A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro-in vivo translation understanding for early therapeutic insight.

Inconsistencies in rater-based assessments mainly affect borderline candidates: but using simple heuristics might improve pass-fail decisions.

INTRODUCTION: Research in various areas indicates that expert judgment can be highly inconsistent. However, expert judgment is indispensable in many contexts. In medical education, experts often function as examiners in rater-based assessments. Here, disagreement between examiners can have far-reaching consequences. The literature suggests that inconsistencies in ratings depend on the level of performance a to-be-evaluated candidate shows. This possibility has not been addressed deliberately and with appropriate statistical methods. By adopting the theoretical lens of ecological rationality, we evaluate if easily implementable strategies can enhance decision making in real-world assessment contexts. METHODS: We address two objectives. First, we investigate the dependence of rater-consistency on performance levels. We recorded videos of mock-exams and had examiners (N=10) evaluate four students' performances and compare inconsistencies in performance ratings between examiner-pairs using a bootstrapping procedure. Our second objective is to provide an approach that aids decision making by implementing simple heuristics. RESULTS: We found that discrepancies were largely a function of the level of performance the candidates showed. Lower performances were rated more inconsistently than excellent performances. Furthermore, our analyses indicated that the use of simple heuristics might improve decisions in examiner pairs. DISCUSSION: Inconsistencies in performance judgments continue to be a matter of concern, and we provide empirical evidence for them to be related to candidate performance. We discuss implications for research and the advantages of adopting the perspective of ecological rationality. We point to directions both for further research and for development of assessment practices.

Health complaints before and at one and five years after removal of dental amalgam restorations - data from a prospective cohort study in Norway.

OBJECTIVE: Health complaints attributed to dental amalgam fillings comprise both intraoral and general health complaints. There are data suggesting that patients with medically unexplained physical symptoms (MUPS) attributed to amalgam fillings show improvement in symptoms after removal of all amalgam fillings. However, data indicating changes of specific health complaints are limited. This study evaluated the changes of health complaints after removal of amalgam restorations in patients with health complaints attributed to dental amalgam fillings. METHOD: Patients with MUPS attributed to dental amalgam (Amalgam cohort) had all their amalgam fillings removed. The participants indicated an intensity of 11 local and 12 general health complaints on numeric rating scales before the treatment and at follow-up after 1 and 5 years. The comparison groups comprising a group of healthy individuals and a group of patients with MUPS without symptom attribution to dental amalgam did not have their amalgam restorations removed. RESULTS: In the Amalgam cohort, mean symptom intensity was lower for all 23 health complaints at follow-up at 1 year compared to baseline. Statistically significant changes were observed for specific health complaints with effect sizes between 0.36 and 0.68. At the 5-year follow-up, the intensity of symptoms remained consistently lower compared to before the amalgam removal. In the comparison groups, no significant changes of intensity of symptoms of health complaints were observed. CONCLUSION: After removal of all amalgam restorations, both local and general health complaints were reduced. Since blinding of the treatment was not possible, specific and non-specific treatment effects cannot be separated.

Mercury, silver and selenium in serum before and after removal of amalgam restorations: results from a prospective cohort study in Norway.

OBJECTIVE: A prospective cohort study on changes of health complaints after removal of amalgam restorations was carried out at the request of the Norwegian Directorate of Health. The aim was to provide and evaluate experimental treatment to patients with health complaints attributed to dental amalgam fillings. METHODS: Patients (n = 32) with medically unexplained physical symptoms (MUPS), which were attributed to dental amalgam restorations had all their amalgam restorations removed and replaced with other dental restorative materials. Samples of blood were collected before and 1 year after removal of the fillings, and concentration of inorganic mercury (I-Hg), methylmercury (MeHg), silver (Ag) and selenium (Se) in serum was determined by inductively coupled plasma-sector field mass spectrometry. The comparison groups (one with MUPS but without attribution to amalgam [n = 28] and one group of healthy individuals [n = 19]) received no treatment. The participants responded to questionnaires at baseline and at follow-up after 1 and 5 years. RESULTS: Concentration of I-Hg and Ag in serum decreased significantly after removal of all amalgam restorations. Concentration of MeHg and Se in serum were not changed. Intensity of health complaints was significantly reduced after amalgam removal, but there were no statistically significant correlations between exposure indicators and health complaints. CONCLUSIONS: Removal of all amalgam restorations is followed by a decrease of concentration of I-Hg and Ag in serum. The results support the hypothesis that exposure to amalgam fillings causes an increase of the daily dose of both I-Hg and Ag. Even though intensity of health complaints decreased after removal of all amalgam restorations there was no clear evidence of a direct relationship between exposure and health complaints. Trial registration: The project is registered at Clinicaltrials.gov (NCT01682278).

What is the effect of independent medical evaluation on days on sickness benefits for long-term sick listed employees in Norway? A pragmatic randomised controlled trial, the NIME-trial.

BACKGROUND: Independent medical evaluations are used to evaluate degree and reason for work disability, uncertainty around the functional status, and/or the employee's rehabilitation potential in several jurisdictions, but not in Norway. The main aim of this trial was to test the return to work effect of independent medical evaluation (IME) (summoning and consultation) compared to treatment as usual (TAU) in Norway, for workers who have been on continuous sick leave for 6 months. METHODS: This was a pragmatic randomised controlled trial including all employees aged 18-65 years, sick-listed by their general practitioner and on full or partial sick leave for the past 26 weeks in Hordaland County, Norway in 2015/16. Trial candidates were drawn from a central register at the Norwegian Labour and Welfare Administration at 22 weeks of sick leave. Pregnant women, individuals with cancer or dementia diagnoses, those with secret address, employed by NAV or sick listed by the specialist health services were excluded. Separate regression analyses were conducted to investigate the "intention-to-treat" and "treatment on the treated" effects, using the ordinary least squares and instrumental variable methods, respectively. RESULTS: After exemption based on predefined exclusion criteria, 5888 individuals were randomised to either IME (n = 2616) or TAU (n = 2599). The final intervention group constitutes 1698 individuals, of which 937 attended the IME consultation. No baseline differences were found between the IME and TAU group regarding gender, age, and previous sick leave. Individuals attending the IME were older than those who cancelled the appointment ((47/45), p = 0.006) and those who did not show up without cancelling ((47/42), p < 0.001). Mainly the IME physician agreed with the regular GP upon level of sick leave. In cases with different assessments, the difference tended to be towards a lower sick leave level. There were no intention to treat or treatment on the treated effect on days of sick leave after randomisation during follow up. CONCLUSIONS: Overall, the analyses showed no effect of IME on changes in sick leave for sick listed employees. This result was consistent for those who were offered an IME consultation (intention to treat) and those who undertook an IME consultation (treatment on the treated). TRIAL REGISTRATION: ClinicalTirals.gov trial number NCT02524392 first registration 14.08.2015.

Experiences with a structured conversation tool: a qualitative study on feasibility in general practice in Norway.

OBJECTIVE: To study the feasibility of a structured conversation tool (ICIT) in Norwegian general practice. DESIGN AND PARTICIPANTS: A structured conversation tool with elements from Cognitive Behavioral Therapy (CBT) was developed for use at the encounter in general practice to increase patient's self-coping ability and the GPs management and sick leave assessment in patients with MUPS. Eight GPs received training and used the ICIT on 49 patients with MUPS. The physicians were gathered into two focus groups. The interviews were recorded on tape, transcribed, and analyzed with systematic text condensation. MAIN OUTCOME MEASURES: The aim of our study was to examine any benefit and the feasibility of the ICIT in general practice. RESULTS: The physicians found the ICIT helpful to sort out, clarify and concretize the patients' issues. They felt less fatigued as patients took on a greater responsibility for their own recovery and reported a greater satisfaction and better management with the patients. A salutogenic approach gave the physicians greater insight into their patients' lives and their issues, opening for new treatment options and aiding in recovery. By focusing on the patient's potential capabilities despite their medical condition, some physicians experienced that patients on sick leave returned to work quicker. CONCLUSIONS: The GPs in this study reported that the ICIT was helpful in consultations with patients due to unspecific medical conditions and facilitated a sense of competence for the physician. KEY POINTSGPs need communication skill training for integrated treatment and sick leave assessment for patients with Medically Unexplained Physical Symptoms (MUPS).•The GPs experienced that the structured conversation tool was beneficial in structuring, clarifying, and substantiating the patient's problems.•The GPs experienced a greater insight into their patients and their issues, opening new treatment options and aiding in recovery.•The GPs experienced patients' quicker recovery and returns to work by starting immediate treatment using the conversation tool.

A bistable, multiport valve enables microformulators creating microclinical analyzers that reveal aberrant glutamate metabolism in astrocytes derived from a tuberous sclerosis patient.

There is a need for valves and pumps that operate at the microscale with precision and accuracy, are versatile in their application, and are easily fabricated. To that end, we developed a new rotary planar multiport valve to faithfully select solutions (contamination = 5.22 ± 0.06 ppb) and a rotary planar peristaltic pump to precisely control fluid delivery (flow rate = 2.4 ± 1.7 to 890 ± 77 µL/min). Both the valve and pump were implemented in a planar format amenable to single-layer soft lithographic fabrication. These planar microfluidics were actuated by a rotary motor controlled remotely by custom software. Together, these two devices constitute an innovative microformulator that was used to prepare precise, high-fidelity mixtures of up to five solutions (deviation from prescribed mixture = ±|0.02 ± 0.02| %). This system weighed less than a kilogram, occupied around 500 cm3, and generated pressures of 255 ± 47 kPa. This microformulator was then combined with an electrochemical sensor creating a microclinical analyzer (µCA) for detecting glutamate in real time. Using the chamber of the µCA as an in-line bioreactor, we compared glutamate homeostasis in human astrocytes differentiated from human-induced pluripotent stem cells (hiPSCs) from a control subject (CC-3) and a Tuberous Sclerosis Complex (TSC) patient carrying a pathogenic TSC2 mutation. When challenged with glutamate, TSC astrocytes took up less glutamate than control cells. These data validate the analytical power of the µCA and the utility of the microformulator by leveraging it to assess disease-related alterations in cellular homeostasis.

Removal of dental amalgam restorations in patients with health complaints attributed to amalgam: A prospective cohort study.

BACKGROUND: The Norwegian Ministry of Health and Care Services initiated a project including experimental treatment for patients with health complaints attributed to amalgam restorations. OBJECTIVE: The aim was to evaluate changes of general health complaints in patients who participated in the project and had all amalgam restorations removed. METHODS: The project was designed as a prospective cohort study and organised by the Dental Biomaterials Adverse Reaction Unit in Bergen, Norway. The dental treatment was provided by the patient's local dentist. The main target group consisted of patients with medically unexplained physical symptoms, attributed to dental amalgam restorations (Amalgam cohort). The primary comparison group consisted of patients with medically unexplained physical symptoms without attribution to dental amalgam restorations (MUPS cohort). Primary outcome was self-reported general health complaints (GHC index) at follow-up 12-months after completed amalgam removal. RESULTS: In the Amalgam cohort, a significant reduction of GHC index from 43.3 (SD 17.8) at baseline to 30.5 (SD 14.4) at follow-up (mean reduction 12.8, SD 15.9; n = 32; P < .001) was observed. The change scores for GHC index indicated that the reduction of complaints was significantly higher (P = .004) in the Amalgam cohort compared with the MUPS cohort (mean reduction 1.2, SD 12.3, n = 28). After adjustment for age, gender, education and baseline GHC index, the mean adjusted difference was -8.0 (95% confidence interval from -15.4 to -0.5; P = .036). CONCLUSION: In a group of patients with medically unexplained physical symptoms, which they attributed to dental amalgam restorations, removal of amalgam restorations was followed by a significant reduction of health complaints.

Tverrfaglig behandlingstilbud til pasienter med ryggsmerter ved et lokalsykehus.

BACKGROUND: Low back pain is considered to be the most common single cause of sickness absence. In 2010, Sørlandet Hospital Arendal established an interdisciplinary treatment programme through the Faster Return-to-Work scheme, based on the relevant guidelines for patients with low back pain. In this study we present our experiences from six years of the treatment programme. MATERIAL AND METHOD: Patients who were referred to Sørlandet Hospital in Arendal in the period 2011-16 due to long-term symptoms of low back pain were offered interdisciplinary treatment. This included a one-to-one consultation with a doctor, four weeks of group-based low back school, and physiotherapist-led exercise as well as eight weeks of either physiotherapist-led exercise or home exercise. The degree of sick leave and functional level using scores on the Roland-Morris Disability Questionnaire (RMDQ) were reported at the outset and after 4 and 12 weeks. RESULTS: A total of 43 patients in employment completed the treatment programme. The average age was 41.9 years and 52 % were women. Altogether 57 % were on certified sick leave at the outset and the remainder were assessed as being at high risk of going on sick leave. A total of 7.5 % were placed on sick leave during the observation period, while 28.5 % of those on sick leave were declared completely fit. Altogether 52.7 % of the patients had a clinically significant reduction in RMDQ scores (> 3.5 points). INTERPRETATION: The interdisciplinary treatment programme appears to improve function and reduce sickness absent in patients with long-term low back pain. This study has a short follow-up time and no control group; the observations must therefore be interpreted with caution.

Stochastic unfolding of nanoconfined DNA: Experiments, model and Bayesian analysis.

Nanochannels provide a means for detailed experiments on the effect of confinement on biomacromolecules, such as DNA. Here we introduce a model for the complete unfolding of DNA from the circular to linear configuration. Two main ingredients are the entropic unfolding force and the friction coefficient for the unfolding process, and we describe the associated dynamics by a non-linear Langevin equation. By analyzing experimental data where DNA molecules are photo-cut and unfolded inside a nanochannel, our model allows us to extract values for the unfolding force as well as the friction coefficient for the first time. In order to extract numerical values for these physical quantities, we employ a recently introduced Bayesian inference framework. We find that the determined unfolding force is in agreement with estimates from a simple Flory-type argument. The estimated friction coefficient is in agreement with theoretical estimates for motion of a cylinder in a channel. We further validate the estimated friction constant by extracting this parameter from DNA's center-of-mass motion before and after unfolding, yielding decent agreement. We provide publically available software for performing the required image and Bayesian analysis.

A focus group study to understand biases and confounders in a cluster randomized controlled trial on low back pain in primary care in Norway.

BACKGROUND: Cluster randomized controlled trials are often used in research in primary care but creates challenges regarding biases and confounders. We recently presented a study on low back pain from primary care in Norway with equal effects in the intervention and the control group. In order to understand the specific mechanisms that may produce biases in a cluster randomized trial we conducted a focus group study among the participating health care providers. The aim of this study was to understand how the participating providers themselves influenced on the study and thereby possibly on the results of the cluster randomized controlled trial. METHODS: The providers were invited to share their experiences from their participation in the COPE study, from recruitment of patients to accomplishment of either the intervention or control consultations. Six clinicians from the intervention group and four from the control group took part in the focus group interviews. The group discussions focused on feasibility of the study in primary care and particularly on identifying potential biases and confounders in the study. The audio-recorded interviews were transcribed verbatim and analyzed according to a systematic text condensation. The themes for the analysis emerged from the group discussions. RESULTS: A personal interest for back pain, logistic factors at the clinics and an assessment of the patients' capacity to accomplish the study prior to their recruitment was reported. The providers were allowed to provide additional therapy to the intervention and it turned out that some of these could be regarded as opposed to the messages of the intervention. The providers seemed to select different items from the educational package according to personal beliefs and their perception of the patients' acceptance. CONCLUSION: The study disclosed several potential biases to the COPE study which may have impacted on the study results. Awareness of these is highly important when planning and conducting a cluster randomized controlled trial. Procedures in the recruitment of both providers and patients seem to be key factors and the providers should be aware of their role in a scientific study in order to standardize the provision of the intervention.

The capacity to work puzzle: a qualitative study of physicians' assessments for patients with common mental disorders.

BACKGROUND: Entitlement to sickness benefits is a legal process requiring health-related reduced work capacity confirmed by a physician via a sickness certificate. However, there is a knowledge gap concerning physicians' clinical practice of work capacity assessments for patients with common mental disorders (CMD). Physicians claim more knowledge and skills in how to actually do the assessments. The aim of this study was to explore physicians' tacit knowledge of performing assessments of capacity to work and the need for sickness absence in patients with depression and anxiety disorders. METHODS: We performed a qualitative study with open-ended interviews and a short video vignette of a physician and a patient with depression as stimuli. Participating physicians (n = 24) were specialized in general practice, occupational health or psychiatry and experienced in treating patients with depression and anxiety. Interviews were audio-recorded and transcribed verbatim. Inductive content analysis was used as the analytical tool. RESULTS: Five categories were identified. Category 1 identified work capacity assessment as doing a jigsaw puzzle without any master model. The physicians both identified and created the pieces of the puzzle, mainly by facilitating strategies to make the patient a better supplier of essential information. The finished puzzle made up a highly individualized comprehensive picture required for adequate assessment. Categories 2-4 identified the particular essential pieces of information the participants used, relating to the patient's disorder, capacity in the work place and contextual everyday life. For the sickness absence assessment, apart from decreased work capacity, the physicians also took particulars of the work place into account; e.g. could the work place handle an employee with reduced capacity. CONCLUSIONS: Physicians' tacit knowledge of assessing work capacity and the need for sickness absence for patients with CMD was identified as doing a jigsaw puzzle. The physicians became identifiers and creators of the pieces of the puzzle using a broad palette of essential information. Our findings contribute to the knowledge gap on clinical assessment and can be used as an educational tool. Because they are based on the professions' tacit knowledge, acceptance of the model can be expected to be high.

The impact of psychological factors on condition-specific, generic and individualized patient reported outcomes in low back pain.

BACKGROUND: An individualized patient reported outcome (PRO) has recently been recommended within LBP research, but no study has evaluated this instrument with commonly applied PROs. Moreover, the impact of psychological factors has mostly been assessed for disease-specific instruments. The objective of this study was to assess the predictive value of illness perceptions, pain catastrophizing and psychological distress on 12 month outcomes assessed by specific, generic and individualized PROs recommended in low back pain (LBP). METHODS: Secondary analysis of patients with sub-acute or chronic LBP recruited for a cluster randomized controlled trial in primary care who completed a self-administered questionnaire at baseline and 12 months. 12 month scores for the Roland Morris Disability Questionnaire (RMDQ), the EuroQol (EQ-5D), and the Patient Generated Index (PGI) were dependent variables in hierarchical regression analysis. Independent variables included baseline scores for the Brief Illness Perceptions Questionnaire (Brief IPQ), Hopkins Symptom Check List (HSCL-25), Pain Catastrophizing Scale (PCS), health/clinical and sociodemographic variables. RESULTS: Of the 216 eligible patients included, 203 patients responded to the baseline questionnaire and 150 (74%) responded at 12 months. The mean age was 38.3 (SD 10.2) years and 57.6% were female. The Brief IPQ showed a statistically significant variation in the 12-months score of all the PROs, explaining 2.5% in RMDQ, 7.9% in EQ-5D, and 3.6% in PGI. Most of the explained variation for EQ-5D scores related to illness perceptions. The PCS explained 3.7% of the RMDQ and 2.5% in the EQ-5D scores. The HSCL-25 did not make a significant contribution. CONCLUSION: Illness perceptions and pain catastrophizing were associated with 12-month outcomes as assessed by condition-specific, generic and individualized PROs. The Brief IPQ and PCS have relevance to applications in primary care that include interventions designed to enhance psychological aspects of health and where the contribution of such variables to outcomes is of interest. Further studies should assess whether the Brief IPQ perform similarly in LBP populations in other health care settings.

Protocol for the effect evaluation of independent medical evaluation after six months sick leave: a randomized controlled trial of independent medical evaluation versus treatment as usual in Norway.

BACKGROUND: It has been discussed whether the relationship between a patient on sick leave and his/her general practitioner (GP) is too close, as this may hinder the GP's objective evaluation of need for sick leave. Independent medical evaluation involves an independent physician consulting the patient. This could lead to new perspectives on sick leave and how to follow-up the patient. METHODS/DESIGN: The current study is a randomized controlled trial in a Norwegian primary care context, involving an effect evaluation, a cost/benefit analysis, and a qualitative evaluation. Independent medical evaluation will be compared to treatment as usual, i.e., the physicians' and social insurance agencies' current management of long-term sick-listed patients. Individuals aged 18-65 years, sick listed by their GP and on full or partial sick leave for the past 6 months in Hordaland county will be included. Exclusion criteria are pregnancy, cancer, dementia or an ICD-10 diagnosis. A total sample of 3800 will be randomly assigned to either independent medical evaluation or treatment as usual. Official register data will be used to measure the primary outcome; change in sickness benefits at 7, 9 and 12 months. Sick listed in other counties will serve as a second control group, if appropriate under the "common trend" assumption. DISCUSSION: The Norwegian effect evaluation of independent medical evaluation after 6 months sick leave is a large randomized controlled trial, and the first of its kind, to evaluate this type of intervention as a means of getting people back to work after long-term sickness absence. TRIAL REGISTRATION: ClinicalTrials.gov NCT02524392 . Registered June 23, 2015.

Vacuum pressure generation via microfabricated converging-diverging nozzles for operation of automated pneumatic logic.

Microfluidic devices with integrated pneumatic logic enable automated fluid handling without requiring external control instruments. These chips offer the additional advantage that they may be powered by vacuum and do not require an electricity source. This work describes a microfluidic converging-diverging (CD) nozzle optimized to generate vacuum at low input pressures, making it suitable for microfluidic applications including powering integrated pneumatic logic. It was found that efficient vacuum pressure was generated for high aspect ratios of the CD nozzle constriction (or throat) width to height and diverging angle of 3.6(o). In specific, for an inlet pressure of 42.2 psia (290.8 kPa) and a volumetric flow rate of approximately 1700 sccm, a vacuum pressure of 8.03 psia (55.3 kPa) was generated. To demonstrate the capabilities of our converging - diverging nozzle device, we connected it to a vacuum powered peristaltic pump driven by integrated pneumatic logic and obtained tunable flow rates from 0 to 130 µL/min. Finally, we demonstrate a proof of concept system for use where electricity and vacuum pressure are not readily available by powering a CD nozzle with a bicycle tire pump and pressure regulator. This system is able to produce a stable vacuum sufficient to drive pneumatic logic, and could be applied to power automated microfluidics in limited resource settings.

Visualizing the Nonhomogeneous Structure of RAD51 Filaments Using Nanofluidic Channels.

RAD51 is the key component of the homologous recombination pathway in eukaryotic cells and performs its task by forming filaments on DNA. In this study we investigate the physical properties of RAD51 filaments formed on DNA using nanofluidic channels and fluorescence microscopy. Contrary to the bacterial ortholog RecA, RAD51 forms inhomogeneous filaments on long DNA in vitro, consisting of several protein patches. We demonstrate that a permanent "kink" in the filament is formed where two patches meet if the stretch of naked DNA between the patches is short. The kinks are readily seen in the present microscopy approach but would be hard to identify using conventional single DNA molecule techniques where the DNA is more stretched. We also demonstrate that protein patches separated by longer stretches of bare DNA roll up on each other and this is visualized as transiently overlapping filaments. RAD51 filaments can be formed at several different conditions, varying the cation (Mg(2+) or Ca(2+)), the DNA substrate (single-stranded or double-stranded), and the RAD51 concentration during filament nucleation, and we compare the properties of the different filaments formed. The results provide important information regarding the physical properties of RAD51 filaments but also demonstrate that nanofluidic channels are perfectly suited to study protein-DNA complexes.

Correspondence in Stakeholder Assessment of Health, Work Capacity and Sick Leave in Workers with Comorbid Subjective Health Complaints? A Video Vignette Study.

Purpose The purpose of this study is to test if there is correspondence in stakeholders' assessments of health, work capacity and sickness certification in four workers with comorbid subjective health complaints based on video vignettes. Methods A cross sectional survey among stakeholders (N = 514) in Norway in 2009/2010. Logistic regression and multinomial logistic regression was used to obtain the estimated probability of stakeholders choosing 100 % sick leave, partial sick leave or work and the estimation of odds ratio of stakeholder assessment compared to the other stakeholders for the individual worker. Results The supervisors were less likely to assess poor health and reduced work capacity, and more likely to suggest partial sick leave and full time work compared to the GPs for worker 1. The public was less likely to assess comorbidity and reduced work capacity, and 6 and 12 times more likely to suggest partial sick leave and full time work compared to the GPs for worker 1. Stakeholders generally agreed in their assessments of workers 2 and 3. The public was more likely to assess poor health, comorbidity and reduced work capacity, and the supervisors more likely to assess comorbidity and reduced work capacity, compared to the GPs for worker 4. Compared to the GPs, all other stakeholders were less likely to suggest full time work for this worker. Conclusions Our results seem to suggest that stakeholders have divergent assessments of complaints, health, work capacity, and sickness certification in workers with comorbid subjective health complaints.

How nanochannel confinement affects the DNA melting transition within the Poland-Scheraga model.

When double-stranded DNA molecules are heated, or exposed to denaturing agents, the two strands are separated. The statistical physics of this process has a long history and is commonly described in terms of the Poland-Scheraga (PS) model. Crucial to this model is the configurational entropy for a melted region (compared to the entropy of an intact region of the same size), quantified by the loop factor. In this study, we investigate how confinement affects the DNA melting transition, by using the loop factor for an ideal Gaussian chain. By subsequent numerical solutions of the PS model, we demonstrate that the melting temperature depends on the persistence lengths of single-stranded and double-stranded DNA. For realistic values of the persistence lengths, the melting temperature is predicted to decrease with decreasing channel diameter. We also demonstrate that confinement broadens the melting transition. These general findings hold for the three scenarios investigated: 1. homo-DNA, i.e., identical basepairs along the DNA molecule, 2. random sequence DNA, and 3. "real" DNA, here T4 phage DNA. We show that cases 2 and 3 in general give rise to broader transitions than case 1. Case 3 exhibits a similar phase transition as case 2 provided the random sequence DNA has the same ratio of AT to GC basepairs (A - adenine, T - thymine, G - guanine, C - cytosine). A simple analytical estimate for the shift in melting temperature is provided as a function of nanochannel diameter. For homo-DNA, we also present an analytical prediction of the melting probability as a function of temperature.