Observations during development of an internal medicine residency training program in cardiovascular limited ultrasound examination.

Background: Despite the future potential of using ultrasound stethoscopes to augment the bedside cardiac physical, few data exist on a general cardiovascular imaging protocol that can be taught to physicians on a perpetual basis as a curriculum in graduate medical education.

Methods: During the past decade, we developed and integrated a cardiovascular limited ultrasound training program within the confines of an internal medicine residency. The evidence-based rationale for the exam, the teaching methods, and curriculum are delineated, and subsequent observations regarding program requirements, proficiency, and academic outcomes are explored.

Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.

The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder.

Biomolecular simulation: a computational microscope for molecular biology.

Molecular dynamics simulations capture the behavior of biological macromolecules in full atomic detail, but their computational demands, combined with the challenge of appropriately modeling the relevant physics, have historically restricted their length and accuracy. Dramatic recent improvements in achievable simulation speed and the underlying physical models have enabled atomic-level simulations on timescales as long as milliseconds that capture key biochemical processes such as protein folding, drug binding, membrane transport, and the conformational changes critical to protein function. Such simulation may serve as a computational microscope, revealing biomolecular mechanisms at spatial and temporal scales that are difficult to observe experimentally.

Preliminary examination of the reliability and concurrent validity of the attention-deficit/hyperactivity disorder self-report scale v1.1 symptom checklist to rate symptoms of attention-deficit/hyperactivity disorder in adolescents.

Objective: To validate the attention-deficit/hyperactivity disorder (ADHD) Self-Report Scale (ASRS) v1.1 Symptom Checklist versus the clinician-administered ADHD Rating Scale (ADHD-RS) in adolescents with ADHD.

Method: A total of 88 adolescents with ADHD aged 13-17 years participated in the study.

Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and D-cycloserine.

Rationale And Objective: Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, D: -cycloserine (DCS), in C57BL/6 mice were compared.

Materials And Methods: Following a palatability test (Experiment 1), Experiments 2-6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined.

Reducing the harmful effects of alcohol misuse: the ethics of sobriety testing in criminal justice.

Alcohol use and abuse play a major role in both crime and negative health outcomes in Scotland. This paper provides a description and ethical and legal analyses of a novel remote alcohol monitoring scheme for offenders which seeks to reduce alcohol-related harm to both the criminal and the public. It emerges that the prospective benefits of this scheme to health and public order vastly outweigh any potential harms.

Refinement of protein structure homology models via long, all-atom molecular dynamics simulations.

Accurate computational prediction of protein structure represents a longstanding challenge in molecular biology and structure-based drug design. Although homology modeling techniques are widely used to produce low-resolution models, refining these models to high resolution has proven difficult. With long enough simulations and sufficiently accurate force fields, molecular dynamics (MD) simulations should in principle allow such refinement, but efforts to refine homology models using MD have for the most part yielded disappointing results.

Ethicovigilance in clinical trials.

This article provides an ethical critique of the Good Clinical Practice (GCP) and Declaration of Helsinki (DoH) documents. While the previous criticisms of GCP are entirely correct, there is much more wrong with the document than has previously been acknowledged, including a circular definition and an astonishing vagueness about ethical principles. In addition to its failure to provide adequate ethical protection of participants, the procedurally dense nature of GCP lends itself to a box-ticking culture where important ethical issues are overlooked because they are not 'mentioned on the form'.

Mechanism of voltage gating in potassium channels.

The mechanism of ion channel voltage gating-how channels open and close in response to voltage changes-has been debated since Hodgkin and Huxley's seminal discovery that the crux of nerve conduction is ion flow across cellular membranes. Using all-atom molecular dynamics simulations, we show how a voltage-gated potassium channel (KV) switches between activated and deactivated states. On deactivation, pore hydrophobic collapse rapidly halts ion flow.

Systematic validation of protein force fields against experimental data.

Molecular dynamics simulations provide a vehicle for capturing the structures, motions, and interactions of biological macromolecules in full atomic detail. The accuracy of such simulations, however, is critically dependent on the force field--the mathematical model used to approximate the atomic-level forces acting on the simulated molecular system. Here we present a systematic and extensive evaluation of eight different protein force fields based on comparisons of experimental data with molecular dynamics simulations that reach a previously inaccessible timescale.

Structure and dynamics of the M3 muscarinic acetylcholine receptor.

Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences.

Structure and dynamics of an unfolded protein examined by molecular dynamics simulation.

The accurate characterization of the structure and dynamics of proteins in disordered states is a difficult problem at the frontier of structural biology whose solution promises to further our understanding of protein folding and intrinsically disordered proteins. Molecular dynamics (MD) simulations have added considerably to our understanding of folded proteins, but the accuracy with which the force fields used in such simulations can describe disordered proteins is unclear. In this work, using a modern force field, we performed a 200 μs unrestrained MD simulation of the acid-unfolded state of an experimentally well-characterized protein, ACBP, to explore the extent to which state-of-the-art simulation can describe the structural and dynamical features of a disordered protein.

Improving Sampling by Exchanging Hamiltonians with Efficiently Configured Nonequilibrium Simulations.

Molecular simulations aim to sample all of the thermodynamically important states; when the sampling is inadequate, inaccuracy follows. A widely used technique to enhance sampling in simulations is Hamiltonian exchange. This technique introduces auxiliary Hamiltonians under which sampling is computationally efficient and attempts to exchange the molecular states among the auxiliary and the original Hamiltonians.

"We are what we eat!" Invasive intestinal mucormycosis: A case report and review of the literature.

Gastrointestinal mucormycosis is an uncommon, life-threatening, angioinvasive infection with only one previous report of disease involving the jejunum. We present a case of invasive jejunal mucormycosis and review the literature, highlighting the rare clinical presentation and the value of molecular diagnostic methods. Given the global increase in patient populations at risk of mucormycosis, clinicians need to maintain a high index of suspicion and perform timely and appropriate evaluation to improve patient outcome.

Place visualization: conventional or unconventional practice?

This paper explores the traditional notion that two discrete forms of medicine exist. One being bio-medically led, the other being holistic in origin. A qualitative study of place visualization in nursing is used to illustrate how health care may not always fit neatly into one of these paradigms.

The future of molecular dynamics simulations in drug discovery.

Molecular dynamics simulations can now track rapid processes--those occurring in less than about a millisecond--at atomic resolution for many biologically relevant systems. These simulations appear poised to exert a significant impact on how new drugs are found, perhaps even transforming the very process of drug discovery. We predict here future results we can expect from, and enhancements we need to make in, molecular dynamics simulations over the coming 25 years, and in so doing set out several Grand Challenges for the field.

Results of accelerated postoperative rehabilitation using novel "suture frame" repair of Achilles tendon rupture.

The management of Achilles tendon rupture is a much-debated subject. In recent years, there has been much interest in early postoperative mobilization. We present the results of our Achilles tendon repair technique and accelerated rehabilitation program.

Staff and students' perceptions and experiences of teaching and assessment in Clinical Skills Laboratories: interview findings from a multiple case study.

Background: The Clinical Skills Laboratory has become an essential structure in nurse education and several benefits of its use have been identified. However, the literature identifies the need to examine the transferability of skills learned there into the reality of practice.

Objective: This research explored the role of the Clinical Skills Laboratory in preparing nursing students for the real world of practice.

How fast-folding proteins fold.

An outstanding challenge in the field of molecular biology has been to understand the process by which proteins fold into their characteristic three-dimensional structures. Here, we report the results of atomic-level molecular dynamics simulations, over periods ranging between 100 μs and 1 ms, that reveal a set of common principles underlying the folding of 12 structurally diverse proteins. In simulations conducted with a single physics-based energy function, the proteins, representing all three major structural classes, spontaneously and repeatedly fold to their experimentally determined native structures.

Activation mechanism of the β2-adrenergic receptor.

A third of marketed drugs act by binding to a G-protein-coupled receptor (GPCR) and either triggering or preventing receptor activation. Although recent crystal structures have provided snapshots of both active and inactive functional states of GPCRs, these structures do not reveal the mechanism by which GPCRs transition between these states. Here we propose an activation mechanism for the β(2)-adrenergic receptor, a prototypical GPCR, based on atomic-level simulations in which an agonist-bound receptor transitions spontaneously from the active to the inactive crystallographically observed conformation.

Priming effect of dengue and yellow fever vaccination on the immunogenicity, infectivity, and safety of a tetravalent dengue vaccine in humans.

A dengue vaccine effective against all four serotypes is urgently needed. However, safety and immunogenicity could be affected by prior exposure to flaviviruses. This open, controlled, phase IIa study was conducted in 35 healthy adults who had received monovalent, live attenuated Vero cell-derived dengue vaccine against dengue virus 1 (VDV1) or 2 (VDV2) or yellow fever (YF) vaccine 1 year before or who were flavivirus-naïve.

Medication adherence and symptom reduction in adults treated with mixed amphetamine salts in a randomized crossover study.

Objectives: The study objectives were to 1) evaluate medication adherence for adults with attention-deficit/hyperactivity disorder (ADHD) treated with 3 times daily (TID) mixed amphetamine salts immediate release (MAS IR) versus once-daily (qAM) MAS extended release (MAS XR) in a randomized, crossover study; and 2) to examine the associations between adherence and efficacy for MAS IR and MAS XR.

Methods: Sixty-two adults with ADHD were enrolled and 49 completed the study. The treatment condition order (TID-qAM or qAM-TID) was counterbalanced across participants, with an intervening washout period of ≥ 7 days.

Preliminary reliability and validity of a new time-sensitive ADHD symptom scale in adolescents with ADHD.

Objectives: To validate the Time-Sensitive ADHD Symptom Scale (TASS) in the assessment of symptom change during the day in adolescents with attention-deficit/hyperactivity disorder (ADHD).

Methods: A total of 40 participants with ADHD aged 13 to 17 years completed 1 or 2 visits, 1 to 9 weeks apart. The TASS and the ADHD Rating Scale-IV (ADHD-RS-IV) were completed twice at each visit: at the time of the clinic visit (in-clinic assessment) and 2 to 6 hours afterwards (evening assessment).