Assessment of cochlear synaptopathy by electrocochleography to low frequencies in a preclinical model and human subjects

Cochlear synaptopathy is the loss of synapses between the inner hair cells and the auditory nerve despite survival of sensory hair cells. The findings of extensive cochlear synaptopathy in animals after moderate noise exposures challenged the long-held view that hair cells are the cochlear elements most sensitive to insults that lead to hearing loss. However, cochlear synaptopathy has been difficult to identify in humans. We applied novel algorithms to determine hair cell and neural contributions to electrocochleographic (ECochG) recordings from the round window of animal and human subjects. Gerbils with normal hearing provided training and test sets for a deep learning algorithm to detect the presence of neural responses to low frequency sounds, and an analytic model was used to quantify the proportion of neural and hair cell contributions to the ECochG response. The capacity to detect cochlear synaptopathy was validated in normal hearing and noise-exposed animals by using neurotoxins to reduce or eliminate the neural contributions. When the analytical methods were applied to human surgical subjects with access to the round window, the neural contribution resembled the partial cochlear synaptopathy present after neurotoxin application in animals. This result demonstrates the presence of viable hair cells not connected to auditory nerve fibers in human subjects with substantial hearing loss and indicates that efforts to regenerate nerve fibers may find a ready cochlear substrate for innervation and resumption of function

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Bring it on home: Home drug testing and the relocation of the war on drugs

The award-winning movie American Beauty provides a popular depiction of what we suggest is an extension of anti-drug initiatives in which drug testing, coterminous with a change in the anti-drug discourse, is introduced into the homes of white middle-class America. The story unfolds in a stereotypical, middle-class suburb. In one scene an attractive, white, teenage boy sells marijuana to his middle-aged neighbor. The neighbor asks about a container of yellow liquid and the boy responds that it is urine. His parents, he explains, drug test him. This article explores this most recent extension of America's anti-drug initiatives into a new and relatively untouched space, the realm of middleclass domesticity. Widely proclaimed failures of the "war on drugs" have prompted a renewed emphasis on attempts to eradicate the demand for drugs. In the process, the metaphor of drug use as a "disease" has been revived. This trope works in the context of a distinctive constellation of actors, institutions, and interests to advance home drug testing as a potential solution to one manifestation of America's drug problem. Parental drug testing of teenagers advances anti-drug initiatives into the home and into a child's body by effectively deputizing parents, making them unique articulations of private police. We argue that the use of such tests is characteristic of wider trends in neoliberal approaches to governing crime. Home drug testing is part of a turn to technology in governmental strategies which suggests that analysts must pay greater attention to the minutiae of such tools and the social factors that help to position them as potential solutions to crime problems. However, the drug testing example indicates that rather than being embraced exclusively due to their demonstrated abilities to reduce crime risks, governmental technologies can be adopted for a host of less rational reasons. In the process, they can also prompt some highly distinctive forms of resistance. We draw from various research sources, including approximately 50 websites dealing with drug testing, numerous hard-copy pamphlets and informational packages pertaining to such tests, and advertisements in specialty magazines aimed at drug users. Telephone interviews were conducted with five representatives of companies that market home drug tests. The minutes of hearings into the regulation of home tests by the US Food and Drug Administration provided valuable insights into who originally advocated on behalf of these tests, and the types of problems they thought these technologies might solve (Food and Drug Administration, 1997)

Bring it on home: Home drug testing and the relocation of the war on drugs

While the war on drugs is often claimed to have failed in multifarious ways, anti-drug strategies in the United States continue. The discourses through which anti-drug sentiments and policies are forwarded are, however, being reinvented in light of this failure, favoring an inclusionary and less state-centered disease trope for certain populations of drug users. In this article we argue that the privileging of the disease trope within anti-drug rhetoric facilitates the introduction of home drug testing as a means of 'state-free' drug regulation offered to specific populations. The advent of home drug testing is congruent with neoliberal trends towards mobilizing private entities like the family to engage in regulatory practices that were previously concerns of the state. A market for home drug testing has evolved out of rhetoric around private security, and the commodification of notions of safety. Home drug testing is theorized as a tool of surveillance that offers a very particular scientific gaze trained on the seemingly indefensible adolescent body. Teens, however, are not defenseless in this scheme. We document the concomitant rise of resistance technologies and tactics designed to assist teens and others to 'beat' the tests