When I heard about the concept of immunotherapeutics, I immediately loved it. Everything I had learned about medicine, cancer biology, genetics and oncology indicated to me that this was a potent approach, and at the time, completely untapped. I figured that since we had been unable to cure most metastatic solid tumors, something completely different needed to be employed. Realistically, “magic bullets” are not easy to find and therefore something that can be combined with other therapies, for enhanced synergy without overlapping adverse events, would be appealing.
adenovirus; cancer; gene therapy; immunotherapy; oncolytic virus
Steric constraints, charged interactions and many other forces important to protein structure and function can be explored by mutagenic experiments. Research of this kind has led to a wealth of knowledge about what stabilizes proteins in their folded states. To gain a more complete picture requires that we perturb these structures in a continuous manner, something mutagenesis cannot achieve. With high pressure crystallographic methods it is now possible to explore the detailed properties of proteins while continuously varying thermodynamic parameters. In this paper, we detail the structural response of the cavity-containing mutant L99A of T4 lysozyme, as well as its pseudo wild-type (WT*) counterpart, to hydrostatic pressure. Surprisingly, the cavity has almost no effect on the pressure response: virtually the same changes are observed in WT* as in L99A under pressure. The cavity is most rigid, while other regions deform substantially. This implies that while some residues may increase the thermodynamic stability of a protein, they may also be structurally irrelevant. As recently shown, the cavity fills with water at pressures above 100 MPa while retaining its overall size. The resultant picture of the protein is one in which conformationally fluctuating side groups provide a liquid-like environment, but which also contribute to the rigidity of the peptide backbone.
The principle of respect for autonomy has shaped much of the bioethics' discourse over the last 50 years, and is now most commonly used in the meaning of respecting autonomous choice. This is probably related to the influential concept of informed consent, which originated in research ethics and was soon also applied to the field of clinical medicine. But while available choices in medical research are well defined, this is rarely the case in healthcare. Consideration of ordinary medical practice reveals that the focus on patient choice does not properly grasp the moral aspects involved in healthcare. Medical decisions are often portrayed as if doctors and patients in confidence confront specific decisions about examinations or treatment, yet the reality often involves many different participants, with decisions being made over time and space. Indeed, most of the decisions are never even presented to patients, as it would be unethical to suggest something that is not medically justifiable. The options patients do confront are somewhat arbitrarily constructed within the narrow framework of both what is deemed to be medically appropriate and how the healthcare system is organised practically. While the autonomy discourse has proven valuable, a failure to distinguish between the fields of medical research and clinical medicine has generated a focus on patient choice that does not reflect what is really at stake in healthcare settings. This is alarming, because the current discourse misrepresents medical practice in a way that actually contributes to bioethical self-delusion.
Personal autonomy; bioethics; medical ethics; professional practice; delivery of healthcare; applied and professional ethics; philosophy of medicine; informed consent
A methodology for inducing spawning in captivity of the lancelet
Branchiostoma lanceolatum has been developed recently with
animals collected at the Racou beach, in the southern coast of France. An
increasing amount of laboratories around the world are now working on the
evolution of developmental mechanisms (Evo-Devo) using amphioxus collected in
this site. Thus, today, the development of new aquaculture techniques for
keeping amphioxus in captivity is needed and the study of the natural conditions
at which amphioxus is exposed in the Racou beach during their spawning season
becomes necessary. We have investigated the amphioxus distribution, size
frequency, and population structure in the Racou beach during its natural
spawning season using multivariate methods (redundancy analysis and multiple
regression). We found a clear preference of amphioxus for sandy sites, something
that seems to be a general behaviour of different amphioxus species around the
world. We have also estimated the amphioxus growth rate and we show how the
animals are preferentially localized in shallow waters during April and
To develop and implement learning activities within an advanced pharmacy practice experience (APPE) to improve students' cultural competence.
During their AAPE at Community Access Pharmacy, students participated in topic discussions with faculty members, used interpreters to interview Hispanic patients, visited a Mexican grocery store, evaluated nontraditional medicine practices in the Hispanic community, and served as part of a patient care team at a homeless shelter and an HIV/AIDS clinic. The students reflected on these activities in daily logs and completed a final evaluation of their experiences.
Forty-three students completed the rotation from 2004-2007. Almost all learned something new about counseling patients with cultural/language differences (98%) and became more aware of financial barriers to health care and potential solutions to overcome them (93%). Students' reflections were positive and showed progression toward cultural competence.
A culturally diverse patient population provided opportunities for APPE students to develop the skills necessary to become culturally competent pharmacists. Future work should focus on potential evaluation tools to assess curricular cultural competency outcomes in APPE's.
experiential education; cultural competency; diversity
Comparisons between completely sequenced metazoan genomes have generally emphasized how similar their encoded protein content is, even when the comparison is between phyla. Given the manifest differences between phyla and, in particular, intuitive notions that some animals are more complex than others, this creates something of a paradox. Simplistic explanations have included arguments such as increased numbers of genes; greater numbers of protein products produced through alternative splicing; increased numbers of regulatory non-coding RNAs and increased complexity of the cis-regulatory code. An obvious value of complete genome sequences lies in their ability to provide us with inventories of such components. I examine progress being made in linking genome content to the pattern of animal evolution, and argue that the gap between genomic and phenotypic complexity can only be understood through the totality of interacting components.
comparative genomics; evolution; Metazoa; transcription factors; ultraconserved regions
Using national survey data collected in 2004 in Burkina Faso, Ghana, Malawi, and Uganda with 12–19 year olds, we examine the prevalence of sex in exchange for money or gifts in the 12 months prior to the survey and its association with adolescents’ social and economic vulnerability and condom use. Receiving something in exchange for sex is very common among sexually active, unmarried female adolescents and there are no significant differences by household economic status, orphan status, level of schooling completed or age difference between partners. Condom use at last sex in the 12 months prior to the survey is not associated with receiving gifts or money. Qualitative data based on focus group discussions and in-depth interviews collected in 2003 with adolescents suggest that receiving money or gifts for sex is not necessarily a coercive force, but rather can be a routine aspect of dating.
transactional sex; adolescents; condom use
We examined performance on a self-referenced memory (SRM) task for higher functioning children with autism (HFA) and a matched comparison group. SRM performance was examined in relation to symptom severity and social cognitive tests of mentalizing.
Sixty-two children (31 HFA, 31 comparison; 8–16 years) completed a SRM task in which they read a list of words and decided whether the word described something about them, something about Harry Potter, or contained a certain number of letters. They then identified words that were familiar from a longer list. Dependent measures were memory performance (d′) in each of the three encoding conditions as well as a self-memory bias score (d′ self-d′ other). Children completed The Strange Stories Task and The Children’s Eyes Test as measures of social cognition. Parents completed the SCQ and ASSQ as measures of symptom severity.
Children in the comparison sample showed the standard SRM effect in which they recognized significantly more self-referenced words relative to words in the other-referenced and letter conditions. In contrast, HFA children showed comparable rates of recognition for self- and other-referenced words. For all children, SRM performance improved with age and enhanced SRM performance was related to lower levels of social problems. These associations were not accounted for by performance on the mentalizing tasks.
Children with HFA did not show the standard enhanced processing of self- vs. other-relevant information. Individual differences in the tendency to preferentially process self-relevant information may be associated with social cognitive processes that serve to modify the expression of social symptoms in children with autism.
In industry, hospital, clinic, laboratory or office, professionals are continually faced with “all size” of problems which can be successfully answered by using investigative scientific methods.
The recognition and formulation of an existing problem followed by the desire to seek an answer are the first major steps. Collecting and analyzing data, followed by valid scientific conclusion completes the picture.
Professional success means knowing most about something, not something about most. Investigation-research is a particular pattern in weaving, made of organized curiosity, skillful analysis, inventive thinking and professional objectivity.
The purpose of the article remains to identify fundamental questions which emerge from clinical observations and practice, to identify and project needed research and to guide the finding of scientific answers.
Rehabilitation is an essential and integral part of burn treatment. It is not something which takes place following healing of skin grafts or discharge from hospital; instead it is a process that starts from day one of admission and continues for months and sometimes years after the initial event. Burns rehabilitation is not something which is completed by one or two individuals but should be a team approach, incorporating the patient and when appropriate, their family. The term ‘Burns Rehabilitation’ incorporates the physical, psychological and social aspects of care and it is common for burn patients to experience difficulties in one or all of these areas following a burn injury. Burns can leave a patient with severely debilitating and deforming contractures, which can lead to significant disability when left untreated. The aims of burn rehabilitation are to minimise the adverse effects caused by the injury in terms of maintaining range of movement, minimising contracture development and impact of scarring, maximising functional ability, maximising psychological wellbeing, maximising social integration
Burn rehabilitation; splintage; range of movements; post burn physiotherapy
Cancer treatments are complex, involving multiple clinicians, toxic therapies, and uncertain outcomes. Consequently, patients are vulnerable when breakdowns in care occur. This study explored cancer patients' perceptions of preventable, harmful events; the impact of these events; and interactions with clinicians after such events.
Patients and Methods
In-depth telephone interviews were conducted with cancer patients from three clinical sites. Patients were eligible if they believed: something “went wrong” during their cancer care; the event could have been prevented; and the event caused, or could have caused, significant harm. Interviews focused on patients' perceptions of the event, its impact, and clinicians' responses to the event.
Ninety-three of 416 patients queried believed something had gone wrong in their care that was preventable and caused or could have caused harm. Seventy-eight patients completed interviews. Of those interviewed, 28% described a problem with medical care, such as a delay in diagnosis or treatment; 47% described a communication problem, including problems with information exchange or manner; and 24% described problems with both medical care and communication. Perceived harms included physical and emotional harm, disruption of life, effect on family members, damaged physician-patient relationship, and financial expense. Few clinicians initiated discussion of the problematic events. Most patients did not formally report their concerns.
Cancer patients who believe they experienced a preventable, harmful event during their cancer diagnosis or care often do not formally report their concerns. Systems are needed to encourage patients to report such events and to help physicians and health care systems respond effectively.
Air pollution contributes to poor respiratory and cardiovascular health. Susceptible individuals may be advised to mitigate effects of air pollution through actions such as reducing outdoor physical activity on days with high pollution. Our analysis identifies the extent to which susceptible individuals changed activities due to bad air quality. This cross-sectional study included 10,898 adults from the National Health and Nutrition Examination Survey (NHANES) 2007–2010. Participants reported if they did something differently when air quality was bad. Susceptible categories included respiratory conditions, cardiovascular conditions and older age (≥65 years). Analyses accounted for complex survey design; logistic regression models controlled for gender, race, education, smoking, and body mass index. 1305 individuals reported doing something differently (12.0%, 95% confidence interval (CI): 10.9, 13.1). This percentage was 14.2% (95% CI: 11.6, 16.8), 25.1% (95% CI: 21.7, 28.6), and 15.5% (95% CI: 12.2, 18.9) among older adults, those with a respiratory condition, and those with a cardiovascular condition, respectively. In adjusted regression models the following were significantly more likely to have changed activity compared to those who did not belong to any susceptible group: respiratory conditions (adjusted odds ratio (aOR): 2.61, 95% CI: 2.03, 3.35); respiratory and cardiovascular conditions (aOR: 4.36, 95% CI: 2.47, 7.69); respiratory conditions and older age (aOR: 3.83; 95% CI: 2.47, 5.96); or all three groups (aOR: 3.52; 95% CI: (2.33, 5.32). Having cardiovascular conditions alone was not statistically significant. Some individuals, especially those with a respiratory condition, reported changing activities due to poor air quality. However, efforts should continue to educate the public about air quality and health.
How does one design something that is complex? Or something that is simple? Why should one try to reduce or increase complexity? What is complexity? There are a large number of different uses of the word, including many in mathematics and physics. Most of these are not useful in attempting to fit the word to the problems of the design of systems and devices for medicine. In this paper the concept has been defined to apply to health care, which has led to some conclusions about the future development of medical systems and devices.
complexity; design; patient safety
The current study presented 1,933 adolescents from 13 schools with a scenario about a hypothetical peer's plan to “do something dangerous” at school and asked how likely they would be to respond with four different actions: intervene directly, tell a teacher or principal, discuss it with a friend but not an adult, and do nothing. High school students were less likely than those in middle school to say they would approach the peer directly or confide in a teacher or principal. Students were most likely to favor taking action on their own over all of the other response strategies. Students with positive perceptions of their schools were more likely to say they would do something rather than ignore their peer's dangerous intentions. These relationships were mediated by students’ beliefs that confiding in a teacher may have unfavorable consequences. Findings from this study support the important role schools play in creating a culture where students take responsibility for one another.
school climate; adolescents; teachers; intervention; peers
It is common to refer to all sorts of clear-cut differences between the sexes as something that is biologically almost inevitable. Although this does not reflect the status of evolutionary theory on sex determination and sexual dimorphism, it is probably a common view among evolutionary biologists as well, because of the impact of sexual selection theory. To get away from thinking about biological sex and traits associated with a particular sex as something static, it should be recognized that in an evolutionary perspective sex can be viewed as a reaction norm, with sex attributes being phenotypically plastic. Sex determination itself is fundamentally plastic, even when it is termed “genetic”. The phenotypic expression of traits that are statistically associated with a particular sex always has a plastic component. This plasticity allows for much more variation in the expression of traits according to sex and more overlap between the sexes than is typically acknowledged. Here we review the variation and frequency of evolutionary changes in sex, sex determination and sex roles and conclude that sex in an evolutionary time-frame is extremely variable. We draw on recent findings in sex determination mechanisms, empirical findings of morphology and behaviour as well as genetic and developmental models to explore the concept of sex as a reaction norm. From this point of view, sexual differences are not expected to generally fall into neat, discrete, pre-determined classes. It is important to acknowledge this variability in order to increase objectivity in evolutionary research.
Phenotypic plasticity; Sexual selection; Sex determination; Sex change; Sex role reversal; Gender bias
One important concept in traditional Chinese medicine (TCM) is "treating different diseases with the same therapy". In TCM practice, some patients with Rheumatoid Arthritis (RA) and some other patients with Coronary Heart Disease (CHD) can be treated with similar therapies. This suggests that there might be something commonly existed between RA and CHD, for example, biological networks or biological basis. As the amount of biomedical data in leading databases (i.e., PubMed, SinoMed, etc.) is growing at an exponential rate, it might be possible to get something interesting and meaningful through the techniques developed in data mining.
Based on the large data sets of Western medicine literature (PubMed) and traditional Chinese medicine literature (SinoMed), by applying data slicing algorithm in text mining, we retrieved some simple and meaningful networks. The Chinese herbs used in treatment of both RA and CHD, might affect the commonly existed networks between RA and CHD. This might support the TCM concept of treating different diseases with the same therapy.
First, the data mining results might show the positive answer that there are biological basis/networks commonly existed in both RA and CHD. Second, there are basic Chinese herbs used in the treatment of both RA and CHD. Third, these commonly existed networks might be affected by the basic Chinese herbs. Forth, discrete derivative, the data slicing algorithm is feasible in mining out useful data from literature of PubMed and SinoMed.
The founding disciplines of HTA are clearly scientific, and have been firmly based among the natural sciences. However, common definitions of HTA indicate that HTA is something more than the “pure application of science”. This article investigates whether this “something” also makes HTA an art. The question of whether HTA is a science or an art is pursued in two specific and historically rich directions. The first is whether HTA is an art in the same way that medicine is described as an art. It has been argued extensively that medicine is based on two different and partly incompatible cultures, i.e., the natural sciences and humanities. Medicine is based on disciplines within the natural sciences, while its value judgments have been placed in the humanities camp. This dichotomy is present in HTA as well, and the first part of the investigation illustrates how HTA is an art in terms of its inherent and constitutive value-judgments. The second part of the science/art-scrutiny leads us to the ancient (Hippocratic) concept of art, téchne, where we find an etymological and a conceptual link between HTA and art. It demonstrates HTA is not an arbitrary process, even though it involves value judgments and relates complex decision making processes. As an art (téchne) HTA has a specific subject matter, requires inquiry and mastery of general rational principles, and is oriented to a specific end. In conclusion, the science-or-art-question makes sense in two specific perspectives, illustrating that HTA is a science based art. This has implications for the practice of HTA, for its education, and for the status of its results.
science; art; accountability; philosophy; téchne; phronesis
There has been an increased interest in the role of a human rights framework to mobilize resources for health.
This paper argues that the human rights framework does provide us with an appropriate understanding of what values should guide a nation's health policy, and a potentially powerful means of moving the health agenda forward. It also, however, argues that appeals to human rights may not necessarily be effective at mobilizing resources for specific health problems one might want to do something about. Specifically, it is not possible to argue that a particular allocation of scarce health care resources should be changed to a different allocation, benefiting other groups. Lack of access to health care services by some people only shows that something has to be done, but not what should be done.
The somewhat weak claim identified above together with the obligation to realize progressively a right to health can be used to mobilize resources for health.
Are dreams subjective experiences during sleep? Is it like something to dream, or is it only like something to remember dreams after awakening? Specifically, can dream reports be trusted to reveal what it is like to dream, and should they count as evidence for saying that dreams are conscious experiences at all? The goal of this article is to investigate the relationship between dreaming, dream reporting and subjective experience during sleep. I discuss different variants of philosophical skepticism about dream reporting and argue that they all fail. Consequently, skeptical doubts about the trustworthiness of dream reports are misguided, and for systematic reasons. I suggest an alternative, anti-skeptical account of the trustworthiness of dream reports. On this view, dream reports, when gathered under ideal reporting conditions and according to the principle of temporal proximity, are trustworthy (or transparent) with respect to conscious experience during sleep. The transparency assumption has the status of a methodologically necessary default assumption and is theoretically justified because it provides the best explanation of dream reporting. At the same time, it inherits important insights from the discussed variants of skepticism about dream reporting, suggesting that the careful consideration of these skeptical arguments ultimately leads to a positive account of why and under which conditions dream reports can and should be trusted. In this way, moderate distrust can be fruitfully combined with anti-skepticism about dream reporting. Several perspectives for future dream research and for the comparative study of dreaming and waking experience are suggested.
dreaming; subjective experience; dream reports; first-person reports; philosophy of mind; scientific dream research; skepticism; inference to the best explanation
Rewards that are not immediately available are discounted compared to rewards that are immediately available. The more a person discounts a delayed reward, the more likely that person is to have a range of behavioral problems, including clinical disorders. This latter observation has motivated the search for interventions that reduce discounting. One surprisingly simple method to reduce discounting is an “explicit-zero” reframing that states default or null outcomes. Reframing a classical discounting choice as “something now but nothing later” versus “nothing now but more later” decreases discount rates. However, it is not clear how this “explicit-zero” framing intervention works. The present studies delineate and test two possible mechanisms to explain the phenomenon. One mechanism proposes that the explicit-zero framing creates the impression of an improving sequence, thereby enhancing the present value of the delayed reward. A second possible mechanism posits an increase in attention allocation to temporally distant reward representations. In four experiments, we distinguish between these two hypothesized mechanisms and conclude that the temporal attention hypothesis is superior for explaining our results. We propose a model of temporal attention whereby framing affects intertemporal preferences by modifying present bias.
delay discounting; hidden-zero effect; temporal attention; reward sequences; priming; humans
There is tremendous pressure on industry and laboratories to develop
increasingly complex procucts: for example catalysts, chiral
chemicals, drugs and ceramics; conform to regulations; cope with
increasingly severe competition; and meet steadily increasing costs.
It is difficult, in this situation, to remain productive and competitive.
It is vital to be equipped with, and be able to use appropriately,
all the suitable methodologies and technologies. Working methods
and personnel have to be appropriate. The future depends on three
interdependent domains: automation in the broadest sense of the
word, instrumentation and information systems. The easy work
has already been done. Between 1984 and 1990, it was a question
of going from nothing to something; now, it is necessary to increase
Therefore, the crucial question is now: ‘how can we go
quicker in experimentation and acquire more knowledge,
while spending less money?’ One solution is to use all
the aspects of automation (robotics, instrumentation, data).
Successful laboratory automation depends.on: shortened time to
market; improved efficiency/cost ratio; motivation/competence/
expertise; communication; and knowledge acquisition. This paper
examines some of the major technological areas of application.
To date, open stone surgery is now performed in a very limited number of selected cases. A review of our own cases revealed that open surgery constituted 1% of all procedures. These procedures were mostly ablative, or operations to deal with complications of failed minimally invasive therapies. Given two continuing trends towards sub-specialisation in urology on the one hand, and minimally invasive therapy on the other, the question arises whether and how sub-specialised stone surgeons should and can learn open stone surgery. Is it merely a lost art not to be bothered with, or is it something worthwhile preserving? This article discusses the pros and cons of the argument and suggests centralisation of complex stone cases as a possible way out of the dilemma.
Open surgery; Stone surgery; Urology training; Surgical training
Applying principles of critical appraisal to evidence for lipid screening in family practice, one concludes that elevations of triglyceride are not a defined risk for coronary heart disease at present and screening cannot be justified. In contrast, there is now good evidence that elevated cholesterol is not only a primary risk factor for, but also a cause of coronary heart disease. There has been no randomized trial of cholesterol screening to date, leaving the physician in the position of knowing something should be done about the problem, but the best methods are yet to be clarified.
Lipids; screening; prevention
The neurosciences have advanced to the point that we can now treat consciousness as a scientific problem like any other. The problem is to explain how brain processes cause consciousness and how consciousness is realized in the brain. Progress is impeded by a number of philosophical mistakes, and the aim of this paper is to remove nine of those mistakes: (i) consciousness cannot be defined; (ii) consciousness is subjective but science is objective; (iii) brain processes cannot explain consciousness; (iv) the problem of 'qualia' should be set aside; (v) consciousness is epiphenomenal; (vi) consciousness has no evolutionary function; (vii) a causal account of consciousness is necessarily dualistic; (viii) science is reductionistic, so a scientific account of consciousness would show it reducible to something else; and (ix) an account of consciousness must be an information processing account.
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized clinically by dementia and neuropathologically by accumulation of senile plaques and neurofibrillary tangles. Identification of their constituents in the mid 1980s led to an exponential expansion of knowledge pertaining to metabolic pathways of amyloid-β (Aβ) and tau, in terms of normal human physiology and pathophysiology of neurodegeneration. Forgotten is the fact that our experience with AD pathology is based on end-stage lesions that have an imperfect correlation with clinical dementia in terms of lesion burden and affected brain region, and that the an AD is based on lesions that also occur in cognitively intact elderly. Attempts at addressing this fundamental defect now focus on toxic intermediates, namely Aβ oligomers, and their potential direct involvement of the synapse. Current thinking on AD pathology includes the concept that hallmark lesions may be non-toxic- something we have long been suggesting. We favor the interpretation that AD pathology represents a host response to an upstream pathophysiological process, and targeting lesions, including toxic intermediates, will not likely be beneficial so long as the host response is directly deleterious. Therefore, renewed efforts directed at basic age-related processes, such as oxidative stress and/or inflammatory mediators, are warranted.
Alzheimer’s disease; amyloid; tau