Diverse methodological approaches to a Circumpolar multi-site case study which upholds and responds to local and Indigenous community research processes in the Arctic.

This paper outlines the methodological approaches to a multi-site Circumpolar case study exploring the impacts of COVID-19 on Indigenous and remote communities in 7 of 8 Arctic countries. Researchers involved with the project implemented a three-phase multi-site case study to assess the positive and negative societal outcomes associated with the COVID-19 pandemic in Arctic communities from 2020 to 2023. The goal of the multi-site case study was to identify community-driven models and evidence-based promising practices and recommendations that can help inform cohesive and coordinated public health responses and protocols related to future public health emergencies in the Arctic. Research sites included a minimum of 1 one community each from Canada (Nunavut,) United States of America (Alaska), Greenland, Iceland, Norway, Sweden, Finland. The approaches used for our multi-site case study provide a comprehensive, evidence-based account of the complex health challenges facing Arctic communities, offering insights into the effectiveness of interventions, while also privileging Indigenous local knowledge and voices. The mixed method multi-site case study approach enriched the understanding of unique regional health disparities and strengths during the pandemic. These methodological approaches serve as a valuable resource for policymakers, researchers, and healthcare professionals, informing future strategies and interventions.

Public health restrictions, directives, and measures in Arctic countries in the first year of the COVID-19 pandemic.

Beginning January of 2020, COVID-19 cases detected in Arctic countries triggered government policy responses to stop transmission and limit caseloads beneath levels that would overwhelm existing healthcare systems. This review details the various restrictions, health mandates, and transmission mitigation strategies imposed by governments in eight Arctic countries (the United States, Canada, Greenland, Norway, Finland, Sweden, Iceland, and Russia) during the first year of the COVID-19 pandemic, through 31 January 2021s31 January 2021. We highlight formal protocols and informal initiatives adopted by local communities in each country, beyond what was mandated by regional or national governments. This review documents travel restrictions, communications, testing strategies, and use of health technology to track and monitor COVID-19 cases. We provide geographical and sociocultural background and draw on local media and communications to contextualise the impact of COVID-19 emergence and prevention measures in Indigenous communities in the Arctic. Countries saw varied case rates associated with local protocols, governance, and population. Still, almost all regions maintained low COVID-19 case rates until November of 2020. This review was produced as part of an international collaboration to identify community-driven, evidence-based promising practices and recommendations to inform pan-Arctic collaboration and decision making in public health during global emergencies.

Ethnic discrimination and mental health in the Sámi population in Sweden: The SámiHET study.

AIMS: To assess the association between experiences of discrimination and mental health among the Sámi population in Sweden. METHODS: Cross-sectional study among the self-identified Sámi population living in Sweden in 2021, registered in the electoral roll of the Sámi Parliament, the reindeer mark register and the 'Labour statistics based on administrative sources'. The analysis was based on a final sample of 3658 respondents aged between 18 and 84 years. Adjusted prevalence ratios aPRs for psychological distress (Kessler scale), self-reported anxiety and depression were estimated for four different forms of discrimination (direct experience of discrimination, offended because of ethnicity, historical trauma, and combined discrimination). RESULTS: Higher aPRs of psychological distress, anxiety and depression were observed in women experiencing direct discrimination because of their ethnicity, having been offended because of their ethnicity, and those with a family history of discrimination. Among men, higher aPRs for psychological distress were observed in those experiencing the four different forms of discrimination, but not for anxiety. Depression was only detected in the case of having been offended. Adding experiences of discrimination was associated with a higher prevalence of negative outcomes for all the indicators in women and for psychological distress in men. CONCLUSIONS: The observed association between experiences of discrimination and mental health problems would support a gender approach when considering ethnic discrimination in public health policies concerning the Sámi in Sweden.

Methods to assess validity of positioning systems in team sports: can we do better?

Objectives: There is previously reported a large variety of criterion measures and reference systems applied to validate position tracking systems in sports. This study aims to investigate the effect of different criterion measures and reference systems on the outcome of accuracy assessments of tracking systems in sports. Methods: Data from a commercially available standalone global navigation satellite system (GNSS) were compared with two different reference systems: a high-end differential GNSS and a tape measure. Differences in accuracy outcomes of position (static and dynamic), distance and speed (mean and instantaneous) were investigated in team sport imitation courses. Results: The mean horizontal position error was larger when athletes were in motion (dynamic position; 1.53±0.82 m) compared with static measurements (1.10±0.60 m). Measured distances of the courses were markedly different (+6% to -17%) between the two reference systems, causing differences in error. Differences in error were also found between mean speed and instantaneous speed (0.10 vs 0.28 m). Errors in mean speed were highly affected by the time over which speed was averaged. Conclusion: Choice of criterion measure and reference system has a substantial impact on the accuracy assessments of tracking systems. Specifically, assessing static position is not a substitute for dynamic position, and mean speed is not a substitute for instantaneous speed. Therefore, the outcomes of validation studies should always be interpreted in light of the reference methods that were used.

A population-based study on health and living conditions among Sámi in Sweden: the SámiHET study.

The aim of this paper was to describe the study design, data collection procedure and participation of the population-based study "Sámi Health on Equal Terms" (SámiHET) conducted among the Sámi in Sweden in 2021. A Sámi sample was constructed, drawing from three pre-existing-registers: the Sámi electoral roll, the reindeer mark register and the "Labour statistics based on administrative sources" register to identify reindeer herding businesses. All identified persons aged 18-84 were invited to participate during February-May 2021. Among the 9,249 invitations, 3,779 answered the survey (participation rate of 40.9%). More women than men participated, and the age group 45-64 was the most common in both sexes. Around 10% of participants were in the youngest group. A majority of participants were residents of Norrbotten (48%), while almost one fourth were living outside Sápmi (22%). SámiHET has been demonstrated to be a feasible and cost-effective way of investigating health and living conditions among the Sámi in Sweden, providing information easy to compare with Swedish data. The knowledge to be produced may be used to inform policy to guide and improve Sámi health, thus contributing to realising the equal health rights of the Indigenous Sámi in Sweden.

Quality of clinical management of cardiometabolic risk factors in patients with severe mental illness in a specialist mental health care setting.

PURPOSE: Cardiometabolic disease in patients with severe mental illness is a major cause of shortened life expectancy. There is sparse evidence of real-world clinical risk prevention practice. We investigated levels of assessments of cardiometabolic risk factors and risk management interventions in patients with severe mental illness in the Norwegian mental health service according to an acknowledged international standard. METHODS: We collected data from 264 patients residing in six country-wide health trusts for: (a) assessments of cardiometabolic risk and (b) assessments of levels of risk reducing interventions. Logistic regressions were employed to investigate associations between risk and interventions. RESULTS: Complete assessments of all cardiometabolic risk variables were performed in 50% of the participants and 88% thereof had risk levels requiring intervention according to the standard. Smoking cessation advice was provided to 45% of daily smokers and 4% were referred to an intervention program. Obesity was identified in 62% and was associated with lifestyle interventions. Reassessment of psychotropic medication was done in 28% of the obese patients. Women with obesity were less likely to receive dietary advice, and use of clozapine or olanzapine reduced the chances for patients with obesity of getting weight reducing interventions. CONCLUSIONS: Nearly nine out of the ten participants were identified as being at cardiometabolic high risk and only half of the participants were adequately screened. Women with obesity and patients using antipsychotics with higher levels of cardiometabolic side effects had fewer adequate interventions. The findings underscore the need for standardized recommendations for identification and provision of cardiometabolic risk reducing interventions in all patients with severe mental illness.

The Tankyrase Inhibitor OM-153 Demonstrates Antitumor Efficacy and a Therapeutic Window in Mouse Models.

The catalytic enzymes tankyrase 1 and 2 (TNKS1/2) alter protein turnover by poly-ADP-ribosylating target proteins, which earmark them for degradation by the ubiquitin-proteasomal system. Prominent targets of the catalytic activity of TNKS1/2 include AXIN proteins, resulting in TNKS1/2 being attractive biotargets for addressing of oncogenic WNT/ß-catenin signaling. Although several potent small molecules have been developed to inhibit TNKS1/2, there are currently no TNKS1/2 inhibitors available in clinical practice. The development of tankyrase inhibitors has mainly been disadvantaged by concerns over biotarget-dependent intestinal toxicity and a deficient therapeutic window. Here we show that the novel, potent, and selective 1,2,4-triazole-based TNKS1/2 inhibitor OM-153 reduces WNT/ß-catenin signaling and tumor progression in COLO 320DM colon carcinoma xenografts upon oral administration of 0.33-10 mg/kg twice daily. In addition, OM-153 potentiates anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint inhibition and antitumor effect in a B16-F10 mouse melanoma model. A 28-day repeated dose mouse toxicity study documents body weight loss, intestinal damage, and tubular damage in the kidney after oral-twice daily administration of 100 mg/kg. In contrast, mice treated oral-twice daily with 10 mg/kg show an intact intestinal architecture and no atypical histopathologic changes in other organs. In addition, clinical biochemistry and hematologic analyses do not identify changes indicating substantial toxicity. The results demonstrate OM-153-mediated antitumor effects and a therapeutic window in a colon carcinoma mouse model ranging from 0.33 to at least 10 mg/kg, and provide a framework for using OM-153 for further preclinical evaluations. Significance: This study uncovers the effectiveness and therapeutic window for a novel tankyrase inhibitor in mouse tumor models.

"Mapping suicide prevention initiatives targeting Indigenous Sámi in Nordic countries".

BACKGROUND: Suicide is a major public health issue among Indigenous Sámi in Nordic countries, and efforts to prevent suicide in the Sámi context are increasing. However, there is no literature on suicide prevention initiatives among Sámi. The aim of the study was to map suicide prevention initiatives targeting Sámi in Norway, Sweden, and Finland during 2005-2019. METHOD: Initiatives were identified and described through utilizing networks among stakeholders in the field of suicide prevention among Sámi, acquiring documentation of initiatives and utilizing the authors first-hand experiences. The described initiatives were analyzed inspired by the "What is the problem represented to be?" (WPR)-approach. RESULTS: Seventeen initiatives targeting Sámi were identified during 2005-2019, including nine in Sweden, five in Norway, one in Finland and two international initiatives. Analysis with the WPR-approach yielded 40 problematizations regarding how to prevent suicide among Sámi, pertaining to shortcomings on individual (5), relational (15), community/cultural (3), societal (14) and health systems levels (3). All initiatives were adapted to the Sámi context, varying from tailor-made, culture-specific approaches to targeting Sámi with universal approaches. The most common approaches were the gatekeeper and mental health literacy training programs. The initiatives generally lacked thorough evaluation components. CONCLUSION: We argue that the dominant rationales for suicide prevention were addressing shortcomings on individual and relational levels, and raising awareness in the general public. This threatens obscuring other, critical, approaches, such as broadening perspectives in prevention planning, improving health systems for Sámi, and promoting cultural empowerment among Sámi. Nevertheless, the study confirms considerable efforts have been invested into suicide prevention among Sámi during the last 15 years, and future initiatives might include a broader set of prevention rationales. To improve evaluation and identify the most promising practices, increased support regarding development of plans and implementation of evaluation components is needed.

Suicide among reindeer herding Sámi in Sweden, 1961-2017.

This study analyses suicides amongst reindeer herding Sámi in Sweden using information from the database of the National Board of Forensic Medicine. Suicides were identified using registers (39 suicides from 1961-2000) and key informants (11 suicides from 2001-2017). A great majority of cases were males (43 males, 7 females), and 50% occurred in the northernmost region. The mean age was 37.4 years with a peak in the group 20-29 years of age. Shooting was the most common (56%) method, followed by hanging. Blood alcohol concentration measures available from 1993 were above 0.2 g/l in 76% of the cases. There was a maximum incidence of suicides between 1981 and 1990. An accumulation of suicides in the months of May (N = 8) and November (N = 7) was seen. The annual suicide rate was estimated to be between 17.5 and 43.9 per 100 000 population. There was a clear gradient in suicide incidence with the highest being in the southernmost region (Jämtland/Härjedalen) and the lowest in the northernmost county (Norrbotten). For strengthened suicide prevention in this group, future research should address sex differences, the role of alcohol use and the general conditions for reindeer herding.

TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting ß-CATENIN and AKT Signaling in Colorectal Cancer.

Overactivation of the WNT/ß-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond positively to TNKS inhibition in vitro and in vivo Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor-sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/ß-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts in vivo At the highest doses, tumor xenograft growth was halted without affecting the body weight of the tested animals.Implications: Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. Mol Cancer Res; 16(3); 543-53. ©2017 AACR.

Cannabis use in first-treatment bipolar I disorder: relations to clinical characteristics.

AIMS: The aim of this study was to investigate the associations between recent cannabis use, current symptomatology and age at onset of first manic, depressive and psychotic episodes in a large sample with first-treatment bipolar I disorder (BD I). METHODS: One hundred one patients with first-treatment Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) bipolar I disorder were included as part of the Thematically Organized Psychosis study. The Structural Clinical Interview for DSM-IV was used for DSM-IV diagnosis and identification of episodes of illness. Earlier suicide attempts were recorded. Manic, depressive and psychotic symptoms were rated using the Young Mania Rating Scale, Inventory of Depressive Symptoms and Positive and Negative Syndrome Scale correspondingly. Cannabis use within the six last months was recorded. RESULTS: After controlling for confounders, recent cannabis use was significantly associated with lower age at onset of first manic and psychotic episode, but not with onset of first depressive episode (both P < 0.05). Recent use was also associated with more lifetime suicide attempts (P < 0.01). No group differences were found on symptom levels. CONCLUSIONS: The present study confirms earlier findings of an association between cannabis use and a lower age at onset. Recent cannabis use was also associated with more lifetime suicide attempts. The current findings suggest that recent cannabis use is associated with a more severe course of illness in the early phase of BD I.

"We are like lemmings": making sense of the cultural meaning(s) of suicide among the indigenous Sami in Sweden.

BACKGROUND: Suicide is a widespread problem among indigenous people residing in the circumpolar Arctic. Though the situation among the indigenous Sami in northern Scandinavia is better than among some other indigenous people, suicide is still regarded as a major public health issue. To adapt prevention strategies that are culturally attuned one must understand how suicide is understood within context. That is, the cultural meaning(s) of suicide. OBJECTIVE: To explore and make sense of the cultural meaning(s) of suicide among Sami in Sweden. DESIGN: Open-ended focus group discussions (FGDs) on the topic "suicide among Sami" were carried out in 5 Sami communities in Sweden, with in total 22 strategically selected Sami participants. FGDs were recorded, transcribed verbatim and analyzed through employing content analysis. RESULTS: From the FGDs 4 themes emerged including "The Sami are fighting for their culture and the herders are in the middle of the fight," "Suicide as a consequence of Sami losing (or having lost) their identity," "A wildfire in the Sami world" and "Difficult to get help as a Sami." CONCLUSIONS: Findings indicate that Sami in Sweden make sense of suicide in relation to power and identity within a threatened Sami cultural context. Suicide is then understood as an act that takes place and makes sense to others when a Sami no longer has the power to maintain a Sami identity, resulting in being disconnected from the Sami world and placed in an existential void where suicide is a solution. The findings are useful in development of culturally attuned suicide prevention among Sami in Sweden.

Regular atrial tachycardias developing after cryoballoon pulmonary vein isolation: incidence, characteristics, and predictors.

AIMS: Cryoballoon ablation (CBA) is a well-used technique when performing pulmonary vein (PV) isolation in patients with paroxysmal atrial fibrillation (AF). Our aim is to describe incidence, characteristics, and clinical predictors for developing atrial tachycardias (ATs) after cryoballoon PV isolation in patients with paroxysmal AF. METHODS AND RESULTS: The study population consisted of 181 consecutive patients undergoing a first CBA. All patients received an event-recorder before cryoablation and transmitted daily electrocardiogram (ECG) during 1 month before ablation and 3 months after. Further follow-up consisted of 24 h Holter monitoring and ECG registration every 3 months and also in patients presenting with symptoms. A mean follow-up period was 497.9 ± 283.9 days, and 175 patients completed follow-up. In 14 (8%) patients regular ATs were registered. In multivariate logistic regression model, the following parameters were independently associated with ATs after ablation: an additional right PV, treatment with beta-blockers, and presence of AT on event-recording strips before ablation. Seven (4%) patients with registered AT underwent a redo procedure. In two (1.1%) patients ATs were originated in reconnected PVs. In other patients no left AT was induced. No macro re-entrant left AT was documented in any patient. During follow-up, after a redo ablation, no AT was registered. CONCLUSION: The incidence of left AT after CBA is low, and no left atrial macro re-entrant tachycardia was found. The following independent predictors of AT development have been identified: an additional right PV, regular AT registered before ablation, and the use of beta-blockers.

Outcome when adrenaline (epinephrine) was actually given vs. not given - post hoc analysis of a randomized clinical trial.

PURPOSE OF THE STUDY: IV line insertion and drugs did not affect long-term survival in an out-of-hospital cardiac arrest (OHCA) randomized clinical trial (RCT). In a previous large registry study adrenaline was negatively associated with survival from OHCA. The present post hoc analysis on the RCT data compares outcomes for patients actually receiving adrenaline to those not receiving adrenaline. MATERIALS AND METHODS: Patients from a RCT performed May 2003 to April 2008 were included. Three patients from the original intention-to-treat analysis were excluded due to insufficient documentation of adrenaline administration. Quality of cardiopulmonary resuscitation (CPR) and clinical outcomes were compared. RESULTS: Clinical characteristics were similar and CPR quality comparable and within guideline recommendations for 367 patients receiving adrenaline and 481 patients not receiving adrenaline. Odds ratio (OR) for being admitted to hospital, being discharged from hospital and surviving with favourable neurological outcome for the adrenaline vs. no-adrenaline group was 2.5 (CI 1.9, 3.4), 0.5 (CI 0.3, 0.8) and 0.4 (CI 0.2, 0.7), respectively. Ventricular fibrillation, response interval, witnessed arrest, gender, age and endotracheal intubation were confounders in multivariate logistic regression analysis. OR for survival for adrenaline vs. no-adrenaline adjusted for confounders was 0.52 (95% CI: 0.29, 0.92). CONCLUSION: Receiving adrenaline was associated with improved short-term survival, but decreased survival to hospital discharge and survival with favourable neurological outcome after OHCA. This post hoc survival analysis is in contrast to the previous intention-to-treat analysis of the same data, but agrees with previous non-randomized registry data. This shows limitations of non-randomized or non-intention-to-treat analyses.

Patients Referred to a Norwegian Trauma Centre: effect of transfer distance on injury patterns, use of resources and outcomes.

BACKGROUND: Triage and interhospital transfer are central to trauma systems. Few studies have addressed transferred trauma patients. This study investigated transfers of variable distances to OUH (Oslo University Hospital, Ullevål), one of the largest trauma centres in Europe. METHODS: Patients included in the OUH trauma registry from 2001 to 2008 were included in the study. Demographic, injury, management and outcome data were abstracted. Patients were grouped according to transfer distance: ≤20 km, 21-100 km and > 100 km. RESULTS: Of the 7.353 included patients, 5.803 were admitted directly, and 1.550 were transferred. The number of transfers per year increased, and there was no reduction in injury severity during the study period. Seventy-six per cent of the transferred patients were severely injured. With greater transfer distances, injury severity increased, and there were larger proportions of traffic injuries, polytrauma and hypotensive patients. With shorter distances, patients were older, and head injuries and injuries after falls were more common. The shorter transfers less often activated the trauma team: ≤20 km -34%; 21-100 km -51%; > 100 km -61%, compared to 92% of all directly admitted patients. The mortality for all transferred patients was 11%, but was unequally distributed according to transfer distance. CONCLUSION: This study shows heterogeneous characteristics and high injury severity among interhospital transfers. The rate of trauma team assessment was low and should be further examined. The mortality differences should be interpreted with caution as patients were in different phases of management. The descriptive characteristics outlined may be employed in the development of triage protocols and transfer guidelines.

Excessive cannabis use is associated with earlier age at onset in bipolar disorder.

The aim of the study was to investigate which factors are associated with age at onset in bipolar disorder with a specific focus on excessive alcohol and cannabis use, and the sequence of the onsets of excessive substance use and bipolar disorder. We investigated a naturalistic sample of 151 patients with bipolar I and II disorder receiving psychiatric treatment. Whether the presence of excessive substance use prior to bipolar disorder onset or the type of substance used (alcohol or cannabis) was associated with differences in age at onset was investigated using hierarchical and multiple linear regression analyses, adjusting for potential confounders. Patients with excessive alcohol use had a significantly later onset compared with patients with excessive cannabis use. Excessive general substance use prior to bipolar disorder onset was associated with a later onset. However, excessive cannabis use was associated with an earlier onset whether it preceded or followed bipolar disorder onset, also after adjusting for possible confounders. Excessive use of alcohol or other substances was not independently associated with age at onset in multivariate analyses. Alcohol use was associated with a later onset compared with cannabis use, suggesting different relationships to the onset of bipolar disorder. Lifetime use of cannabis predicted an earlier onset, independent of the sequence of onsets. This indicates that an early onset may increase the risk of cannabis use and that cannabis use may trigger bipolar disorder in vulnerable individuals.

Added mass in human swimmers: age and gender differences.

In unstationary swimming (changing velocity), some of the water around the swimmer is set in motion. This can be thought of as an added mass (M(a)) of water. The purpose of this study was to find added mass on human swimmers and investigate the effect of shape and body size. Thirty subjects were connected to a 2.8m long bar with handles, attached with springs (stiffness k = 318 N/m) and a force cell. By oscillating this system vertically and registering the period of oscillations it was possible to find the added mass of the swimmer, given the known masses of the bar and swimmer. Relative added mass (M(a)%) for boys, women and men were, respectively, 26.8 +/- 2.9%, 23.6 +/- 1.6% and 26.8 +/- 2.3% of the subjects total mass. This study reported significantly lower added mass (p < 0.001) and relative added mass (p < 0.002) for women compared to men, which indicate that the possible body shape differences between genders may be an important factor for determining added mass. Boys had significantly lower (p < 0.001) added mass than men. When added mass was scaled for body size there were no significant differences (p = 0.996) between boys and men, which indicated that body size is an important factor that influences added mass. The added mass in this study seems to be lower and within a smaller range than previously reported (Klauck, 1999; Eik et al., 2008). It is concluded that the added mass in human swimmers, in extended gliding position, is approximately 1/4 of the subjects' body mass.

Analysis of illegitimate genomic integration mediated by zinc-finger nucleases: implications for specificity of targeted gene correction.

BACKGROUND: Formation of site specific genomic double strand breaks (DSBs), induced by the expression of a pair of engineered zinc-finger nucleases (ZFNs), dramatically increases the rates of homologous recombination (HR) between a specific genomic target and a donor plasmid. However, for the safe use of ZFN induced HR in practical applications, possible adverse effects of the technology such as cytotoxicity and genotoxicity need to be well understood. In this work, off-target activity of a pair of ZFNs has been examined by measuring the ratio between HR and illegitimate genomic integration in cells that are growing exponentially, and in cells that have been arrested in the G2/M phase. RESULTS: A reporter cell line that contained consensus ZFN binding sites in an enhanced green fluorescent protein (EGFP) reporter gene was used to measure ratios between HR and non-homologous integration of a plasmid template. Both in human cells (HEK 293) containing the consensus ZFN binding sites and in cells lacking the ZFN binding sites, a 3.5 fold increase in the level of illegitimate integration was observed upon ZFN expression. Since the reporter gene containing the consensus ZFN target sites was found to be intact in cells where illegitimate integration had occurred, increased rates of illegitimate integration most likely resulted from the formation of off-target genomic DSBs. Additionally, in a fraction of the ZFN treated cells the co-occurrence of both specific HR and illegitimate integration was observed. As a mean to minimize unspecific effects, cell cycle manipulation of the target cells by induction of a transient G2/M cell cycle arrest was shown to stimulate the activity of HR while having little effect on the levels of illegitimate integration, thus resulting in a nearly eight fold increase in the ratio between the two processes. CONCLUSIONS: The demonstration that ZFN expression, in addition to stimulating specific gene targeting by HR, leads to increased rates of illegitimate integration emphasizes the importance of careful characterization of ZFN treated cells. In order to reduce off-target events, reversible cell cycle arrest of the target cells in the G2/M phase is an efficient way for increasing the ratio between specific HR and illegitimate integration.

Excessive substance use in bipolar disorder is associated with impaired functioning rather than clinical characteristics, a descriptive study.

BACKGROUND: There is a strong association between bipolar disorder (BD) and substance use disorder (SUD). The clinical and functional correlates of SUD in BD are still unclear and little is known about the role of excessive substance use that does not meet SUD criteria. Thus, the aims of the current study were to investigate lifetime rates of illicit substance use in BD relative to the normal population and if there are differences in clinical and functional features between BD patients with and without excessive substance use. METHODS: 125 consecutively recruited BD in- and outpatients from the Oslo University Hospitals and 327 persons randomly drawn from the population in Oslo, Norway participated. Clinical and functional variables were assessed. Excessive substance use was defined as DSM-IV SUD and/or excessive use according to predefined criteria. RESULTS: The rate of lifetime illicit substance use was significantly higher among patients compared to the reference population (OR = 3.03, CI = 1.9-4.8, p < .001). Patients with excessive substance use (45% of total) had poorer educational level, occupational status, GAF-scores and medication compliance, with a trend towards higher suicidality rates, compared to patients without. There were no significant group differences in current symptom levels or disease course between groups. CONCLUSION: The percentage of patients with BD that had tried illicit substances was significantly higher than in the normal population. BD patients with excessive substance use clearly had impaired functioning, but not a worse course of illness compared to patients without excessive substance use. An assessment of substance use beyond SUD criteria in BD is clinically relevant.