Force-Field-Dependent DNA Breathing Dynamics: A Case Study of Hoogsteen Base Pairing in A6-DNA.

The Hoogsteen (HG) base pairing conformation, commonly observed in damaged and mutated DNA helices, facilitates DNA repair and DNA recognition. The free energy difference between HG and Watson-Crick (WC) base pairs has been computed in previous studies. However, the mechanism of the conformational transition is not well understood. A detailed understanding of the process of WC to HG base pair transition can provide a deeper understanding of DNA repair and recognition. In an earlier study, we explored the free energy landscape for this process using extensive computer simulation with the CHARMM36 force field. In this work, we study the impact of force field models in describing the WC to HG base pairing transition using meta-eABF enhanced sampling, quasi-harmonic entropy calculation, and nonbonded energy analysis. The secondary structures of both base pairing forms and the topology of the free energy landscapes were consistent over different force field models, although the relative free energy, entropy, and the interaction energies tend to vary. The relative stability of the WC and HG conformations is dictated by a delicate balance between the enthalpic stabilization and the reduced entropy of the structurally rigid HG structure. These findings highlight the impact that subtleties in force field models can have on accurately modeling DNA base pair dynamics and should stimulate further computational investigations into other dynamically important motions in DNA.

Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories.

We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays a weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-time-scale biomolecular processes from short atomistic molecular dynamics simulations. M-WEM is tested on the Müller-Brown potential model, the conformational switching in alanine dipeptide, and the millisecond time-scale protein-ligand unbinding in a trypsin-benzamidine complex. Not only can M-WEM predict the kinetics of these processes with quantitative accuracy but it also allows for a scheme to reconstruct a multidimensional free-energy landscape along additional degrees of freedom, which are not part of the milestoning progress coordinate. For the ligand-receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM within a simulation time of a few hundreds of nanoseconds, which is a fraction of the computational cost of other currently available methods, and close to 4 orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost, the M-WEM approach can find potential applications in kinetics and free-energy-based computational drug design.

Directions for advancing the study of work transitions in the 21st century.

OBJECTIVES: The purpose of this article is to share the details, outcomes and deliverables from an international workshop on work transitions in London, Ontario, Canada. PARTICIPANTS: Researchers, graduate students, and community group members met to identity ways to advance the knowledge base of strategies to enhance work participation for those in the most disadvantaged groups within society. METHODS: A participatory approach was used in this workshop with presentations by researchers and graduate students. This approach included dialogue and discussion with community members. In addition, small group dialogue and debate, world cafe discussions, written summaries of group discussion and reflection boards were used to bring new ideas to the discussion and to build upon what we know. FINDINGS: Two research imperatives and six research recommendations were identified to advance global dialogue on work transitions and to advance the knowledge base. Occupational justice can be used to support future research directions in the study of work transitions. CONCLUSIONS: Moving forward requires a commitment of community of researchers, clinicians and stakeholders to address work disparities and implement solutions to promote participation in work.

Remote participants' experiences with a group-based stroke self-management program using videoconference technology.

INTRODUCTION: Telehealth is an all-inclusive term for the provision of health services using information and communication technology. Videoconference delivery is one form of telehealth whereby a synchronous, two-way audio and visual connection is made between two or more sites. Videoconference is used in remote areas to improve access to healthcare, perform individual clinical assessments and deliver group education. Moving On after Stroke (MOST®) is a group-based, self-management program for stroke survivors and their caregivers, which consists of information sharing, facilitated discussion, goal-setting, and exercise. This program was delivered simultaneously to local participants onsite in Thunder Bay, Canada, and distant participants in smaller, remote communities in Northwestern Ontario using videoconferencing (MOST-Telehealth Remote). The objective of this study was to explore the experiences of remote participants, their perceptions regarding factors that enable or limit videoconference participation, and to obtain suggestions for enhanced delivery of videoconferenced group programs. METHODS: This qualitative study used an interpretive methodology. Semi-structured interviews were conducted in person with remote MOST-Telehealth Remote (MOST-TR) participants within one year post-program. Participants were recruited using purposive sampling and included both male and female stroke survivors and caregivers, those who participated alone and those who participated with others at the remote site. Twenty-seven people were approached, eight declined, and 19 agreed to participate. The average age of participants was 66.2 years (range 48-84). The interviews were transcribed and coded using NVivo v2.0 (www.gsrinternational.com). Data were analyzed for common categories using qualitative descriptive methods. RESULTS: All participants valued access to the program without having to travel long distances. They felt safe in discussions and when exercising with the group across videoconference. Many reported 'feeling as if they were in the same room' but also acknowledged that there were limitations to participating via videoconference. Participants recognized a loss of subtleties in communication and the group facilitators found it difficult to discern whether participants were finding the exercises too difficult or too easy. The videoconference medium also limited participants' ability to privately or informally address concerns. Factors facilitating engagement and participation were similar to factors in face-to-face groups. Additionally, the importance of collaboration with onsite coordinators, volunteers, and other local participants was highlighted. Facilitators have the added responsibility of including all participants more explicitly, especially those offsite. Suggestions to improve group cohesion and participation included a preliminary face-to-face meeting with all participants, implementing technical strategies, and ongoing onsite support. CONCLUSIONS: For MOST-TR participants, videoconference participation was valuable. Addressing the limitations of videoconference connection and enhanced local support may improve the experience for remote participants in small-group, videoconferenced, self-management programs. Using videoconference technology to participate in existing programs greatly increases accessibility for people living in remote areas.

Enabling university teaching for Canadian academics with multiple sclerosis through problem-focused coping.

BACKGROUND: Research shows that sustained employment contributes to a higher quality of life for those with multiple sclerosis (MS). Occupational therapists can work to create therapeutic interventions that assist people with MS with maintaining employment. PURPOSE: To detail the problem-focused coping strategies that academics with MS employ to enable them to teach in universities. METHODS: Semi-structured interviews were conducted with 45 Canadian academics with MS. Thematic analysis was used to generate findings. FINDINGS: While there is flexibility in research and service work tasks, teaching tasks are the most seemingly inflexible. This necessitated the development of problem-focused coping strategies to enable teaching. Three categories of strategies were employed: (1) organizational; (2) before/after teaching; and (3) during teaching. IMPLICATIONS: This brief report is intended to serve as a resource for occupational therapists and others wanting to gain a better understanding of the types of therapeutic interventions useful to those teaching in universities.

Aging with long-term physical impairments: the significance of social support.

This article examines the living situations and access to social support for community-dwelling people between the ages of 50 and 65, and who have lived with significant physical impairment for more than 15 years. Data were gathered through in-depth, semi-structured interviews with eight men and women. Findings suggest that coping with long-term impairment may be a lonely experience when the individual lacks a strong network of family and/or friends to offer emotional support. Participants felt their experiences of aging with significant long-term impairment were improved when they shared thoughts, feelings, and problems with others. Findings also show the significance of gender regarding access to social support and point towards the importance of using subjective understanding when ascertaining the level of social support available to individuals. More generally, findings underscore the broader point that individuals aging with impairments are immersed in and wish to maintain reciprocal relationships.

Patient concerns posthaemorrhagic stroke: a study of the Internet narratives of patients with ruptured arteriovenous malformation.

AIMS: To identify and describe the experiences and concerns of a sample of young haemorrhagic stroke patients who experienced a ruptured arteriovenous malformation and determine whether there are gender differences. BACKGROUND: Patients with arteriovenous malformation haemorrhage tend to be young adults, but little is known about their experiences and concerns. Some research suggest that there is a need to take gender into account when investigating their experiences and concerns. DESIGN: A content analysis of a sample of narratives posted by survivors of an arteriovenous malformation haemorrhage on an Internet site, to determine the extent to which writers discuss similar concerns and experiences. METHODS: The sample consists of 83 narratives. The author and a research assistant carefully considered the content of each narrative, created categories based upon this reading and then coded men and women's narratives separately, according to the topic discussed. RESULTS: Five main categories of topics were identified: 'symptoms', 'doctors and hospitals', 'rehabilitation and recovery', 'disabilities' and 'miscellaneous reflections'. The latter category contained the sub-categories 'arteriovenous malformation website', 'thanks', 'life now' and 'feelings'. Narratives varied greatly regarding how much each topic was addressed, but there were few gender differences. Overall, most attention was paid to discussing doctors and hospitals and most writers also paid significant attention to the importance of being able to share experiences with other survivors. CONCLUSIONS: For these narrators, the experience of being evaluated and treated for arteriovenous malformation haemorrhage is traumatic, leaves a lasting impact and men and women share similar concerns and experiences. Narrators show a need to talk about their experiences, especially with others who may share similar experiences. RELEVANCE TO CLINICAL PRACTICE: Knowing the concerns and perspectives of a sample of arteriovenous malformation patients may help nurses anticipate the concerns of their own haemorrhagic stroke patients and help improve patients' psychosocial well-being.

Accelerated closure of biopsy-type wounds by mechanical stimulation.

OBJECTIVE: To determine whether a device designed to provide low-intensity, low-frequency mechanical stimulation improves healing time of acute wounds. DESIGN: Repeated measures using mechanical stimulation on one side of a rat and sham stimulation on the contralateral side. SETTING: Academic animal facility. PARTICIPANTS: Six male Sprague-Dawley rats, approximately 400 g. INTERVENTION: Mechanical stimulation of 4-mm biopsy wounds in rats was produced through the use of permanent magnets cyclically attracted and repelled by activation of an electromagnet by a square wave generator at a frequency of 1 Hz and a force equivalent to 64 mm Hg pressure. MAIN OUTCOME MEASURE: Days to complete closure of 4-mm biopsy punch wounds. MAIN RESULTS: This form of stimulation reduced time to close the biopsy wounds by nearly 50%. Mechanically stimulated wounds closed in 3.8 +/- 1.6 days (mean +/- SD) compared with 6.8 +/- 1.9 days for sham-stimulated wounds (P = .0002). CONCLUSION: Production of a mechanical stimulation device with a miniaturized controller and power source and trials on humans are needed to determine the efficacy and potential cost savings of such a device in the management of wounds.

Reactions to invisible disability: the experiences of young women survivors of hemorrhagic stroke.

PURPOSE: To discuss how young, female and invisibly disabled, long-term survivors of hemorrhagic stroke experience the reactions of others as they negotiate the social environment. METHOD: Open-ended and in-depth interviews were conducted with 22 women to learn about their post-stroke experiences, and the interviews were analyzed for common issues and themes. RESULTS: Participants expressed concerns about the reactions of others in the context of discussing popular understandings about who is affected by stroke, and the significance of having invisible disabilities. Participants' experiences were mediated by the cultural belief that stroke is a disease of old age, and by the belief that disabilities worth taking seriously are readily visible. The existence of these beliefs about stroke and disability made it difficult for participants to deal with the reactions of others. CONCLUSIONS: Participants must negotiate their everyday lives within a social context that they are ill-prepared to deal with. Rehabilitation practices need to take this into account and counsel stroke survivors about what to expect and what they need to do for a good QOL in the community.

Routine sucrose analgesia during the first week of life in neonates younger than 31 weeks' postconceptional age.

OBJECTIVE: To determine the efficacy of sucrose analgesia for procedural pain during the first week of life in preterm neonates in neonatal intensive care units on enhancing later clinical outcomes. METHODS: A total of 107 preterm neonates who were born at <31 weeks' postconceptional age (PCA) entered this double-blind, randomized, controlled trial within 48 hours of birth at 3 level III university-affiliated neonatal intensive care units in Canada, and 103 completed the study. Sucrose (0.1 mL of 24%) or sterile water was administered orally up to 3 times, 2 minutes apart, for every invasive procedure during a 7-day period. Motor development and vigor, and alertness and orientation components of the Neurobehavioral Assessment of the Preterm Infant were measured at 32, 36, and 40 weeks' PCA; Score for Neonatal Acute Physiology was measured on the last day of intervention; and Neuro-Biological Risk Score (NBRS) was measured at 2 weeks of age and at discharge. Primary analyses of covariance were applied for each outcome to compare group differences followed by secondary analyses using standard linear regression within each group to determine predictors of outcomes. RESULTS: Although there were no differences between the groups on any outcomes, there were significant dose-related effects within each group. In the sucrose group only, higher number of doses of sucrose predicted lower scores on motor development and vigor, and alertness and orientation at 36 weeks', lower motor development and vigor at 40 weeks', and higher NBRS at 2 weeks' postnatal age. Higher number of invasive procedures was predictive of higher NBRS both times in the water group. CONCLUSIONS: Repeated use of sucrose analgesia in infants <31 weeks' PCA may put infants at risk for poorer neurobehavioral development and physiologic outcomes. Additional study is needed to determine the most appropriate age and duration of sucrose analgesia in preterm infants.