The emphasis in human pluripotent stem cell (hPSC) technologies has shifted from cell therapy to in vitro disease modelling and drug screening. This review examines why this shift has occurred, and how current technological limitations might be overcome to fully realise the potential of hPSCs. Details are provided for all disease‐specific human induced pluripotent stem cell lines spanning a dozen dysfunctional organ systems. Phenotype and pharmacology have been examined in only 17 of 63 lines, primarily those that model (...) neurological and cardiac conditions. Drug screening is most advanced in hPSC‐cardiomyocytes. Responses for almost 60 agents include examples of how careful tests in hPSC‐cardiomyocytes have improved on existing in vitro assays, and how these cells have been integrated into high throughput imaging and electrophysiology industrial platforms. Such successes will provide an incentive to overcome bottlenecks in hPSC technology such as improving cell maturity and industrial scalability whilst reducing cost. (shrink)

In the United States, screening the urine of employees or job applicants for the presence of drugs has become commonplace. A survey of 794 large- and mediumsized companies, conducted by the American Management Association in January 1994, found that 87 percent of them now test job applicants for drug use. In 1987, a similar survey found that 22 percent screened job applicants. Federally mandated drug testing programs with random testing requirements affect millions of workers in the transportation (...) industry, the nuclear power industry, and the United States civil and military services.As some of these programs pass their fifth anniversary since being instituted, it is important to assess the forces that led to their creation. Whether or not these programs are considered successful depends on what one expects to achieve by such widespread testing. (shrink)

In the United States, screening the urine of employees or job applicants for the presence of drugs has become commonplace. A survey of 794 large- and mediumsized companies, conducted by the American Management Association in January 1994, found that 87 percent of them now test job applicants for drug use. In 1987, a similar survey found that 22 percent screened job applicants. Federally mandated drug testing programs with random testing requirements affect millions of workers in the transportation (...) industry, the nuclear power industry, and the United States civil and military services.As some of these programs pass their fifth anniversary since being instituted, it is important to assess the forces that led to their creation. Whether or not these programs are considered successful depends on what one expects to achieve by such widespread testing. (shrink)

Considerable hope surrounds the use of disease‐specific pluripotent stem cells to generate models of human disease allowing exploration of pathological mechanisms and search for new treatments. Disease‐specific human embryonic stem cells were the first to provide a useful source for studying certain disease states. The recent demonstration that human somatic cells, derived from readily accessible tissue such as skin or blood, can be converted to embryonic‐like induced pluripotent stem cells (hiPSCs) has opened new perspectives for modelling and understanding a larger (...) number of human pathologies. In this review, we examine the opportunities and challenges for the use of disease‐specific pluripotent stem cells in disease modelling and drug screening. Progress in these areas will substantially accelerate effective application of disease‐specific human pluripotent stem cells for drug screening. (shrink)

Mass drug screening offers a deceptively simple solution to the problem of drug use among workers. Even a very effective test is subject to error. In any given group of tested individuals, some will unavoidably be falsely accused. Even though scientific tests appear to provide efficient solutions to social and legal problems, these tests should not be accepted unless they also meet our standards for fair dealing.

Spinal muscular atrophy (SMA) is the most common genetic disease that causes infant mortality. Its treatment and prevention represent the paradigmatic example of the ethical dilemmas of 21st‐century medicine. New therapies (nusinersen and AVXS‐101) hold the promise of being able to treat, but not cure, the condition. Alternatively, genomic analysis could identify carriers, and carriers could be offered in vitro fertilization and preimplantation genetic diagnosis. In the future, gene editing could prevent the condition at the embryonic stage. How should these (...) different options be evaluated and compared within a health system? In this paper, we discuss the ethical considerations that bear on the question of how to prioritize the different treatments and preventive options for SMA, at a policy level. We argue that despite the tremendous value of what we call ‘ex‐post’ approaches to treating SMA (such as using pharmacological agents or gene therapy), there is a moral imperative to pursue ‘ex‐ante’ interventions (such as carrier screening in combination with prenatal testing and preimplantation genetic diagnosis, or gene editing) to reduce the incidence of SMA. There are moral reasons relating to autonomy, beneficence and justice to prioritize ex‐ante methods over ex‐post methods. (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)

In this article C. L. Tsou, of the Institute of Biophysics, Beijing, criticizes the use of the expression I50, the inhibitor concentration to produce 50% inhibition of a particular enzyme as a ‘most unfortunate’ parameter, when screening enzyme inhibitors designed as drugs. Comments on Dr Tsou's point of view will be welcomed from readers.

OBJECTIVE: To review the ethical and legal implications of the involvement of medical practitioners in workplace screening for drug misuse. CONCLUSIONS: Workplace screening for drugs of abuse raises many ethical issues. If screening is considered as being part of medical practice with the involvement of occupational health physicians, as suggested by the Faculty of Occupational Medicine, then the ethical requirements of a normal medical consultation are fully applicable. The employee's full and informed consent to the process (...) must be obtained and the employee should have an unfettered right of access to all the relevant records and to the urine sample he/she has provided in the event that he/she wishes to challenge the opinion expressed by the physician. If the process is not part of medical practice then employees should have the same rights as they would have if required to provide intimate body samples in the course of a criminal investigation, given the potentially serious consequences of an erroneous positive finding for their livelihood. (shrink)

The use of opioid contracts, which often require patients to submit to random drug screens, have become widespread amongst physicians using opioids to treat chronic pain. The main purpose of the contract is to improve care through better adherence to opioid therapy but there is little evidence as to its efficacy. The author suggests the use of opioid contracts and random drug testing destroys patients' trust which impacts health outcomes, and that physicians' motivation for their use are concerns (...) about prosecution, medication abuse and misuse, and addiction. Statistics are provided to counter fears, and evidence is offered suggesting opioid contracts are unenforceable and lack efficacy; random drug testing is often inconclusive, and a patient's trust improves adherence to treatment. (shrink)

It is common for physicians who prescribe opioids for chronic pain to have their patients sign an opioid contract in order to receive opioid therapy. A vast majority of these contracts contain a stipulation requiring patients to submit to random drug testing which screens for both licit and illicit drugs. Physicians who prescribe opioids may be concerned about prosecution and disciplinary actions; medication abuse and misuse; and addiction. Steven Passik et al. write, “…physicians still fear the risk of abuse (...) or addiction as well as the potential legal consequences of their prescribing.”Issues surrounding OC/RDT need a closer look with a focus on enforceability and efficacy of the opioid contract; accuracy and complications of drug screens and their interpretation; and the importance of trust between patient and physician. In addition, it is vital to dispel fears with facts regarding prosecutions, nonmedical use of prescription opioids, and addiction. (shrink)

The article by Gustavsson et al 1 addresses the important question how to handle new medications with focus on drug candidates that reduce Aβ or tau in the brain, for individuals with Alzheimer’s disease, where the need for a disease-modifying drug is enormous. There are several ethical issues to deal with. The challenges and ethical implications associated with whom should be eligible for treatment are thoroughly discussed in the article. Should treatment only be available to those with mild (...) symptoms and/or to those with no symptoms but with risk for AD? Where do we draw the line between who will be eligible for treatment and who will not? Who will be responsible for the prioritisation? There are many ethical problems with both population screening and screening of those with high risk well discussed in the article. Indeed, the first immunotherapy drug Aducanumab was approved by the US Food and Drug Administration in …. (shrink)

Drug design methods have made significant new advances over the last ten years, mainly in the areas of molecular modelling. In more recent times important developments in theory have led to a different type of modelling becoming possible, the so‐called de novo or automated design algorithms. In this new method the programs perform much of the chemist's thinking, in finding appropriately sized chemical groups to fit into a target site. However this is a combinatoric problem which has no general (...) analytical solution; it is ripe for optimization. Other advances, such as combinatorial chemical synthesis and screening, will dramatically influence the search for new lead structures for target sites, which at present are poorly understood. Already these methods are being applied to peptide libraries. Peptides do not make good drug compounds because of their poor bioavailability; further, their flexibility reduces their affinity. In some cases peptide backbones can be removed and replaced with rigid non‐peptide scaffolds. (shrink)

Virtual screening is the most critical process in drug discovery, and it relies on machine learning to facilitate the screening process. It enables the discovery of molecules that bind to a specific protein to form a drug. Despite its benefits, virtual screening generates enormous data and suffers from drawbacks such as high dimensions and imbalance. This paper tackles data imbalance and aims to improve virtual screening accuracy, especially for a minority dataset. For a dataset (...) identified without considering the data’s imbalanced nature, most classification methods tend to have high predictive accuracy for the majority category. However, the accuracy was significantly poor for the minority category. The paper proposes a K-mean algorithm coupled with Synthetic Minority Oversampling Technique to overcome the problem of imbalanced datasets. The proposed algorithm is named as KSMOTE. Using KSMOTE, minority data can be identified at high accuracy and can be detected at high precision. A large set of experiments were implemented on Apache Spark using numeric PaDEL and fingerprint descriptors. The proposed solution was compared to both no-sampling method and SMOTE on the same datasets. Experimental results showed that the proposed solution outperformed other methods. (shrink)

Drug development regularly has to deal with complex circumstances on two levels: the local level of pharmacological intervention on specific target proteins, and the systems level of the effects of pharmacological intervention on the organism. Different development strategies in the recent history of early drug development can be understood as competing attempts at coming to grips with these multi-level complexities. Both rational drug design and high-throughput screening concentrate on the local level, while traditional empirical search strategies (...) as well as recent systems biology approaches focus on the systems level. The analysis of these strategies reveals serious obstacles to integrating the study of interventive and systems complexity in a systematic, methodical way. Due to some fairly general properties of biological networks and the available options for pharmaceutical intervention, drug development is captured in an obstinate methodological dilemma. It is argued that at least in typical cases, drug development therefore remains dependent on coincidence, serendipity or plain luck to bridge the gap between development methodology and actual therapeutic success. (shrink)

This article recovers the importance of film, and its relations to other media, in communicating the philosophies and methods of ‘natural childbirth’ in the post-war period. It focuses on an educational film made in South Africa around 1950 by controversial British physician Grantly Dick-Read, who had achieved international fame with bestselling books arguing that relaxation and education, not drugs, were the keys to freeing women from pain in childbirth. But he soon came to regard the ‘vivid’ medium of film as (...) a more effective means of disseminating the ‘truth of [his] mission’ to audiences who might never have read his books. I reconstruct the history of a film that played a vital role in teaching Dick-Read's method to both the medical profession and the first generation of Western women to express their dissatisfaction with highly drugged, hospitalized maternity care. The article explains why advocates of natural childbirth such as Dick-Read became convinced of the value of film as a tool for recruiting supporters and discrediting rivals. Along the way, it offers insight into the British medical film industry and the challenges associated with producing, distributing and screening a depiction of birth considered unusually graphic for the time. (shrink)

While pharmaceutical industry involvement in producing, interpreting, and regulating medical knowledge and practice is widely accepted and believed to promote medical innovation, industry-favouring biases may result in prioritizing corporate profit above public health. Using diabetes as our example, we review successive changes over forty years in screening, diagnosis, and treatment guidelines for type 2 diabetes and prediabetes, which have dramatically expanded the population prescribed diabetes drugs, generating a billion-dollar market. We argue that these guideline recommendations have emerged under pervasive (...) industry influence and persisted, despite weak evidence for their health benefits and indications of serious adverse effects associated with many of the drugs they recommend. We consider pharmaceutical industry conflicts of interest in some of the research and publications supporting these revisions, and in related standard-setting committees and oversight panels. We raise concern over the long-term impact of these multifaceted involvements. Rather than accept industry conflicts of interest as normal, needing only to be monitored and managed, we suggest challenging that normalcy, and ask: what are the real costs of tolerating such industry participation? We urge the development of a broader focus to fully understand and curtail the systemic nature of industry’s influence over medical knowledge and practice. (shrink)

In the USA, there are missed opportunities to diagnose hepatitis C virus in pregnancy because screening is currently risk-stratified and thus primarily limited to individuals who disclose history of injection drug use or sexually transmitted infection risks. Over the past decade, the opioid epidemic has dramatically increased incidence of HCV and a feasible, well-tolerated cure was introduced. Considering these developments, recent evidence suggests universal HCV screening in pregnancy would be cost-effective and several professional organisations have called for (...) updated national policy. Historically, universal screening has been financially disincentivised on the healthcare system level, particularly since new diagnoses may generate an obligation to provide expensive treatments to a population largely reliant on public health resources. Here, we provide ethical arguments supporting universal HCV screening in pregnancy grounded in obligations to respect for persons, beneficence and justice. First, universal prenatal HCV screening respects pregnant women as persons by promoting their long-term health outside of pregnancy. Additionally, universal screening would optimise health outcomes within current treatment guidelines and may support research on treatment during pregnancy. Finally, universal screening would avoid potential harms of risk-stratifying pregnant women by highly stigmatised substance use and sexual behaviours. (shrink)

The Alzheimer field is in desperate need for an effective treatment. After decades of research, the available drugs treat only symptoms, and even their effectiveness is disputed. Because brain changes precede the clinical symptoms by years to decades, disease-modifying treatments should probably be started early, when the first symptoms occur—or even before. But how to determine who to treat? In this issue, Erik Gustavsson c.s. approach this question by addressing the benefits, harms and ethical issues encountered when using different modes (...) of screening for ‘preclinical’ or early symptomatic Alzheimer disease.1 Their overall conclusion is clear—screening for high risk of developing AD dementia to select those who are eligible for treatment is ethically problematic, unless extremely effective treatment becomes available. An additional major challenge is that diagnostic test accuracy is generally poor, with a particularly high risk of false-positive results, that is, biological evidence of Alzheimer pathology in persons who will never develop dementia. The risk of overmedicalisation is serious, and the potential harms of screening for AD should not be ignored, as Le Couteur c.s. previously argued.2 In short, there is no evidence base for any form of screening for AD whether in a preclinical stage (an …. (shrink)

BackgroundDrug user networks and community-based organizations advocate for greater, meaningful involvement of people with lived experience of drug use in research, programs and services, and policy initiatives. Community-based approaches to research provide an opportunity to engage people who use drugs in all stages of the research process. Conducting community-based participatory research with people who use drugs has its own ethical challenges that are not necessarily acknowledged or supported by institutional ethics review boards. We conducted a scoping review to identify (...) ethical issues in CBPR with people who use drugs that were documented in peer-reviewed and grey literature.MethodsThe search strategy focused on three areas; community-based research, ethical issues, and drug use. Searches of five academic databases were conducted in addition to a grey literature search, hand-searching, and consultation with organizational partners and key stakeholders. Peer reviewed literature and community reports published in English between 1985 and 2013 were included, with initial screening conducted by two reviewers.ResultsThe search strategy produced a total of 874 references. Twenty-five references met the inclusion criteria and were included in our thematic analysis. Five areas were identified as important to the ethics of CBPR with people who use drugs: 1) participant compensation, 2) drug user perspectives on CBPR, 3) peer recruitment and representation in CBPR, 4) capacity building, and 5) participation and inclusion in CBPR.ConclusionsWe critically discuss implications of the emerging research in this field and provide suggestions for future research and practice. (shrink)

In Gustavsson et al,1 we discussed the ethical issues that arise when identifying the relevant population for disease-modifying drugs targeting Alzheimer disease. More specifically, we focused on novel immunotherapies aimed at amyloid β and tau, two relevant biomarkers. The commentaries to our paper2 3 acknowledge our conclusion: screening for AD involve ethical costs that cannot be justified unless a drug with clinically relevant effect becomes available. Since Aduhelm is the only immunotherapy targeting AD currently approved by the Food (...) and Drug Administration, we use that as a …. (shrink)

Background This paper examines the degree of agreement among simple dichotomous self-report, validated screening results, and biochemical screening results of prenatal alcohol and other drug use among pregnant women. Method Secondary analysis was conducted on a cohort of pregnant women 16 years or older, presenting for prenatal care in the greater Cape Town, South Africa. Dichotomous verbal screening is a standard of care, and pregnant patients reporting alcohol and other drug use in dichotomous verbal screenings (...) were asked to engage in screening using the Alcohol Smoking and Substance Involvement Screening Test and urinalysis. Results Significant agreements between dichotomous and ASSIST scores were observed. A higher rate of self-reported alcohol use was detected, relative to urine screening with a predictive value of 34.9; while underreporting of illicit substance use was observed with an overall predictive value of 50.0. Conclusion Dichotomous verbal screening was considered valid after comparison with the ASSIST; however, combined use with urine screenings can be recommended especially for identifying illicit substance use in order to accurately detect alcohol and other drug use in pregnancy, so that women can be identified and referred for appropriate interventions where needed. (shrink)

Issues of privacy and employee health screening rank as two of the most important ethical concerns organizations will face in the next five years. Despite the increasing numbers of social scientists researching personal privacy and the current focus on workplace privacy rights as one of the most dynamic areas of employment law, the concept of privacy remains relatively abstract. Understanding how the courts define privacy and use the expectation of privacy standards is paramount given the strategic importance of the (...) law as a legal socializing agent. This article reports on two federal court decisions involving employer drug and HIV testing whose determinations relied on assumptions about the psychological dimensions of privacy. How the courts define privacy, the outcome of this definition and the ethical ramifications as it affects the employee/employer relationship are discussed. (shrink)

Putnam says that "In one way of conceiving it, realism is an empirical theory." In the present work it is maintained that, in another way of conceiving it, realism is a grammatical thesis. That is, many of the principles taken to be definitive of realism, e.g., "Truth is objective," "Truth is mind-independent," Dummett's "a thought can be true only if there is something in virtue of which it is true," are what Wittgenstein would have called "grammatical remarks." They simply call (...) attention to certain features of the grammar of truth and related concepts. Thus, e.g., it is a feature of the way we use "is true" that statements are not spoken of as true for one person and not true for another. ;The character of grammar and of grammatical remarks in general is spelled out in some detail; it is argued in particular that Wittgenstein is not intending to provide, by means of these notions, a particular account of necessary truth. He is suggesting, rather, that looking upon certain philosophical claims as grammatical is a way of "deflating" them, stripping them of their appearance of profundity. Neither can grammatical remarks imply substantive philosophical theses. This is why realism, conceived as comprising grammatical remarks, does not imply scepticism, as is often supposed, and is not itself a controversial or exciting doctrine. ;There are of course some controversial formulations of realism, versions which are not simply underwritten by grammar. Thus some philosophers have held that, because the truth conditions of a proposition are essentially independent of any evidence we may have for the proposition, truth may not be accessible at all. I believe, however, that Putnam has shown, by means of an argument which is instructively viewed as a grammatical investigation, that truth is accessible, at least to an "ideal" theory. ;Recent expressions of idealism are argued to provide helpful accounts of language use and understanding, but fail to establish that truth is nothing but warranted assertibility, or that it must in some sense "arise within us." Such a conclusion runs afoul of the grammar of truth, of which realism is shown to provide the proper account. (shrink)

Children who experience well-being are engaging more confidently and positively with their caregiver and peers, which helps them to profit more from available learning opportunities and support current and later life outcomes. The goodness-of-fit theory suggests that children’s well-being might be a result of the interplay between their temperament and the environment. However, there is a lack of studies that examined the association between children’s temperament and well-being in early childhood education and care, and whether this association is affected by (...) ECEC process quality. Using a multilevel random coefficient approach, this study examines the association between toddlers’ temperament and well-being in Norwegian ECEC and investigates whether process quality moderates this association. Results reveal an association between temperament and well-being. Staff-child conflict moderates the association between shyness and well-being, and between activity and well-being. Moreover, high emotional behavioral support moderates the association between activity and well-being. Extra attention should be paid by the staff to these children’s needs. (shrink)

In The Ethics of Food, Gregory E. Pence brings together a collection of voices who share the view that the ethics of genetically modified food is among the most pressing societal questions of our time. This comprehensive collection addresses a broad range of subjects, including the meaning of food, moral analyses of vegetarianism and starvation, the safety and environmental risks of genetically modified food, issues of global food politics and the food industry, and the relationships among food, evolution, and human (...) history. (shrink)

In this paper we address the ethical challenges of research on cytoplasmic hybrid embryos, or “cybrids”. The controversial pronouncement of the UK’s Human Embryology and Fertilisation Authority of September 2007 on the permissibility of this area of research is the starting point of our discussion, and we argue in its favour. By a rigorous definition of the entities at issue, we show how the terms “chimera” and “hybrid” are improper in the case of cybrids, and how their use can bias (...) the debate creating moral prejudices. After analysing the scientific aspects of cybrids research and sketching out current alternatives, we enter the ethical debate, starting from the premise that research on early human embryos is ethically permissible under some circumstances. We emphasise how research on cybrids has positive consequences in terms of scientific and therapeutic applications, since it allows the derivation of human embryonic stem cells genetically tailored to the somatic cell donor. Such cell lines offer a unique in vitro model both for studies of human pathogenesis and for drug screening and discovery. Research on cybrids also circumvents the problem of the scarcity of human oocytes and their ethically dubious donation. Finally, we object to the most common arguments against cybrids research, that is, moral repugnance, the slippery slope argument, the appeal to “nature”, and the unfair distribution of economical resources. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:It's Not Always Just a RashAdam BossertI looked at the emergency department track board and saw a patient waiting for a provider who was "roomed" in a hallway stretcher with a chief complaint of a rash. I briefly considered his ultimate disposition, "He's probably fine. He can't be that sick if he was triaged as safe for the hallway." I was tired and close to the end of an (...) overnight shift and thought he would be a quick turnaround, likely discharged, since rashes are typically benign. I walked over to his stretcher after a quick chart biopsy that highlighted his mildly increased heart [End Page 24] rate on arrival as well as his history of polysubstance use and homelessness."Hey doc, I don't feel so good.""I'm sorry to hear that. What's specifically bothering you?""I am itching all over with these bumps. My skin is red, and I also think I'm withdrawing since I have body aches and chills."The interview continued.I discovered his last heroin use was approximately eight hours prior to arrival. I thought he was an ideal candidate for buprenorphine since he was actively withdrawing. I was recently licensed to prescribe this medication and excited to use my license for the first time. He declined the suggestion, however, preferring methadone instead. Buprenorphine can precipitate withdrawal if not given long enough after opioid use or if an incorrect dose is given; thus, many patients are hesitant to take it. He also stated he was predominantly here for his rash and did not want rehabilitation placement. I ordered our initiation methadone dose as well as a screening COVID-19 test and a urine drug screen test, which are both needed for rehabilitation placement in case he changed his mind.His rash was highly suspicious for scabies. He was covered with red bumps that spared only his face, some in linear distributions, and was actively scratching his arms and legs during the interview. I prefer oral ivermectin over topical permethrin for the homeless population simply for ease of administration, lower cost, and increased compliance. He received ivermectin for his scabies and knew he could return to the emergency department for a repeat dose if he was unable to fill a prescription.What happened next is, in my experience, an all-too-common scenario.The patient told me that the methadone is "doing nothing." I explained he could no longer take buprenorphine since he already received methadone, which only made him more frustrated. Unfortunately, I am restricted with the amount of methadone I can give in the emergency department, largely due to the drug's long half-life, and thus I was unable to give him more, let alone attempt titrating to his tolerance.Opioid withdrawal is not a life-threatening diagnosis; these patients are not typically admitted to the hospital. The management consists of initiating either methadone or buprenorphine, symptomatic treatment and then outpatient referral or rehabilitation placement. I explained the options to him, and he requested to be discharged since he was deferring rehabilitation. He was discharged. I was able to treat his rash but his chronic illness, opioid use disorder, was not controlled.I discharge a patient in opioid withdrawal or who has opioid use disorder almost every day, and I think most emergency medicine physicians would echo that statement. The disposition is not wrong from the perspective of the individual physician, but it feels like the system has failed these patients when I think of the frequency that they return and their baffling risk of overdose. The latter can be reduced by giving patients Narcan, the drug to reverse opioid overdose, upon discharge but this is just placing a bandage over the problem and not all emergency departments can fund this risk-reduction tool.I saw my patient's COVID-19 result return as I wrapped up my shift. It was positive. And, of course, he was in our department's hallway the whole time, only intermittently using his mask. I suddenly realized that while yes, he was withdrawing, he also may have had a symptomatic COVID-19 infection! I quickly reopened his chart, only to... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:The Tincture of the Doctor's TimeHolland KaplanI first thought of Mr. H as a "difficult patient" while reading the written hand-off I received on him as I was preparing to take over an inpatient general medicine service—"He leaves all the time to smoke." I don't think the statement was meant to imply anything about the patient; if anything, it may have been included for context to prepare me for (...) the patient's intermittent absence. But, reading this, I felt a familiar sense of annoyance rising in my chest. Every few months, I take care of a patient who seems to never be in his room. The patient is consistently out smoking, in the cafeteria, or in another unknown location, seemingly doing an undisclosed activity. This is frustrating because it means I have to work around the patient's schedule of smoke breaks and jaunts to the cafeteria to evaluate the patient on a daily basis. The thoughts inevitably cross my mind: Does this patient even want care in the hospital if he's never in his room? Is he actually sick enough to need to be in the hospital if he's able to spend so much time outside of the hospital? Why is he leaving so frequently—is he doing drugs?This particular patient had been in perfect health until two months before I met him when he was shot multiple times during an encounter at a gas station. One of the bullets had lodged in his back, shattering a vertebra. Another had decimated the bones in his right upper arm, which were now held in place by screws and plates. Several had landed in his abdomen, necessitating the removal of part of his bowel. Finally, a bullet had sliced through the lower part of his right kidney, shredding his ureter and mandating surgical reconstruction of his urinary system. After over a month in the intensive care unit with multiple reparative surgeries, he was discharged to a rehabilitation facility. But he started having fevers and fast heart rates; ultimately, he was admitted to the hospital again for multiple infected fluid collections that had formed at the sites of his surgeries. He left the hospital prior to getting treated for these infections, purportedly "against medical [End Page 12] advice." And now, several weeks later, he was here in the hospital for the same reason.The first time I went to see Mr. H, he was, of course, not in his room. I went to the nursing station to ask if the clerk knew where he was. She knowingly said, "Oh yeah, he goes out a lot. I can give him a call to let him know the doctor is here to see him if you'd like." I assented, thanked the clerk for calling him, and proceeded, annoyed, in seeing the rest of my patients. I considered how I would address Mr. H's behavior when I was finally able to talk to him. I had seen others take many different approaches—negotiation about the timing and frequency of these extramural expeditions, ultimatums about getting discharged, mandating urine drug screens upon return, and silent, frustrated tolerance. I resolved to wait to speak to him to determine which approach might be most suitable. An hour later, I received a call from the clerk that Mr. H had returned to his room to see me.The first time I met Mr. H, he informed me he had taken the bus to midtown to make a run to the grocery store. I was internally incredulous. He felt well enough to go to the grocery store? Why was he in the hospital then? At that moment, I opted not to discuss his frequent departures yet, as I was frustrated and realized I wouldn't be able to identify the best way to address them. I reviewed his medical issues with him, asked specific questions about how he was feeling, performed a physical exam, and reiterated his current plan of care. Mr. H made it very clear that he would like to get out of the hospital as soon as possible. I tried to set the expectation that he... (shrink)

We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made (...) in the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell‐based regenerative medicine for diseases of lung and airways. (shrink)

In this study a combination of computer tools for coupling and virtual screening is detailed, in 108 active molecules and 3620 decoys to find stabilizers for G quadruplex. To have more precise results, combinations of coupling programs with fifteen energy scoring functions were applied. The validation and evaluation of the metrics was done with the CompScore genetic algorithm. The results showed an increase in BEDROC and EF of 50% compared to other strategies, as well as reflecting early recognition of (...) active molecules. From these results it is possible to work with the molecules that showed a good early recognition and evaluate their effect as G4 stabilizers. This ensures more efficient and accurate results in the preclinical stage for the development of anticancer drugs. Keywords: Enrichment metrics; telomere; G quadruplex ; CompScore. References [1]M. Porru, P. Zizza, M. Franceschin, C. Leonetti and A. Biroccio. «EMICORON: A multi-targeting G4 ligand with a promising preclinical profile» 2017. Biochimica et Biophysica Acta - General Subjects, 1861, 1362–1370. [Online]. Available: https://doi.org/10.1007/s00294-018-0836-6. [2]K. Tomita. «How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis». Current Genetics, 64, 1177–1181. 2018. [Online]. Available: https://doi.org/10.1016/j.bbagen. 2016.11.010. [3]M. Jafri, S. Ansari, M. Alqahtani and J. Shay. «Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine., 2016. [Online]. Available: https://doi.org/10.3390/ijms19020482. [4]J. Huppert and S. Balasubramanian. «G-quadruplexes in promoters throughout the human genome». 35, 406–413. 2007. [Online]. Available: https://doi.org/10.1016/j.bbapap.2017.06.012. [5]S. Joy, Vijayakumar, S. Choi and H. Sunhye. «Role of computer-aided drug design in modern drug discovery». Archives of Pharmacal Research. 2015. [Online]. Available: https://doi.org/10.1007/s12272-015-0640-5. [6]S. Asamitsu, S. Obata, Z. Yu, T. Bando and H. Sugiyama. «Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy». Molecules, 24, 429. 2019. [En línea]. Available: https://doi.org/10.3390/molecules24030429. [7]R. Monsen and J. Trent. «Biochimie G-quadruplex virtual drug screening : A review». Biochimie, 152, 134–148. 2018. [Online]. Available: https://doi.org/10.1039/c9cc06748e. [8]J. Beauvarlet, P. Bensadoun, E. Darbo, G. Labrunie, E. Richard, I. Draskovic and M. Djavaheri-mergny. «Modulation of the ATM / autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells». 1–18. 2019. [Online]. Available: https://doi.org/10.1093/nar/gkz095. [9].Z. Crees, J. Girard, Z. Rios, G. Botting, K. Harrington and C. Shearrow. « Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy».2014. [Online]. Available: https://doi.org/10.2174/1381612820666140630100702. [10].M. Meier, A. Moya-torres, N. Krahn, M. Mcdougall, L. Orriss, E. Mcrae and T. Patel. «Structure and hydrodynamics of a DNA Gquadruplex with a cytosine bulge»., 1–13. 2018. [Online]. Available: https://doi.org/10.1093/nar/gky307. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:An Epidemic of Difficult PatientsKeva SouthwellAs the opioid epidemic marches on, we have all become familiar with a particular breed of "difficult patient," the intravenous drug user. Most teams try to get through these admissions with as few interactions as possible. Nurses will tell you how much they hate caring for these patients, often citing "they did this to themselves" as they experience prolonged admissions due to infections (...) resulting from Intravenous Drug Use (IVDU). Most services try to get out of admitting these patients, saying they are more appropriate with infectious disease, cardiology, or "anywhere but with me." These patients often use drugs in the hospital, threaten to leave AMA, and are dangerous, liable to assault or abuse the very staff trying to help them. The general consensus is that taking care of these patients is a dirty job … why do I have to do it?That's where I come in. It's a dirty job … and that's exactly why I do it. I run a unique service, where my preferred patients are those admitted for 6–8 weeks of IV antibiotics to treat their endocarditis. Some of these patients survive after discharge, but most don't. I know this. But it's my job to help them anyway. It just turns out that in these cases, help doesn't always look the way you think it will.In a perfect world, having a life-threatening infection would be the rock bottom these young people need to embrace a new way of life. Unfortunately, this world is far from perfect. Just as having diabetes doesn't make you stop wanting junk food, having endocarditis does not make you stop wanting drugs. In fact, it can be the opposite. [End Page 26] Drugs are often the coping tool these patients turn to. Happy? Use drugs. Sad? Use drugs. Scared? Use drugs. That's why it's hard. Addiction defies logic; it can be cunning, baffling, and powerful. Until you understand addiction, you'll never really find a way to treat these patients, let alone a way to enjoy treating them.We all have patients who change things for us. They shift our perspective, make us view our practice, our patients, and ourselves differently; patients who teach us the lessons not learned in school. I will never forget Jack, one of those "difficult patients." He taught me how to care for people who really can't be medically helped. It's a lesson that can take years to learn: You've got to let go of the outcome, and some solutions don't look the way you think they should. In this way, he helped me continue in this difficult work.I was a nearly new hospitalist, having just moved into this work from outpatient addiction care. Jack was a young man, 32 years old. He had presented to our hospital with endocarditis of the aortic and tricuspid valves secondary to IVDU. He was referred to my service when he was ineligible for valve replacement due to septic emboli in his brain and subsequent micro hemorrhage. The surgery team wanted him to recover from these events before considering surgical treatment.Jack was a big guy, over 6'2", with a weight to match. He was covered in tattoos—his back, arms, chest, and neck—not an inch was bare. His physical presence might be considered intimidating. Jack was a man of few words: he complained of very little, was often asleep during medical visits, never really left his room, and had no visitors. About four days after his arrival, nursing became concerned about illicit drug use. Despite the fact he had no orders for narcotics or other sedating meds, he was sleeping all the time. His drug screens were negative. Despite the lack of specific evidence, I was asked to take measures to ensure he was not using illicit drugs, which included placing him on a contract and ordering 1:1 observation.His fatigue was concerning, though not for drug use. A repeat ECHO showed that his aortic insufficiency was worsening. His tricuspid insufficiency was very bad from the start. His belly began to swell, followed by his... (shrink)

This paper argues that many ethical issues in neuroeducational research cannot be appropriately addressed using the principles and guidance available in one of these areas alone, or by applying these in simple combination. Instead, interdisciplinary and public dialogue will be required to develop appropriate normative principles. In developing this argument, it examines neuroscientific and educational perspectives within three broad categories of ethical issue arising at the interface of cognitive neuroscience and education: issues regarding the carrying out of interdisciplinary research, the (...) scrutiny and communication of findings and concepts, and the application of research and associated issues of policy likely to arise in the future. To help highlight the need for interdisciplinary and public discussion, we also report the opinions of a group of educators (comprising trainee teachers, teachers and head teachers) on the neuroeducational ethics of cognitive enhancing drugs, infant screening, genetic profiling and animal research. (shrink)

Snake venoms are recognized here as a grossly under‐explored resource in pharmacological prospecting. Discoveries in snake systematics demonstrate that former taxonomic bias in research has led to the neglect of thousands of species of potential medical use. Recent discoveries reveal an unexpectedly vast degree of variation in venom composition among snakes, from different species down to litter mates. The molecular mechanisms underlying this diversity are only beginning to be understood. However, the enormous potential that this resource represents for pharmacological prospecting (...) is clear. New high‐throughput screening systems offer greatly increased speed and efficiency in identifying and extracting therapeutically useful molecules. At the same time a global biodiversity crisis is threatening the very snake populations on which hopes for new venom‐derived medications depend. Biomedical researchers, pharmacologists, clinicians, herpetologists, and conservation biologists must combine their efforts if the full potential of snake venom‐derived medications is to be realized. (shrink)

Port-wine birthmarks (PWBs) are caused by somatic, mosaic mutations in the G protein guanine nucleotide binding protein alpha subunit q (GNAQ) and are characterized by the formation of dilated, dysfunctional blood vessels in the dermis, eyes, and/or brain. Cutaneous PWBs can be treated by current dermatologic therapy, like laser intervention, to lighten the lesions and diminish nodules that occur in the lesion. Involvement of the eyes and/or brain can result in serious complications and this variation is termed Sturge-Weber syndrome (SWS). (...) Some of the biggest hurdles preventing development of new therapeutics are unanswered questions regarding disease biology and lack of models for drug screening. In this review, we discuss the current understanding of GNAQ signaling, the standard of care for patients, overlap with other GNAQ-associated or phenotypically similar diseases, as well as deficiencies in current in vivo and in vitro vascular malformation models. (shrink)

Industrial drug design methodology has undergone remarkable changes in the recent history. Up to the 1970s, the screening of large numbers of randomly selected substances in biological test system was often a crucial step in the development of novel drugs. From the early 1980s, such ‘blind’ screening was increasingly rejected by many pharmaceutical researchers and gave way to ‘rational drug design’, a method that grounds the design of new drugs on a detailed mechanistic understanding of the (...) drug action. Surprisingly, however, the chance-based method of random screening returned to center stage of industrial drug development in the 1990s in the form of ‘high-throughput screening’ (HTS). I will argue in this paper that this to-and-fro in the prominence of random screening comes with fundamental changes in the epistemic significance of chance experiments in pharmaceutical development. While up to the 1970s, random screening used to be chosen as an empirical search strategy primarily because suffi- cient knowledge of the mechanistic basis of drug action was lacking, it has turned with high-throughput screening into an experimental method that employs chance variation and testing to illuminate this mechanistic basis. As a consequence, research into the underlying mechanisms of drug action and the development of new drugs have become closely integrated. The rise of HTS therefore not only shows how chance experiments have assumed a new epistemic role in drug development. It also allows for a detailed study of the much debated emergence of a new relationship between scientific understanding and the development of technological artifacts. (shrink)