Generic Utilization Rates, Real Pharmaceutical Prices, and Research and Development Expenditures

Generic utilization rates have risen substantially since the enactment of The Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) in 1984. In the year Hatch-Waxman was enacted, generic utilization rates were 19 percent; in contrast, today, the generic utilization rate is approximately 70 percent. Striking a balance between access to existing medicines and access to yet-to-be-discovered (and developed) drugs, through research incentives, was the principal objective of this landmark legislation. However, given the current rate of generic utilization, it seems plausible, if not likely, that any balance achieved by the 1984 Act has since shifted away from research incentives and towards improved access, ceteris paribus. Among other factors, recent mandatory substitution laws in most states have driven up generic utilization rates. In the current paper, we employ semi-annual data from 1992 to 2008 to examine the link between generic utilization rates and real U.S. prescription drug prices. This link is important because previous research has identified a causal relationship between real drug prices in the U.S. and industry-level R&D investment intensity. We identify a statistically significant, positive relationship between generic utilization rates in the U.S. and real U.S. prescription drug prices. Specifically, we estimate an elasticity of real drug prices to generic utilization rates of -0.15. This finding, when coupled with previous empirical work on the determinants of pharmaceutical R&D intensity, suggests an elasticity of R&D to generic utilization rates of about 0.090. While the magnitude of this elasticity is modest, as theory would predict—the effect of greater generic erosion of brand sales at patent expiration is heavily discounted due to the long time horizon to generic erosion when an R&D project is in clinical development. However, because there has been a very substantial increase in generic utilization rates since 1984, the impact on R&D is nevertheless quite large. We explore this and other issues in the current paper.

Mathematical modelling of anisotropy in fibrous connective tissue

We present two modelling frameworks for studying dynamic anistropy in connective tissue, motivated by the problem of fibre alignment in wound healing. The first model is a system of partial differential equations operating on a macroscopic scale. We show that a model consisting of a single extracellular matrix material aligned by fibroblasts via flux and stress exhibits behaviour that is incompatible with experimental observations. We extend the model to two matrix types and show that the results of this extended model are robust and consistent with experiment. The second model represents cells as discrete objects in a continuum of ECM. We show that this model predicts patterns of alignment on macroscopic length scales that are lost in a continuum model of the cell population

Age-related risk of household transmission of COVID-19 in Singapore.

Prior to the implementation of social distancing measures, we monitored the close family contacts of the first 400 cases of COVID-19 in Singapore for SARS-CoV-2 infection to determine the risk of infection with age. Adjusting for gender and household size, the risk of COVID-19 infection in household contacts was found to increase with age

Simple Clinical and Laboratory Predictors of Chikungunya versus Dengue Infections in Adults

10.1371/journal.pntd.0001786PLoS Neglected Tropical Diseases69

Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Post exertion malaise is one of the most debilitating aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, yet the neurobiological consequences are largely unexplored. The objective of the study was to determine the neural consequences of acute exercise using functional brain imaging. Fifteen female Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients and 15 healthy female controls completed 30 min of submaximal exercise (70% of peak heart rate) on a cycle ergometer. Symptom assessments (e.g. fatigue, pain, mood) and brain imaging data were collected one week prior to and 24 h following exercise. Functional brain images were obtained during performance of: 1) a fatiguing cognitive task – the Paced Auditory Serial Addition Task, 2) a non-fatiguing cognitive task – simple number recognition, and 3) a non-fatiguing motor task – finger tapping. Symptom and exercise data were analyzed using independent samples t-tests. Cognitive performance data were analyzed using mixed-model analysis of variance with repeated measures. Brain responses to fatiguing and non-fatiguing tasks were analyzed using linear mixed effects with cluster-wise (101-voxels) alpha of 0.05. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients reported large symptom changes compared to controls (effect size ≥0.8, p \u3c 0.05). Patients and controls had similar physiological responses to exercise (p \u3e 0.05). However, patients exercised at significantly lower Watts and reported greater exertion and leg muscle pain (p \u3c 0.05). For cognitive performance, a significant Group by Time interaction (p \u3c 0.05), demonstrated pre- to post-exercise improvements for controls and worsening for patients. Brain responses to finger tapping did not differ between groups at either time point. During number recognition, controls exhibited greater brain activity (p \u3c 0.05) in the posterior cingulate cortex, but only for the pre-exercise scan. For the Paced Serial Auditory Addition Task, there was a significant Group by Time interaction (p \u3c 0.05) with patients exhibiting increased brain activity from pre- to post-exercise compared to controls bilaterally for inferior and superior parietal and cingulate cortices. Changes in brain activity were significantly related to symptoms for patients (p \u3c 0.05). Acute exercise exacerbated symptoms, impaired cognitive performance and affected brain function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. These converging results, linking symptom exacerbation with brain function, provide objective evidence of the detrimental neurophysiological effects of post-exertion malaise

Acetyl-L-Carnitine in Attention-Deficit/Hyperactivity Disorder: A Multi-Site, Placebo-Controlled Pilot Trial

Objective: To determine whether acetyl-L-carnitine (ALC), a metabolite necessary for energy metabolism and essential fatty acid anabolism, might help attention-deficit/hyperactivity disorder (ADHD). Trials in Down’s syndrome, migraine, and Alzheimer’s disease showed benefit for attention. A preliminary trial in ADHD using L-carnitine reported significant benefit. Method: A multi-site 16-week pilot study randomized 112 children (83 boys, 29 girls) age 5-12 with systematically diagnosed ADHD to placebo or ALC in weight-based doses from 500 to 1500 mg b.i.d. The 2001 revisions of the Conners’ parent and teacher scales (including DSM-IV ADHD symptoms) were administered at baseline, 8, 12, and 16 weeks. Analyses were ANOVA of change from baseline to 16 weeks with treatment, center, and treatment-by-center interaction as independent variables. Results: The primary intent-to-treat analysis, of 9 DSM-IV teacher-rated inattentive symptoms, was not significant. However, secondary analyses were interesting. There was significant (p = 0.02) moderation by subtype: superiority of ALC over placebo in the inattentive type, with an opposite tendency in combined type. There was also a geographic effect (p = 0.047). Side effects were negligible; electrocardiograms, lab work, and physical exam unremarkable. Conclusion: ALC appears safe, but with no effect on the overall ADHD population (especially combined type). It deserves further exploration for possible benefit specifically in the inattentive type

Field measurements of sonic boom penetration into the ocean

Author Posting. © Acoustical Society of America, 2000. This article is posted here by permission of Acoustical Society of America for personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 107 (2000): 3073-3083, doi:10.1121/1.429336.Six sonic booms, generated by F-4 aircraft under steady flight at a range of altitudes (610–6100 m) and Mach numbers (1.07–1.26), were measured just above the air/sea interface, and at five depths in the water column. The measurements were made with a vertical hydrophone array suspended from a small spar buoy at the sea surface, and telemetered to a nearby research vessel. The sonic boom pressure amplitude decays exponentially with depth, and the signal fades into the ambient noise field by 30–50 m, depending on the strength of the boom at the sea surface. Low-frequency components of the boom waveform penetrate significantly deeper than high frequencies. Frequencies greater than 20 Hz are difficult to observe at depths greater than about 10 m. Underwater sonic boom pressure measurements exhibit excellent agreement with predictions from analytical theory, despite the assumption of a flat air/sea interface. Significant scattering of the sonic boom signal by the rough ocean surface is not detected. Real ocean conditions appear to exert a negligible effect on the penetration of sonic booms into the ocean unless steady vehicle speeds exceed Mach 3, when the boom incidence angle is sufficient to cause scattering on realistic open ocean surfaces.This work was funded by the NASA Langley Research Center (Technical Monitor, Dr. Kevin Shepherd)

Adapted motivational interviewing to improve the uptake of treatment for glaucoma in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: Glaucoma is a chronic eye disease associated with irreversible visual loss. In Africa, glaucoma patients often present late, with very advanced disease. One-off procedures, such as laser or surgery, are recommended in Africa because of lack of or poor adherence to medical treatment. However, acceptance of surgery is usually extremely low. To prevent blindness, adherence to treatment needs to improve, using acceptable, replicable and cost-effective interventions. After reviewing the literature and interviewing patients in Bauchi (Nigeria) motivational interviewing (MI) was selected as the intervention for this trial, with adaptation for glaucoma (MIG). MI is designed to strengthen personal motivation for, and commitment to a specific goal by eliciting and exploring a person's reasons for change within an atmosphere of acceptance and compassion. The aim of this study is to assess whether MIG increases the uptake of laser or surgery amongst glaucoma patients where this is the recommended treatment. The hypothesis is that MIG increases the uptake of treatment. This will be the first trial of MI in Africa. METHODS: This is a hospital based, single centre, randomized controlled trial of MIG plus an information sheet on glaucoma and its treatment (the latter being "standard care") compared with standard care alone for glaucoma patients where the treatment recommended is surgery or laser.Those eligible for the trial are adults aged 17 years and above who live within 200 km of Bauchi with advanced glaucoma where the examining ophthalmologist recommends surgery or laser. After obtaining written informed consent, participants will be randomly allocated to MIG plus standard care, or standard care alone. Motivational interviewing will be delivered in Hausa or English by one of two MIG trained personnel. One hundred and fifty participants will be recruited to each arm. The primary outcome is the proportion of participants undergoing laser or surgery within two months of the date given to re attend for the procedure. MIG quality will be assessed using the validated MI treatment integrity scale. DISCUSSION: Motivational interviewing may be an important tool to increase the acceptance of treatment for glaucoma. The approach is potentially scalable and may be useful for other chronic conditions in Africa. TRIAL REGISTRATION: ISRCTN79330571 (Controlled-Trials.com)

Robotic ubiquitous cognitive ecology for smart homes

Robotic ecologies are networks of heterogeneous robotic devices pervasively embedded in everyday environments, where they cooperate to perform complex tasks. While their potential makes them increasingly popular, one fundamental problem is how to make them both autonomous and adaptive, so as to reduce the amount of preparation, pre-programming and human supervision that they require in real world applications. The project RUBICON develops learning solutions which yield cheaper, adaptive and efficient coordination of robotic ecologies. The approach we pursue builds upon a unique combination of methods from cognitive robotics, machine learning, planning and agent- based control, and wireless sensor networks. This paper illustrates the innovations advanced by RUBICON in each of these fronts before describing how the resulting techniques have been integrated and applied to a smart home scenario. The resulting system is able to provide useful services and pro-actively assist the users in their activities. RUBICON learns through an incremental and progressive approach driven by the feed- back received from its own activities and from the user, while also self-organizing the manner in which it uses available sensors, actuators and other functional components in the process. This paper summarises some of the lessons learned by adopting such an approach and outlines promising directions for future work