MCell4 with BioNetGen: A Monte Carlo simulator of rule-based reaction-diffusion systems with Python interface.

Biochemical signaling pathways in living cells are often highly organized into spatially segregated volumes, membranes, scaffolds, subcellular compartments, and organelles comprising small numbers of interacting molecules. At this level of granularity stochastic behavior dominates, well-mixed continuum approximations based on concentrations break down and a particle-based approach is more accurate and more efficient. We describe and validate a new version of the open-source MCell simulation program (MCell4), which supports generalized 3D Monte Carlo modeling of diffusion and chemical reaction of discrete molecules and macromolecular complexes in solution, on surfaces representing membranes, and combinations thereof. The main improvements in MCell4 compared to the previous versions, MCell3 and MCell3-R, include a Python interface and native BioNetGen reaction language (BNGL) support. MCell4's Python interface opens up completely new possibilities for interfacing with external simulators to allow creation of sophisticated event-driven multiscale/multiphysics simulations. The native BNGL support, implemented through a new open-source library libBNG (also introduced in this paper), provides the capability to run a given BNGL model spatially resolved in MCell4 and, with appropriate simplifying assumptions, also in the BioNetGen simulation environment, greatly accelerating and simplifying model validation and comparison.

Rethinking Substance Use as Social History: Charting a Way Forward.

Physicians have traditionally asked about substance use within the Social History section of the consultation note. Drawing on social science theory and using the authors' own experiences as generalists and addiction scholars, we consider the possible unintended harms associated with this approach. The inclusion of the substance use history within the Social History reproduces the discourse of substance use disorders as "life-style choices" rather than medical conditions, and reinforces stigma among healthcare workers through the attribution of personal responsibility for complications associated with problematic substance use. The ongoing placement of the substance use history within the Social History may lead to a failure to diagnose and make appropriate management plans for clients with substance use disorders. These missed opportunities may include inadequate withdrawal management leading to discharge before medically advised, insufficient use of evidence-based pharmacotherapy and psychotherapy, polypharmacy, medical complications, and repeated admissions to hospital. We argue instead that the Substance Use History should be a stand-alone section within the consultation note. This new section would reduce the invisibility of substance use disorders within our medical systems and model that these chronic medical conditions are amenable to prevention, treatment and harm reduction through the application of evidence-based practices.

Nutrition Interventions on Muscle-Related Components of Sarcopenia in Females: A Systematic Review of Randomized Controlled Trials.

Sarcopenia is a skeletal muscle disease categorized by low muscle strength, muscle quantity or quality, and physical performance. Sarcopenia etiology is multifaceted, and while resistance training is widely agreed upon for prevention and treatment, disease progression is also highly related to poor diet. The incidence of sarcopenia appears sex-specific and may be increased in females, which is problematic because dietary quality is often altered later in life, particularly after menopause. Identifying effective nutrition or supplementation interventions could be an important strategy to delay sarcopenia and related comorbidities in this vulnerable population. This systematic review examined randomized controlled trials (RCTs) of nutrition strategies on muscle-related components of sarcopenia in middle-aged and older females. A protocol was registered (PROSPERO CRD42022382943) and a systematic search of MEDLINE and CINAHL was undertaken. RCTs from 2013 to 2023 that assessed nutrition-only interventions on muscle mass, muscle strength, and physical function in female participants were included. Fourteen RCTs were included based on selection criteria. Study designs and interventions were heterogeneous in supplementation type and amount, age, and duration. Six RCTs reported beneficial effects of protein, Vitamin D, Vitamin D and Magnesium (Mg), and fish oil on muscle protein synthesis, muscle strength, and/or muscle function. Eight studies that examined various protein interventions, VitD alone, Mg alone, and dairy derivatives did not demonstrate any effect. Exercise appeared to modulate results in several studies. Nutrition interventions alone are likely to have a limited but positive effect on muscle-related components of sarcopenia in females. Current evidence suggests that a combination of dietary intervention and exercise is likely to be key to preventing and treating sarcopenia in middle aged and older females and there is a need for well-designed nutrition based studies in this population.

Characterizing Use of Supervised Consumption Services among Street-involved Youth and Young Adults in the Context of an Overdose Crisis.

In response to an increase in overdose deaths, there was a rapid scale-up of supervised consumption services (SCS), including federally sanctioned SCS and low-barrier SCS known as overdose prevention sites (OPS), in Vancouver, Canada, beginning in December 2016. However, little is known about the use of such services among adolescents and young adults (AYA) in this context. We therefore sought to characterize factors associated with the use of federally sanctioned SCS and OPS among street-involved AYA who inject drugs in Vancouver during an overdose crisis. From December 2016 to March 2020, data were collected from a prospective cohort of street-involved AYA aged 14 to 26 at baseline. Using multivariable generalized estimating equation analyses, we identified factors associated with recent use of federally sanctioned SCS and OPS, respectively. Among 298 AYA who inject drugs, 172 (57.8%) and 149 (50.0%) reported using federally sanctioned SCS and OPS during the study period, respectively. In multivariable analyses, public injecting, negative police interactions, and residing or spending time ≥ weekly in the Downtown Eastside neighborhood were all positively associated with the use of federally sanctioned SCS and OPS, respectively. Additionally, ≥ daily unregulated opioid use and residential eviction were positively associated with federally sanctioned SCS use, while requiring help injecting was inversely associated. Self-identified female or non-binary gender was also positively associated with OPS use (all p < 0.05). Both federally sanctioned SCS and OPS successfully engaged AYA at heightened risk of adverse health outcomes. However, the lack of accommodation of AYA who require manual assistance with injecting at federally sanctioned SCS may be inhibiting service engagement.

A prospective, controlled multisite trial of yoga in pediatric inflammatory bowel disease.

AIM: To investigate whether a structured yoga program improves health-related quality of life (HRQOL) and self-efficacy in pediatric patients receiving care for inflammatory bowel disease (IBD). METHODS: IBD patients who were 10-17 years old participated in a 12 week, in-person yoga intervention at two clinical sites. Outcomes were measured at time of consent (T0), start of yoga (T1), and completion of yoga (T2) and 3 months after yoga completion (T3) using the IMPACT-III, Pediatric Quality of Life Inventory (PedsQL), and General Self Efficacy (GSE) scales. RESULTS: Seventy-eight patients were enrolled. Fifty-six patients completed nine or more classes. 73.2% had Crohn's disease and 26.8% ulcerative colitis or IBD-unclassified. A significant increase in IMPACT-III was seen from T1 to T3 (mean change of 5.22, SD = 14.33, p = 0.010), in the PedsQL (mean change = 2.3, SD = 10.24, p = 0.050), and GSE (mean change = 1, SD = 3.60, p = 0.046). 85.2% of patients reported yoga helped them to control stress. Long-term data was available for 47 subjects with 31.9% (n = 15) continuing to practice yoga one to 3 years after study completion. CONCLUSION: This structured 12-week yoga program showed significant improvements in HRQOL and general self-efficacy, particularly 3 months after classes were concluded suggesting that yoga's benefits may persist. Yoga is a safe and effective adjunct to standard medical care to improve QOL and self-efficacy in youth with IBD.

Exercise and diet support in breast and prostate cancer survivors: findings from focus groups.

PURPOSE: Cancer survival is improving, making optimal management of long-term treatment-related adverse effects increasingly important. Exercise and a healthy diet are beneficial and regularly recommended in cancer survivorship guidelines; however, few cancer survivors meet these recommendations so there is a need to explore why. This study aimed to understand experiences receiving exercise and diet support among Australian breast and prostate cancer survivors during and following treatment, and to explore what support they would like to receive. METHODS: Adults who completed active treatment for breast or prostate cancer were recruited via a private cancer care centre. Using a qualitative descriptive study design, participants attended in-person focus groups that were recorded, transcribed, then analysed using reflexive thematic analysis. RESULTS: In total, 26 cancer survivors (15 breast, 11 prostate) participated in one of seven focus groups (4 breast, 3 prostate). Two themes were developed: 1) It was just brushed over, and 2) Wanting more. Theme 1 reports that exercise, and especially diet, were rarely discussed. If they were, it was often limited to general recommendations. Theme 2 shows that participants wanted more specific and personalised support, and information about how exercise and/or diet could benefit their cancer treatment. CONCLUSION: Despite strong interest in receiving personalised exercise and diet support, neither are routinely provided to Western Australian breast and prostate cancer survivors. If support was provided, there was inconsistency in the level and type of support provided. These findings identify important gaps in exercise and diet support provision to cancer survivors and will inform future strategies aiming to improve cancer survivorship care.

INCOG 2.0 Guidelines for Cognitive Rehabilitation Following Traumatic Brain Injury, Part IV: Cognitive-Communication and Social Cognition Disorders.

INTRODUCTION: Moderate to severe traumatic brain injury causes significant cognitive impairments, including impairments in social cognition, the ability to recognize others' emotions, and infer others' thoughts. These cognitive impairments can have profound negative effects on communication functions, resulting in a cognitive-communication disorder. Cognitive-communication disorders can significantly limit a person's ability to socialize, work, and study, and thus are critical targets for intervention. This article presents the updated INCOG 2.0 recommendations for management of cognitive-communication disorders. As social cognition is central to cognitive-communication disorders, this update includes interventions for social cognition. METHODS: An expert panel of clinicians/researchers reviewed evidence published since 2014 and developed updated recommendations for interventions for cognitive-communication and social cognition disorders, a decision-making algorithm tool, and an audit tool for review of clinical practice. RESULTS: Since INCOG 2014, there has been significant growth in cognitive-communication interventions and emergence of social cognition rehabilitation research. INCOG 2.0 has 9 recommendations, including 5 updated INCOG 2014 recommendations, and 4 new recommendations addressing cultural competence training, group interventions, telerehabilitation, and management of social cognition disorders. Cognitive-communication disorders should be individualized, goal- and outcome-oriented, and appropriate to the context in which the person lives and incorporate social communication and communication partner training. Group therapy and telerehabilitation are recommended to improve social communication. Augmentative and alternative communication (AAC) should be offered to the person with severe communication disability and their communication partners should also be trained to interact using AAC. Social cognition should be assessed and treated, with a focus on personally relevant contexts and outcomes. CONCLUSIONS: The INCOG 2.0 recommendations reflect new evidence for treatment of cognitive-communication disorders, particularly social interactions, communication partner training, group treatments to improve social communication, and telehealth delivery. Evidence is emerging for the rehabilitation of social cognition; however, the impact on participation outcomes needs further research.

INCOG 2.0 Guidelines for Cognitive Rehabilitation Following Traumatic Brain Injury, Part III: Executive Functions.

INTRODUCTION: Moderate-to-severe traumatic brain injury (MS-TBI) causes debilitating and enduring impairments of executive functioning and self-awareness, which clinicians often find challenging to address. Here, we provide an update to the INCOG 2014 guidelines for the clinical management of these impairments. METHODS: An expert panel of clinicians/researchers (known as INCOG) reviewed evidence published from 2014 and developed updated recommendations for the management of executive functioning and self-awareness post-MS-TBI, as well as a decision-making algorithm, and an audit tool for review of clinical practice. RESULTS: A total of 8 recommendations are provided regarding executive functioning and self-awareness. Since INCOG 2014, 4 new recommendations were made and 4 were modified and updated from previous recommendations. Six recommendations are based on level A evidence, and 2 are based on level C. Recommendations retained from the previous guidelines and updated, where new evidence was available, focus on enhancement of self-awareness (eg, feedback to increase self-monitoring; training with video-feedback), meta-cognitive strategy instruction (eg, goal management training), enhancement of reasoning skills, and group-based treatments. New recommendations addressing music therapy, virtual therapy, telerehabilitation-delivered metacognitive strategies, and caution regarding other group-based telerehabilitation (due to a lack of evidence) have been made. CONCLUSIONS: Effective management of impairments in executive functioning can increase the success and well-being of individuals with MS-TBI in their day-to-day lives. These guidelines provide management recommendations based on the latest evidence, with support for their implementation, and encourage researchers to explore and validate additional factors such as predictors of treatment response.

INCOG 2.0 Guidelines for Cognitive Rehabilitation Following Traumatic Brain Injury, Part V: Memory.

INTRODUCTION: Memory impairments affecting encoding, acquisition, and retrieval of information after moderate-to-severe traumatic brain injury (TBI) have debilitating and enduring functional consequences. The interventional research reviewed primarily focused on mild to severe memory impairments in episodic and prospective memory. As memory is a common focus of cognitive rehabilitation, clinicians should understand and use the latest evidence. Therefore, the INCOG ("International Cognitive") 2014 clinical practice guidelines were updated. METHODS: An expert panel of clinicians/researchers reviewed evidence published since 2014 and developed updated recommendations for intervention for memory impairments post-TBI, a decision-making algorithm, and an audit tool for review of clinical practice. RESULTS: The interventional research approaches for episodic and prospective memory from 2014 are synthesized into 8 recommendations (6 updated and 2 new). Six recommendations are based on level A evidence and 2 on level B. In summary, they include the efficacy of choosing individual or multiple internal compensatory strategies, which can be delivered in a structured or individualized program. Of the external compensatory strategies, which should be the primary strategy for severe memory impairment, electronic reminder systems such as smartphone technology are preferred, with technological advances increasing their viability over traditional systems. Furthermore, microprompting personal digital assistant technology is recommended to cue completion of complex tasks. Memory strategies should be taught using instruction that considers the individual's functional and contextual needs while constraining errors. Memory rehabilitation programs can be delivered in an individualized or mixed format using group instruction. Computer cognitive training should be conducted with therapist guidance. Limited evidence exists to suggest that acetylcholinesterase inhibitors improve memory, so trials should include measures to assess impact. The use of transcranial direct current stimulation (tDCS) is not recommended for memory rehabilitation. CONCLUSION: These recommendations for memory rehabilitation post-TBI reflect the current evidence and highlight the limitations of group instruction with heterogeneous populations of TBI. Further research is needed on the role of medications and tDCS to enhance memory.

Impact of vascular screening interventions on perceived threat, efficacy beliefs and behavioural intentions: a systematic narrative review.

Health-related behaviours contribute to the global burden of cardiovascular disease (CVD). Cardiovascular imaging can be used to screen asymptomatic individuals for increased risk of CVD to enable earlier interventions to promote health-related behaviours to prevent or reduce CVD risk. Some theories of behaviour and behaviour change assume that engagement in a given behaviour is a function of individual threat appraisals, beliefs regarding the performance of behaviour, self-efficacy for performing the desired behaviour and/or dispositions to act (e.g. behavioural intentions). To date, little is known about the impact of cardiovascular imaging interventions on these constructs. This article summarises evidence related to perceived threat, efficacy beliefs, and behavioural intentions after CVD screening. We identified 10 studies (2 RCTs and 8 non-randomised studies, n = 2498) through a combination of screening citations from published systematic reviews and meta-analyses and searching electronic databases. Of these, 7 measured behavioural intentions and perceived susceptibility and 3 measured efficacy beliefs. Findings showed largely encouraging effects of screening interventions on bolstering self-efficacy beliefs and strengthening behavioural intentions. Imaging results that suggest the presence of coronary or carotid artery disease also increased perceived susceptibility to CVD. However, the review also identified some gaps in the literature, such as a lack of guiding theoretical frameworks and assessments of critical determinants of health-related behaviours. By carefully considering the key issues highlighted in this review, we can make significant strides towards reducing CVD risks and improving population health.

This systematic narrative review sought to comprehensively report evidence related to individual responses to cardiovascular screening interventions. Theoretically, the study builds upon theories based on the cognitive perspective (e.g. Health Belief Model, Protection Motivation Theory), which supports the examination of individual perceptions of negative health-related outcomes or health risk, beliefs regarding the performance of a behaviour or outcome expectancies (e.g. perceived benefits of behavioural performance), personal control or capacity to perform a behaviour and/or willingness to invest the effort to engage in behaviour after behavioural intervention delivery. These concepts are considered key predictors of health-related behaviours and have been examined in several public health interventions. Using a variety of search strategies, studies that reported outcomes of interest were identified. Some studies showed that cardiovascular screening interventions may help people form the desired intention to engage in health-related behaviours. We also observed (largely) encouraging effects of cardiovascular screening interventions on individual confidence to engage in health-related behaviours and understanding of personal health risks. However, we identified some limitations in the design, delivery and outcomes assessed in the studies included. For future research, key recommendations to inform the design and delivery of health behaviour interventions are provided.

Room to Improve: An Audit of In-Hospital End-of-Life Care for Oncology Patients in a Tertiary Cancer Centre in Ireland During the COVID-19 Pandemic.

The COVID-19 pandemic compounded isolation for patients through social distancing measures and staff shortages. We were concerned about the impact of COVID-19 on the quality of care provided at end-of-life in 2021 in a national cancer centre, and instigated the first ever review of the care of the dying. Quality of care was assessed retrospectively using a validated instrument developed by the United Kingdom's National Quality Board. Sixty-six patient deaths occurred in our cancer centre in 2021. The 'risk of dying' was documented in 65.2% of records. Palliative care services were involved in 77%, and pastoral care in 10.6%. What was important to the patient was documented in 24.2%. The 'quality-of-death' score was satisfactory for most but poor in 21.2%. Our study prompted change, including appointment of an end-of-life coordinator, development of a checklist to ensure comprehensive communication, expansion of the end-of-life committee to include junior doctors, and regular audit.

Discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain with and without opioid use disorder in British Columbia, Canada: A retrospective cohort study.

BACKGROUND: The overdose crisis in North America has prompted system-level efforts to restrict opioid prescribing for chronic pain. However, little is known about how discontinuing or tapering prescribed opioids for chronic pain shapes overdose risk, including possible differential effects among people with and without concurrent opioid use disorder (OUD). We examined associations between discontinuation and tapering of prescribed opioids and risk of overdose among people on long-term opioid therapy for pain, stratified by diagnosed OUD and prescribed opioid agonist therapy (OAT) status. METHODS AND FINDINGS: For this retrospective cohort study, we used a 20% random sample of residents in the provincial health insurance client roster in British Columbia (BC), Canada, contained in the BC Provincial Overdose Cohort. The study sample included persons aged 14 to 74 years on long-term opioid therapy for pain (≥90 days with ≥90% of days on therapy) between October 2014 and June 2018 (n = 14,037). At baseline, 7,256 (51.7%) persons were female, the median age was 55 years (quartile 1-3: 47-63), 227 (1.6%) persons had been diagnosed with OUD (in the past 3 years) and recently (i.e., in the past 90 days) been prescribed OAT, and 483 (3.4%) had been diagnosed with OUD but not recently prescribed OAT. The median follow-up duration per person was 3.7 years (quartile 1-3: 2.6-4.0). Marginal structural Cox regression with inverse probability of treatment weighting (IPTW) was used to estimate the effect of prescribed opioid treatment for pain status (discontinuation versus tapered therapy versus continued therapy [reference]) on risk of overdose (fatal or nonfatal), stratified by the following groups: people without diagnosed OUD, people with diagnosed OUD receiving OAT, and people with diagnosed OUD not receiving OAT. In marginal structural models with IPTW adjusted for a range of demographic, prescription, comorbidity, and social-structural exposures, discontinuing opioids (i.e., ≥7-day gap[s] in therapy) was associated with increased overdose risk among people without OUD (adjusted hazard ratio [AHR] = 1.44; 95% confidence interval [CI] 1.12, 1.83; p = 0.004), people with OUD not receiving OAT (AHR = 3.18; 95% CI 1.87, 5.40; p < 0.001), and people with OUD receiving OAT (AHR = 2.52; 95% CI 1.68, 3.78; p < 0.001). Opioid tapering (i.e., ≥2 sequential decreases of ≥5% in average daily morphine milligram equivalents) was associated with decreased overdose risk among people with OUD not receiving OAT (AHR = 0.31; 95% CI 0.14, 0.67; p = 0.003). The main study limitations are that the outcome measure did not capture overdose events that did not result in a healthcare encounter or death, medication dispensation may not reflect medication adherence, residual confounding may have influenced findings, and findings may not be generalizable to persons on opioid therapy in other settings. CONCLUSIONS: Discontinuing prescribed opioids was associated with increased overdose risk, particularly among people with OUD. Prescribed opioid tapering was associated with reduced overdose risk among people with OUD not receiving OAT. These findings highlight the need to avoid abrupt discontinuation of opioids for pain. Enhanced guidance is needed to support prescribers in implementing opioid therapy tapering strategies with consideration of OUD and OAT status.

Building the plane while it's flying: implementation lessons from integrating a co-located exercise clinic into oncology care.

BACKGROUND: Despite its therapeutic role during cancer treatment, exercise is not routinely integrated into care and implementation efforts are largely absent from the literature. The aim of this study was to evaluate a strategy to integrate the workflow of a co-located exercise clinic into routine care within a private oncology setting in two clinics in the metropolitan region of Western Australia. METHODS: This prospective evaluation utilised a mixed methods approach to summarise lessons learned during the implementation of an integrated exercise workflow and supporting implementation plan. Data collection was informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Reports detailing utilisation of the exercise service and its referral pathways, as well as patient surveys and meeting minutes documenting the implementation process informed the evaluation. RESULTS: The co-located exercise service achieved integration into routine care within the clinical oncology setting. Patient utilisation was near capacity (reach) and 100% of clinicians referred to the service during the 13-month evaluation period (adoption). Moreover, ongoing adaptations were made to improve the program (implementation) and workflows were integrated into standard operating practices at the clinic (maintenance). The workflow performed as intended for ~70% of exercise participants (effectiveness); however, gaps were identified in utilisation of the workflow by both patients and clinicians. CONCLUSION: Integration of exercise into standard oncology care is possible, but it requires the ongoing commitment of multiple stakeholders across an organisation. The integrated workflow and supporting implementation plan greatly improved utilisation of the co-located exercise service, demonstrating the importance of targeted implementation planning. However, challenges regarding workflow fidelity within and across sites limited its success highlighting the complexities inherent in integrating exercise into clinical oncology care in a real-world setting.

Difficulty accessing supervised consumption services during the COVID-19 pandemic among people who use drugs in Vancouver, Canada.

BACKGROUND: The overdose crisis in Canada has worsened since the emergence of the COVID-19 pandemic. Although this trend is thought to be driven in part by closures or reduced capacity of supervised consumption services (SCS), little is known about the factors that may impede access to such services during the COVID-19 pandemic among people who use drugs. This study sought to characterize the prevalence and correlates of having difficulty accessing SCS during the COVID-19 pandemic among people who use drugs in Vancouver, Canada. METHODS: Cross-sectional data from two open prospective cohorts of people who use drugs were collected via phone or videoconferencing interviews conducted between July 2020 and November 2020. Multivariable logistic regression analyses were used to examine factors associated with experiencing difficulty accessing SCS. RESULTS: Among the 428 people who use drugs who participated in the study, 223 (54.7%) self-identified as men and the median age was 51 years (1st to 3rd quartile: 42-58). A total of 58 (13.6%) participants reported experiencing difficulty accessing SCS. In a multivariable analysis, factors positively associated with difficulty accessing SCS included daily crystal methamphetamine use (Adjusted odds ratio [AOR] = 2.60; 95% confidence interval [CI] 1.28-5.30), active injection drug use (AOR = 4.06; 95% CI 1.38-11.90), recent non-fatal overdose (AOR = 2.45; 95% CI 1.24-4.85), and unstable housing (AOR = 2.14; 95% CI 1.08-4.23). Age was inversely associated with the outcome (AOR = 0.96; 95% CI 0.93-0.99) in multivariable analyses. The most commonly reported reasons for experiencing difficulty accessing SCS were: COVID-19-related site closure or shortened hours (42.9%) and having to wait too long to use a site (39.3%). CONCLUSIONS: We found that people who use drugs with markers of structural vulnerability and drug-related risk were more likely to experience difficulty accessing SCS during the COVID-19 pandemic. These findings point to the need for strategies to support access to such services as part of pandemic response efforts.

Memory and Executive Functions Subserving Judgments of Learning: Cognitive Reorganization After Traumatic Brain Injury.

We investigated relationships between psychometric measures of memory, executive functions (EFs), and task-based measures of Judgments of Learning (JOLs) in individuals with and without Traumatic Brain Injury (TBI), to study functional reorganization after TBI. We hypothesized that, in controls, accuracy of immediate JOLs would be associated with short-term memory and EFs (but not long-term memory, LTM), while accuracy of delayed JOLs would be associated primarily with LTM. We hypothesized that those with good recovery from TBI would demonstrate functional reorganization of the relationships between memory, EFs, and JOLs. Eighteen individuals with TBI and 18 matched controls completed eight neuropsychological tests of memory and EFs. They studied word-pairs, made immediate and delayed JOLs, and took a cued-recall test for the studied word-pairs. Stepwise regression and Lasso analyses generated a predictive model of JOL accuracy for each group. Accuracy of immediate JOLs in controls was predicted by short-term memory, inhibition, switching, and cognitive fluency, while accuracy of delayed JOLs was predicted by verbal recall. In individuals with TBI, inhibition predicted immediate JOL accuracy and switching predicted delayed JOL accuracy. Cognitive reorganization in those with good long-term recovery from TBI may account for the ability to make JOLs with accuracy similar to controls.

Amplification of neurotoxic HTTex1 assemblies in human neurons.

Huntington's disease (HD) is a genetically inherited neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) repeat in the exon-1 of huntingtin protein (HTT). The expanded polyQ enhances the amyloidogenic propensity of HTT exon 1 (HTTex1), which forms a heterogeneous mixture of assemblies with a broad neurotoxicity spectrum. While predominantly intracellular, monomeric and aggregated mutant HTT species are also present in the cerebrospinal fluids of HD patients, however, their biological properties are not well understood. To explore the role of extracellular mutant HTT in aggregation and toxicity, we investigated the uptake and amplification of recombinant HTTex1 assemblies in cell culture models. We find that small HTTex1 fibrils preferentially enter human neurons and trigger the amplification of neurotoxic assemblies; astrocytes or epithelial cells are not permissive. The amplification of HTTex1 in neurons depletes endogenous HTT protein with non-pathogenic polyQ repeat, activates apoptotic caspase-3 pathway and induces nuclear fragmentation. Using a panel of novel monoclonal antibodies and genetic mutation, we identified epitopes within the N-terminal 17 amino acids and proline-rich domain of HTTex1 to be critical in neural uptake and amplification. Synaptosome preparations from the brain homogenates of HD mice also contain mutant HTT species, which enter neurons and behave similar to small recombinant HTTex1 fibrils. These studies suggest that amyloidogenic extracellular mutant HTTex1 assemblies may preferentially enter neurons, propagate and promote neurodegeneration.

Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator.

Calmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca2+ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. Using agent-based models, we computationally investigate the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule, Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that Ng plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase, CaMKII monomers integrate over Ca2+ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase, CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1, providing a mechanism to precisely control the sensitivity of synapses to calcium signals. Author Summary not valid for PLOS ONE submissions.

Monolayer Doping of Germanium with Arsenic: A New Chemical Route to Achieve Optimal Dopant Activation.

Reported here is a new chemical route for the wet chemical functionalization of germanium (Ge), whereby arsanilic acid is covalently bound to a chlorine (Cl)-terminated surface. This new route is used to deliver high concentrations of arsenic (As) dopants to Ge, via monolayer doping (MLD). Doping, or the introduction of Group III or Group V impurity atoms into the crystal lattice of Group IV semiconductors, is essential to allow control over the electronic properties of the material to enable transistor devices to be switched on and off. MLD is a diffusion-based method for the introduction of these impurity atoms via surface-bound molecules, which offers a nondestructive alternative to ion implantation, the current industry doping standard, making it suitable for sub-10 nm structures. Ge, given its higher carrier mobilities, is a leading candidate to replace Si as the channel material in future devices. Combining the new chemical route with the existing MLD process yields active carrier concentrations of dopants (>1 × 1019 atoms/cm3) that rival those of ion implantation. It is shown that the dose of dopant delivered to Ge is also controllable by changing the size of the precursor molecule. X-ray photoelectron spectroscopy (XPS) data and density functional theory (DFT) calculations support the formation of a covalent bond between the arsanilic acid and the Cl-terminated Ge surface. Atomic force microscopy (AFM) indicates that the integrity of the surface is maintained throughout the chemical procedure, and electrochemical capacitance voltage (ECV) data shows a carrier concentration of 1.9 × 1019 atoms/cm3 corroborated by sheet resistance measurements.

A multi-state model of the CaMKII dodecamer suggests a role for calmodulin in maintenance of autophosphorylation.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme's subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of a twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous experimental measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other's binding to CaMKII. Our results suggest a functional mechanism for the so-called "CaM trapping" phenomenon, wherein Ca2+/CaM may structurally exclude phosphatase binding and thereby prolong CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity.

We have the program, what now? Development of an implementation plan to bridge the research-practice gap prevalent in exercise oncology.

BACKGROUND: Exercise has emerged as a promising therapy for people with cancer. Novel programs have been developed to translate research into practice; however, implementation barriers have limited their success in part because successful translation of exercise oncology research into practice requires context-specific implementation plans. The aim of this study was to employ the implementation mapping protocol to develop an implementation plan to support programming of a co-located exercise clinic and cancer treatment center. METHODS: The Implementation Mapping protocol, which consists of five specific iterative tasks, was used. A stakeholder advisory group advised throughout the process. RESULTS: A comprehensive needs assessment was used to identify the organization's general manager as the program adopter; oncologists, center leaders, and various administrative staff as program implementers; and the operations manager as the program maintainer. Twenty performance objectives were identified. The theoretical domains framework was used to identify likely determinants of change, which informed the selection of eight individual implementation strategies across the individual and organizational levels. Finally, an evaluation plan was developed which will be used to measure the success of the implementation plan in the project's next phase. CONCLUSION: The Implementation Mapping protocol provided a roadmap to guide development of a comprehensive implementation plan that considered all ecological domains, was informed by theory, and demonstrated an extensive understanding of the implementation context. Strong research-practitioner partnerships and effective stakeholder engagement were critical to development of the plan.