Mechanistic reasoning and informed consent

Evidence‐based medicine (EBM) proponents have argued that mechanistic evidence concerning medical treatments should be considered secondary to evidence derived from randomized controlled trials (RCTs). One common criticism of RCTs is that they often do not yield results that are generalizable to clinical practice, and that for clinical practice application, mechanistic evidence is needed. However, proponents of EBM have argued that mechanistic reasoning is often unreliable and thus not very useful. Here we suggest an important role of mechanistic explanation that has been left out of this discussion entirely, namely, its importance in a patient’s decision of whether or not to take certain drugs. We argue that in certain cases, knowing how a treatment works is just as important for the patient as knowing whether it does. In this paper, we explore how and why giving patients mechanistic information can be an important factor in obtaining informed consent for medical treatment, focusing on the example case of hormonal contraceptives.     

God’S Laboratory: Religious Rationalities And Modernity In Ecuadorian In Vitro Fertilization

Catholicism is the only major world religion that unequivocally bans the use of in vitro fertilization (IVF). Nevertheless, in Ecuador, Catholic IVF practitioners declare God’s dominion over their IVF laboratories and clinics in explaining pregnancy outcomes. My analysis of this routine combination of spiritual and material causal models in Ecuadorian IVF contributes to two ongoing discussions about (1) the tensions between “institutional” and popular forms of Catholic religiosity and (2) the proper boundaries of science in modernity. The Catholic Church’s historical and contemporary struggle to determine control of the miraculous has usually been characterized as a conflict between educated clergy and humble peasants. In the case of Ecuadorian IVF, we find, instead, educated elites and middle classes participating in this same contestation with the Church, proclaiming their direct ability to harness the power of God to effect material change on earth. This spiritual power to affect clinical outcomes does not take place just anywhere, but in clinic and lab, disrupting another set of presumptions about modern scientific practice and subjectivity. Like other Ecuadorian elites and middle classes, IVF practitioners are heirs to Enlightenment thought, and experience themselves as modern in their participation in these high-tech endeavors. But their spiritual approach to laboratory rationality does not trouble these IVF practitioners’ experience of themselves as moderns, prompting a reevaluation of the narratives of scientific modernity that limit their scope to Europe and North America.     

A New Class of Completely Self‐Designing Clinical Trials

A flexible method is proposed for group sequentially performed clinical trials which allows for an adaptive, data‐driven sample size reassessment at each stage. By also adaptively assigning different weights to the several stages the total number of study parts can be steered to an intended early or late end of the trial in dependence on all information available prior to a stage. Although at each stage the null hypothesis is tested on rejection, the full level‐α‐test is preserved at the end of the study. The proposed method is not restricted to normally distributed responses. The discussed adaptive designing is a useful tool provided that a priori information about parameters involved in the trial are not available or subject to uncertainty. The presented learning algorithm enables the complete self‐designing of a study.     

Stroke--possibilities for prevention]

The practice of stroke medicine varies enormously. This is not just because of variable resources, access to services and preferences among patients, clinicians, medical centres, governments and societies, but also often because of poor evidence about the effectiveness and cost of many components of stroke care. Although the past 20 years have seen a huge increase in randomised controlled trials, the results have not always had much influence on clinical practice, perhaps because many trials used confusing outcome measures or were too small (limited statistical power) or because the findings could not easily be generalised. Our purpose is to review the best evidence for stroke treatment and prevention.     

Talking Pleasures,Writing Dialects. Outlining Research on Schmecka

This text is written in English so that it may reach an international academic audience. However, if all academic research comes to be outlined in English we are to lose a lot. Here, we argue this by presenting the case of schmecka. Drawing on fieldwork done in the Austrian region of Vorarlberg, we suggest that the word schmecka differs from the factual ‘flavour perception’ investigated in physiology; from the culturally informed ‘sensory experiences’ explored by anthropologists and even from the sociological ‘tasting in practice’. For one, schmecka is shared between modest good food and assembled eaters; two, it draws together the English ‘tasting’ and ‘smelling’; and three, it has positive overtones. This means that using schmecka is not just judicious when writing about ‘others’, here the people of Vorarlberg. It also, more interestingly, allows ‘us’ to write in another way: one that foregrounds valuing rather than facting.     

Endpiece: Ideas must be comforting

ObjectivesTo explore general practitioners’ perceptions of effective health care and its application in their own practice; to examine how these perceptions relate to assumptions about clinicians’ values and behaviour implicit in the evidence based medicine approach.DesignA qualitative study using semistructured interviews.SettingEight general practices in North Thames region that were part of the Medical Research Council General Practice Research Framework.Participants24 general practitioners, three from each practice.ResultsThree categories of definitions emerged: clinical, patient related, and resource related. Patient factors were the main reason given for not practising effectively; others were lack of time, doctors’ lack of knowledge and skills, lack of resources, and “human failings.” Main sources of information used in situations of clinical uncertainty were general practitioner partners and hospital doctors. Contact with hospital doctors and observation of hospital practice were just as likely as information from medical and scientific literature to bring about changes in clinical practice.ConclusionsThe findings suggest that the central assumptions of the evidence based medicine paradigm may not be shared by many general practitioners, making its application in general practice problematic. The promotion of effective care in general practice requires a broader vision and a more pragmatic approach which takes account of practitioners’ concerns and is compatible with the complex nature of their work.

Key messages

• Evidence based medicine has emerged as a new paradigm to prevent inappropriate variations in clinical practice
• This study explored the extent to which evidence based medicine’s emphasis on clinical effectiveness, self analysis, and information seeking is congruent with the modes of thinking and behaviour of general practitioners
• General practitioners’ definitions of effective health care fell into three categories of clinical, patient related, and resource related; their main reason for not practising effectively was patient factors, and others were lack of time, lack of knowledge and skills, lack of resources, and “human failings”; and their main sources of information in cases of clinical uncertainty were general practitioner partners and hospital doctors
• The central assumptions of the evidence based medicine paradigm may not be shared by many general practitioners, making its application in general practice problematic
• Promotion of effective care in general practice requires a broader vision and a more pragmatic approach that takes account of practitioners’ concerns and is compatible with the complex nature of their work

     

Effects of brown trout (Salmo trutta L.) stocking and catch‐release practice on angling catches in the River South Rena in southeast Norway

Preserving of fish species and populations is important whether it is for exploitation or just for conservation. Management of fisheries aim to maintain fishable stocks that are attractive to anglers, and different means are performed. In this study from the River South Rena in southeastern Norway, conducted during 1991–2005, the effects of supportive stocking of hatchery reared brown trout (Salmo trutta L.) from 1996, and bag limit (BL) and catch‐release (CR) practice for the target species brown trout, from 2002, were explored. Effects of supplemental brown trout stocking was not noticeable, except from one year following a year of exceptional high number of stocked fish, actually 41% of the catches, whereas in the following years this proportion remained constant about 10%, and the catches remained high in 2003 and 2004, mainly due to increased angling success rate after BL‐CR introduction.     

黏蛋白阿克曼菌辅助治疗恶性肿瘤的研究进展

恶性肿瘤是威胁人类健康的全球重大公共卫生问题,多种方法联合,特别是以靶向治疗联合免疫治疗为主的治疗手段,在一定程度延缓了恶性肿瘤的发展,提高了患者的近期生存率,但这些治疗方法并不能覆盖所有患者,远期疗效仍然有限。因此,如何提高患者的生存质量和远期生存率,降低死亡率,成为当前亟待解决的关键问题。近年来越来越多的研究显示肠道微生物的分布与恶性肿瘤的发生、发展密切相关,或可成为治疗恶性肿瘤的新辅助方法,特别是嗜黏蛋白阿克曼菌（Akkermansia muciniphila）的报道较多,然而,关于该菌在恶性肿瘤辅助治疗中安全性和有效性的文献报道尚不多见。因此,本文旨在通过收集近年来嗜黏蛋白阿克曼菌在恶性肿瘤方面的文献,将其研究成果和应用结果进行归纳、分析,以期为临床综合治疗提供一定的药物选择。     

What constitutes fair shared decision-making in global health research collaborations?

Funders (located primarily in high-income countries) and high-income country researchers have historically dominated decision-making within global health research collaborations: from setting agendas and research design to determining how data are collected and analysed and what happens with findings and outputs. The ethical principle of shared decision-making has been proposed as a way to help address these imbalances within collaborations and to reduce semicolonial and exploitative forms of global health research. It is important to be clear about what shared decision-making means in order to ensure that it is not done in a tokenistic, shallow way. Thus far, the principle’s content has not been examined and articulated in detail. This paper aims to start the process of delineating a concept of fair shared decision-making as a minimum standard for global health research. Using two hypothetical case examples, the paper will demonstrate that global health research practice is often inconsistent with ideal shared decision-making. In such instances, it can be difficult to decide whether shared decision-making within collaborations is fair. The paper describes how the two cases do not meet criteria for unfair or non-ideal shared decision-making, despite having potentially morally troubling features. The nuances of these examples of research practice help to generate clearer ideas about how to judge fairness in shared decision-making. The paper concludes by presenting ideas about when soft power can be fairly employed between high-income-country and low- and middle-income-country partners and what fair compromise agreements may look like in shared decision-making.     

Tuning the mechanical stability of fibronectin type III modules through sequence variations

Cells can switch the functional states of extracellular matrix proteins by stretching them while exerting mechanical force. Using steered molecular dynamics, we investigated how the mechanical stability of FnIII modules from the cell adhesion protein fibronectin is affected by natural variations in their amino acid sequences. Despite remarkably similar tertiary structures, FnIII modules share low sequence homology. Conversely, the sequence homology for the same FnIII module across multiple species is notably higher, suggesting that sequence variability is functionally significant. Our studies find that the mechanical stability of FnIII modules can be tuned through substitutions of just a few key amino acids by altering access of water molecules to hydrogen bonds that break early in the unfolding pathway. Furthermore, the FnIII hierarchy of mechanical unfolding can be changed by environmental conditions, such as pH for FnIII10, or by forming complexes with other molecules, such as heparin binding to FnIII13.     

Olfactory Sex Attraction and Mating Behaviour in the Pine Sawyer Monochamus galloprovincialis (Coleoptera: Cerambycidae)

The pine sawyer Monochamus galloprovincialis Olivier (Coleoptera: Cerambycidae) is a vector of the pine wood nematode Bursaphelenchus xylophilus (Steiner and Buhrer) Nickle. Male and females of this species have a kairomonal attraction to host volatiles and Ips semiochemicals. Once on the host tree, males and females copulate and oviposition occurs. Bioassays using Y-tube olfactometry revealed that females were attracted to volatile compounds produced by males, but not to volatiles produced by females. However, immature males did not seem to release attractants for mature females and immature females did not show any attraction for mature males. A experiment designed to know about mating behaviour in this specie revealed that most of the males encountered females while they were walking. In all pairs both sexes contacted with antennae before copulation, however, in some occasions copulation did not proceed just after antennal contact. On the contrary, in all pairs observed, the male licked the elytra of the female with his mouth palpi just before copulation (licking); immediately afterwards, the male grabbed the female with his forelegs and mounted her suggesting a chemically mediated mate recognition by males.     

Doctors' experience with handheld computers in clinical practice: qualitative study

Objective To examine doctors'' perspectives about their experiences with handheld computers in clinical practice.Design Qualitative study of eight focus groups consisting of doctors with diverse training and practice patterns.Setting Six practice settings across the United States and two additional focus group sessions held at a national meeting of general internists.Participants 54 doctors who did or did not use handheld computers.Results Doctors who used handheld computers in clinical practice seemed generally satisfied with them and reported diverse patterns of use. Users perceived that the devices helped them increase productivity and improve patient care. Barriers to use concerned the device itself and personal and perceptual constraints, with perceptual factors such as comfort with technology, preference for paper, and the impression that the devices are not easy to use somewhat difficult to overcome. Participants suggested that organisations can help promote handheld computers by providing advice on purchase, usage, training, and user support. Participants expressed concern about reliability and security of the device but were particularly concerned about dependency on the device and over-reliance as a substitute for clinical thinking.Conclusions Doctors expect handheld computers to become more useful, and most seem interested in leveraging (getting the most value from) their use. Key opportunities with handheld computers included their use as a stepping stone to build doctors'' comfort with other information technology and ehealth initiatives and providing point of care support that helps improve patient care.     

Is Rukun Dead? Ethnographic Interpretations of Social Change and Javanese Culture

Within the ethnography of Indonesia in general and Java in particular, the Javanese notion of rukun, the appearance of harmony and helpfulness, has frequently been interpreted as referring not only to social harmony, but also to economic egalitarianism. Hence ‘traditional’ Javanese economic practices such as open harvests, the distribution of harvest shares and the use of the finger-knife in rice harvesting have been seen as explicable by reference to rukun. Changes in harvesting practices with the introduction of ‘modern’ techniques, such as the use of contract labourers, have been depicted as signalling the death of rukun, both as an economic practice and as a cultural value. This article argues that such a view of social change in Java is theoretically and empirically flawed. Rukun is not a practice but rather a central ideological concept through which Javanese contextualise and apprehend their lives, their aspirations, their motivations and their social relations. In this sense, the ‘traditional’ notion of rukun is equally applicable to contemporary Java, and contemporary Javanese are just as likely to interpret the ‘modern’ world in terms of rukun.     

基于分子和形态学证据确定传统中药白花蛇舌草及其替代品的学名(英文)

白花蛇舌草是我国重要的传统中药,主要是指茜草科(Rubiaceae)钮扣草族(Spermacoceae)的Oldenlandia diffusa,但伞房花耳草(O.corymbosa)在民间或中药市场也常被作为替代品使用。由于长期以来Hedyotis-Oldenlandia复合群的分类存在许多争论,因此白花蛇舌草有时被归入非洲耳草属(Oldenlandia L.),有时又作为广义耳草属(Hedyotis L.s.l.)的成员。为了澄清白花蛇舌草命名上的问题,基于7个叶绿体片段和2个核基因片段对钮扣草族85个分类群进行了系统发育分析。结果表明,白花蛇舌草不属于以上两属中的任何一属,而应为蛇舌草属[Scleromitrion(WightArn.)Meisn.]的成员。依此结果,对5种植物进行了新组合,并提供了白花蛇舌草和伞房花耳草的形态学比较,以有助于在实践中更好地进行区分。     

A steered molecular dynamics method with direction optimization and its applications on ligand molecule dissociation

In this paper, a steered molecular dynamics method with pulling direction optimization is proposed to dissociate ligand molecule from receptor. A multi-population genetic algorithm based on the information entropy is developed to search the optimal pulling direction. By imposing an optimization phase in the conventional steered molecular dynamics simulation, a better substrate-exit channel for the buried active site can be found. The novel simulation method has been used to dissociate the substrate-bound complex structure of cytochrome P450 3A4-metyrapone. The results show that the new pathway obtained by the proposed method has advantages such as lower energy barrier, less dissociation time and shorter motion trajectory than that by the conventional steered molecular dynamics.     

Learning from the voiceless

This article is concerned with understanding what is at stake in the everyday lives of family members facing Huntington's Disease (HD). The methodological and analytical point of departure is German critical psychology, particularly the category of conduct of everyday life (Holzkamp, 1995; Dreier, 1999). Specifically, I address questions of accessing and understanding the conduct of everyday life of persons facing HD who are not visibly visibly active with respect to this circumstance. The question of access is not merely about getting in touch with persons who are not known to the research, professional and HD communities, but also about the consequences of establishing contact with persons who have not made an entry onto any of these public areanas themselves. The question of understanding is about developing an analysis from a first-person perspective on the personal conduct of everyday life that is not visibly active. The development of such an understanding has broader implications, not just for further research and health care practices, but importantly also for the prevailing moral and ethical demands made on persons living at risk of hereditary diseases.     

Effects of moth size on velocity and steering during upwind flight toward a sex pheromone source byLymantria dispar (Lepidoptera: Lymantriidae)

Free-flying male gypsy moths (Lymantria dispar)head upwind in response to sex pheromone. Males typically fly in a zigzag path, with mean ground speeds modulated by pheromone concentration and ambient temperature, but not by wind speed. We studied the effect of male size on ground speeds and additional flight track parameters. Mean net ground speed along the wind line was fastest among large males and was slower in medium and small males. Similarly, mean airspeeds and ground speeds along the flight tracks increased from small to large males. Males from all three size classes steered similar mean course angles. Small males, however, had larger mean track angles than larger males, and mean drift angles were also larger for small males. Turning rates (frequency of turns across the wind line) and interturn distances (net crosswind displacement between turn apices) were not significantly different among the three size classes; however, large males had a trend toward a reduced mean turning rate and increased mean interturn distance. The steering of similar course angles by males from all three size classes and the higher airspeeds among larger males (the two variables males can actively control during free flight) suggest that changes in other flight parameters are a result primarily of increased ground speed among large males.     

Glomerulosomes: morphologically distinct nuclear organelles of unknown nature

The nucleus of some representatives of the genus Pelomyxa (Amoebozoa, Archamoebae, Pelobiontida) contains specific bodies (membrane-less organelles). They may be either embedded in the nucleolar mass or detached from the nucleolus. We termed these nuclear bodies the glomerulosomes for their characteristic ultrastructural appearance. The glomerulosomes are distinct nuclear bodies, about 1 μm in diameter. The morphological and diagnostic unit of a glomerulosome is an electron-dense thread/string, about 30–40 nm in thickness. These threads are not direct continuation of the nucleolar material. The threads create the unique geometric appearance of the glomerulosome by being organized into precisely parallel rows/cords. Each cord of the threads can curve at different angles within the glomerulosome body, but the threads themselves are not coiled. Nowadays, the glomerulosomes have been discovered in P. palustris, P. stagnalis, P. paradoxa, and Pelomyxa sp. Despite the unique appearance of glomerulosomes, their existence may be a more common phenomenon in eukaryotic cells than just a specific feature of the nucleus of elected pelomyxes.

     

Use of Long-Term Stored Vector Information in the Neotropical Ant <Emphasis Type="BoldItalic">Gigantiops destructor</Emphasis>

We investigated how the formicine ant Gigantiops destructor can use vector information to navigate within the cluttered environment of the rain forest. Displaced foragers use skylight information to move in the theoretical feeder-to-nest direction, whether they are prevented from updating their path-integrator during foraging or captured at the departure from their nest, i.e. with a current accumulator state very close to zero. Only ants that have collected food are able to download a long-term stored reference vector pointing in the nest direction, irrespective of the current accumulator state of their path-integrator stored in a working memory and independent of familiar landmarks. Depending on the release sites, ants that became lost at a maximum distance of 50 cm could still hit and recognize their familiar route, or they engaged in a systematic search for it centered on the release sites. In contrast to Cataglyphis desert ants, Gigantiops ants do not rely primarily on the current accumulator state of their egocentric path integrator. Such a long-term vector-based navigation primed by food capture is well adapted for a tropical ant foraging during periods spanning several hours. This could prevent the numerous cumulative errors in the evaluation of the angles steered that might result from a continuously running path-integrator operating during complex foraging patterns performed at ground or arboreal levels and during passive displacement in response to heavy rain.     

Piecewise All-Atom SMD Simulations Reveal Key Secondary Structures in Luciferase Unfolding Pathway

Although the folding of single-domain proteins is well characterized theoretically and experimentally, the folding of large multidomain proteins is less well known. Firefly luciferase, a 550 residue three-domain protein, has been commonly used as a substrate to study chaperone reactions and as a model system for the study of folding of long polypeptide chains, including related phenomena such as cotranslational folding. Despite being characterized by various experimental techniques, the atomic-level contributions of various secondary structures of luciferase to its fold’s mechanical stability remain unknown. Here, we developed a piecewise approach for all-atom steered molecular dynamics simulations to examine specific secondary structures that resist mechanical unfolding while minimizing the amount of computational resources required by the large water box of standard all-atom steered molecular dynamics simulations. We validated the robustness of this approach with a small NI3C protein and used our approach to elucidate the specific secondary structures that provide the largest contributions to luciferase mechanostability. In doing so, we show that piecewise all-atom steered molecular dynamics simulations can provide novel atomic resolution details regarding mechanostability and can serve as a platform for novel mutagenesis studies as well as a point for comparison with high-resolution force spectroscopy experiments.