed in 74%, with an average door-to-balloon time of 95 ± 77 minutes, and TTM was used in 51%. Forty-four percent of patients had full neurologic recovery (CPC score 1) and 55% had good neurologic function. Overall in-hospital survival rate was 66%. Independent predictors of in-hospital survival with good neurologic function were: receiving bystander cardiopulmonary resuscitation, location of arrest, receiving drug-eluting stents, and not experiencing a recurrent cardiac arrest.Short-term survival for patients with STEMI and OHCA undergoing emergent coronary angiography and revascularization with TTM in this contemporary, multicenter registry was high and neurologic outcome was good in more than half of patients.

This paper provides two illustrative examples on how a choice of social welfare criterion (conditional vs. unconditional utility) can generate different welfare implications. The first example is based on the standard linear-quadratic permanent income model, and the other example uses a simple two-country DSGE model under autarky and under complete markets. When the conditional welfare criterion is used—with the social discount factor set at the private discount factor—we obtain the well-known results that the government should not intervene when there are no market imperfections and that complete markets generate risk sharing gains over autarky. In contrast, using an unconditional welfare criterion—which effectively implies that the social discount factor is set to unity—can generate unconventional welfare results.

We examine dynamic revenue effects of a permanent tax cut on labor and capital income using a small open two-sector dynamic general equilibrium model. We use a dynamic scoring technique to calculate long-run as well as transitional effects on fiscal revenue when a tax cut is financed by either a lump-sum tax or consumption tax. We show that the revenue loss from an income tax cut becomes substantially smaller when agents can use international financial markets compared to the case of the closed economy. Responses of tradable and nontradable sectors to the capital income tax cut display a stark contrast in both long-run equilibrium and transitional dynamics due to different factor intensities. Capital income tax cut in the tradable sector is the most efficient policy instrument in terms of minimizing fiscal revenue loss. These simulation results suggest that fiscal sustainability issue when implementing a tax cut could be overstated.

(ProQuest: ... denotes formulae omitted.)I. INTRODUCTIONIn recent years, Korea has successfully signed free-trade agreements (FTA) with a number of partners including the U.S., EU and ASEAN. Korea and China officially launched FTA negotiations in May 2012 and a major breakthrough recently happened after 14 rounds of negotiations in November 2014, when the two parties signed on the final chapter of the agreement. Under the agreement, the two countries will remove their import duties on about 90 percent of all import items over the next twenty years. China will remove tariffs on 20 percent of the Korean items that it buys immediately after the deal takes effect and Korea will do so for 50 percent of the total imported items from China. This is equivalent to 44% (52%) of import goods into China (Korea) based on the import value. The FTA agreement is expected to take effect in 2015 after ratification by the congress in both countries.The FTA between Korea and China can have a significant impact on the Korean economy because of the close economic relationship between the two countries. Korea is the world's 12th largest economy with $1.6 trillion GDP and 49 million consumers while China is the world's 2nd largest economy with $12.6 trillion GDP and 1,350 million consumers.1 The Korea-China bilateral trade in 2012 was about $256 billion.2 China is Korea's biggest trading partner, while Korea is China's third-largest export market and its second-largest source of imports.Free trade agreements (FTAs) have a potential to significantly affect the economies of participating countries. They can increase the volume of trade and significantly affect the pattern of specialization and trade. Some industries, which do not have competitive advantage, may be negatively affected, while competitive industries may expand dramatically. The employment in those industries would be significantly affected as well. A free trade agreement may also affect countries other than those signing the agreement. For example, if Korea and China sign an FTA, some goods that were previously imported to Korea from Singapore may now be imported from China instead. This phenomenon is called trade diversion.The Korea-China FTA can give several advantages to Korea. First, since the US and EU already have FTAs with Korea but not with China, the Korea-China FTA can give Korea a strong advantage in penetrating Chinese markets before the EU and US. Korea can playa "Hub" country role in connecting trades between China and the West through FTAs. Second, the Korea-China FTA can provide institutional framework in China to protect Korean firms and people working in China. It is believed that more than 22,000 Korean firms are currently operating in China. Third, using the already-implemented FTA with ASEAN, Korea can play a crucial role in leading potential Asian economic cooperation including East Asia and ASEAN.This paper examines the potential effects of the Korea-China FTA on the Korean economy, in particular industry structure and employment, using a computable general equilibrium (CGE) model.3 The model is based on solid economic theory and has been tested and evaluated in previous studies (Yaylaci and Shikher, 2014). Specifically, the model has been found to accurately predict the effects of NAFTA (Shikher, 2012a). Our forecast predicts which Korean industries would grow as the result of the FTA. In those industries, existing firms would increase sales and new firms would enter business. Our forecast can also predict which Korean industries would experience a decline in sales and, therefore, employment.The model in this paper covers 53 countries and 15 industries. Trade in the model is affected by technology, trade costs, cross-industry supply of intermediate goods, and tastes. For each industry and country, the model can predict changes in trade, output, employment, prices, cost of production, wages, and welfare. We also plan to quantify the magnitude of the trade diversion that would occur as the result of the FTA. …

The aim of the study was to evaluate the tooth extracted use as autologous tooth graft after endodontic root canal therapies used for socket preservation. To this purpose, the Tooth Transformer shredding and decontamination machine has been used. The graft obtained in this way, was inserted at the time of the extraction or at a second surgery altogether with the chosen regenerative therapy. This clinical trial enrolled patients with post-estractive defects requiring the restoration bone dimension and shape in the maxillary and mandibular zone. In addition, 98 patients with 119 extraction sockets were enrolled across 10 standardized centers. An innovative preparation method, using the dedicated automated device Tooth Transformer, able to transform autologous teeth in suitable grafting material, has been used. The extracted tooth was cleaned and treated using a Tooth Transformer and made a socket preservation. Thirteen Biopsies were realized to analyze the histologic outcomes at the average time of four months to demonstrate that the autologous tooth graft made from root after endodontic therapy should be used in human bone regeneration as graft for dental implant placement.

Percutaneous hemodynamic support with use of the Impella CP device is increasingly utilized during high-risk percutaneous coronary intervention (HRPCI). We sought to compare a novel hybrid technique combining two Perclose in conjunction with one Angioseal vascular closure device (VCD) to a

This paper solves the multi-country RBC model described in den Haan, Judd and Juillard (2010) and Juillard and Villemot (2010), using a perturbation method. We explain how to apply first- and second-order versions of the gensys2.m algorithm to this model. The perturbation method is computationally cheap and can easily be applied to large models with possibly hundreds of state variables.

Transradial cardiac catheterization is increasing in the United States due to the advantages of less access site complications and patient preference. A compression device is most commonly used to achieve hemostasis following sheath removal, however the optimal weaning strategy to expedite TR-band

We describe an algorithm for calculating second order approximations to the solutions to nonlinear stochastic rational expectations models. The paper also explains methods for using such an approximate solution to generate forecasts, simulated time paths for the model, and evaluations of expected welfare differences across different versions of a model. The paper gives conditions for local validity of the approximation that allow for disturbance distributions with unbounded support and allow for non-stationarity of the solution process.

We analyze the sources of macroeconomic fluctuations in the emerging countries in the Middle East and North Africa (MENA) region using a dynamic stochastic general equilibrium model. The model economy captures some important structural characteristics of the MENA countries and is able to replicate the main properties of their business cycles. The results suggest that a substantial fraction of cyclical fluctuations in the MENA countries is explained by terms of trade shocks. In particular, these shocks account for more than 60 percent of the variation in aggregate output. They also explain the bulk of cyclical fluctuations in aggregate consumption. Domestic productivity shocks explain close to 40 percent of business cycle variation in aggregate output. While government spending shocks and world interest shocks are also important in accounting for the volatility of business cycles in certain macroeconomic variables, their overall impact on the dynamics of aggregate output appears to be relatively small.

This paper analyzes the impact of global integration on the dynamics of economic growth and business cycles in the emerging economies of Middle East and North Africa (MENA) and Asia. In particular, the paper examines the evolution of structural characteristics, growth dynamics, and business cycle properties of these countries during the 1960-2000 period. Although both groups of countries became more open and were able to diversify their industrial structures and export bases over time, the MENA countries lagged behind the Asian economies in both trade integration and the extent of diversification of exports during the globalization period (1986-2000). Although economic growth slowed in both groups during the period of globalization, the extent of the slowdown was much sharper in the MENA countries. Moreover, business cycle fluctuations in the MENA countries were much more volatile than in the Asian economies. In addition, although both groups of countries witnessed a moderation in the amplitude of macroec...

In this paper, we investigate the welfare implications of alternative financial market structures in a two-country endowment economy model. In particular, we obtain an analytic expression for the expected lifetime utility of the representative household when sovereign bonds are the only internationally traded asset, and we compare this welfare level with that obtained under complete asset markets. The welfare cost of incomplete markets is negligible if agents are very patient and shocks are not very persistent, but this cost is dramatically larger if agents are relatively impatient and shocks are highly persistent. For realistic cases in which agents are very patient and shocks are highly persistent (that is, the discount factor and the first-order autocorrelation are both near unity), the welfare cost of incomplete markets is highly sensitive to the specific values of these parameters. Finally, using a non-linear solution algorithm, we confirm that a two-country production economy with endogenous labor supply has qualitatively similar welfare properties.