The Law, Economics, and Medicine of Off-Label Prescribing

There is a major dissonance in the current structure of regulating new drugs that have more than one medical indication. Physicians are authorized to prescribe these drugs for all indications including those beyond their approved purposes. However, product manufacturers are expressly prohibited from marketing or promoting their drugs for any purpose other than those which have been specifically indicated. While prescribing physicians are encouraged to gain medical information on any additional indications, they cannot obtain it from one of its most likely sources: the drug’s supplier. The Second Circuit Court of Appeals’ recent opinion in United States v. Caronia has challenged this regulatory structure. For the three states in the Second Circuit, although not the rest of the country, the FDA’s regulations prohibiting promotion of non-approved indications have been restricted. In this Article, we review the legal, economic, and medical aspects of the FDA’s current regulatory approach, and explore the likely consequences of a widespread adoption of the Caronia rule

The Law, Economics, and Medicine of Off-Label Prescribing

There is a major dissonance in the current structure of regulating new drugs that have more than one medical indication. Physicians are authorized to prescribe these drugs for all indications including those beyond their approved purposes. However, product manufacturers are expressly prohibited from marketing or promoting their drugs for any purpose other than those which have been specifically indicated. While prescribing physicians are encouraged to gain medical information on any additional indications, they cannot obtain it from one of its most likely sources: the drug’s supplier. The Second Circuit Court of Appeals’ recent opinion in United States v. Caronia has challenged this regulatory structure. For the three states in the Second Circuit, although not the rest of the country, the FDA’s regulations prohibiting promotion of non-approved indications have been restricted. In this Article, we review the legal, economic, and medical aspects of the FDA’s current regulatory approach, and explore the likely consequences of a widespread adoption of the Caronia rule

“You can’t be a person and a doctor”. The work-life balance of doctors in training: a qualitative study

Objectives Investigate the work–life balance of doctors in training in the UK from the perspectives of trainers and trainees. Design Qualitative semistructured focus groups and interviews with trainees and trainers. Setting Postgraduate medical training in London, Yorkshire and Humber, Kent, Surrey and Sussex, and Wales during the junior doctor contract dispute at the end of 2015. Part of a larger General Medical Council study about the fairness of postgraduate medical training. Participants 96 trainees and 41 trainers. Trainees comprised UK graduates and International Medical Graduates, across all stages of training in 6 specialties (General Practice, Medicine, Obstetrics and Gynaecology, Psychiatry, Radiology, Surgery) and Foundation. Results Postgraduate training was characterised by work–life imbalance. Long hours at work were typically supplemented with revision and completion of the e-portfolio. Trainees regularly moved workplaces which could disrupt their personal lives and sometimes led to separation from friends and family. This made it challenging to cope with personal pressures, the stresses of which could then impinge on learning and training, while also leaving trainees with a lack of social support outside work to buffer against the considerable stresses of training. Low morale and harm to well-being resulted in some trainees feeling dehumanised. Work–life imbalance was particularly severe for those with children and especially women who faced a lack of less-than-full-time positions and discriminatory attitudes. Female trainees frequently talked about having to choose a specialty they felt was more conducive to a work–life balance such as General Practice. The proposed junior doctor contract was felt to exacerbate existing problems. Conclusions A lack of work–life balance in postgraduate medical training negatively impacted on trainees' learning and well-being. Women with children were particularly affected, suggesting this group would benefit the greatest from changes to improve the work–life balance of trainees

Perceived causes of differential attainment in UK postgraduate medical training: a national qualitative study

Objectives: Explore trainee doctors’ experiences of postgraduate training and perceptions of fairness in relation to ethnicity and country of primary medical qualification. Design: Qualitative semistructured focus group and interview study. Setting: Postgraduate training in England (London, Yorkshire and Humber, Kent Surrey and Sussex) and Wales. Participants: 137 participants (96 trainees, 41 trainers) were purposively sampled from a framework comprising: doctors from all stages of training in general practice, medicine, obstetrics and gynaecology, psychiatry, radiology, surgery or foundation, in 4 geographical areas, from white and black and minority ethnic (BME) backgrounds, who qualified in the UK and abroad. Results: Most trainees described difficult experiences, but BME UK graduates (UKGs) and international medical graduates (IMGs) could face additional difficulties that affected their learning and performance. Relationships with senior doctors were crucial to learning but bias was perceived to make these relationships more problematic for BME UKGs and IMGs. IMGs also had to deal with cultural differences and lack of trust from seniors, often looking to IMG peers for support instead. Workplace-based assessment and recruitment were considered vulnerable to bias whereas examinations were typically considered more rigorous. In a system where success in recruitment and assessments determines where in the country you can get a job, and where work–life balance is often poor, UK BME and international graduates in our sample were more likely to face separation from family and support outside of work, and reported more stress, anxiety or burnout that hindered their learning and performance. A culture in which difficulties are a sign of weakness made seeking support and additional training stigmatising. Conclusions: BME UKGs and IMGs can face additional difficulties in training which may impede learning and performance. Non-stigmatising interventions should focus on trainee–trainer relationships at work and organisational changes to improve trainees’ ability to seek social support outside work

Similarity-Detection and Localization

The detection of similarities between long DNA and protein sequences is studied using concepts of statistical physics. It is shown that mutual similarities can be detected by sequence alignment methods only if their amount exceeds a threshold value. The onset of detection is a continuous phase transition which can be viewed as a localization-delocalization transition. The ``fidelity'' of the alignment is the order parameter of that transition; it leads to criteria for the selection of optimal alignment parameters.Comment: 4 pages including 4 figures (308kb post-script file

Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS: A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS: Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION: Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING: This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship

Calculus on the Sierpinski Gasket I: Polynomials, Exponentials and Power Series

We study the analog of power series expansions on the Sierpinski gasket, for analysis based on the Kigami Laplacian. The analog of polynomials are multiharmonic functions, which have previously been studied in connection with Taylor approximations and splines. Here the main technical result is an estimate of the size of the monomials analogous to x^n/n!. We propose a definition of entire analytic functions as functions represented by power series whose coefficients satisfy exponential growth conditions that are stronger than what is required to guarantee uniform convergence. We present a characterization of these functions in terms of exponential growth conditions on powers of the Laplacian of the function. These entire analytic functions enjoy properties, such as rearrangement and unique determination by infinite jets, that one would expect. However, not all exponential functions (eigenfunctions of the Laplacian) are entire analytic, and also many other natural candidates, such as the heat kernel, do not belong to this class. Nevertheless, we are able to use spectral decimation to study exponentials, and in particular to create exponentially decaying functions for negative eigenvalues

Improved Algorithms for Approximate String Matching (Extended Abstract)

The problem of approximate string matching is important in many different areas such as computational biology, text processing and pattern recognition. A great effort has been made to design efficient algorithms addressing several variants of the problem, including comparison of two strings, approximate pattern identification in a string or calculation of the longest common subsequence that two strings share. We designed an output sensitive algorithm solving the edit distance problem between two strings of lengths n and m respectively in time O((s-|n-m|)min(m,n,s)+m+n) and linear space, where s is the edit distance between the two strings. This worst-case time bound sets the quadratic factor of the algorithm independent of the longest string length and improves existing theoretical bounds for this problem. The implementation of our algorithm excels also in practice, especially in cases where the two strings compared differ significantly in length. Source code of our algorithm is available at http://www.cs.miami.edu/\~dimitris/edit_distanceComment: 10 page