Conant v. Walters: A Misapplication of Free Speech Rights in the Doctor-Patient Relationship

In Conant v. Walters, the United States Court of Appeals for the Ninth Circuit addressed the application of the First Amendment\u27s right of free speech to a federal policy that prohibited the recommendation of medical marijuana by physicians. This class action suit, brought by physicians and severely ill patients, successfully enjoined the federal government from enforcing its policy revoking the federal prescriptive licenses of physicians who recommend or approve of marijuana use by patients suffering from certain severe illnesses. The federal government\u27s policy, issued in 1996 through a statement of Barry McCaffrey, director of the Office of National Drug Control Policy (ONDCP), responded directly to recent legislation in California decriminalizing the use of marijuana under certain medically-approved circumstances. The California legislation also protected physicians from prosecution under state law for recommending marijuana use. Entering an injunction against the federal policy, the United States District Court held that, although the federal government had the right to regulate the distribution and use of marijuana, it could not interfere with First Amendment interests by precluding doctors and patients from discussing marijuana as a treatment for medical conditions. On appeal, the majority affirmed on the basis of the First Amendment implications of the government policy. The concurring opinion, however, expressed another reason for enjoining the government from enforcing its policy, specifically the Commandeering Doctrine, which prohibits the federal government from requiring that states address a particular problem or enforce a federal regulatory program. The Supreme Court denied certiorari on October 14, 2003. This Note explores federal laws that pertain to marijuana use, as well as California\u27s policies on medical marijuana and physician recommendations, considering the implications of both the First Amendment and the Commerce Clause in the resolution of this case

Stress-Induced Out-of-Context Activation of Memory

An intensely stressful experience can itself activate memories that are unrelated to the stressful experience. This previously unknown property of stress could help explain how traumatic memories become pathological

Low Frequency Variants in the Exons Only Encoding Isoform A of HNF1A Do Not Contribute to Susceptibility to Type 2 Diabetes

Background: There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8-10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1-7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8-10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D. Methodology and principal findings: We performed targeted capillary resequencing of HNF1A exons 8-10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (≤ 45 years) and/or family history of T2D (≥ 1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9-24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rd61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected. Conclusions and significance: We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion

Combining Information from Common Type 2 Diabetes Risk Polymorphisms Improves Disease Prediction

BACKGROUND: A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (~20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. METHODS AND FINDINGS: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. CONCLUSIONS: Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases

SMN Protein Can Be Reliably Measured in Whole Blood with an Electrochemiluminescence (ECL) Immunoassay: Implications for Clinical Trials

Spinal muscular atrophy (SMA) is caused by defects in the survival motor neuron 1 (SMN1) gene that encodes survival motor neuron (SMN) protein. The majority of therapeutic approaches currently in clinical development for SMA aim to increase SMN protein expression and there is a need for sensitive methods able to quantify increases in SMN protein levels in accessible tissues. We have developed a sensitive electrochemiluminescence (ECL)-based immunoassay for measuring SMN protein in whole blood with a minimum volume requirement of 5μL. The SMN-ECL immunoassay enables accurate measurement of SMN in whole blood and other tissues. Using the assay, we measured SMN protein in whole blood from SMA patients and healthy controls and found that SMN protein levels were associated with SMN2 copy number and were greater in SMA patients with 4 copies, relative to those with 2 and 3 copies. SMN protein levels did not vary significantly in healthy individuals over a four-week period and were not affected by circadian rhythms. Almost half of the SMN protein was found in platelets. We show that SMN protein levels in C/C-allele mice, which model a mild form of SMA, were high in neonatal stage, decreased in the first few weeks after birth, and then remained stable throughout the adult stage. Importantly, SMN protein levels in the CNS correlated with SMN levels measured in whole blood of the C/C-allele mice. These findings have implications for the measurement of SMN protein induction in whole blood in response to SMN-upregulating therapy

Binary Contamination in the SEGUE sample: Effects on SSPP Determinations of Stellar Atmospheric Parameters

Using numerical modeling and a grid of synthetic spectra, we examine the effects that unresolved binaries have on the determination of various stellar atmospheric parameters for SEGUE targets measured using the SEGUE Stellar Parameter Pipeline (SSPP). To model undetected binaries that may be in the SEGUE sample, we use a variety of mass distributions for the primary and secondary stars in conjunction with empirically determined relationships for orbital parameters to determine the fraction of G-K dwarf stars, as defined by SDSS color cuts, that will be blended with a secondary companion. We focus on the G-K dwarf sample in SEGUE as it records the history of chemical enrichment in our galaxy. To determine the effect of the secondary on the spectroscopic parameters, we synthesize a grid of model spectra from 3275 to 7850 K (~0.1 to 1.0 \msun) and [Fe/H]=-0.5 to -2.5 from MARCS model atmospheres using TurboSpectrum. We analyze both "infinite" signal-to-noise ratio (S/N) models and degraded versions, at median S/N of 50, 25 and 10. By running individual and combined spectra (representing the binaries) through the SSPP, we determine that ~10% of the blended G-K dwarf pairs with S/N>=25 will have their atmospheric parameter determinations, in particular temperature and metallicity, noticeably affected by the presence of an undetected secondary. To account for the additional uncertainty from binary contamination at a S/N~10, uncertainties of ~140 K and ~0.17 dex in [Fe/H] must be added in quadrature to the published uncertainties of the SSPP. (Abridged)Comment: 68 pages, 20 figures, 9 table

Ethical, legal, and social issues in the Earth BioGenome Project.

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project's technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP's Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not-and cannot-provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP's work

Ethical, legal, and social issues in the Earth BioGenome Project

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project’s technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP’s Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not—and cannot—provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP’s work