The DNA hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) improve survival and transfusion independence in myelodysplastic syndrome (MDS) and enable a low intensity cytotoxic treatment for aged AML patients unsuitable for intensive chemotherapy, particularly in combination with novel agents. The proposed mechanism of AZA and DAC relies on active DNA replication and therefore patient responses are only observed after multiple cycles of treatment. Although extended dosing may provide the optimal scheduling, the reliance of injectable formulation of (...) the drug limits it to intermittent treatment. Recently, an oral formulation of AZA demonstrated significantly improved patient relapse free survival (RFS) and overall survival (OS) when used as maintenance after chemotherapy for AML. In addition, both DAC and AZA were found to be highly effective to improve survival in elderly patients with AML through combination with other drugs. These recent exciting results have changed the therapeutic paradigm for elderly patients with AML. In light of this, we review current knowledge on HMA mechanism of action, clinical trials exploring dosing and scheduling, and recent HMA combination therapies to enhance efficacy. (shrink)

Self-experimentation is a valuable companion to self-management in the benefit of pharmaco-cognitive-behavior combination therapies. However, data on individuals participating as active therapeutic agents are sparse. Smoking cessation therapy is an example. Roberts' self-experimentation suggests trying more diversity in research to generate new ideas. This may inform current approaches to the cessation of smoking.

The Gardner report, recently published in the UK, showing a correlation between incidence of childhood leukaemia and paternal exposure to ionising radiations (amongst fathers working in nuclear power plants) has added a new element to debates about both the risk factors in nuclear power plants and the relationships between ionising radiations and leukaemogenesis. The epidemiologic and genetic evidence concerning leukaemias is reviewed here and it is concluded that the leukaemogenic agent, whose existence is indicated in the Gardner report, is unlikely (...) to be paternal radiation dose per se but rather exposure to another factor that is correlated with paternal radiation dose received. (shrink)

Sound is one of the types of waves that can be felt by the sense of hearing (ears). In physics, the definition of sound is something that is produced from objects that vibrate. Objects that produce sound are called sound sources. The sound source that vibrates will vibrate the molecules into the air around it. Sound is mechanical compression or longitudinal waves that propagate through the medium. This medium or intermediate agent can be liquid, solid, gas. So, sound waves can (...) propagate for example in water, coal, or air. Most sounds are a combination of various vibratory signals composed of harmonic waves, but pure sound can theoretically be explained by oscillating vibrational speed or frequency measured in Hertz (Hz) vibration units and amplitude or loudness of sound with measurements in decibels (dB). The effect sounds can have on us humans is simply astounding. While everyday life becomes stressful, overcrowded and increasingly hectic, we seek ways for inner peace and balance. The power of music, felt through overtone-rich sound therapy and sound massage, can be a solution. No matter how much scientific explanation is behind it, healing through music remains fascinating, even magical. This paper introduces a new field called cymatics and sound healing with their plausible impact to spirituality and consciousness research. (shrink)

A central principle of bioethics is “subject autonomy,” the acknowledgement of the primacy of the informed consent of the subject of research. Autonomy requires informed consent — the assurance that the research participant is informed about the possible risks and benefits of the research. In fact, informed consent is difficult when a single drug is being tested, although subjects have a baseline understanding of the testing of a pharmacological agent and the understanding that they can stop taking the drug if (...) there were an adverse event. However, informed consent is even less easily achieved in the modern arena of complex new molecular and cellular therapies. In this article, we argue that as science confronts new issues such as transplantation of stem cell products, which may live within the participant for the rest of their lives, researchers must carefully consider and constantly re-examine how they properly inform subjects considering participation trials of these novel therapeutic strategies.For example, the manufacture of a vial of a cell product that consists of a collection of growing cells is very different than the production of a vial of identical pills, which can be presumed to be identical. The scientific concepts on which these cellular approaches are based may seem alien and incomprehensible to a research subject, who thinks of a clinical trial as simply the selection and testing of the most efficacious pharmaceutical agent already proven to work in preclinical animal studies. The research subject would be wrong. (shrink)

Race is not a scientific category, but African Americans have increased prevalence and severity of heart failure. The African American Heart Failure trial showed the benefit of a combination of isosorbide dinitrate and hydralazine . Future research may unmask the reason for cardiovascular differences in therapy.

Johanna Knapstein,1 Daniel Grimm,1 Marcus A Wörns,1 Peter R Galle,1 Hauke Lang,2 Tim Zimmermann111st Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany; 2Department of General, Visceral and Transplantation Surgery, Johannes Gutenberg-University, Mainz, GermanyIntroduction: Hepatitis C virus reinfection occurs universally after liver transplantation, with accelerated cirrhosis rates of up to 30% within 5 years after liver transplantation. Dual antiviral therapy with pegylated interferon-2a and ribavirin only reaches sustained virological response rates of ~30% after liver transplantation. With the approval of viral NS3/4A (...) protease inhibitors telaprevir, boceprevir, and simeprevir and the NS5B polymerase inhibitor sofosbuvir, combination therapy offers new therapeutic options for HCV-infected patients, resulting in considerably higher sustained virological response rates in the nontransplant setting. Case presentation: We report three cases of TVR-based triple antiviral therapy in HCV genotype 1 reinfected patients after liver transplantation, of whom a 57-year-old Caucasian female and a 43-year-old Caucasian male were therapy naïve, and a 49-year-old Caucasian male patient was pretreated ineffectively. After 4 weeks of therapy, viral load decreased one to three log10 and became negative in weeks 6 to 8 in the therapy naïve patients. The pretreated patient showed a negative viral load in week 4. TVR was administered over 12 weeks, 750 mg thrice daily. Doses of immunosuppression with cyclosporine were reduced four to six fold. Initial peg-IFN and RBV doses ranged from 135–180 µg/week and 800–1,200 mg/day, according to the patient's body weight. Doses of peg-IFN and RBV were adapted to 90–135 µg/week and 400–800 mg/day after 2 to 12 weeks of protease inhibitor therapy. Dual therapy was continued for 36 weeks with total treatment duration of 48 weeks in the therapy naïve patients leading to a sustained virological response 12 weeks after the end of therapy. In the pretreated patient a breakthrough was detected in week 24 and therapy was discontinued. Overall, antiviral therapy was well tolerated. Side effects included dysgeusia and anemia leading to erythropoietin application and blood transfusions. Conclusion: This case series emphasizes that triple therapy with TVR is an efficient treatment for therapy naïve HCV genotype 1 reinfected patients after liver transplantation. But therapeutic options for pretreated patients require improvement. Keyword: cyclosporine, interferon, ribavirin, hepatitis C, protease inhibitor. (shrink)

Visuomotor adaptation to novel environments can occur via non-physical means, such as observation. Observation does not appear to activate the same implicit learning processes as physical practice, rather it appears to be more strategic in nature. However, there is evidence that interspersing observational practice with physical practice can benefit performance and memory consolidation either through the combined benefits of separate processes or through a change in processes activated during observation trials. To test these ideas, we asked people to practice aiming (...) to targets with visually rotated cursor feedback or engage in a combined practice schedule comprising physical practice and observation of projected videos showing successful aiming. Ninety-three participants were randomly assigned to one of five groups: massed physical practice, distributed physical practice, or one of 3 types of combined practice: alternating blocks, or all observation before or after blocked physical practice. Participants received 100 practice trials. All groups improved in adaptation trials and showed savings across the 24-h retention interval relative to initial practice. There was some forgetting for all groups, but the magnitudes were larger for physical practice groups. The Act and Obs_During groups were most accurate in retention and did not differ, suggesting that observation can serve as a replacement for physical practice if supplied intermittently and offers advantages above just resting. However, after-effects associated with combined practice were smaller than those for physical practice control groups, suggesting that beneficial learning effects as a result of observation were not due to activation of implicit learning processes. Reaction time, variable error, and post-test rotation drawings supported this conclusion that adaptation for observation groups was promoted by explicit/strategic processes. (shrink)

I want to examine critically a certain strategy of moral justification which I shall call instrumentalism. By this I mean the view that a moral theory is rationally justified if the actions, life-plan, or set of social arrangements it prescribes can be shown to be the best means to the achievement of an agent's final ends, whatever these may be. Instrumentalism presupposes a commitment to what I shall call the Humean conception of the self. By this I mean a certain (...) way of conceiving the motivational and structural constituents of the self. Briefly, the self on this conception is motivated by its desires for states of affairs that are temporally or spatiotemporally external to the self. And it is structured by the normative requirements of instrumental rationality: The self is conceived as rationally coherent to the extent that theoretical reason calculates and schedules the satisfaction of as many of its desires as possible, with the minimum necessary costs. The motivational and structural elements of the Humean conception of the self combine to form a familiar explanatory model of human agency: We make sense of an agent's behavior by ascribing to her the desire to achieve the ends that she does in fact achieve, and the theoretically rational belief that, given the information and resources available to her, behaving as she did was the most efficient way to do so. I shall want to argue that to the extent that instrumentalism is successful in providing an objective justification of a moral theory - and I shall contend that it cannot be completely successful - it cannot provide a moral justification. But when we attempt to modify it so as to produce a specifically moral justification, we see that either it is impossible to do this, or else the Humean notion of instrumental rationality is doing no justificatory work. (shrink)

A lesson from cognitive behavior therapy (CBT) is that it is possible for people to change their beliefs and attitudes in ways that enhance mood. This chapter discusses mainly how the ideas from positive psychology combined with the therapeutic methods developed in CBT might provide ways of helping individuals to enhance their mood and increase happiness. The best single perspective from which to gain an understanding of positive psychology is that of evolutionary psychology, even though it is underdeveloped and contentious. (...) Evolutionary psychology bridges the gap between individual history and the general features of the human condition that helps to explain both our capacity for happiness and some of the barriers to achieving it. The modern general evolutionary view of emotions is that they help animals in regulating their effort: how they behave at any one time and how they apportion their time and energy between different types of behavior. (shrink)

This thesis examines Kant's and Nietzsche's treatments of the moral agent. It argues for three broad conclusions. Firstly, it argues that, although Nietzsche's explicit criticisms of Kant's conception of the moral agent can be understood only in the context of Nietzsche's broader moral philosophy, neither these criticisms nor their context are well understood by the prevailing literature. The thesis thus engages with existing scholarship on the nature of Nietzsche's moral philosophy and with the scanty literature on the relationship between Kant's (...) and Nietzsche's moral philosophies. Secondly, the thesis argues that Kant's conception of the moral agent is not undermined by the criticisms which Nietzsche explicitly levels at it, or, indeed, by others which are commonly made in Nietzsche's name. In doing so, the thesis combines original interpretations of Kant with elements of recent Kant scholarship. Finally, however, the thesis argues that neglected elements of Nietzsche's own moral philosophy provide for a more sophisticated, telling, and, indeed, original critical engagement with Kant's conception of the moral agent is not undermined by the criticisms which Nietzsche explicitly levels at it, or, indeed, by others which are commonly made in Nietzsche's name. In doing so, the thesis combines original interpretations of Kant with elements of recent Kant scholarship. Finally, however, the thesis argues that neglected elements of Nietzsche's own moral philosophy provide for a more sophisticated, telling, and, indeed, original critical engagement with Kant's conception of the moral agent. Thus the thesis defends an original interpretation of Nietzsche's moral philosophy and its critical relation to Kant's, and demonstrates the pertinence of a certain neglected critical approach to Kant's conception of the moral agent. On the basis of these conclusions, the thesis ultimately defends a conception of the moral agent which, although Kantian, owes something to both Kant and Nietzsche. (shrink)

Wana Manitpisitkul1, Sabrina Lee2, Matthew Cooper31Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD, USA; 2Solid Organ Transplant Program, University of Utah Health Care, Salt Lake City, UT, USA; 3Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA: Addition of mycophenolate mofetil to calcineurin-based immunosuppressive therapy has led to a significant improvement in graft survival and reduction of acute rejection in renal transplant recipients. However, in clinical practice, MMF dose reduction, interruption, or discontinuation due to hematological (...) and gastrointestinal side-effects occurred in up to 50% of the patients. Large retrospective analyses have demonstrated that patients requiring MMF dose manipulation due to adverse events experienced a higher rate of rejection and graft loss. Enteric-coated mycophenolate sodium was developed with the goal of improving upper GI side-effects. Here, we review the efficacy and safety of EC-MPS in de novo kidney transplant recipient, and in stable renal transplant patients who were converted from MMF. The changes in GI-related adverse events using patient-reported outcome instruments are also reviewed.Keywords: enteric-coated mycophenolate sodium, mycophenolate mofetil, kidney transplant, efficacy, gastrointestinal tolerability. (shrink)

Buddhist philosophical traditions share the Hellenistic orientation toward therapy, particularly with regard to therapeutic interventions in our emotional life. As Pierre Hadot and Martha Nussbaum have ably argued, for the Hellenistic philosophers, philosophy itself is a therapy of the emotions. In this paper, I shift the focus of the contemporary philosophical literature on therapies of the emotions, which investigates almost exclusively the Hellenistic philosophers, and instead draw on the therapies developed by Tibetan Buddhist philosophers and yogis, in particular Gampopa (1079–1153), (...) Tsongkhapa (1357–1419), and Patrul Rinpoche (1808–87). The texts I use are in the genre of Tibetan literature called lo jong (blo sbyong), or mind (blo)- training (sbyong). I argue that the philosophical analysis of the Tibetan Buddhist therapies gives us a model of moral improve- ment that is both novel and promising. This model focuses on the morally improving agent’s capacity for self-awareness and relaxation, her playful approach to emotional-ethical obstacles, and the cultivation of sophisticated, context-sensitive and appropriately flexible judgments about her emotional-ethical life. I also offer a rough taxonomy of Tibetan therapies of the emotions, which will serve as a vehicle to understanding the view of moral improvement described above. (shrink)

Psychedelics such as psilocybin reliably produce significantly altered states of consciousness with a variety of subjectively experienced effects. These include certain changes to perception, cognition, and affect,1 which we refer to here as the acute subjective effects of psychedelics. In recent years, psychedelics such as psilocybin have also shown considerable promise as therapeutic agents when combined with talk therapy, for example, in the treatment of major depression or substance use disorder.2 However, it is currently unclear whether the aforementioned acute subjective (...) effects are necessary to bring about the observed therapeutic effects of psilocybin and other psychedelics. This uncertainty has sparked a lively—though still largely hypothetical—debate on whether psychedelics without subjective effects (“nonsubjective psychedelics” or “non-hallucinogenic psychedelics”) could still have the same therapeutic impact, or whether the acute subjective effects are in fact necessary for this impact to be fully realized.3,4,5. (shrink)

This article discusses the potential of using interactive environments in autism therapy. We specifically address issues relevant to the Aurora project, which studies the possible role of autonomous, mobile robots as therapeutic tools for children with autism. Theories of mindreading, social cognition and imitation that informed the Aurora project are discussed and their relevance to the project is outlined. Our approach is put in the broader context of socially intelligent agents and interactive environments. We summarise results from trials with a (...) particular mobile robot. Finally, we draw some comparisons to research on interactive virtual environments in the context of autism therapy and education. We conclude by discussing future directions and open issues. (shrink)

The article combines a criticism of public understanding of science with the sociology of expectations to examine how particular expectations toward scientific progress have performative effects for the construction of publics as citizens of science. By analyzing a particular controversy about gene therapy in Denmark, the article demonstrates how different sets of expectations can be used to discriminate among three different assemblages: the assemblage of consumption, the assemblage of comportment, and the assemblage of heroic action. Each of these assemblages makes (...) medical science, scientific citizenship, politics, patients, doctors, and expectations toward the future emerge in particular ways. By their radically different expectations toward science and their different constructions of what it means to be a scientific citizen, the assemblages construct the objectives of the governance of science in three very different ways. (shrink)

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)

New class of therapies, including bipolar therapies (BPT) and paradoxical unipolar therapies (PUT) were firstly proposed in relation to a clinical insight and to some results of biological investigations, then they gave rise to mathematical modeling which brought a justification of these therapies, at least from a theoretical point of view. After recalling the mathematical model for the regulation of agonistic antagonistic couples, and reporting the fundamental types of control simulation by means of it, we point out the validity of (...) therapeutical applications inferred from this model. These therapy modalities, including BPT and PUT, now concern the following diseases: astrocytomas, epilepsia and trials on multiple sclerosis. Even if such attempts are in their early stage, noticeably for the last case where biological changes have mainly been studied, it seems that a large span of treatments is open to BPT and PUT. Improvement of these techniques in the future depends, in our opinion, on a parallel working on the dynamics of the mathematical model and the dynamics, perceived by clinical insight and confirmed by biological investigations, of the body reactions to such strategies. Justification of BPT and PUT was given, by resorting to the notion of pathological homeostasis which, too often, intervenes in order to nullify the effects of unilateral (not paradoxical) therapies. This research has elicited some therapies which use two agents with antagonistic effects or only an agent with effects similar to the agent already in excess in the body - in both cases at nearly physiological doses. (shrink)

Computer science advocates institutional frameworks as an effective tool for modelling policies and reasoning about their interplay. In practice, the rules or policies, of which the institutional framework consists, are often specified using a formal language, which allows for the full verification and validation of the framework (e.g. the consistency of policies) and the interplay between the policies and actors (e.g. violations). However, when modelling large-scale realistic systems, with numerous decision-making entities, scalability and complexity issues arise making it possible only (...) to verify certain portions of the problem without reducing the scale. In the social sciences, agent-based modelling is a popular tool for analysing how entities interact within a system and react to the system properties. Agent-based modelling allows the specification of complex decision-making entities and experimentation with large numbers of different parameter sets for these entities in order to explore their effects on overall system performance. In this paper we describe how to achieve the best of both worlds, namely verification of a formal specification combined with the testing of large-scale systems with numerous different actor configurations. Hence, we offer an approach that allows for reasoning about policies, policy making and their consequences on a more comprehensive level than has been possible to date. We present the institutional agent-based model methodology to combine institutional frameworks with agent-based simulations). We furthermore present J-InstAL, a prototypical implementation of this methodology using the InstAL institutional framework whose specifications can be translated into a computational model under the answer set semantics, and an agent-based simulation based on the jason tool. Using a simplified contract enforcement example, we demonstrate the functionalities of this prototype and show how it can help to assess an appropriate fine level in case of contract violations. (shrink)

During the COVID-19 crisis there have been many difficult decisions governments and other decision makers had to make. E.g. do we go for a total lock down or keep schools open? How many people and which people should be tested? Although there are many good models from e.g. epidemiologists on the spread of the virus under certain conditions, these models do not directly translate into the interventions that can be taken by government. Neither can these models contribute to understand the (...) economic and/or social consequences of the interventions. However, effective and sustainable solutions need to take into account this combination of factors. In this paper, we propose an agent-based social simulation tool, ASSOCC, that supports decision makers understand possible consequences of policy interventions, but exploring the combined social, health and economic consequences of these interventions. (shrink)

The paper considers two-agent order acceptance scheduling problems with different scheduling criteria. Two agents have a set of jobs to be processed by a single machine. The processing time and due date of each job are known in advance. In the order accepting scheduling problem, jobs are allowed to be rejected. The objective of the problem is to maximize the net revenue while keeping the weighted number of tardy jobs for the second agent within a predetermined value. A mixed-integer linear (...) programming formulation is provided to obtain the optimal solution. The problem is considered as an NP-hard problem. Therefore, MILP can be used to solve small problem instances optimally. To solve the problem instances with realistic size, heuristic and metaheuristic algorithms have been proposed. A heuristic method is used to determine and secure a quick solution while the metaheuristic based on particle swarm optimization is designed to obtain the near-optimal solution. A numerical experiment is piloted and conducted on the benchmark instances that could be obtained from the literature. The performances of the proposed algorithms are tested through numerical experiments. The proposed PSO can obtain the solution within 0.1% of the optimal solution for problem instances up to 60 jobs. The performance of the proposed PSO is found to be significantly better than the performance of the heuristic. (shrink)

The COVID-19 pandemic has resulted in more than 524 million cases and 6 million deaths worldwide. Various drug interventions targeting multiple stages of COVID-19 pathogenesis can significantly reduce infection-related mortality. The current within-host mathematical modeling study addresses the optimal drug regimen and efficacy of combination therapies in the treatment of COVID-19. The drugs/interventions considered include Arbidol, Remdesivir, Interferon and Lopinavir/ritonavir. It is concluded that these drugs, when administered singly or in combination, reduce the number of infected cells and (...) viral load. Four scenarios dealing with the administration of a single drug, two drugs, three drugs and all four are discussed. In all these scenarios, the optimal drug regimen is proposed based on two methods. In the first method, these medical interventions are modeled as control interventions and a corresponding objective function and optimal control problem are formulated. In this framework, the optimal drug regimen is derived. Later, using the comparative effectiveness method, the optimal drug regimen is derived based on the basic reproduction number and viral load. The average number of infected cells and viral load decreased the most when all four drugs were used together. On the other hand, the average number of susceptible cells decreased the most when Arbidol was administered alone. The basic reproduction number and viral load decreased the most when all four interventions were used together, confirming the previously obtained finding of the optimal control problem. The results of this study can help physicians make decisions about the treatment of the life-threatening COVID-19 infection. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Bringing Cancer Care to Those who Don't Have ItLawrence N. ShulmanI have been treating cancer patients in the Harvard Medical School hospitals since 1977, and in those 35 years we have made tremendous progress. Though work still needs to be done, and far too many patients still die of cancer, many are cured. In particular, children and young adults have a high rate of cure from such diseases as (...) Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and childhood sarcoma. Patients with breast cancer in the US have a greater than 80% chance for long-term survival. The death rate from cervical cancer in the US is very low. These results have been achieved by making diagnoses earlier, in many cases surgical excision, and often systemic therapies such as chemotherapy, hormonal therapy, radiation therapy, and more recently by using so-called "targeted" therapies—those directed at particular molecular characteristics of the cancer cells.Princess Dina Mired has said that the opportunity to survive cancer should not be an accident of geography. In cases where we already have effective and inexpensive tools to cure cancer, these treatments should be considered a basic human right, a life-saving medical service.I met Patty, a young woman living in the U.S. during November of her senior year in high school, after she discovered a small lump above her left collar bone. Though she felt entirely well, she called her primary care doctor who saw her the next day, felt the enlarged lymph node, and referred her to a surgeon, who did a biopsy later that week. Her primary care doctor also called me, and we scheduled a visit when the pathology results were available. The following week the pathologist notified Patty's pediatrician that the biopsy showed Hodgkin's lymphoma. When I met Patty, she was a bright and focused young woman, waiting to hear about her college applications and enjoying her senior year. Her cancer diagnosis was completely out of context with her life as she planned it, but with the support of her family and boyfriend, she seemed prepared to take things one step at a time. A PET CT scan demonstrated a modest mass in the mediastinum (chest), but no other disease. She was in an early stage of the disease with an excellent prognosis. We recommended and administered six months of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine—four chemotherapy agents that are off-patent, and relatively inexpensive. She lost her hair, not a trivial issue for her, but otherwise felt reasonably well during the treatment. She was determined to graduate with her classmates, and was able continue to attend school and keep up with her work. In June, seven months into her cancer diagnosis and treatment, she graduated with honors, and was on track to enroll in college in September.Like other 18-year-old women with Hodgkin's lymphoma, Patty had an over 80% chance for cure with the potential for a long and productive life ahead of her because we could perform a biopsy, make a diagnosis, and safely and effectively treat her with four inexpensive, off-patent, chemotherapy drugs. She had nearly the same likelihood of living a long and fruitful life as her classmates, and had the same chances for childbearing. In my line of work, with the knowledge we now possess, to allow someone like Patty to die without a chance of curative care is simply unacceptable. Treatment of curable cancers should be considered on par with the right to clean water, adequate nutrition, treatment for infectious disease, and access to maternal and child healthcare services.But in many places in the world, people with cancers we could easily eradicate in Boston have no access to cancer services, and do die unnecessarily. The local healthcare infrastructure has no [End Page E10] capacity to evaluate a patient, perform or process a biopsy, make a diagnosis, or treat the patient with potentially curative surgery, chemotherapy and radiation. I have rounded on the wards of hospitals in developing countries, stopping to talk with numerous patients like Patty: young women, some of whom might have had Hodgkin's lymphoma, but no... (shrink)

Objective: We aimed to analyze the characteristics and psychological mechanism of depressive symptoms in elderly patients with alcohol dependence under the COVID-19 epidemic and to observe the effect of acupuncture combined with emotional therapy of Chinese medicine treatment on depressive symptoms in elderly patients with alcohol dependence.Methods: Sixty patients were randomly divided into two groups. One group was treated by a set of emotional therapy of Chinese medicine treatment for 12 weeks. One group was treated by a set of acupuncture (...) combined with emotional therapy of Chinese medicine treatment for 12 weeks. We compared the curative effect between the control group and the treatment group, the mean alcohol consumption, the SF-36 scores before and after treatment, and the scores of Hamilton Depression Scale before and after treatment of 3, 6, and 9 weeks.Results: Based on the cognitive behavior model, the characteristics and psychological mechanism of depression in elderly patients with alcohol dependence under the COVID-19 epidemic situation were summarized. The total effective rate of the control group was 60%, and that of the treatment group was 100%. After 12 weeks of treatment, there were significant differences in PF, RF, physical pain, general health status, energy, and mental health between the treatment group and the control group. Before and after treatment, there were significant differences in PF, RF, physical pain, general health, energy, emotional function, and mental health of the treatment group. The PF, energy, and mental health of the control group were significantly different before and after treatment. There was no significant difference between the treatment group and the control group in the scores of Hamilton Depression Scale before treatment. There was significant difference between the treatment group and the control group in the scores of Hamilton Depression Scale at 3, 6, and 9 weeks after treatment.Conclusion: Attention, cognition, emotion, behavior, and physical response reinforce each other, creating a vicious cycle that reinforces and sustains the depressive symptoms of elderly alcohol dependence under the COVID-19 epidemic, and acupuncture combined with emotional therapy of Chinese medicine treatment for improving the depressive symptoms of elderly alcohol dependence during the epidemic period of COVID-19 has a brilliant therapeutic effect. (shrink)

This paper discusses the meaning that interactive software agents and robots have in the context of mental therapy. This theoretical discussion is undertaken from a psychological and sociological perspective. It investigates what happens when interactive agents are introduced into current social situations. Methods of mental therapy vary from therapeutic conversation between clients and human therapists to interaction between clients and therapeutic animals such as dogs. This paper focuses on applications of interactive software agents and robots that substitute as autonomous artifacts (...) behaving like humans for human therapists. In addition, some implications and policies for applications of interactive software agents and robots in mental therapy are discussed. (shrink)

Diagnostik und Klassifikation der akuten myeloischen Leukämie (AML) beruhen auf zytologischen und zytogenetischen Charakteristika. Eine Individualisierung der Diagnostik und Therapie wird für AML mit normalem Karyotyp (CN-AML) durch den Nachweis spezifischer Genmutationen zunehmend ermöglicht. In einem systematischen Literaturreview und Metanalyse wurde die Mutation FLT3-ITD bei CN-AML untersucht. Eine systematische Literaturrecherche aller Veröffentlichungen der Datenbanken Embase, Pubmed, Healthstar, BIOSIS, ISI Web of Knowledge und Cochrane wurde für den Zeitraum 2000 bis März 2012 im Hinblick auf die Mutation FLT3-ITD bei Patienten mit (...) CN-AML und einem Alter von 15–65 Jahren durchgeführt. Der Literaturrecherche folgte eine Literaturselektion, eine Datenextraktion und eine qualitative sowie quantitative Informationssynthese in Form einer Metaanalyse. Achtzehn Veröffentlichungen konnten in die qualitative Analyse zur CN-AML eingeschlossen werden. Daten von 3 Publikationen zum Gesamtüberleben mit insgesamt 1.203 Patienten gingen mit Bezug auf den Marker FLT3-ITD in die Metaanalyse ein. Für FLT3-ITD zeigte sich eine statistisch signifikante schlechtere Prognose mit einer hazard ratio von 2,19 für das Gesamtüberleben bei CN-AML. FLT3-ITD ist im Vergleich zum Wildtyp mit einer schlechteren Prognose in Bezug auf den Krankheitsverlauf bei AML assoziiert. Die Analyse von FLT3 sollte bei der AML berücksichtigt werden. (shrink)

We extend stit logic by adding a spatial dimension. This enables us to distinguish between powers and opportunities of agents. Powers are agent-specific and do not depend on an agent’s location. Opportunities do depend on locations, and are the same for every agent. The central idea is to define the real possibility to see to the truth of a condition in space and time as the combination of the power and the opportunity to do so. The focus on agent-relative (...) powers and space-relative opportunities firmly roots effectivity of an autonomous choice making agent in a space–time picture. Our space–time view will be classically Newtonian, since we will assume relativistic phenomena do not play a role in agentive effectivity. We show how our semantics naturally distinguishes between different kinds of histories; histories that reflect real possibilities and histories that reflect counterfactual possibilities. Furthermore, we discuss how the spatial picture sheds light on conceptual problems plaguing the central stit property of ‘independence of agency’. At several points in the article we will emphasise and defend the differences with Belnap’s theory of agency in relativistic branching space–times. (shrink)

How can health plans make fair determinations about when “experimental” (and costly) treatments such as high dose chemotherapy with autologous bone marrow transplantation should be covered despite lack of clear clinical consensus about their benefits? Different models for managing “last chance” therapies evolving in some health plans offer promising examples of how issues of fairness and legitimacy in decisionmaking can be addressed.

This paper considers two kinds of stochastic reentrant job shop scheduling problems, i.e., the SRJSSP with the maximum tardiness criterion and the SRJSSP with the makespan criterion. Owing to the NP-complete complexity of the considered RJSSPs, an effective differential evolutionary algorithm combined with two uncertainty handling techniques, namely, DEA_UHT, is proposed to address these problems. Firstly, to reasonably control the computation cost, the optimal computing budget allocation technique is applied for allocating limited computation budgets to assure reliable evaluation and identification (...) for excellent solutions or individuals, and the hypothesis test technique is added to execute a statistical comparison to reduce some unnecessary repeated evaluation. Secondly, a reentrant-largest-order-value rule is designed to convert the DEA’s individual to the SRJSSP’s solution. Thirdly, a conventional active decoding scheme for the job shop scheduling problem is extended to decode the solution for obtaining the criterion value. Fourthly, an Insert-based exploitation strategy and an Interchange-based exploration strategy are devised to enhance DEA’s exploitation ability and exploration ability, respectively. Finally, the test results and comparisons manifest the effectiveness and robustness of the proposed DEA_UHT. (shrink)

Condorcet's jury theorem shows that when the members of a group have noisy but independent information about what is best for the group as a whole, majority decisions tend to outperform dictatorial ones. When voting is supplemented by communication, however, the resulting interdependencies between decision makers can strengthen or undermine this effect: they can facilitate information pooling, but also amplify errors. We consider an intriguing non-human case of independent information pooling combined with communication: the case of nest-site choice by honeybee (...) (Apis mellifera) swarms. It is empirically well documented that when there are different nest sites that vary in quality, the bees usually choose the best one. We develop a new agent-based model of the bees' decision process and show that its remarkable reliability stems from a particular interplay of independence and interdependence between the bees. (shrink)

The development of photodynamic therapy and anti-vascular endothelial growth factor agents have revolutionized the treatment of retinal diseases, transforming the retina subspecialty by ushering in an age of pharmacological treatments for a wide range of diseases, including age-related macular degeneration.

This paper delves into a two-agent scheduling problem in which two agents are competing for a single resource. Each agent has a set of jobs to be processed by a single machine. The processing time, release time, weight, and the due dates of each job are known in advance. Both agents have their objectives, which are conflicting in nature. The first agent tries to minimize the total completion time, while the second agent tries to minimize the number of tardy jobs. (...) The two agents’ scheduling problem, an NP-hard problem, has a wide variety of applications ranging from the manufacturing industry to the cloud computing service provider. Due to the wide applicability, each variation of the problem requires a different algorithm, adapted according to the user’s requirements. This paper provides mathematical models, heuristic algorithms, and two nature-based metaheuristic algorithms to solve the problem. The algorithm’s performance was gauged against the optimal solution obtained from the AMPL-CPLEX solver for both solution quality and computational time. The outlined metaheuristics produce a solution that is comparable with a short computational time. The proposed metaheuristics even have a better solution than the CPLEX solver for medium-size problems, whereas the computation times are much less than the CPLEX solvers. (shrink)

Depression is a highly recurrent disorder with limited treatment alternatives for reducing risk of subsequent episodes. Acceptance and commitment therapy (ACT) and attention bias modification (ABM) separately have shown some promise in reducing depressive symptoms. This study investigates (a) if group-based ACT had a greater impact in reducing residual symptoms of depression over a 12-month follow-up than a control condition, and (b) if preceding ACT with ABM produced added benefits. This multisite study consisted of two phases. In phase 1, participants (...) with a history of depression, currently in remission (N= 244), were randomized to either receive 14 days of ABM or a control condition. In phase 2, a quasi- experimental design was adopted, and only phase-1 participants from the Sørlandet site (N= 124) next received an 8-week group-based ACT intervention. Self-reported and clinician-rated depression symptoms were assessed at baseline, immediately after phase 1 and at 1, 2, 6, and 12 months after the conclusion of phase 1. At 12-month follow-up, participants who received ACT exhibited fewer self-reported and clinician-rated depressive symptoms. There were no significant differences between ACT groups preceded by ABM or a control condition. There were no significant differences between ACT groups preceded by ABM or a control condition. Group-based ACT successfully decreased residual symptoms in depression over 12 months, suggesting some promise in preventing relapse. (shrink)

The fight to find effective, long-lasting treatments for cancer has led many researchers to consider protein degrading entities. Recent developments in PROteolysis TArgeting Chimeras (PROTACs) have signified their potential as possible cancer therapies. PROTACs are small molecule, protein degraders that function by hijacking the built-in Ubiquitin-Proteasome pathway. This review mainly focuses on the general design and functioning of PROTACs as well as current advancements in the development of PROTACs as anticancer therapies. Particular emphasis is given to PROTACs designed against various (...) types of Leukemia/Blood malignancies. (shrink)

The goal of this paper is to present a succinct overview, from a clinician’s perspective, of the importance and implications of research on heart failure in African Americans. It first gives a brief outline of the rationale and results of the African-American Heart Failure Trial, which showed evidence for the effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine, marketed as BiDil, in this population. Finally, it underscores the necessity of treating African Americans with evidence-based medicine given that humanistic (...) physicians and other clinicians strive to provide holistic treatment to their patients.Most researchers and clinicians recognize the difficulty with utilizing race as a category for inclusion in trials. While race lacks any true biologic definition, it is potentially beneficial as a consideration in clinical studies, based on prior evidence of certain potential differences across self-identified racial/ethnic groups in morbidity and mortality and responses to medicine. Even though use of race as a classification is a problematic distinction, it should not be ignored. If clinical trials demonstrate significant improvement with targeted treatment in African Americans, clinicians should not withhold life-saving drugs that result from such studies. (shrink)

BackgroundFreezing of gait is a disabling burden for Parkinson’s disease patients with poor response to conventional therapies. Combined deep brain stimulation of the subthalamic nucleus and substantia nigra moved into focus as a potential therapeutic option to treat the parkinsonian gait disorder and refractory FoG. The mechanisms of action of DBS within the cortical-subcortical-basal ganglia network on gait, particularly at the cortical level, remain unclear.MethodsTwelve patients with idiopathic PD and chronically-implanted DBS electrodes were assessed on their regular dopaminergic medication in (...) a standardized stepping in place paradigm. Patients executed the task with DBS switched off, conventional STN DBS and combined STN+SN DBS and were compared to healthy matched controls. Simultaneous high-density EEG and kinematic measurements were recorded during resting-state, effective stepping, and freezing episodes.ResultsClinically, STN+SN DBS was superior to conventional STN DBS in improving temporal stepping variability of the more affected leg. During resting-state and effective stepping, the cortical activity of PD patients in STIM OFF was characterized by excessive over-synchronization in the theta, alpha, and high-beta band compared to healthy controls. Both active DBS settings similarly decreased resting-state alpha power and reduced pathologically enhanced high-beta activity during resting-state and effective stepping compared to STIM OFF. Freezing episodes during STN DBS and STN+SN DBS showed spectrally and spatially distinct cortical activity patterns when compared to effective stepping. During STN DBS, FoG was associated with an increase in cortical alpha and low-beta activity over central cortical areas, while with STN+SN DBS, an increase in high-beta was prominent over more frontal areas.ConclusionsSTN+SN DBS improved temporal aspects of parkinsonian gait impairment compared to conventional STN DBS and differentially affected cortical oscillatory patterns during regular locomotion and freezing suggesting a potential modulatory effect on dysfunctional cortical-subcortical communication in PD. (shrink)

The specific aims of this research study were to examine the differential effect of three different music interventions, namely the interactive music playing therapy, interaction music singing therapy, and receptive music therapy studying the varying latency periods in the response time it took 3-year-old children diagnosed with autism spectrum disorder to elicit the target word vocally; and assess the index of happiness of children with ASD after the implementation of the three music interventions, which can, in turn, be used to (...) influence their overall quality of life through this specific intervention. This study used a combined single-subject research design consisting of delayed multiple baseline across the participants and a multielement design to compare the effects of each music intervention technique targeting the child’s verbal response during playback of a practiced song. Findings demonstrated “singing” to be associated with the lowest latency compared to the other two interventions across participants. Additionally, happiness levels varied from neutral to happy, signifying an overall positive experience during participation in the music applied behavior analysis intervention. (shrink)

Pharmacoresistant schizophrenia is a significant impediment to the successful management of the disease. The expression and function of P‐glycoprotein (P‐gp) has recently been implicated in this phenomenon. P‐gp is a multidrug efflux transporter that prevents drug substrates from crossing the blood–brain barrier (BBB). Although the direct interaction between individual antipsychotic agents and P‐gp has been demonstrated, the effect of antipsychotic drug combinations used in disease management on P‐gp transport function remains to be elucidated. This could have important clinical implications in (...) some individuals as dosage adjustments based on plasma drug concentration changes may not always be appropriate if drug–drug interactions and the resulting changes in drug concentration in the brain are not considered. This paper introduces the potential impact that combination antipsychotic therapy may have on P‐gp function at the BBB and discusses the consequences of this in the prevention and circumvention of unfavourable therapeutic response in schizophrenic disorders. BioEssays 30:183–188, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Abstractβ‐Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of β‐catenin function in normal T‐cell development and T‐cell acute lymphoblastic leukemia (T‐ALL). The integration of the existing literature offers a state‐of‐the‐art dissection of the complexity of β‐catenin function in leukemia initiation and maintenance in both Notch‐dependent and independent contexts. In addition, β‐catenin mutations are screened for in T‐ALL primary samples, and it is found that (...) they are rare and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T‐ALL cohorts indicates that the expression of these genes may correlate with T‐ALL subtypes and/or therapy outcomes. (shrink)

The 19th century saw the development of an eclectic medical marketplace in both the United Kingdom and the United States, with mesmerists, herbalists and hydrotherapists amongst the plethora of medical ‘sectarians’ offering mainstream (or ‘allopathic’) medicine stiff competition. Foremost amongst these competitors were homoeopaths, a group of practitioners who followed Samuel Hahnemann (1982[1810]) in prescribing highly dilute doses of single-drug substances at infrequent intervals according to the ‘law of similars’ (like cures like). The theoretical sophistication of homoeopathy, compared to other (...) medical sectarian systems, alongside its institutional growth after the mid-19th-century cholera epidemics, led to homoeopathy presenting a challenge to allopathy that the latter could not ignore. Whilst the subsequent decline of homoeopathy at the beginning of the 20th century was the result of multiple factors, including developments within medical education, the Progressive movement, and wider socio-economic changes, this article focuses on allopathy’s response to homoeopathy’s conceptual challenge. Using the theoretical framework of Berger and Luckmann (1991[1966]) and taking a Tory historiographical approach (Fuller, 2002) to recover more fully 19th-century homoeopathic knowledge, this article demonstrates how increasingly sophisticated ‘nihilative’ strategies were ultimately successful in neutralising homoeopathy and that homoeopaths were defeated by allopaths (rather than disproven) at the conceptual level. In this process, the therapeutic use of ‘nosodes’ (live disease products) and the language of bacteriology were pivotal. For their part, homoeopaths failed to mount a counter-attack against allopaths with an explanatory framework available to them. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Autonomy, Experience, and TherapyDominic Murphy (bio)The contemporary philosophical idea of autonomy has a psychological implication, to wit, that there exists a comprehensive set of ideal competences, realized in our mind/brain, that enable a person to be self-governing. Autonomy is normally accorded individuals who enjoy a certain kind of psychological functioning and, perhaps, a certain sort of psychological history (Christman 1991). We think that autonomous individuals critically evaluate their life (...) and actions, endorse them as self-determined rather than imposed from without, and guide their own lives in accordance with the plans and values they have worked out for themselves. Such self-government has to depend on some psychological structures, but philosophers have tended to theorize about what these structures might be at a considerable distance from what the behavioral sciences can tell us. Anderson and Lux's paper is a welcome contribution to the growing literature that tries to connect issues in ethics with empirical considerations. This sort of methodological, as opposed to merely metaphysical, naturalism, is only just coming into vogue in ethics, even in moral psychology.1 Anderson and Lux are, as far as I am aware, the first people to reflect seriously on what we can learn about autonomy from clinical experience. Theirs is a very suggestive and fruitful paper that looks at real-life cases of loss of autonomy and tries to reach conclusions about what the deficits in performance tell us about the psychological preconditions of autonomy. Their paper also opens the way for an investigation into the precise neurologic and computational underpinnings of these capacities, which is essential if we are to get a serious moral psychology underway.I find little to quarrel with in the story that Anderson and Lux tell, but I will try to modify it slightly to bring out what I think is the important psychological point they make and explore some ramifications. I begin by claiming that they have scored a decisive point in favor of an external conception of autonomy. Second, I suggest that what Anderson and Lux have really put their finger on is less a requirement of accurate self-assessment than a requirement of sensitivity to feedback from the environment. I conclude by raising some of these issues about the relations between autonomy and assessments of psychological function when the deficit responsible is less amenable to clear cut neurologic identification.The External Perspective on AutonomyOne way of taking the paper (although this goes beyond anything that Anderson and Lux suggest) is that there is a smooth naturalistic picture of the cognitive basis of autonomy. When people have a normally functioning neurocomputational setup in their heads, we should assume that they are autonomous, and vice versa. However, autonomy cannot simply be identifiable with a mind that is working as some scientific theory says it should, because a mind that is [End Page 303] in that sense working correctly could, nonetheless, be directed by forces other than the agent. Servile or deluded individuals might endorse their lives even if those lives are the product of indoctrination, self-deception, or internalized oppression (Mackinnon 1997; Mele 1995). Normal mechanisms of belief fixation, for example, may not foster one's autonomy if the only context in which they are exercised is one in which many possible ways of life are simply unavailable for consideration, having been excluded from consideration by the dominant forces around one. We might, then, think of full autonomy as depending on relational rather than intrinsic properties. Perhaps autonomy requires a subject to have both normal psychological capacities and the right sort of environment in which to exercise them. I do not follow-up on this suggestion, but I mention it because it introduces two dimensions, within the subject and around the subject, where the externalist perspective on autonomy can get a grip. I discuss the former, but I do not mean to suggest that the latter is not important. A full account must deal with both. But even the psychological structures that foster autonomy cannot be identified with a mind working according to some scientific theory, as we shall see.Many writers on autonomy argue that we must recognize appropriate, objective constraints... (shrink)

Introduction: There is evidence from earlier trials for the efficacy of music therapy in the treatment of depression among working-age people. Starting therapy sessions with relaxation and revisiting therapeutic themes outside therapy have been deemed promising for outcome enhancement. However, previous music therapy trials have not investigated this issue.Objective: To investigate the efficacy of two enhancers, resonance frequency breathing and listening homework, when combined with an established music therapy model.Methods: In a 2 × 2 factorial randomised controlled trial, working-age individuals (...) with depression were allocated into groups based on four conditions derived from either the presence or absence of two enhancers. All received music therapy over 6 weeks. Outcomes were observed at 6 weeks and 6 months. The primary outcome was the Montgomery Åsberg Depression Rating Scale score.Results: There was a significant overall effect of treatment for the primary outcome favouring the breathing group. The effect was larger after adjustment for potential confounders. Treatment effects for secondary outcomes, including anxiety and quality of life, were also significant, favouring the breathing group. The homework enhancer did not reach significant treatment effects.Conclusion: We found that the addition of RFB to a music therapy intervention resulted in enhanced therapeutic outcome for clients with depression. (shrink)

Using a longitudinal case study design, we have tracked the recovery of motor function following severe traumatic brain injury (TBI) through a multimodal neuroimaging approach. In 2006, Canadian Soldier Captain (retired) Trevor Greene (TG) was attacked with an axe to the head while on tour in Afghanistan. TG continues intensive daily rehabilitation, which recently included the integration of physical therapy (PT) with neuromodulation using translingual neurostimulation (TLNS) to facilitate neuroplasticity. Recent findings with PT+TLNS demonstrated that recovery of motor function occurred (...) beyond conventional time limits, currently extending past 14-years post-injury. To investigate whether PT+TLNS similarly resulted in associated cognitive function improvements, we examined event-related potentials (ERPs) with the brain vital signs framework. In parallel with motor function improvements, brain vital signs detected significant increases in basic attention (as measured by P300 response amplitude) and cognitive processing (as measured by contextual N400 response amplitude). These objective cognitive improvements corresponded with TG’s self-reported improvements, including a noteworthy and consistent reduction in ongoing symptoms of post-traumatic stress disorder (PTSD). The findings provide valuable insight into the potential importance of non-invasive neuromodulation in cognitive rehabilitation, in addition to initial indications for physical rehabilitation. (shrink)