The value of an anticipated rewarding event is a crucial component of the decision to engage in its pursuit. But little is known of the networks responsible for encoding and retrieving this value. Using biosensors and pharmacological manipulations, we found that basolateral amygdala (BLA) glutamatergic activity tracks and mediates the encoding and retrieval of the state-dependent incentive value of a palatable food reward. Projection-specific, bidirectional chemogenetic and optogenetic manipulations revealed the orbitofrontal cortex (OFC) supports the BLA in these processes. Critically, the function of ventrolateral (lOFC) and medial (mOFC) OFC→BLA projections is doubly dissociable. Whereas lOFC→BLA projections are necessary and sufficient for encoding of the positive value of a reward, mOFC→BLA projections are necessary and sufficient for retrieving this value from memory. These data reveal a new circuit for adaptive reward valuation and pursuit and provide insight into the dysfunction in these processes that characterizes myriad psychiatric diseases.

In situ graft fenestration to preserve the left subclavian artery after deliberate coverage during endovascular repair of a thoracic aortic aneurysm appears feasible in this initial clinical application. There are uncertainties regarding the long-term stability of the fabric tears that are an inherent part of this technique.

The pediatric exclusivity program has been successful in encouraging drug studies in children. However, the dissemination of these results in the peer-reviewed literature is limited. Mechanisms to more widely disperse this information through publication warrant further evaluation.

Context In 1997, Congress authorized the US Food and Drug Administration (FDA) to grant 6-month extensions of marketing rights through the Pediatric Exclusivity Program if industry sponsors complete FDA-requested pediatric trials. The program has been praised for creating incentives for studies in children and has been criticized as a "windfall" to the innovator drug industry. This critique has been a substantial part of congressional debate on the program, which is due to expire in 2007. Objective To quantify the economic return to industry for completing pediatric exclusivity trials. Design and Setting A cohort study of programs conducted for pediatric exclusivity. Nine drugs that were granted pediatric exclusivity were selected. From the final study reports submitted to the FDA (2002-2004), key elements of the clinical trial design and study operations were obtained, and the cost of performing each study was estimated and converted into estimates of after-tax cash outflows. Three-year market sales were obtained and converted into estimates of after-tax cash inflows based on 6 months of additional market protection. Net economic return (cash inflows minus outflows) and net return-to-costs ratio (net economic return divided by cash outflows) for each product were then calculated. Main Outcome Measures Net economic return and net return-to-cost ratio. Results The indications studied reflect a broad representation of the program: asthma, tumors, attention-deficit/hyperactivity disorder, hypertension, depression/ generalized anxiety disorder, diabetes mellitus, gastroesophageal reflux, bacterial infection, and bone mineralization. The distribution of net economic return for 6 months of exclusivity varied substantially among products (net economic return ranged from −$8.9 million to $507.9 million and net return-to-cost ratio ranged from −0.68 to 73.63). Conclusions The economic return for pediatric exclusivity is variable. As an incentive to complete much-needed clinical trials in children, pediatric exclusivity can generate lucrative returns or produce more modest returns on investment.

Checkpoint controls ensure that events of the cell-division cycle are completed with fidelity and in the correct order. In budding yeast with a mutation in the motor protein dynein, the mitotic spindle is often misaligned and therefore slow to enter the neck between mother cell and budding daughter cell. When this occurs, cytokinesis (division of the cytoplasm into two) is delayed until the spindle is properly positioned. Here we describe mutations that abolish this delay, indicating the existence of a new checkpoint mechanism. One mutation lies in the gene encoding the yeast homologue of EB1, a human protein that binds the adenomatous polyposis coli (APC) protein, a tumour suppressor. EB1 is located on microtubules of the mitotic spindle and is important in spindle assembly. EB1 may therefore, by associating with microtubules, contribute to the sensor mechanism that activates the checkpoint. Another mutation affects Stt4, a phosphatidylinositol-4-OH kinase. Cold temperature is an environmental stimulus that causes misalignment of the mitotic spindle in yeast and appears to activate this checkpoint mechanism.