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Shortly after the initial isolation of marine ladder polyether natural products, biomimetic epoxide-opening cascade reactions were proposed as an efficient strategy for the synthesis of these compounds. However, difficulties in assembling the cascade precursors have limited the realization of these cascades. In this report, we describe strategies that provide convergent access to cascade precursors via regioselective allylation and efficient fragment coupling. We then investigate epoxide-opening cascades promoted by strong bases for the formation of fused tetrahydropyrans. These strategies are evaluated in the context of the synthesis of rings CDEFG of brevisulcenal F.

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Lawn mower-related injuries to children are relatively common and can result in severe injury or death. Many amputations during childhood are caused by power mowers. Pediatricians have an important role as advocates and educators to promote the prevention of these injuries.

Each year in the United States, fire and burn injury is responsible for a high degree of morbidity and mortality. In 1996-1998, Wisconsin's mortality rate from unintentional fire and burn injury (1.22 deaths/100,000 population) was similar to the average United States mortality rate for such injuries (1.40), and significant morbidity leads to hospitalization, invasive procedures, and psychological trauma. This article describes the common types of product-related burn hazards in the home, the injuries associated with these hazards, prevention measures, and the health professional's important role in burn injury prevention.

During the past decade, many advances have been made in motor vehicle safety restraint systems, and these advancements have brought changes in the recommendations for child passenger safety. In spite of these advances, a high morbidity and mortality rate continues to be attributed to improper or absent child restraint use. Child transportation safety is a complex issue. Lack of public awareness and incomplete laws contribute to the confusion. The solution involves professional and public education, further technological advances, and advocacy for improved legislation and regulation. Physicians have a unique opportunity to incorporate advice about proper restraint use into their daily practice; however, that requires a clear understanding of the current recommendations. Both the age and weight of the child determine the appropriate child restraint system. Understanding, practicing, and promoting these recommendations will save lives. This article reviews the current recommendations for proper child restraint while traveling in a motor vehicle.

The final components of Wisconsin's graduated driver licensing (GDL) statute [Biennial state budget act 1999 Wisconsin Act 9] went into effect on September 1, 2000. The GDL system seeks to reduce the number of teen motor vehicle collisions and fatalities by gradually introducing young drivers to all driving situations, beginning with the easiest and progressing to the more difficult. The stages of licensing are defined by the degree of risk involved. When teen drivers demonstrate the ability to drive safely in a restricted setting with high levels of supervision, they "graduate" to the next licensing level with fewer restrictions. Numerous factors are associated with the high rate of teen motor vehicle crashes and fatalities. Such factors include driver inexperience and easy distractibility, alcohol use and lack of seat belt use. The GDL addresses all of these risk factors. This article reviews the injury prevention strategies incorporated in the GDL and outlines the basic components of Wisconsin's law.

The theoretical tissue model-based estimates of phase 1 and phase 2 duration of biphasic waveforms are considerably shorter than the pulse widths currently used in ICDs with standard tilt. This study used a tissue resistance/capacitance (RC) model to identify optimal biphasic pulse widths. By paired step-down defibrillation threshold (DFT) testing, the efficacy of standard versus "tuned" biphasic waveforms was evaluated in 91 patients. Standard waveforms consisted of a phase 1 set to 65% tilt and phase 2 = phase 1. The tuned waveform was based on an RC model of membrane characteristics with a time constant of 3.5 ms. The optimal phase 1 truncation point is at the peak of membrane response. The optimal phase 2 duration ends with a membrane response near or just below 0. In paired analysis, no significant differences were found in DFT or impedance between standard and tuned waveforms. In patients with DFTs > 400 V, the tuned waveform lowered the DFT by an average of 38 V (P < 0.05). Multivariate analyses showed a significant inverse relationship between DFT and impedance (P < 0.001). As impedance increased, the tuned waveform was associated with DFTs comparable to the standard waveform with shorter pulse duration and lower delivered energy. No single tilt value allowing an easy calculation of delivered energy was related to ICD waveform efficacy. The use of ICDs with tuned optimal pulse durations offer a greater flexibility of choice for patients with high DFTs.

The goals of this two-part series on children with histories of early recurrent otitis media with effusion (OME) were to assess the risk for speech disorder with and without hearing loss and to develop a preliminary descriptive-explanatory model for the findings. Recently available speech analysis programs, lifespan reference data, and statistical techniques were implemented with three cohorts of children with OME and their controls originally assessed in the 1980s: 35 typically developing 3-year-old children followed since infancy in a university-affiliated pediatrics clinic, 50 typically developing children of Native American background followed since infancy in a tribal health clinic, and (in the second paper) 70 children followed prospectively from 2 months of age to 3 years of age and older. Dependent variables included information from a suite of 10 metrics of speech production (Shriberg, Austin, Lewis, McSweeny, & Wilson, 1997a, 1 997b). Constraints on available sociodemographic and hearing status information limit generalizations from the comparative findings for each database, particularly data from the two retrospective studies. The present paper reports findings from risk analysis of conversational speech data from the first two cohorts, each of which included retrospective study of children for whom data on hearing loss were not available. Early recurrent OME was not associated with increased risk for speech disorder in the pediatrics sample but was associated with approximately 4.6 (CI = 1.10-20.20) increased risk for subclinical or clinical speech disorder in the children of Native American background. Discussion underscores the appropriateness of multifactorial risk models for this subtype of child speech disorder.

All hospitals should set policies that require the discharge of every newborn in a car safety seat that is appropriate for the infant's maturity and medical condition. Discharge policies for newborns should include a parent education component, regular review of educational materials, and periodic in-service education for responsible staff. Appropriate child restraint systems should become a benefit of coverage by Medicaid, managed care organizations, and other third-party insurers.

Children with special health care needs should have access to proper resources for safe transportation. This statement reviews important considerations for transporting children with special health care needs and provides current guidelines for the protection of children with specific health care needs, including those with a tracheostomy, a spica cast, challenging behaviors, or muscle tone abnormalities as well as those transported in wheelchairs.

The presence of air bags in motor vehicles has been credited with saving thousands of lives in frontal, high-speed collisions. However, air bags have also contributed to the deaths of some children and adults in the driver and front-passenger positions in low-speed crashes. It is important for physicians to understand the relative benefits and risks of air bags and to inform the public repeatedly that all motor vehicle occupants should be buckled at all times and that all children ages 12 and under should ride properly restrained in the back seat. With very few exceptions, air bags should NOT be deactivated. Through in-office counseling and community speaking and writing, physicians have the opportunity to give advice that could save many lives in motor vehicle crashes.