The NBER Orange Book Dataset: A user's guide.

This paper introduces a newly digitized, open-access version of the Food and Drug Administration's "Orange Book"-a linkage between approved small-molecule drugs and the patents that protect them. The Orange Book also reports any applicable regulatory exclusivity that prevents competitive entry. We summarize the Orange Book's coverage and discuss the opportunities and challenges associated with using these data for research. Empirical validations against various administrative datasets suggest that Orange Book records are, largely, complete and accurate. We conclude with a specific use case-calculating legal exclusivity periods for drugs-to highlight the types of choices that researchers must make when using this resource.

Parieto-Occipital Injury on Diffusion MRI Correlates with Poor Neurologic Outcome following Cardiac Arrest.

BACKGROUND AND PURPOSE: MR imaging of the brain provides unbiased neuroanatomic evaluation of brain injury and is useful for neurologic prognostication following cardiac arrest. Regional analysis of diffusion imaging may provide additional prognostic value and help reveal the neuroanatomic underpinnings of coma recovery. The purpose of this study was to evaluate global, regional, and voxelwise differences in diffusion-weighted MR imaging signal in patients in a coma after cardiac arrest. MATERIALS AND METHODS: We retrospectively analyzed diffusion MR imaging data from 81 subjects who were comatose for >48 hours following cardiac arrest. Poor outcome was defined as the inability to follow simple commands at any point during hospitalization. ADC differences between groups were evaluated across the whole brain, locally by using voxelwise analysis and regionally by using ROI-based principal component analysis. RESULTS: Subjects with poor outcome had more severe brain injury as measured by lower average whole-brain ADC (740 [SD, 102] × 10-6 mm2/s versus 833 [SD, 23] × 10-6 mm2/s, P < .001) and larger average volumes of tissue with ADC below 650 × 10-6 mms/s (464 [SD, 469] mL versus 62 [SD, 51] mL, P < .001). Voxelwise analysis showed lower ADC in the bilateral parieto-occipital areas and perirolandic cortices for the poor outcome group. ROI-based principal component analysis showed an association between lower ADC in parieto-occipital regions and poor outcome. CONCLUSIONS: Brain injury affecting the parieto-occipital region measured with quantitative ADC analysis was associated with poor outcomes after cardiac arrest. These results suggest that injury to specific brain regions may influence coma recovery.

Fixing The FDA's Orange Book.

The modern regime for balancing innovation and competition in pharmaceuticals was established through the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act. This regime needs updating. The process that Hatch-Waxman established for listing patents and challenging patents on the Food and Drug Administration's Orange Book is one important area for reform.

Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations

Objective To report the ESICM consensus and clinical practice recommendations on fluid therapy in neurointensive care patients. Design A consensus committee comprising 22 international experts met in October 2016 during ESICM LIVES2016. Teleconferences and electronic-based discussions between the members of the committee subsequently served to discuss and develop the consensus process. Methods Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles generated. The consensus focused on three main topics: (1) general fluid resuscitation and maintenance in neurointensive care patients, (2) hyperosmolar fluids for intracranial pressure control, (3) fluid management in delayed cerebral ischemia after subarachnoid haemorrhage. After an extensive literature search, the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system were applied to assess the quality of evidence (from high to very low), to formulate treatment recommendations as strong or weak, and to issue best practice statements when applicable. A modified Delphi process based on the integration of evidence provided by the literature and expert opinions­using a sequential approach to avoid biases and misinterpretations­was used to generate the final consensus statement. Results The final consensus comprises a total of 32 statements, including 13 strong recommendations and 17 weak recommendations. No recommendations were provided for two statements. Conclusions We present a consensus statement and clinical practice recommendations on fluid therapy for neurointensive care patients.

Evergreening, patent challenges, and effective market life in pharmaceuticals.

Observers worry that generic patent challenges are on the rise and reduce the effective market life of drugs. A related concern is that challenges disproportionately target high-sales drugs, reducing market life for these "blockbusters." To study these questions, we examine new data on generic entry over the past decade. We show that challenges are more common for higher sales drugs. We also demonstrate a slight increase in challenges over this period, and a sharper increase for early challenges. Despite this, effective market life is stable across drug sales categories, and has hardly changed over the decade. To better understand these results, we examine which patents are challenged on each drug, and show that lower quality and later expiring patents disproportionately draw challenges. Overall, this evidence suggests that challenges serve to maintain, not reduce, the historical baseline of effective market life, thereby limiting the effectiveness of "evergreening" by branded firms.

Evaluation of apolipoprotein A-II as a positional candidate gene for familial Type II diabetes, altered lipid concentrations, and insulin resistance.

AIMS/HYPOTHESIS: We hypothesized that apolipoprotein A-II sequence variation was responsible for the observed linkage of Type II (non-insulin-dependent) diabetes mellitus to the apolipoprotein A-II region in Northern European families ascertained for multiple diabetic siblings, and might also influence insulin sensitivity and secretion, non-esterified fatty acids, and lipids. METHODS: We recruited 698 members of 63 families for pedigree studies and additional unrelated people providing 117 diabetic and 130 control subjects. We screened the apolipoprotein A-II gene by single strand conformation polymorphism analysis and fluorescent sequence analysis. Variants were typed by oligonucleotide ligation assay, restriction digest of amplification products, or radioactive fragment analysis for the microsatellite polymorphism. Association of each variant with Type II diabetes was tested in the case-control population by chi-square analysis, or using transmission disequilibrium test in families. Haplotypes were established in families using SIMWALK and tested for association with diabetes and quantitative traits. RESULTS: No detected variant altered the coding sequence of the gene. Three single nucleotide polymorphisms showed modest evidence for an association, but no variant or haplotype was associated with diabetes in families. Similarly, we found no association with non-esterified fatty acid concentrations, HDL concentrations, or fasting insulin. In contrast, we found evidence for an association of some haplotypes and individual variants with 2-h post-challenge glucose and measures of insulin secretion. CONCLUSION/INTERPRETATION: Apolipoprotein A-II is not likely to explain the observed linkage of Type II diabetes, but variation in this gene could alter insulin secretion and post-challenge glucose.

Regional distribution of cerebral blood flow in experimental intrauterine growth retardation.

The regional distribution of cerebral blood flow was assessed in eight control and eight morphometrically growth-retarded fetal lambs to determine whether perfusion patterns within the cerebral circulation are altered in this model of intrauterine growth retardation. Growth retardation was induced by repetitive embolization of the uterine circulation, and flow distribution was assessed by use of microspheres. Distribution to 22 separate areas, expressed as a flow/weight ratio, was virtually identical in the two groups. Cortical gray matter received 56% of total cerebral flow, and cortical white matter received 7%. However, flow X gm-1 in cortical white matter was 85% of that in cortical gray matter. We conclude that perfusion patterns within the cerebral circulation are not altered in this model of intrauterine growth retardation and that, compared to gray matter, cortical white matter has a high flow X gm-1 in fetal life.

Alcoholism: the response of a public hospital.

This report presents an analysis of the Alcohol Intervention Program (AIP) at Parkland Memorial Hospital in Dallas, Texas. This pilot project was initiated in January of 1983. A total of 1,822 patients were screened by two trained counselors. Operated in the emergency room, the project significantly reduced the rate of both hospital admissions and readmissions for patients with alcohol-related illnesses. This project demonstrated its effectiveness by making appropriate referrals to local alcoholism service providers. A total of 387 patients were referred directly to Alcoholics Anonymous and 440 were referred to residential alcoholism programs. Of the latter group, follow-up documentation demonstrated that nearly half of those referred remained in treatment for the duration of the program.

Influence of immediate dentures on oral motor skill and speech.

An investigation was designed to test whether the precision of finely coordinated orofacial movements is influenced by the transition from natural to artificial dentition. The oral motor skill of 16 patients was tested before extraction and within 2 weeks of wearing immediate dentures. Speech recordings were employed to detect changes in voice quality and speech sound production. Results showed that the loss of natural teeth and the wearing of immediate dentures did not alter sensorimotor pathways significant to the precision of oral motor skills. It was also determined that physical characteristics of dentures are significant factors in the production of acceptable speech.