The 1940s and 1950s were marked by intense debates over the origin of drug resistance in microbes. Bacteriologists had traditionally invoked the notions of ‘training’ and ‘adaptation’ to account for the ability of microbes to acquire new traits. As the field of bacterial genetics emerged, however, its participants rejected ‘Lamarckian’ views of microbial heredity, and offered statistical evidence that drug resistance resulted from the selection of random resistant mutants. Antibiotic resistance became a key issue among those disputing (...) physiological vs. genetic explanations of variation in bacteria. Postwar developments connected with the Lysenko affair gave this debate a new political valence.Proponents of the neo-Darwinian synthesis weighed in with support for the genetic theory. However, certain features of drug resistance seemed inexplicable by mutation and selection, particularly the phenomenon of ‘multiple resistance’—the emergence of resistance in a single strain against several unrelated antibiotics. In the late 1950s, Tsutomu Watanabe and his collaborators solved this puzzle by determining that resistance could be conferred by cytoplasmic resistance factors rather than chromosomal mutation. These R factors could carry resistance to many antibiotics and seemed able to promote their own dissemination in bacterial populations. In the end, the vindication of the genetic view of drug resistance was accompanied by a recasting of the ‘gene’ to include extrachromosomal hereditary units carried on viruses and plasmids. (shrink)

Drug‐resistant bacterial infections constitute a major threat to global public health. Several key bacteria that are becoming increasingly resistant are among those that are ubiquitously carried by human beings and usually cause no symptoms (i.e. individuals are asymptomatic carriers) until and/or unless a precipitating event leads to symptomatic infection (and thus disease). Carriers of drug‐resistant bacteria can also transmit resistant pathogens to others, thus putting the latter at risk of resistant infections. Accumulating evidence suggests that such transmission (...) occurs not only in hospital settings but also in the general community, although considerably more data are needed to assess the extent of this problem. Asymptomatic carriage of drug‐resistant bacteria raises important ethical questions regarding the appropriate public health response, including the degree to which it would be justified to impose burdens on asymptomatic carriers (and others) in order to prevent transmission. In this paper, we (i) summarize current evidence regarding the carriage of key drug‐resistant bacteria, noting important knowledge gaps; and (ii) explore the particular implications of existing public health ethics frameworks for policy‐making regarding asymptomatic carriers. Inter alia, we argue that the relative burdens imposed by public health measures on healthy carriers (as opposed to sick individuals) warrant careful consideration and should be proportionate to the expected public health benefits in terms of risks averted. We conclude that more surveillance and research regarding community transmission will be needed in order to clarify relevant risks and design proportionate policies, although extensive community surveillance itself would also require careful ethical consideration. (shrink)

Antimicrobial resistance is a critical public health challenge, and the contribution of the widespread use of antimicrobials in food animals to bacterial drug resistance and human infection demands greater policymaker attention. Global consumption of antimicrobials in food animal production by 2030 is projected to rise by two-thirds due to increases in both food animal production and demand for animal products. In the United States, the volume of antibiotics sold for use in food-producing animals is at least three times (...) greater than that sold for human use. A One Health approach that emphasizes the connections among the health of humans, animals, and the environment is needed to address antibiotic resistance in an integrated manner. This approach holds the promise of collaboration across multiple disciplines, including doctors, veterinarians, food safety professionals, and environmental health experts. (shrink)

Antibiotic resistance in bacteria has become a great threat to global public health. Tigecycline is a next‐generation tetracycline that is the final line of defense against severe infections by pan‐drug‐resistant bacterial pathogens. Unfortunately, this last‐resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high‐level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next‐generation tetracyclines, and a basic framework for understanding the molecular (...) epidemiology and resistance mechanisms of them is presented. However, further large‐scale epidemiological and functional studies are urgently needed to better understand the prevalence and dissemination of these newly discovered Tet(X) orthologs among Gram‐negative bacteria in both human and veterinary medicine. (shrink)

Foucauldian analyses of civil society depart from classical approaches in that they don´t consider civil society to be a site of societal change or resistance as classical analyses do, but rather one of society’s multiple locations where so-called governmentality hits the ground. Although Foucauldian investigations have provided the prevailing discussion with a necessary departure from excessively idealistic images of civil society organizations as sites of resistance and societal transformation, what may have resulted in turn are overly pessimistic analyses that have (...) overlooked the emancipatory aspects of civil society organizations as sites where Foucauldian “care of the self” becomes possible. This article provides the reader with an analysis of these kind of aspects in civil society organizations’ work and, more importantly, of the conditions of their existence. The study contributes to the prevailing discussion by offering examples of the possibilities that civil society organizations have to act as a counterbalance and addition to states institutions. The context is Finnish drug treatment policies that took a client-centered and user-friendly approach at the turn of 21st century. Since then new kinds of methods to work with drug users have been initiated, which have helped the users to recast their identities and find new ways of living as a drug user. (shrink)

Drugs targeting a single TK/RTK in the treatment of solid cancers has not had the same success seen in blood cancers. This is, in part, due to acquired resistance in solid cancers arising from a range of mechanisms including the upregulation of compensatory RTK signalling. Rather than attempting to inhibit individual compensatory RTK—requiring knowledge of which RTKs are upregulated in any given tumour—strategies to universally inhibit signalling from multiple RTKs may represent an effective alternative. Endosomal trafficking of RTKs is a (...) common conduit that can regulate signalling from multiple RTKs simultaneously. As such, we posit that targeting endosomal trafficking—in particular, aberrant post‐translational modifications in cancers that contribute to dysregulated endosomal trafficking—could inhibit oncogenic signalling driven by multiple RTKs and pave the way for the development of a novel class of inhibitors that shift the trafficking of RTKs to inhibit tumour growth. (shrink)

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The “highly active antiretroviral therapy” (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open (...) debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-α, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART. BioEssays 23:1070–1080, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

In the past few years, two new DNA topoisomerases have been discovered in bacteria, bringing the total number of DNA topoisomerases in E. coli to four. Two classes of topoisomerases, type 1 and type 2, are distinguishable by their amino acid homology and their apparent reaction mechanism. Of the four E. coli topoisomerases, there are two type 1 and two type 2 enzymes. In eukaryotes, the existence of multiple type 1 and type 2 enzymes has also become apparent. The existence (...) of these multiple enzymes provokes a question whose answer has both evolutionary and physiological implications: are these topoisomerases functionally redundant, or have they acquired sufficient specialization that they now perform unique biological reactions? In bacteria, there is evidence for both specialization and redundancy in the functions of topoisomerases. (shrink)

ABSTRACT This paper reviews the dynamics behind, and ethical issues associated with, the phenomenon of drug resistance. Drug resistance is an important ethical issue partly because of the severe consequences likely to result from the increase in drug resistant pathogens if more is not done to control them. Drug resistance is also an ethical issue because, rather than being a mere quirk of nature, the problem is largely a product of drug distribution. Drug resistance (...) results from the over‐consumption of antibiotics by the wealthy; and it, ironically, results from the under‐consumption of antibiotics, usually by the poor or otherwise marginalized. In both kinds of cases the phenomenon of drug resistance illustrates why health (care) – at least in the context of infectious disease – should be treated as a (global) public good. The point is that drug resistance involves ‘externalities’ affecting third parties. When one patient develops a resistant strain of disease because of her over‐ or under‐consumption of medication, this more dangerous malady poses increased risk to others. The propriety of free‐market distribution of goods subject to externalities is famously dubious – given that the ‘efficiency’ rationale behind markets assumes an absence of externalities. Market failure in the context of drug resistance is partly revealed by the fact that no new classes of antibiotics have been developed since 1970. I conclude by arguing that the case of drug resistance reveals additional reasons – to those traditionally appealed to by bioethicists – for treating health care as something special when making policy decisions about its distribution. (shrink)

Effectiveness is a key criterion in assessing the justification of antibiotic resistance interventions. Depending on an intervention’s effectiveness, burdens and costs will be more or less justified, which is especially important for large scale population-level interventions with high running costs and pronounced risks to individuals in terms of wellbeing, integrity and autonomy. In this paper, we assess the case of routine hospital screening for multi-drug-resistant Gram-negative bacteria (MDRGN) from this perspective. Utilizing a comparison to screening programs for Methicillin-Resistant Staphylococcus (...) aureus (MRSA) we argue that current screening programmes for MDRGN in low endemic settings should be reconsidered, as its effectiveness is in doubt, while general downsides to screening programs remain. To accomplish justifiable antibiotic stewardship, MDRGN screening should not be viewed as a separate measure, but rather as part of a comprehensive approach. The program should be redesigned to focus on those at risk of developing symptomatic infections with MDRGN rather than merely detecting those colonised. (shrink)

This Open Access volume provides in-depth analysis of the wide range of ethical issues associated with drug-resistant infectious diseases. Antimicrobial resistance is widely recognized to be one of the greatest threats to global public health in coming decades; and it has thus become a major topic of discussion among leading bioethicists and scholars from related disciplines including economics, epidemiology, law, and political theory. Topics covered in this volume include responsible use of antimicrobials; control of multi-resistant hospital-acquired infections; privacy and (...) data collection; antibiotic use in childhood and at the end of life; agricultural and veterinary sources of resistance; resistant HIV, tuberculosis, and malaria; mandatory treatment; and trade-offs between current and future generations. As the first book focused on ethical issues associated with drug resistance, it makes a timely contribution to debates regarding practice and policy that are of crucial importance to global public health in the 21st century. (shrink)

In all domains of life, transmembrane proteins from the ATP‐binding cassette (ABC) transporter family drive the translocation of diverse substances across lipid bilayers. In pathogenic fungi, the ABC transporters of the pleiotropic drug resistance (PDR) subfamily confer antibiotic resistance and so are of interest as therapeutic targets. They also drive the quest for understanding how ABC transporters can generally accommodate such a wide range of substrates. The Pdr5 transporter from baker's yeast is representative of the PDR group and, ever (...) since its discovery more than 30 years ago, has been the subject of extensive functional analyses. A new perspective of these studies has been recently provided in the framework of the first electron cryo‐microscopy structures of Pdr5, as well as emergent applications of machine learning in the field. Taken together, the old and the new developments have been used to propose a mechanism for the transport process in PDR proteins. This mechanism involves a “flippase” step that moves the substrates from one leaflet of the bilayer to the other, as a central element of cellular efflux. (shrink)

This article critically examines current responses to multi-drug resistant tuberculosis and argues that bioethics needs to be willing to engage in a more radical critique of the problem than is currently offered. In particular, we need to focus not simply on market-driven models of innovation and anti-microbial solutions to emergent and re-emergent infections such as TB. The global community also needs to address poverty and the structural factors that entrench inequalities—thus moving beyond the orthodox medical/public health frame of reference.

The rapid evolution of drug resistance remains a major obstacle for HIV therapy. The capacity of the virus for recombination is widely believed to facilitate the evolution of drug resistance. Here, we challenge this intuitive view. We develop a population genetic model of HIV replication that incorporates the processes of mutation, cellular superinfection, and recombination. We show that cellular superinfection increases the abundance of low fitness viruses at the expense of the fittest strains due to the mixing of (...) viral proteins during virion assembly. Moreover, we argue that whether recombination facilitates the evolution of drug resistance depends critically on how resistance mutations interact to determine viral fitness. Contrary to the commonly held belief, we find that, under the most plausible biological assumptions, recombination is expected to slow down the rate of evolution of multi‐drug‐resistant virus during therapy. BioEssays 26:180–188, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Chemotherapy is an important therapeutic approach for cancer treatment. However, drug resistance is an obstacle that often impairs the successful use of chemotherapies. Therefore, overcoming drug resistance would lead to better therapeutic outcomes for cancer patients. Recently, studies by our own and other groups have demonstrated that there is an intimate correlation between the loss of the F‐box and WD repeat domain‐containing 7 (FBW7) tumor suppressor and the incurring drug resistance. While loss of FBW7 sensitizes cancer cells (...) to certain drugs, FBW7‐/‐ cells are more resistant to other types of chemotherapies. FBW7 exerts its tumor suppressor function by promoting the degradation of various oncoproteins that regulate many cellular processes, including cell cycle progression, cellular metabolism, differentiation, and apoptosis. Since loss of the FBW7 tumor suppressor is linked to drug resistance, FBW7 may represent a novel therapeutic target to increase drug sensitivity of cancer cells to conventional chemotherapeutics. This paper thus focuses on the new functional aspects of FBW7 in drug resistance. (shrink)

The incident in May-June 2007 involving a U.S. citizen traveling internationally while infected with drug-resistant tuberculosis involved the U.S. federal government's application of its quarantine and isolation powers. The incident and the isolation order raised numerous important issues for public health governance, law, and ethics. This article explores many of these issues by examining how the exercise of quarantine powers provides a powerful lens through which to understand how societies respond to and attempt to govern threats posed by dangerous, (...) contagious pathogens. The article considers historical aspects of governmental power to quarantine and isolate individuals and groups; analyzes the current state of quarantine and isolation law in the United States in light of the recent incident with drug-resistant tuberculosis; and explores global aspects of public health governance and law highlighted by this incident. (shrink)

The unprecedented outbreak of Ebola virus disease in West Africa has raised several novel ethical issues for global outbreak preparedness. It has also illustrated that familiar ethical issues in infectious disease management endure despite considerable efforts to understand and mitigate such issues in the wake of past outbreaks. To improve future global outbreak preparedness and response, we must examine these shortcomings and reflect upon the current state of ethical preparedness. To this end, we focus our efforts in this article on (...) the examination of one substantial area: ethical guidance in pandemic plans. We argue that, due in part to their focus on considerations arising specifically in relation to pandemics of influenza origin, pandemic plans and their existing ethical guidance are ill-equipped to anticipate and facilitate the navigation of unique ethical challenges that may arise in other infectious disease pandemics. We proceed by outlining three reasons why this is so, and situate our analysis in the context of the EVD outbreak and the threat posed by drug-resistant tuberculosis: different infectious diseases have distinct characteristics that challenge anticipated or existing modes of pandemic prevention, preparedness, response, and recovery, clear, transparent, context-specific ethical reasoning and justification within current influenza pandemic plans are lacking, and current plans neglect the context of how other significant pandemics may manifest. We conclude the article with several options for reflecting upon and ultimately addressing ethical issues that may emerge with different infectious disease pandemics. (shrink)

Dramatic events involving dangerous microbes often focus attention on isolation and quarantine as policy instruments. The incident in May-June 2007 involving Andrew Speaker and drug-resistant tuberculosis joins other communicable disease crises that have forced contemplation or actual application of quarantine powers. Implementation of quarantine powers, which encompasses authority for both isolation and quarantine actions, is important not only for the handling of a specific event but also because the use of such authority provides a window on broader issues of (...) public health and the legal rules, ethical principles, and governance systems that support it. Debates about quarantine powers reflect political and social attitudes about public health that often tell us more about this policy endeavor than acts of isolation and quarantine themselves. (shrink)

These teaching materials explore the specific powers of governments to implement control measures in response to communicable disease, in two different contexts:The first context concerns global pandemic diseases. Relevant legal authority includes international law, World Health Organization governance and the International Health Regulations, and regulatory authority of nations.The second context is centered on U.S. law and concerns control measures for drug-resistant disease, using tuberculosis as an example. In both contexts, international and domestic, the point is to understand legal authority (...) to address public health emergencies. (shrink)

Multiple drug resistant strains of HIV and continuing difficulties with vaccine development highlight the importance of psychologi- cal interventions which aim to in uence the psychosocial and emo- tional factors empirically demonstrated to be significant predictors of immunity, illness progression and AIDS mortality in seropositive persons. Such data have profound implications for psychological interventions designed to modify psychosocial factors predictive of enhanced risk of exposure to HIV as well as the neuroendocrine and immune mechanisms mediating the impact of such (...) factors on disease progression. Many of these factors can be construed as unconscious mental ones, and psychoanalytic self-psychology may be a useful framework for conceptualizing psychic and immune de- fence as well as bodily and self-integration in HIV infection. Al- though further prospective studies and cross-cultural validation of research are necessary, existing data suggest that psychoanalytic insights may be useful both in therapeutic interventions and evaluative research which would require an underlying epistemology of the complementarity of mind and matter. (shrink)

Many countries have implemented infection control measures directed at carriers of multidrug-resistant organisms. To explore the ethical implications of these measures, we analyzed 227 consultations about multidrug resistance and compared them with the literature on communicable disease in general. We found that control measures aimed at carriers have a range of negative implications. Although moral dilemmas seem similar to those encountered while implementing control measures for other infectious diseases, 4 distinct features stand out for carriage of multidrug-resistant organisms: carriage presents (...) itself as a state of being; carriage has limited relevance for the health of the carrier; carriage has little relevance outside healthcare settings; and antimicrobial resistance is a slowly evolving threat on which individual carriers have limited effect. These features are of ethical relevance because they influence the way we traditionally think about infectious disease control and urge us to pay more attention to the personal experience of the individual carrier. (shrink)

Non‐genetic forms of antimicrobial (drug) resistance can result from cell‐to‐cell variability that is not encoded in the genetic material. Data from recent studies also suggest that non‐genetic mechanisms can facilitate the development of genetic drug resistance. We speculate on how the interplay between non‐genetic and genetic mechanisms may affect microbial adaptation and evolution during drug treatment. We argue that cellular heterogeneity arising from fluctuations in gene expression, epigenetic modifications, as well as genetic changes contribute to drug (...) resistance at different timescales, and that the interplay between these mechanisms enhance pathogen resistance. Accordingly, developing a better understanding of the role of non‐genetic mechanisms in drug resistance and how they interact with genetic mechanisms will enhance our ability to combat antimicrobial resistance. Also see the video abstract here: https://youtu.be/aefGpdh-bgU. (shrink)

We propose a discrete time branching process to model the appearance of drug resistance under treatment. Under our assumptions at every discrete time a pathogen may die with probability 1−p or divide in two with probability p. Each newborn pathogen is drug resistant with probability μ. We start with N drug sensitive pathogens and with no drug resistant pathogens. We declare the treatment successful if all pathogens are eradicated before drug resistance appears. The model predicts (...) that success is possible only if p<1/2. Even in this case the probability of success decreases exponentially with the parameter m=μN. In particular, even with a very potent drug (i.e. p very small) drug resistance is likely if m is large. (shrink)

Successful surgical treatment of patients with focal drug-resistant epilepsy remains challenging, especially in cases for which it is difficult to define the area of cortex from which seizures originate, the seizure onset zone. Various diagnostic methods are needed to select surgical candidates and determine the extent of resection. Interictal magnetoencephalography with source imaging has proven to be useful for presurgical evaluation, but the use of ictal MEG data remains limited. The purpose of the present study was to determine whether (...) pre-ictal variations of spectral properties of neural activity from ictal MEG recordings are predictive of SOZ location.We performed a 4 h overnight MEG recording in an 8-year-old child with drug-resistant focal epilepsy of suspected right fronto-temporal origin and captured one ~45-s seizure. The patient underwent a right temporal resection from the anterior temporal neocortex and amygdala to the mid-posterior temporal neocortex, sparing the hippocampus proper. She remains seizure-free 21 months postoperatively. The histopathological assessment confirmed frank focal cortical dysplasia type IIa in the MEG-defined SOZ, which was based on source imaging of averaged ictal spikes at seizure onset. We investigated temporal changes together with spatial differences in spectral parameters of background brain activity, namely the aperiodic broadband offset and slope, and assessed how they confounded the interpretation of apparent variations of signal power in typical electrophysiological bands. Our data show that the SOZ was associated with a higher aperiodic offset and exponent during the seizure compared to control regions. Both parameters increased in all regions from 2 min before the seizure onwards. Regions anatomically closer to the SOZ also expressed higher values compared to contralateral regions, potentially indicating ictal spread. We also show that narrow-band power changes were caused by these fluctuations in the aperiodic component of ongoing brain activity. Our results indicate that the broadband aperiodic component of ongoing brain activity cannot be reduced to background noise of no physiological interest, and rather may be indicative of the neuropathophysiology of the SOZ. We believe these findings will inspire future studies of ictal MEG cases and confirm their significance. (shrink)

The introduction of genes into plants encoding potent antibacterial proteins, derived from insects, may significantly augment the level of their resistance to bacterial disease. Using modern techniques, genes of choice can be introduced into plant tissue and this tissue can be manipulated to produce viable plants. The potato has been chosen as the model system, not only because of its plasticity of development, which allows for the relatively easy regeneration of whole plants from transformed tissue, but also because the (...) potato ranks among the top four plants in the world in terms of economic importance. (shrink)

We read Marshall et al.’s paper with great interest but were left with many questions and concerns (Marshall et al., in press). As a group of public health researchers and practitioners (nursing, s...

Taking its direction from references to Black and Indigenous struggles present in Leonard Harris’ oeuvre, this chapter turns to politicized acts of resistance among Black and Indigenous communities. More specifically, the essay traces the functions of cultural pluralism, value relativism, and representative heuristics within solidarity work that enact logics of resistance to settler colonization and anti-Black racism, among other forms of oppression. Through this analysis, we see that Harris’ views about insurrection and normativity entail that both oppression and resistance are (...) the result of multiplicitous forms of agency. (shrink)

Lucius Outlaw and Shannon Sullivan have argued for the preservation of racial distinctiveness and the necessity of racial separatism. This paper articulates and challenges this push for racial separatism and the particular conception of race evoked therein. The author points out that the multiplicity, the multiculturalism, the intersectionality within these communities of resistance is typically belittled, fragmented, or erased. Recognizing the practical use of racial coalitions to combat racism, the author articulates an alternative conception of coalitional agency, one that allows (...) for multiplicitous identities, opening avenues to intercultural communication and impure coalitions of resistance. (shrink)

Medical professionals often deny patients who inject opioids a second or third heart valve replacement, even if such a surgery is medically indicated. However, such a position is not well defended. As this paper demonstrates, the ethical literature on the topic too often fails to develop and apply an ethical lens to analyse the issue of multiple valve replacements. This paper addresses this lacuna by analysing the case of Mr Walsh, a composite case which protects the identity of any one (...) patient, through the principlist approach of Beauchamp and Childress. It argues that the hospital should offer Mr Walsh, a second valve replacement because the procedure is: medically indicated, autonomously requested, non-maleficent, beneficent and does not violate a formal account of justice. The paper concludes with clinical ethical guidelines for valve surgery for patients with opioid use disorder. (shrink)

Epilepsy surgery is the most effective therapeutic approach for children with drug resistant epilepsy. Recent advances in neurosurgery, such as the Laser Interstitial Thermal Therapy, improved the safety and non-invasiveness of this method. Electric and magnetic source imaging plays critical role in the delineation of the epileptogenic focus during the presurgical evaluation of children with DRE. Yet, they are currently underutilized even in tertiary epilepsy centers. Here, we present a case of an adolescent who suffered from DRE for 16 (...) years and underwent surgery at Cook Children's Medical Center. The patient was previously evaluated in a level 4 epilepsy center and treated with multiple antiseizure medications for several years. Presurgical evaluation at CCMC included long-term video electroencephalography, magnetoencephalography with simultaneous conventional EEG and high-density EEG in two consecutive sessions, MRI, and fluorodeoxyglucose - positron emission tomography. Video long-term EEG captured nine focal-onset clinical seizures with a maximal evolution over the right frontal/frontal midline areas. MRI was initially interpreted as non-lesional. FDG-PET revealed a small region of hypometabolism at the anterior right superior temporal gyrus. ESI and MSI performed with dipole clustering showed a tight cluster of dipoles in the right anterior insula. The patient underwent intracranial EEG which indicated the right anterior insular as seizure onset zone. Eventually LITT rendered the patient seizure free. Retrospective analysis of ESI and MSI clustered dipoles found a mean distance of dipoles from the ablated volume ranging from 10 to 25 mm. Our findings highlight the importance of recent technological advances in the presurgical evaluation and surgical treatment of children with DRE, and the underutilization of epilepsy surgery in children with DRE. (shrink)

SummaryIn the 1940s a controversy developed between John H. Northrop (Nobel Laureate, 1946) and Max Delbrück (Nobel Laureate, 1969) on the formation of bacteriophage. From the historiography of molecular biology there emerges a picture of an obstinate Northrop who repudiated the ‘correct’ insights revealed by the experiments of Delbrück. The established reputation of Northrop confronts one with the question of why Delbrück's epoch-making experiments were not convincing for Northrop. It will be argued that this was a consequence of local incommensurability (...) between Northrop's physiological/chemical research style and Delbrück's bacteriological/genetic research style. The analysis of this controversy reveals the elements that made up these two research styles. (shrink)

Mutations in DNA topoisomerase II are often correlated with drug‐resistance in tumor cell lines. Studies of topoisomerase II‐mediated drug‐resistance in various model systems, as well as the sequencing of such mutations from drug‐resistant tumors, have shed light on the functional domains of topoisomerase II, on how it interacts with inhibitors, and on the different mechanisms by which cells avoid the toxic effects of many clinically important anti‐tumor drugs.

Bacterial plasmids are ubiquitous ‘minichromosomes’ that have major importance in clinical microbiology, as agents of pathogenicity and as carriers of antibiotic resistance, and in molecular genetics, through their role as vectors in gene manipulation. Plasmids carry a wide range of dispensable, transiently useful and often bizarre functions.1 Naturally occurring plasmids, in addition to modifying the host cell phenotype, carry genes involved in the control of their own vegetative replication, plasmid copy number2 and stable inheritance. They may also carry determinants (...) for the conjugal transfer of DNA between bacteria.3 Whereas low‐copy‐number plasmids must be partitioned by some active process during cell division, the evidence suggests that multicopy plasmids are distributed randomly between daughter cells. Two independent determinants are necessary for the stable inheritance of multicopy plasmids, and both of these appear to act by maximizing the number of independent plasmid molecules. (shrink)

Obsessive–compulsive disorder is a debilitating mental health disorder that can easily become a treatment-resistant condition. Although effective therapies exist, only about half of the patients seem to benefit from them when we consider treatment refusal, dropout rates, and residual symptoms. Thus, providing effective augmentation to standard therapies could improve existing treatments. Group compassion-focused interventions have shown promise for reducing depression, anxiety, and avoidance related to various clinical problems, but this approach has never been evaluated for OCD individuals. However, cultivating compassion (...) for self and others seems crucial for OCD patients, given the accumulating research suggesting that fear of guilt, along with isolation and self-criticism, can strongly contribute to the development and maintenance of OCD. The primary aim of this pilot study was to evaluate the acceptability, tolerability, and effectiveness of an 8-week group compassion-focused intervention for reducing OCD symptoms, depression, fear of guilt and self-criticism, and increasing common humanity and compassionate self-reassuring skills in treatment-resistant OCD patients. Using a multiple baseline experimental design, the intervention was evaluated in a sample of OCD patients who had completed at least 6 months of CBT treatment for OCD, but who continued to suffer from significant symptoms. Participants were randomized to different baseline assessment lengths; they then received 8 weekly, 120-min group sessions of compassion-focused therapy for OCD, and then were tested again at post-treatment and at 1 month follow up. Despite the adverse external circumstances, by the end of treatment, all participants demonstrated reliable decreases in OCD symptoms, and these improvements were maintained at 4-week follow-up for seven of eight participants. The intervention was also associated with improvements in fear of guilt, self-criticism, and self-reassurance, but less consistent improvements in depression and common humanity. Participants reported high levels of acceptability of and satisfaction with the intervention. Results suggest that the intervention may be beneficial as either a stand-alone treatment or as an augmentation to other treatments. (shrink)

To the extent that antibiotic resistance (ABR) is accelerated by antibiotic consumption and that it represents a serious public health emergency, it is imperative to drastically reduce antibiotic consumption, particularly in high‐income countries. I present the problem of ABR as an instance of the collective action problem known as ‘tragedy of the commons’. I propose that there is a strong ethical justification for taxing certain uses of antibiotics, namely when antibiotics are required to treat minor and self‐limiting infections, such as (...) respiratory tract infections, in otherwise healthy individuals. Taxation would allow a reduction in consumption (given certain behavioural economics assumptions) and/or ensure that individuals internalize or compensate for their contribution to the erosion of the common good of antibiotic effectiveness. I suggest that revenue from the tax could be used to fund conservation and innovation strategies. Taxation might be a coercive policy, especially for certain individuals, but the ethical case for coercive policies is very strong when the good to be preserved is important enough and when they force individuals to do something they have a moral obligation to do anyway. I argue that, in the case of mild and self‐limiting infections, individuals have a moral duty of easy rescue and a moral duty of fairness to make their contribution to the preservation of the common good of antibiotic effectiveness by foregoing antibiotics. I also suggest that taxing antibiotics in such cases is an all things considered ethically justified policy even if it would introduce inequalities in access to healthcare. (shrink)

Each of the antiretroviral drugs that are currently used to stop the progression of HIV infection causes its own specific side effects. Despite the expansion, multiplication, and simplification of treatment options over the past decade, side effects continue to affect people living with HIV. Yet, we see a clear disconnect between the way side effects are normalized, routinized, and framed in clinical practice and the way they are experienced by people living with HIV. This paper builds on the premise that (...) new approaches are needed to understand side effects in a manner that is more reflective of the subjective accounts of people living with HIV. Drawing on the work of Deleuze and Guattari, it offers an original application of the theory of ‘assemblage’. This theory offers a new way of theorizing side effects, and ultimately the relationship between the body and antiretroviral drugs (as technologies). Combining theory with examples derived from empirical data, we examine the multiple ways in which the body connects not only to the drugs but also to people, things, and systems. Our objective is to illustrate how this theory dares us to think differently about side effects and allows us to originally (re)think the experience of taking antiretroviral drugs. (shrink)

Antimicrobial resistance (AMR) is increasingly recognised as a threat to human, animal and environmental health. In an effort to counter this threat, several intervention plans have been proposed and implemented by states and organisations such as the WHO. A One Health policy approach, which targets multiple domains (healthcare, animal husbandry and the environment), has been identified as useful for curbing AMR. Johnson and Matlock have recently argued that One Health policies in the AMR context require special ethical justification because of (...) the so-called least restrictive alternative principle. This article analyses and rejects two assumptions that this argument relies on. The first assumption is that One Health policies are generally more restrictive than their alternatives because they target more domains and impact more people. The second assumption is that the least restrictive alternative principle has a special normative importance in that it establishes a systematic presumption in favour of the least restrictive policy options. Once these assumptions are rejected, the use of One Health policies on AMR can be justified more easily than Johnson and Matlock argue. (shrink)

The dangers presented by antibiotic resistance have now established themselves as a global health security issue. From an international policy perspective, three key pillars have been established: responsible access, conservation, and innovation. These pillars are intrinsically linked, meaning that any attempt to address one must take into account the implications for the other two.An urgent need exists to address the innovation failure in ABR. In the field of anti-bacterials, the pipeline remains anemic in terms of therapeutics with novel mechanisms of (...) action, new drug classes and strategies involving radically different, innovative approaches. The key reasons for this failure have already been well established. The slow development of new antibiotics is the result of a poor and uncertain commercial market and scientific challenges in research and development. (shrink)

In February, the Food and Drug Administration announced a rule imposing new manufacturer labeling requirements for antibiotics. The aim of the new standards is to educate physicians and patients about the dangers of improper antibiotic use. Overprescription of antibiotics, as well as patient failure to comply with treatment regimens, has led to the development of drug-resistant bacteria. “Antibacterial resistance is a serious and growing public health problem in the United States and worldwide,” FDA Commissioner Mark McClellan said in (...) a press release accompanying the rule. “Without effective antibiotic drugs, common infections, that were once easily treated, can create a serious health threat to children and adults alike.”The FDA regulates foods, drugs, and cosmetics introduced into interstate commerce for safety and effectiveness. Currently, the agency requires drug labels to provide “adequate directions for use,” including indications, quantity of dose, frequency, duration, route, and preparation. (shrink)

In February, the Food and Drug Administration announced a rule imposing new manufacturer labeling requirements for antibiotics. The aim of the new standards is to educate physicians and patients about the dangers of improper antibiotic use. Overprescription of antibiotics, as well as patient failure to comply with treatment regimens, has led to the development of drug-resistant bacteria. “Antibacterial resistance is a serious and growing public health problem in the United States and worldwide,” FDA Commissioner Mark McClellan said in (...) a press release accompanying the rule. “Without effective antibiotic drugs, common infections, that were once easily treated, can create a serious health threat to children and adults alike.”The FDA regulates foods, drugs, and cosmetics introduced into interstate commerce for safety and effectiveness. Currently, the agency requires drug labels to provide “adequate directions for use,” including indications, quantity of dose, frequency, duration, route, and preparation. (shrink)

This article examines gay men’s efforts to break into the exclusive traditional fraternity institution by adopting the hegemonic model on their own terms. The authors examined to what extent members of a national gay fraternity, Delta Lambda Phi challenged or modified the entrenched fraternity culture that was hostile to homosexuals and whether they resisted or reproduced hegemonic masculinity in their efforts to redefine the meaning of college fraternities. This research examines gay fraternities in relation to two dimensions of hegemonic masculinity. (...) The authors explore how members of gay fraternities negotiated their stigmatized status among other men—that is, within the internal dimension of hegemonic masculinity. They explore the external dimension of hegemonic masculinity by analyzing how gay brothers, as men, related to all women. The authors further examine the connection between these two hegemonic dimensions and provide evidence showing how these two dimensions are coupled or disjointed. (shrink)

Bacterial populations are heterogeneous, which in many cases can provide a selective advantage during changes in environmental conditions. In some instances, heterogeneity exists at the genetic level, in which significant allelic variation occurs within a population seeded by a single cell. In other cases, heterogeneity exists due to phenotypic differences within a clonal, genetically identical population. A variety of mechanisms can drive this latter strategy. Stochastic fluctuations can drive differential gene expression, but heterogeneity in gene expression can also be (...) driven by environmental changes sensed by individual cells residing in distinct locales. Utilizing multiple single cell approaches, workers have started to uncover the extent of heterogeneity within bacterial populations. This review will first describe several examples of phenotypic and genetic heterogeneity, and then discuss many single cell approaches that have recently been applied to define heterogeneity within bacterial populations. (shrink)