Central Nervous System Distribution of an Opioid Agonist Combination with Synergistic Activity.

Novel combinations of specific opioid agonists like loperamide and oxymorphindole targeting the µ- and δ-opioid receptors, respectively, have shown increased potency with minimized opioid-associated risks. However, whether their interaction is pharmacokinetic or pharmacodynamic in nature has not been determined. This study quantitatively determined whether these drugs have a pharmacokinetic interaction that alters systemic disposition or central nervous system (CNS) distribution. We performed intravenous and oral in vivo pharmacokinetic assessments of both drugs after discrete dosing and administration in combination to determine whether the combination had any effect on systemic pharmacokinetic parameters or CNS exposure. Drugs were administered at 5 or 10 mg/kg i.v. or 30 mg/kg orally to institute for cancer research (ICR) mice and 5 mg/kg i.v. to Friend leukemia virus strain B mice of the following genotypes: wild-type, breast cancer resistance protein (Bcrp-/- ) (Bcrp knockout), Mdr1a/b-/- [P-glycoprotein (P-gp) knockout], and Bcrp-/- Mdr1a/b-/- (triple knockout). In the combination, clearance of oxymorphindole (OMI) was reduced by approximately half, and the plasma area under the concentration-time curve (AUC) increased. Consequently, brain and spinal cord AUCs for OMI in the combination also increased proportionately. Both loperamide and OMI are P-gp substrates, but administration of the two drugs in combination does not alter efflux transport at the CNS barriers. Because OMI alone shows appreciable brain penetration but little therapeutic efficacy on its own, and because loperamide's CNS distribution is unchanged in the combination, the mechanism of action for the increased potency of the combination is most likely pharmacodynamic and most likely occurs at receptors in the peripheral nervous system. This combination has favorable characteristics for future development. SIGNIFICANCE STATEMENT: Opioids have yet to be replaced as the most effective treatments for moderate-to-severe pain and chronic pain, but their side effects are dangerous. Combinations of opioids with peripheral activity, such as loperamide and oxymorphindole, would be valuable in that they are effective at much lower doses and have reduced risks for dangerous side effects because the µ-opioid receptor agonist is largely excluded from the CNS.

FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR-DOR Heteromer.

This report describes the unique pharmacological profile of FBNTI, a potent DOR antagonist that acts as a MOR agonist via an allosteric mechanism. Binding of FBNTI to opioid receptors expressed in HEK 293 cells revealed a 190-fold greater affinity for DOR (Ki = 0.84 nM) over MOR (Ki = 160 nM). In mice, intrathecal FBNTI produced potent antinociception (ED50 = 46.9 pmol/mouse), which was antagonized by selective MOR antagonists (CTOP, ß-FNA). Autoantagonism of the MOR agonism by FBNTI was observed above the ED75 dose, suggesting antagonism of activated MOR. That FBNTI is devoid of agonism in DOR knockout mice is consistent with allosteric activation of the MOR protomer via FBNTI bound to within a MOR-DOR heteromer. This proposed mechanism is supported by calcium mobilization assays, which indicate that FBNTI selectively activates the MOR-DOR heteromer and functionally antagonizes the MOR protomer at >ED75. The unprecedented mode of MOR activation by FBNTI may be responsible for the lack of tolerance after intrathecal (i.t.) administration. FBNTI was highly effective upon topical administration to the ipsolateral hind paw in the Hargreaves assay (EC50 = 0.17 ± 0.08 µM) and without significant contralateral activity, suggesting a lack of systemic exposure.

Combination of a δ-opioid Receptor Agonist and Loperamide Produces Peripherally-mediated Analgesic Synergy in Mice.

BACKGROUND: The long-term use of opioids for analgesia carries significant risk for tolerance, addiction, and diversion. These adverse effects are largely mediated by µ-opioid receptors in the central nervous system. Based on the authors' previous observation that morphine and δ-opioid receptor agonists synergize in spinal cord in a protein kinase Cε-dependent manner, they predicted that this µ-opioid receptor-δ-opioid receptor synergy would take place in the central terminals of nociceptive afferent fibers and generalize to their peripheral terminals. Therefore, the authors hypothesized that loperamide, a highly efficacious µ-opioid receptor agonist that is excluded from the central nervous system, and oxymorphindole, a δ-opioid receptor agonist that was shown to synergize with morphine spinally, would synergistically reverse complete Freund's adjuvant-induced hyperalgesia. METHODS: Using the Hargreaves assay for thermal nociception, the von Frey assay for mechanical nociception and the complete Freund's adjuvant-induced model of inflammatory pain, we tested the antinociceptive and antihyperalgesic effect of loperamide, oxymorphindole, or the loperamide-oxymorphindole combination. Animals (Institute for Cancer Research [ICR] CD1 strain mice; n = 511) received drug by systemic injection, intraplantar injection to the injured paw, or a transdermal solution on the injured paw. Dose-response curves for each route of administration and each nociceptive test were generated, and analgesic synergy was assessed by isobolographic analysis. RESULTS: In naïve animals, the loperamide-oxymorphindole combination ED50 value was 10 times lower than the theoretical additive ED50 value whether given systemically or locally. In inflamed animals, the combination was 150 times more potent systemically, and 84 times more potent locally. All combinations showed statistically significant synergy when compared to the theoretical additive values, as verified by isobolographic analysis. The antihyperalgesia was ablated by a peripherally-restricted opioid antagonist. CONCLUSIONS: From these data we conclude that the loperamide-oxymorphindole combination synergistically reverses complete Freund's adjuvant-induced inflammatory hyperalgesia. The authors also conclude that this interaction is mediated by opioid receptors located in the peripheral nervous system.

Results of Telehealth Electronic Monitoring for Post Discharge Complications and Surgical Site Infections following Arterial Revascularization with Groin Incision.

BACKGROUND: Post-surgical discharge complications result in increased hospital readmissions, cost, and patient dissatisfaction. Telehealth technology to monitor patients, especially those in geographically isolated areas, may reduce post-operative complications and improve health and financial outcomes. The primary objective of this study was to compare outcomes between patients who received TeleHealth Electronic Monitoring (THEM) and those with routine discharge instructions and no monitoring, Standard Of Care (SOC). METHODS: This is a prospective randomized study of vascular surgery patients with infrainguinal incisions. THEM patients received a tablet and home monitoring devices that transmitted information to care managers. Monitoring tools included image capture, weight scales, blood pressure cuffs, thermometers, and oxygen saturation monitors. Care managers used the TeleMed 2020 Enform™ platform to review alerts, real-time patient data, and dialogue with the care team. RESULTS: Eighty patients were screened and 30 enrolled, of which 16 (53.3%) were randomized to the THEM group and 14 (46.7%) to the control group. Average age and body mass index for THEM and control patients were similar (62.5 ± 7.2 vs. 65.7 ± 7.3, P = 0.234; and 27.7 ± 4.3 vs. 29.1 7.1, P = 0.487), respectively. There was a similar number of male participants in each group (THEM 62.5% vs. SOC 42.9%, P = 0.464). There were no significant differences in wound or 30-day readmissions (THEM 6.3% vs. SOC 7.1%, P = 1.000). Interestingly, 30-day infection rates indicated that care managers identified marginally more superficial wound problems in the THEM group (31.3% vs. 7.1%, P = 0.175). Both groups reported an increase in short-form-8 physical summary scores, but was more pronounced in THEM patients (P = 0.076). THEM patients reported a significantly greater improvement in quality of life on 3 of the short-form-8 quality subscales (physical function, role-physical, and role-emotional; THEM delta 7.5 versus Control delta 1.1; THEM delta 8.7 versus Control delta 1.1; and THEM delta 6.3 versus Control delta -0.5; all P < 0.05). THEM patients reported trends for higher satisfaction in terms of general satisfaction, technical quality, and accessibility for Patient Satisfaction Questionnaire-18 survey questions (4.2 vs. 3.7, P = 0.072; 4.5 vs. 4.1, P = 0.081; and 4.2 vs. 3.8, P = 0.063), respectively. CONCLUSIONS: THEM was technically feasible and provided some benefit to patients in geographically disparate areas. THEM was associated with increased patient satisfaction. Additional findings suggested that THEM patients embraced telehealth technology and took advantage of increased access to healthcare professionals. Telehealth successfully merged remotely generated information with care manager interaction. Presently, a larger study, preferably multi-center, is warranted and under consideration.

In vivo optogenetic activation of Nav1.8+ cutaneous nociceptors and their responses to natural stimuli.

Optogenetic methods that utilize expression of the light-sensitive protein channelrhodopsin-2 (ChR2) in neurons have enabled selective activation of specific subtypes or groups of neurons to determine their functions. Using a transgenic mouse model in which neurons natively expressing Nav1.8 (a tetrodotoxin-resistant voltage-gated sodium channel) also express the light-gated channel ChR2, we have been able to determine the functional properties of Nav1.8-expressing cutaneous nociceptors of the glabrous skin in vivo. Most (44 of 53) of the C-fiber nociceptors isolated from Nav1.8-ChR2+ mice were found to be responsive to blue (470 nm) light. Response characteristics, including conduction velocity and responses to mechanical stimuli, were comparable between nociceptors isolated from Nav1.8-ChR2+ and control mice. Interestingly, while none of the non-light-responsive C-fibers were sensitive to heat or cold, nearly all (77%) light-sensitive fibers were excited by mechanical and thermal stimuli, suggesting that Nav1.8 is predominantly expressed by C-fiber nociceptors that are responsive to multiple stimulus modalities. The ability to activate peripheral nociceptors with light provides a method of stimulation that is noninvasive, does not require mechanical interruption of the skin, and accesses receptive fields that might be difficult or impossible to stimulate with standard stimuli while allowing repeated stimulation without injuring the skin.NEW & NOTEWORTHY Transgenic mice that express the blue light-sensitive protein channelrhodopsin2 (ChR2) in nociceptive nerve fibers that contain voltage-gated sodium channel Nav1.8 were used to determine functional properties of these afferent fibers. Electrophysiological recordings in vivo revealed that most nociceptive fibers that possess Nav1.8 are C-fiber nociceptors that respond to multiple stimulus modalities. Furthermore, responses evoked by blue light stimulation were comparable to those elicited by noxious mechanical, heat, and cold stimuli.

Changes over time in the risk of hospitalization for physical diseases among homeless men and women in Stockholm: A comparison of two cohorts.

AIMS: To follow-up hospitalization for physical diseases among homeless men and women compared with a control group from the general population. The study also investigated the changes in the difference between the homeless men and women and the general population over time by comparing two cohorts of homeless people (2000-2002 and 1996). METHODS: A total of 3887 people (24% women) who were homeless during the period 2000-2002 were compared with 11,661 people from the general population with respect to hospitalization for physical diseases and injuries (2000-2010). Indirect comparisons were used to compare the relative risk (RR) of hospitalization between the cohort of people who were homeless in 2000-2002 with a cohort of those who were homeless in 1996. RESULTS: Homeless people have an RR of being hospitalized for physical diseases twice that of the general population. The largest differences were found in skin diseases, infections, injury/poisoning and diseases of the respiratory system. Indirect comparison between people who were homeless in 2000-2002 and 1996 showed an increasing difference between young (18-35 years) homeless men and men in the control group (RR 1.32). The difference had also increased between homeless men and men in the control group for hospitalization for heart disease (RR 1.35), chronic obstructive pulmonary disease (RR 2.60) and poisoning (RR 1.89). Among women, the difference had decreased between homeless women and women in the control group for skin disease (RR 0.20) and injury/poisoning (RR 0.60). There was no significant difference between the sexes in the two homeless cohorts. CONCLUSIONS: There was no improvement in excess hospitalization among homeless people over time. The difference between young homeless men and young men in the general population increased between 1996 and 2000-2002.

What is the impact of flexicurity on the chances of entry into employment for people with low education and activity limitations due to health problems? A comparison of 21 European countries using Qualitative Comparative Analysis (QCA).

BACKGROUND: Employment and unemployment are key determinants of health inequalities and should be a priority when discussing policies to reduce such inequalities. Our aim is to investigate how flexicurity policies across European countries impact on the employment chances for people with low education and activity limitations. METHODS: The longitudinal EU-SILC dataset, pooled 2005-2010, was used to calculate labour market outcomes. The sample consisted of 25 countries and 19,881 individuals. The employment transitions of non-employed people with activity limitations was followed from one year to the next, and the outcomes were rates of return-to work (RTW) among those with low education, and relative equality of RTW between those with low and high education (rate ratio, RR). Data on flexicurity policy and labour market factors were accessed from Eurostat and the OECD. As policy data was only available for OECD countries, the sample was reduced to 21 countries. Fuzzy-set QCA (Qualitative Comparative Analysis) was used to examine how different combinations of the components of flexicurity were linked to the two outcomes. RESULTS: Where high rates of RTW were achieved, high employment rates were always present. In five countries (the Nordic countries and the Netherlands) these factors coexisted with high expenditure on active labour market policies and social services in old age. In three others (The Czech Republic, UK and Estonia) they were combined with low employment protection and low benefit expenditure. For equality in RTW, low unemployment rates were combined with either high benefit expenditure, or low employment protection. CONCLUSION: We found two routes that lead to high RTW: we characterise these as the high road and the low road. Taking the low road (relaxing employment protection and limiting benefits) may be a tempting option for poorly performing countries. However, without measures to stimulate female employment it may not be enough as high overall employment is so important in enabling people with activity limitations to access the labour market. To achieve equality in RTW, it seems that as long as unemployment is low, either flexibility or security is sufficient.

Employment and income among first-time cases diagnosed with non-affective psychosis in Stockholm, Sweden: a follow-up study 2004/2005-2010.

PURPOSE: Non-affective psychoses (F20-F29) are serious conditions causing a high degree of disability. Loss of income and increasing costs for personal care and treatment are severe consequences following the disorders, but less is known about employment and income in different social strata. The aim was to study these conditions among persons with non-affective psychosis compared to the general population, and possible social differentials. METHODS: A population-based follow-up study with 530,350 persons (aged 18-44), including 756 first-time cases diagnosed with non-affective psychosis registered in in- or outpatient psychiatric care in 2005 or 2006. Age-standardised rates of non-employment, disability pension, social assistance and poverty were calculated at baseline and at follow-up in 2010. Odds ratios of poverty were estimated using logistic regression, adjusting for employment status, age, education and country of birth. RESULTS: Before diagnosis, rates of non-employment, disability pension and social assistance were higher among persons with non-affective psychosis compared to the general population. At the follow-up, rates of disability pension had doubled, most pronounced among women with only compulsory education. Rates of social assistance were twice as high for foreign-born women. Among persons with non-affective psychosis, non-employment, lower education (among men) and being foreign born (among women) were associated with an increased risk of poverty at follow-up. CONCLUSIONS: Poor employment and income conditions were found among persons with non-affective psychosis, but the social insurance system seemed to alleviate the poor income conditions. Early and preventative support to encourage employment and income security is needed, which could support recovery.

Comparing healthcare utilization among health survey respondents with the total population - are respondents representative?

BACKGROUND: Surveys are often used for analysis of health status and healthcare utilization in different socioeconomic groups. However, differential non-response rates may bias results. The aim of this study was to compare register data on outpatient healthcare utilization among respondents to a health survey to that of the total population and to investigate whether socioeconomic differences in outpatient healthcare utilization differ between survey respondents and the total population. METHOD: Data from the Stockholm Public Health Survey 2010 (n = 30,767 aged 18 + years) were linked to register data on outpatient healthcare utilization in order to investigate differentials by socioeconomic groups, country of birth and residential areas among respondents, using logistic regression and negative binomial regression. These results were compared to analyses of register data on outpatient healthcare utilization for the total population (n = 1.6 million aged 18 + years) of Stockholm County. RESULTS: Outpatient healthcare utilization was generally higher among survey respondents than in the total population, especially among men. The proportion of individuals having made at least one visit was significantly higher among survey respondents than in the total population but the differences were smaller regarding the average number of visits. Socioeconomic differences in outpatient healthcare utilization between subgroups were largely similar among survey respondents and in the total population. However, individuals born outside Sweden responding to the survey had significantly higher outpatient healthcare utilisation than individuals born outside Sweden in the total population. CONCLUSION: Compared to the total population, a greater proportion of survey respondents had made at least one outpatient visit to the doctor. However, the mean number of registered visits did not differ significantly between survey respondents and the total population. Hence, depending on the outcome measure used survey-based estimates may result in slightly biased prevalence estimates, however, relative differences among survey respondents were to a large degree comparable to relative differences in the total population. In contrast, survey respondents born outside Sweden differed from persons born outside Sweden in the total population to a degree where they may not be representative and comparisons between this group and other subgroups, using survey data, may be biased.

Equity impact of a choice reform and change in reimbursement system in primary care in Stockholm County Council.

BACKGROUND: In 2008 reforms were introduced in primary care in Stockholm County Council to increase patient choice. These reforms included changes to the reimbursement system from one that was primarily based on need-weighted capitation system (75%) to a system largely based on fee-for-service (60%) and freedom of establishment of primary care clinics. The new reimbursement system created incentives for producing many visits and additional primary care clinics were established, particularly in areas that were already well served. This study analyses if and how the choice reform and change of reimbursement system has affected equity in primary care consumption by investigating whether the increase in visits reflects levels of need and to what extent the reform have affected equity in health care between areas. METHODS: Cross-sectional data from the public health survey in Stockholm County 2006 (n = 34,707) and 2010 (n = 30,767) were linked to individual register data on socio-demographic characteristics and health care utilization in 2007 and 2011. Information on self-reported health status and disability pension was used as indicators of need of health care. Negative binomial regression was used to analyse the differences in GP visits between the two years. RESULTS: The total number of visits to GPs increased by 46 % from 2007 to 2011 and the proportion visiting a GP increased by 17%. Both men and women reporting poor mental health and women with limiting longstanding illness and poor self-rated health had significantly smaller increase in number of visits than healthy women and men. Men with poor health status living in disadvantaged areas had a smaller increase than men with poor health status living in other areas of Stockholm County. CONCLUSIONS: The reform did not particularly benefit those with greater health care needs, and there are indications of a negative impact on equity in primary care after the introduction of the reform. There were signs of a lesser increase in total number of visits to GPs among those with poor mental health, among women with poor self-rated health and limiting longstanding illness, and among men living in disadvantaged areas.

The association between immigrant subgroup and poor mental health: a population-based register study.

Ethnicity and immigrant subgroup (classified as refugee or nonrefugee) are associated with poor mental health among immigrants. The aim of this study was to assess whether national origin-based differences in poor mental health can be explained by immigrant subgroup and if its importance varies depending on origin. A cross-sectional, population-based study of Swedish residents was conducted in 2006. The outcome was poor mental health, measured with the proxy variable psychotropic drugs purchased. Explanatory variables included immigrant subgroup and origin. Potential confounders were age, marital status, education, time in Sweden, and children. Logistic regression was carried out. The total population was 5,507,262. Immigrants from countries outside the Organisation for Economic Co-operation and Development (OECD) numbered 298,641. Immigrant subgroup partly explained the higher likelihood of poor mental health among non-OECD immigrants; when each country or area was analyzed separately, most refugees had a higher likelihood than nonrefugees did. Immigrant subgroup partly explained the origin-based differences in mental health, but this varied between different groups of origin.

Socioeconomic differences in healthcare utilization, with and without adjustment for need: an example from Stockholm, Sweden.

AIM: Previous studies have shown varying degrees of inequity of utilization of healthcare in Sweden. Studies based solely on register data cannot take into account differences in health status while studies based solely on self-reported data from surveys may potentially have biased data on healthcare utilization. The aim of this study was to investigate socioeconomic differences in utilization of outpatient healthcare services in Stockholm County, comparing analysis based on only register data, with analysis based on health survey data linked to register data. METHODS: We linked data from a public health survey in Stockholm County 2006 (n = 34,707) to register data on sociodemographic background characteristics and outpatient healthcare utilization in 2007. Negative binomial regression analysis was used to estimate income differentials in healthcare utilization adjusting for self-rated health and limiting longstanding illness. RESULTS: Income differentials in the number of visits to doctors were found in favour of lower-income groups among people aged 25-64 years when only controlling for age. When controlling for health status, income differentials in favour of higher-income groups were observed among men (all ages) and among women aged 65+ years, with higher-income groups having 11-49% more visits than the lowest income group. CONCLUSIONS: The findings suggest that health status should be taken into account when analysing socioeconomic differences in healthcare utilization. When using only register based data there is a risk of underestimating or disregarding differences.

Trends in poverty risks among people with and without limiting-longstanding illness by employment status in Sweden, Denmark, and the United Kingdom during the current economic recession--a comparative study.

BACKGROUND: Previous studies have found higher employment rates and lower risk of relative poverty among people with chronic illness in the Nordic countries than in the rest of Europe. However, Nordic countries have not been immune to the general rise in poverty in many welfare states in recent decades. This study analysed the trends in poverty risks among a particularly vulnerable group in the labour market: people with limiting-longstanding illness (LLSI), examining the experience of those with and without employment, and compared to healthy people in employment in Sweden, Denmark and the United Kingdom. METHODS: Cross-sectional survey data from EU-SILC (European Union Statistics on Income and Living Conditions) on people aged 25-64 years in Sweden, Denmark and the United Kingdom (UK) were analysed between 2005 and 2010. Age-standardised rates of poverty risks (<60% of national median equalised disposable income) were calculated. Odds ratios (ORs) of poverty risks were estimated using logistic regression. RESULTS: In all three countries, non-employed people with LLSI had considerably higher prevalence of poverty risk than employed people with or without LLSI. Rates of poverty risk in the UK for non-employed people with LLSI were higher than in Sweden and Denmark. Over time, the rates of poverty risk for Swedish non-employed people with LLSI in 2005 (13.8% CI=9.7-17.8) had almost doubled by 2010 (26.5% CI=19.9-33.1). For both sexes, the inequalities in poverty risks between non-employed people with LLSI and healthy employed people were much higher in the UK than in Sweden and Denmark. Over time, however, the odds of poverty risk among British non-employed men and women with LLSI compared with their healthy employed counterparts declined. The opposite trend was seen for Swedish men: the odds of poverty risk for non-employed men with LLSI compared with healthy employed men increased from OR 2.8 (CIs=1.6-4.7) in 2005 to OR 5.3 (CIs=3.2-8.9) in 2010. CONCLUSIONS: The increasing poverty risks among the non-employed people with LLSI in Sweden over time are of concern from a health equity perspective. The role of recent Swedish social policy changes should be further investigated.

Age-specific and sex-specific risks for HCC in African-born persons with chronic hepatitis B without cirrhosis.

BACKGROUND: The international recommendations of HCC surveillance for African-born persons with chronic hepatitis B (CHB) without cirrhosis are divergent, probably due to scarce data on incidence rate (IR) for HCC. METHODS: We assembled a cohort with prospectively collected data of Swedish residents of African origin with diagnosed CHB without cirrhosis at baseline from 1990 to 2015. Data from nationwide registers were used to calculate the sex-specific IR and IR ratio (incidence rate ratios) in relation to age, comorbidities, and birth region, using a generalized linear model with a log-link function and Poisson distribution. RESULTS: Among 3865 African-born persons with CHB without cirrhosis at baseline, 31 (0.8%; 77.4% men) developed HCC during a median of 11.1 years of follow-up, with poor survival after HCC diagnosis. The mean age at HCC diagnosis was 46.8 (SD±14.7; range 23-79) in men. HCC IR exceeded the recommended surveillance threshold of 0.2%/year at ages 54 and 59 years in men and women, respectively, and at ages 20-40 years if HCV or HDV co-infection was present. African-born men with CHB had an incidence rate ratios of 10.6 (95% CI 4.4-31.5) for HCC compared to matched African-born peers without CHB, and an incidence rate ratios of 35.3 (95% CI 16.0-88.7) compared to a matched general population. CONCLUSIONS: African-born men with CHB without cirrhosis reached an IR of 0.2%/year between 50 and 60 years, and at younger ages if HCV or HDV co-infection was present. Our findings need further confirmation, and new cost-effectiveness analyses specific for young populations are needed, to provide personalized and cost-effective HCC surveillance.

Gender-related mental health differences between refugees and non-refugee immigrants--a cross-sectional register-based study.

BACKGROUND: Being an immigrant in a high-income country is a risk factor for severe mental ill health. Studies on mental ill health among immigrants have found significant differences in mental health outcome between immigrants from high income countries and low-income countries. Being an asylum seeker or a refugee is also associated with mental ill health. This study aimed to assess if there is a difference in mental ill health problems between male and female refugee and non-refugee immigrants from six low-income countries in Sweden. METHODS: A cross-sectional, population-based study design was used comparing refugees with non-refugees. The study size was determined by the number of persons in Sweden fulfilling the inclusion criteria at the time of the study during 2006. OUTCOME: Mental ill health, as measured with the proxy variable psychotropic drugs purchased. Refugee/Non-refugee: Sweden grants asylum to refugees according to the Geneva Convention and those with a well-grounded fear of death penalty, torture or who need protection due to an internal or external armed conflict or an environmental disaster. The non-refugees were all family members of those granted asylum in Sweden. Covariates: Gender and origin. Potential confounders: Age, marital status, education and duration of stay in Sweden. Background variables were analysed using chi square tests. The association between outcome, exposure and possible confounders was analysed using logistic regression analyses. Multiple logistic regression analysis was used to adjust for potential confounders. RESULTS: The study population comprised 43,168 refugees and non-refugees, of whom 20,940 (48.5%) were women and 24,403 (56.5%) were refugees. Gender, age, origin, marital status and education were all associated with the outcome. For female, but not male, refugees there was a significantly higher likelihood of purchasing psychotropic drugs than non-refugees (OR = 1.27, 95% CI = 1.15-1.40). CONCLUSIONS: Female refugees from low-income countries seem to be a risk group among immigrant women from low-income countries, whereas male refugees had the same risk patterns as non-refugee immigrants from low-income countries. This underlines the need for training of clinicians in order to focus on pre-migration stress and the asylum process, among female newcomers.

Validation of data quality in the National Swedish Kidney Cancer Register.

INTRODUCTION: The National Swedish Kidney Cancer Register (NSKCR) was launched in 2005. It is used for health care quality improvement and research. The aim of this study was to validate the register's data quality by assessing the timeliness, completeness, comparability and validity of the register. MATERIAL AND METHODS: To assess timeliness we evaluated the number of days between date of diagnosis and date of reporting the patient to the NSKCR. For completeness, we used data on number of cancer cases reported to the NSKCR compared to cases reported to the Swedish Cancer Register. Comparability was evaluated by reviewing coding routines and comparing data collected in the NSKCR to national and international guidelines. Validity was assessed by reabstraction of data from medical charts from 431 randomly selected patients diagnosed in 2007, 2010, 2013 and 2016. RESULTS: Timeliness has improved since the register started. In 2016, 76.9% and 96.5% of the patients were reported within 6 and 12 months respectively. Completeness was high, with a 99.5% coverage between 2008 and 2017. Registration forms and manuals were updated according to national and European guidelines. Improvements have been made continuously to decrease the risk of reporting mistakes and misunderstandings. Validity was high where a majority of the variables demonstrated an exact agreement >90% and few missing values. CONCLUSION: Overall, the data quality of the NSKCR is high. Completeness, comparability and validity is high. Timeliness can be further improved, which will make it easier to follow changes and improve the care and research of RCC patients.

Obtaining Tertiary Protein Structures by the ab Initio Interpretation of Small Angle X-ray Scattering Data.

Small angle X-ray scattering (SAXS) is an important tool for investigating the structure of proteins in solution. We present a novel ab initio method representing polypeptide chains as discrete curves used to derive a meaningful three-dimensional model from only the primary sequence and SAXS data. High resolution structures were used to generate probability density functions for each common secondary structural element found in proteins, which are used to place realistic restraints on the model curve's geometry. This is coupled with a novel explicit hydration shell model in order to derive physically meaningful three-dimensional models by optimizing against experimental SAXS data. The efficacy of this model is verified on an established benchmark protein set, and then it is used to predict the lysozyme structure using only its primary sequence and SAXS data. The method is used to generate a biologically plausible model of the coiled-coil component of the human synaptonemal complex central element protein.

Topical Application of Loperamide/Oxymorphindole, Mu and Delta Opioid Receptor Agonists, Reduces Sensitization of C-fiber Nociceptors that Possess NaV1.8.

It was recently shown that local injection, systemic administration or topical application of the peripherally-restricted mu-opioid receptor (MOR) agonist loperamide (Lo) and the delta-opioid receptor (DOR) agonist oxymorphindole (OMI) synergized to produce highly potent anti-hyperalgesia that was dependent on both MOR and DOR located in the periphery. We assessed peripheral mechanisms by which this Lo/OMI combination produces analgesia in mice expressing the light-sensitive protein channelrhodopsin2 (ChR2) in neurons that express NaV1.8 voltage-gated sodium channels. These mice (NaV1.8-ChR2+) enabled us to selectively target and record electrophysiological activity from these neurons (the majority of which are nociceptive) using blue light stimulation of the hind paw. We assessed the effect of Lo/OMI on nociceptor activity in both naïve mice and mice treated with complete Freund's adjuvant (CFA) to induce chronic inflammation of the hind paw. Teased fiber recording of tibial nerve fibers innervating the plantar hind paw revealed that the Lo/OMI combination reduced responses to light stimulation in naïve mice and attenuated spontaneous activity (SA) as well as responses to light and mechanical stimuli in CFA-treated mice. These results show that Lo/OMI reduces activity of C-fiber nociceptors that express NaV1.8 and corroborate recent behavioral studies demonstrating the potent analgesic effects of this drug combination. Because of its peripheral site of action, Lo/OMI might produce effective analgesia without the side effects associated with activation of opioid receptors in the central nervous system.

How to Stabilize Protein: Stability Screens for Thermal Shift Assays and Nano Differential Scanning Fluorimetry in the Virus-X Project.

The Horizon2020 Virus-X project was established in 2015 to explore the virosphere of selected extreme biotopes and discover novel viral proteins. To evaluate the potential biotechnical value of these proteins, the analysis of protein structures and functions is a central challenge in this program. The stability of protein sample is essential to provide meaningful assay results and increase the crystallizability of the targets. The thermal shift assay (TSA), a fluorescence-based technique, is established as a popular method for optimizing the conditions for protein stability in high-throughput. In TSAs, the employed fluorophores are extrinsic, environmentally-sensitive dyes. An alternative, similar technique is nano differential scanning fluorimetry (nanoDSF), which relies on protein native fluorescence. We present here a novel osmolyte screen, a 96-condition screen of organic additives designed to guide crystallization trials through preliminary TSA experiments. Together with previously-developed pH and salt screens, the set of three screens provides a comprehensive analysis of protein stability in a wide range of buffer systems and additives. The utility of the screens is demonstrated in the TSA and nanoDSF analysis of lysozyme and Protein X, a target protein of the Virus-X project.