Preventive and Curative Medical Interventions.

Medical interventions that cure or prevent medical conditions are central to medicine; and thus, understanding them is central to our understanding of medicine. My purpose in this paper is to explore the conceptual foundations of medicine by providing a singular analysis of the concept of a 'preventive or curative medical intervention'. Borrowing a general account of prevention from Phil Dowe (2000, 2001), I provide an analysis of prevention, cure, risk reduction, and a preventive or curative intervention, before turning to preventive and curative medical interventions. The resulting counterfactual-mechanistic account holds that preventive and curative medical interventions reduce the probability of a medical condition in an actual population compared to their counterfactual omission, commonly by disrupting an etiological or constitutive mechanism for the condition.

What are the COVID-19 models modeling (philosophically speaking)?

COVID-19 epidemic models raise important questions for science and philosophy of science. Here I provide a brief preliminary exploration of three: what kinds of predictions do epidemic models make, are they causal models, and how do different kinds of epidemic models differ in terms of what they represent?

Choosing Words Wisely: Residents' Use of Rhetorical Appeals in Conversations About Unnecessary Tests.

PURPOSE: To characterize how residents employ rhetorical appeals (i.e., the strategic use of communication to achieve specifiable goals) when discussing unnecessary diagnostic tests with patients. METHOD: In 2015, senior hematology residents from 10 Canadian universities participating in a national formative objective structured clinical examination (OSCE) completed a resource stewardship communication station. In this communication scenario, a standardized patient (SP) portrayed a patient requesting unnecessary thrombophilia testing following early pregnancy loss. The authors performed a thematic analysis of audio transcripts using a qualitative description approach to identify residents' rhetorical appeals to logic (rational appeals), credibility, and emotion. RESULTS: For persuasive communication, residents (n = 27) relied primarily on rational appeals that fit into 3 categories (with themes) focused on medical evidence (poor utility, professional guidelines and recommendations), avoidance of harm (insurance implications, unnecessary or potentially harmful interventions, patient anxiety), and reassurance to patient (normalizing, clinical pretest probability, criteria for reconsidering testing). Appeals to credibility and emotion were rarely used. CONCLUSIONS: In an OSCE setting, residents relied predominantly on rational appeals when engaging SPs in conversations about unnecessary tests. These observations yield insights into how recent emphasis within residency education on appropriate test utilization may manifest when residents put recommendations into practice in conversations with patients. This study's framework of rational appeals may be helpful in designing communication curricula about unnecessary testing. Future studies should explore rhetoric about unnecessary testing in the clinical environment, strategies to teach and coach residents leading these conversations, and patients' preferences and responses to different appeals.

The Confounding Question of Confounding Causes in Randomized Trials.

It is sometimes thought that randomized study group allocation is uniquely proficient at producing comparison groups that are evenly balanced for all confounding causes. Philosophers have argued that in real randomized controlled trials this balance assumption typically fails. But is the balance assumption an important ideal? I run a thought experiment, the CONFOUND study, to answer this question. I then suggest a new account of causal inference in ideal and real comparative group studies that helps clarify the roles of confounding variables and randomization. 1Confounders and Causes2The Balance Assumption3The CONFOUND Study 3.1CONFOUND 13.2CONFOUND 24Disjunction C and the Ideal Study 4.1The ultimate 'other cause': C4.2The ideal comparative group study4.3Required conditions for causal inference5Confounders as Causes, Confounders as Correlates6Summary.

Universal etiology, multifactorial diseases and the constitutive model of disease classification.

Infectious diseases are often said to have a universal etiology, while chronic and noncommunicable diseases are said to be multifactorial in their etiology. It has been argued that the universal etiology of an infectious disease results from its classification using a monocausal disease model. In this article, I will reconstruct the monocausal model and argue that modern 'multifactorial diseases' are not monocausal by definition. 'Multifactorial diseases' are instead defined according to a constitutive disease model. On closer analysis, infectious diseases are also defined using the constitutive model rather than the monocausal model. As a result, our classification models alone cannot explain why infectious diseases have a universal etiology while chronic and noncommunicable diseases lack one. The explanation is instead provided by the Nineteenth Century germ theorists.

Reasoning, evidence, and clinical decision-making: The great debate moves forward.

When the editorial to the first philosophy thematic edition of this journal was published in 2010, critical questioning of underlying assumptions, regarding such crucial issues as clinical decision making, practical reasoning, and the nature of evidence in health care, was still derided by some prominent contributors to the literature on medical practice. Things have changed dramatically. Far from being derided or dismissed as a distraction from practical concerns, the discussion of such fundamental questions, and their implications for matters of practical import, is currently the preoccupation of some of the most influential and insightful contributors to the on-going evidence-based medicine debate. Discussions focus on practical wisdom, evidence, and value and the relationship between rationality and context. In the debate about clinical practice, we are going to have to be more explicit and rigorous in future in developing and defending our views about what is valuable in human life.

Results of the Scoliosis Research Society Morbidity and Mortality Database 2009-2012: A Report From the Morbidity and Mortality Committee.

INTRODUCTION: Members of the Scoliosis Research Society are required to annually submit complication data regarding deaths, visual acuity loss, neurological deficit and infection (2012-1st year for this measure) for all deformity operations performed. The purpose of this study is to report the 2012 results and the differences in these complications from the years 2009-2012. METHODS: The SRS M&M database is a self-reported complications registry of deformity operations performed by the members. The data from 2009-2012, inclusive, was tabulated and analyzed. Differences in frequency distribution between years were analyzed with Fisher's exact test. Significance was set at α = 0.05. RESULTS: The total number of cases reported increased from 34,332 in 2009 to 47,755 in 2012. Overall mortality ranged from 0.07% in 2011 to 0.12% in 2009. The neuromuscular scoliosis group had the highest mortality rate (0.44%) in 2010. The combined groups' neurological deficit rate increased from 0.44% in 2009 to 0.79% in 2012. Neurological deficits were significantly lower in 2009 compared to 2012 for idiopathic scoliosis >18 years, other scoliosis, degenerative and isthmic spondylolisthesis and other groups. The groups with the highest neurological deficit rates were dysplastic spondylolisthesis and congenital kyphosis. There were no differences in vision loss rates between years. The overall 2012 infection rate was 1.14% with neuromuscular scoliosis having the highest group rate at 2.97%. CONCLUSION: Neuromuscular scoliosis has the highest complication rates of mortality and infection. The neurological deficit rates of all groups combined have slightly increased from 2009 to 2012 with the highest rates consistently being in the dysplastic spondylolisthesis and congenital kyphosis groups. This could be due to a number of factors, including more rigorous reporting.

Theory, experience and practice.

Despite its potential hazards, the activity of questioning theoretical frameworks and proposing solutions is necessary if progress is even to be possible. Intellectual history has by no means ended, so we cannot expect to have all the answers, and from time to time the activity of critical questioning will be frustrating. But intellectual progress requires us to continue the process of asking fundamental questions. The alternative to thinking in this way is indeed unthinkable.

Protein Binding Pocket Dynamics.

The dynamics of protein binding pockets are crucial for their interaction specificity. Structural flexibility allows proteins to adapt to their individual molecular binding partners and facilitates the binding process. This implies the necessity to consider protein internal motion in determining and predicting binding properties and in designing new binders. Although accounting for protein dynamics presents a challenge for computational approaches, it expands the structural and physicochemical space for compound design and thus offers the prospect of improved binding specificity and selectivity. A cavity on the surface or in the interior of a protein that possesses suitable properties for binding a ligand is usually referred to as a binding pocket. The set of amino acid residues around a binding pocket determines its physicochemical characteristics and, together with its shape and location in a protein, defines its functionality. Residues outside the binding site can also have a long-range effect on the properties of the binding pocket. Cavities with similar functionalities are often conserved across protein families. For example, enzyme active sites are usually concave surfaces that present amino acid residues in a suitable configuration for binding low molecular weight compounds. Macromolecular binding pockets, on the other hand, are located on the protein surface and are often shallower. The mobility of proteins allows the opening, closing, and adaptation of binding pockets to regulate binding processes and specific protein functionalities. For example, channels and tunnels can exist permanently or transiently to transport compounds to and from a binding site. The influence of protein flexibility on binding pockets can vary from small changes to an already existent pocket to the formation of a completely new pocket. Here, we review recent developments in computational methods to detect and define binding pockets and to study pocket dynamics. We introduce five different classes of protein pocket dynamics: (1) appearance/disappearance of a subpocket in an existing pocket; (2) appearance/disappearance of an adjacent pocket on the protein surface in the direct vicinity of an already existing pocket; (3) pocket breathing, which may be caused by side-chain fluctuations or backbone or interdomain vibrational motion; (4) opening/closing of a channel or tunnel, connecting a pocket inside the protein with solvent, including lid motion; and (5) the appearance/disappearance of an allosteric pocket at a site on a protein distinct from an already existing pocket with binding of a ligand to the allosteric binding site affecting the original pocket. We suggest that the class of pocket dynamics, as well as the type and extent of protein motion affecting the binding pocket, should be factors considered in choosing the most appropriate computational approach to study a given binding pocket. Furthermore, we examine the relationship between pocket dynamics classes and induced fit, conformational selection, and gating models of ligand binding on binding kinetics and thermodynamics. We discuss the implications of protein binding pocket dynamics for drug design and conclude with potential future directions for computational analysis of protein binding pocket dynamics.

The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration.

The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. Here we show that natural killer cell-derived HMGB1 directly eliminates cancer cells by triggering metabolic cell death. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, thus blocking glucose-driven aerobic respiration. This results in a rapid metabolic shift forcing cells to rely solely on glycolysis for the maintenance of energy production. Cancer cells can acquire resistance to HMGB1 by increasing glycolysis using the dimeric form of PKM2, and employing glutaminolysis. Consistently, we observe an increase in the expression of a key enzyme of glutaminolysis, malic enzyme 1, in advanced colon cancer. Moreover, pharmaceutical inhibition of glutaminolysis sensitizes tumour cells to HMGB1 providing a basis for a therapeutic strategy for treating cancer.

The ins and outs of breath holding: simple demonstrations of complex respiratory physiology.

The physiology of breath holding is complex, and voluntary breath-hold duration is affected by many factors, including practice, psychology, respiratory chemoreflexes, and lung stretch. In this activity, we outline a number of simple laboratory activities or classroom demonstrations that illustrate the complexity of the integrative physiology behind breath-hold duration. These activities require minimal equipment and are easily adapted to small-group demonstrations or a larger-group inquiry format where students can design a protocol and collect and analyze data from their classmates. Specifically, breath-hold duration is measured during a number of maneuvers, including after end expiration, end inspiration, voluntary prior hyperventilation, and inspired hyperoxia. Further activities illustrate the potential contribution of chemoreflexes through rebreathing and repeated rebreathing after a maximum breath hold. The outcome measures resulting from each intervention are easily visualized and plotted and can comprise a comprehensive data set to illustrate and discuss complex and integrated cardiorespiratory physiology.