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Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. Methods: We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. Results: The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Conclusions: Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.

It is not well investigated whether exposure to specific drug classes is associated with COVID-19. We investigated the risk of SARS-CoV-2 infection and severe COVID-19 among healthcare workers according to prescription drug use. We conducted an observational study among Danish healthcare workers. SARS-CoV-2 positivity was defined as a positive PCR/ELISA test throughout 2020 and severe COVID-19 as any above 48-hour hospitalization within 14 days after infection. Patient characteristics came from online surveys while data on SARS-CoV-2, drugs and hospitalizations came from Danish Health Registers. Infected individuals were matched with uninfected controls based on age, sex, and chronic diseases. Drug exposure was defined as any prescription redemption in the past six and one month(s) before infection for each drug class. Models assessing the risk of infection (conditional logistic regression) and severe COVID-19 (logistic regressions) versus drug usage were adjusted for BMI, smoking, alcohol, education, region, and patient contact when possible. We matched 5,710 SARS-CoV-2-infected cases with 57,021 controls. The odds of infection were reduced by calcium channel blocker (adjusted odds ratio (aOR) 0.81, 95% Confidence Interval (CI): 0.66-1.00) and vasoprotective drug (aOR 0.77, CI: 0.62-0.95) usage during the six months before infection compared to no usage. Exposure to antibacterials in the past month increased the odds of infection (aOR 1.27, CI: 1.09-1.48). Among infected participants, the odds of severe COVID-19 were higher with usage of almost any investigated drug, especially, diuretics (crude odds radio (OR) 4.82, CI:2.15-10.83), obstructive airway disease drugs (OR 4.49, CI: 2.49-8.08), and antibacterials (OR 2.74 CI:1.62-4.61). In conclusion, antibacterials were associated with more SARS-CoV-2 infections and calcium channel blockers with less. Once infected, users of prescription drugs had higher odds of developing severe COVID-19. These findings suggest a need for studies to clarify interactions between specific drug groups, behaviour, known risk factors, and disease susceptibility/severity.

BackgroundOvarian cancer is a challenging disease to diagnose and treat effectively with five-year survival rates below 50%. Previous patient experience research in high-income countries highlighted common challenges and opportunities to improve survival and quality of life for women affected by ovarian cancer. However, no comparable data exist for low-and middle-income countries, where 70% of women with the disease live. This study aims to address this evidence gap.MethodsThis is an observational multi-country study set in low- and middle-income countries. We aim to recruit over 2000 women diagnosed with ovarian cancer across multiple hospitals in 24 countries in Asia, Africa and South America. Country sample sizes have been calculated (n = 70-96 participants /country), taking account of varying national five-year disease prevalence rates. Women within five years of their diagnosis, who are in contact with participating hospitals, are invited to take part in the study. A questionnaire has been adapted from a tool previously used in high-income countries. It comprises 57 multiple choice and two open-ended questions designed to collect information on demographics, women's knowledge of ovarian cancer, route to diagnosis, access to treatments, surgery and genetic testing, support needs, the impact of the disease on women and their families, and their priorities for action. The questionnaire has been designed in English, translated into local languages and tested according to local ethics requirements. Questionnaires will be administered by a trained member of the clinical team.ConclusionThis study will inform further research, advocacy, and action in low- and middle-income countries based on tailored approaches to the national, regional and global challenges and opportunities. In addition, participating countries can choose to repeat the study to track progress and the protocol can be adapted for other countries and other diseases.

Epithelial organoids derived from intestinal tissue, called enteroids, recapitulate many aspects of the organ in vitro and can be used for biological discovery, personalized medicine, and drug development. Here, we interrogated the cell signaling environment within the developing human intestine to identify niche cues that may be important for epithelial development and homeostasis. We identified an EGF family member, EPIREGULIN (EREG), which is robustly expressed in the developing human crypt. Enteroids generated from the developing human intestine grown in standard culture conditions, which contain EGF, are dominated by stem and progenitor cells and feature little differentiation and no spatial organization. Our results demonstrate that EREG can replace EGF in vitro, and EREG leads to spatially resolved enteroids that feature budded and proliferative crypt domains and a differentiated villus-like central lumen. Multiomic (transcriptome plus epigenome) profiling of native crypts, EGF-grown enteroids, and EREG-grown enteroids showed that EGF enteroids have an altered chromatin landscape that is dependent on EGF concentration, downregulate the master intestinal transcription factor CDX2, and ectopically express stomach genes, a phenomenon that is reversible. This is in contrast to EREG-grown enteroids, which remain intestine like in culture. Thus, EREG creates a homeostatic intestinal niche in vitro, enabling interrogation of stem cell function, cellular differentiation, and disease modeling.

Abstract The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

BackgroundChronic pain is a major health challenge to those affected. Blended care with psychomotor physiotherapy (PMP) combined with eHealth self-management might be beneficial. ObjectiveThis study aims to explore how patients with chronic pain experience the combination of PMP and the use of EPIO, an eHealth self-management intervention for chronic pain. MethodsIndividual semistructured interviews were conducted with 5 adult patients with chronic pain (ie, participants) who used EPIO in combination with PMP over a period of 10 to 15 weeks. Interviews explored participants’ experiences using this treatment combination in relation to their pain and analyzed their experiences using systematic text condensation. ResultsParticipants described having benefited from using EPIO in combination with PMP in terms of increased awareness of bodily signals and how pain was related to stress and activity. They also described changes in the relationship to themselves in terms of increased self-acceptance, self-assertion, and hope and their relationship to their pain in terms of seeing pain as less harmful and engaging in more active coping strategies. ConclusionsResults indicate that a blended care approach combining eHealth self-management interventions such as EPIO with PMP may be of value to patients living with chronic pain. Trial RegistrationClinicalTrials.gov NCT03705104; https://clinicaltrials.gov/ct2/show/NCT03705104

Conservation and management of large carnivores requires knowledge of female and male dispersal. Such information is crucial to evaluate the population's status and thus management actions. This knowledge is challenging to obtain, often incomplete and contradictory at times. The size of the target population and the methods applied can bias the results. Also, population history and biological or environmental influences can affect dispersal on different scales within a study area. We have genotyped Eurasian lynx (180 males and 102 females, collected 2003-2017) continuously distributed in southern Finland (~23,000 km2) using 21 short tandem repeats (STR) loci and compared statistical genetic tests to infer local and sex-specific dispersal patterns within and across genetic clusters as well as geographic regions. We tested for sex-specific substructure with individual-based Bayesian assignment tests and spatial autocorrelation analyses. Differences between the sexes in genetic differentiation, relatedness, inbreeding, and diversity were analysed using population-based AMOVA, F-statistics, and assignment indices. Our results showed two different genetic clusters that were spatially structured for females but admixed for males. Similarly, spatial autocorrelation and relatedness was significantly higher in females than males. However, we found weaker sex-specific patterns for the Eurasian lynx when the data were separated in three geographical regions than when divided in the two genetic clusters. Overall, our results suggest male-biased dispersal and female philopatry for the Eurasian lynx in Southern Finland. The female genetic structuring increased from west to east within our study area. In addition, detection of male-biased dispersal was dependent on analytical methods utilized, on whether subtle underlying genetic structuring was considered or not, and the choice of population delineation. Conclusively, we suggest using multiple genetic approaches to study sex-biased dispersal in a continuously distributed species in which population delineation is difficult.

We explored the metabolic makeup of urine in prescreened healthy male participants within the PlanHab experiment. The run-in (5 day) and the following three 21-day interventions [normoxic bedrest (NBR), hypoxic bedrest (HBR), and hypoxic ambulation (HAmb)] were executed in a crossover manner within a controlled laboratory setup (medical oversight, fluid and dietary intakes, microbial bioburden, circadian rhythm, and oxygen level). The inspired O2 (FiO2) fraction next to inspired O2 (PiO2) partial pressure were 0.209 and 133.1 ± 0.3 mmHg for the NBR variant in contrast to 0.141 ± 0.004 and 90.0 ± 0.4 mmHg (approx. 4,000 m of simulated altitude) for HBR and HAmb interventions, respectively. 1H-NMR metabolomes were processed using standard quantitative approaches. A consensus of ensemble of multivariate analyses showed that the metabolic makeup at the start of the experiment and at HAmb endpoint differed significantly from the NBR and HBR endpoints. Inactivity alone or combined with hypoxia resulted in a significant reduction of metabolic diversity and increasing number of affected metabolic pathways. Sliding window analysis (3 + 1) unraveled that metabolic changes in the NBR lagged behind those observed in the HBR. These results show that the negative effects of cessation of activity on systemic metabolism are further aggravated by additional hypoxia. The PlanHab HAmb variant that enabled ambulation, maintained vertical posture, and controlled but limited activity levels apparently prevented the development of negative physiological symptoms such as insulin resistance, low-level systemic inflammation, constipation, and depression. This indicates that exercise apparently prevented the negative spiral between the host’s metabolism, intestinal environment, microbiome physiology, and proinflammatory immune activities in the host.

INTRODUCTION:Clinical trials often suffer from significant recruitment barriers, poor adherence, and dropouts, which increase costs and negatively affect trial outcomes. The aim of this study was to examine whether making it virtual and reward-based would enable nationwide recruitment, identify patients with variable disease severity, achieve high adherence, and reduce dropouts. METHODS:In a siteless, virtual feasibility study, individuals with atopic dermatitis (AD) were recruited online. During the 8-week study, subjects used their smartphones weekly to photograph target AD lesions, and completed patient-oriented eczema measure (POEM) and treatment use questionnaires. In return, subjects were rewarded every week with personalized lifestyle reports based on their DNA. RESULTS:Over the course of the 11 day recruitment period, 164 (82% women and 18% men) filled in the form to participate, of which 65 fulfilled the inclusion criteria and signed the informed consent. Ten were excluded as they did not complete the mandatory study task of returning the DNA sample. 55 (91% women, 9% men) subjects returned the DNA sample and were enrolled throughout Denmark, the majority outside the Copenhagen capital region in rural areas with relatively low physician coverage. The mean age was 28.5 (SD ±9.5 years, range 18-52 years). The baseline POEM score was 14.5±5.6 (range 6-28). Based on the POEM, 7 individuals had mild, 28 had moderate, 17 had severe, and 3 had very severe eczema. The retention rate was 96% as 53 out of 55 enrolled completed the study. The adherence was very high, and more than 90% of all study tasks were completed. Follow up of 41 subjects showed that 90% would take part again or continue if the study had been longer. CONCLUSION:A virtual trial design enables recruitment with broad geographic reach and throughout the full spectrum of disease severity. Providing personalized genetic reports as a reward seems to contribute to high adherence and retention.

Knowledge about population genetic structure and dispersal capabilities is important for the development of targeted management strategies for agricultural pest species. The apple fruit moth, Argyresthia conjugella (Lepidoptera, Yponomeutidae), is a pre-dispersal seed predator. Larvae feed on rowanberries (Sorbus aucuparia), and when rowanberry seed production is low (i.e., inter-masting), the moth switches from laying eggs in rowanberries to apples (Malus domestica), resulting in devastating losses in apple crops. Using genetic methods, we investigated if this small moth expresses any local genetic structure, or alternatively if gene flow may be high within the Scandinavian Peninsula (~850.000 km2, 55o - 69o N). Genetic diversity was found to be high (n = 669, mean He = 0.71). For three out of ten tetranucleotide STRs, we detected heterozygote deficiency caused by null alleles, but tests showed little impact on the overall results. Genetic differentiation between the 28 sampling locations was very low (average FST = 0.016, P < 0.000). Surprisingly, we found that all individuals could be assigned to one of two non-geographic genetic clusters, and that a third, geographic cluster was found to be associated with 30% of the sampling locations, with weak but significant signals of isolation-by-distance. Conclusively, our findings suggest wind-aided dispersal and spatial synchrony of both sexes of the apple fruit moth over large areas and across very different climatic zones. We speculate that the species may recently have had two separate genetic origins caused by a genetic bottleneck after inter-masting, followed by rapid dispersal and homogenization of the gene pool across the landscape. We suggest further investigations of spatial genetic similarities and differences of the apple fruit moth at larger geographical scales, through life-stages, across inter-masting, and during attacks by the parasitoid wasp (Microgaster politus).

Abstract Adenosine plays a role in the energy supply of cells and provokes differential, hormone-like functions in circulating cells and various tissues. Its release is importantly regulated by oxygen tension. This renders adenosine and its kinetics interesting to investigate in humans subjected to low oxygen conditions. Especially for space exploration scenarios, hypoxic conditions – together with reduced gravity - represent two foreseen living conditions when planning manned long-duration space missions or planetary habitats. The PlanHab study investigated microgravity through inactivity in bed rest and normobaric hypoxia to examine their independent or combined effect on adenosine and its kinetics. Healthy male subjects (n = 14) completed three 21-day interventions: hypoxic bed rest (HBR); hypoxic ambulatory confinement (HAMB); normoxic bed rest (NBR). The interventions were separated by 4 months. Our hypothesis of a hypoxia-triggered increase in adenosine was confirmed in HAMB but unexpectedly also in NBR. However, the highest adenosine levels were noted following HBR. Furthermore, the percentage of hemolysis was elevated in HBR whereas endothelial integrity markers stayed low in all three interventions. In summary, these data suggest that neocytolysis accounts for these effects while we could reduce evidence for microcirculatory changes.

BackgroundEpidural catheters are state of the art for postoperative analgesic in abdominal surgery. Due to neurolysis it can lead to postoperative urinary tract retention (POUR), which leads to prolonged bladder catheterization, which has an increased risk for urinary tract infections (UTI). Our aim was to identify the current perioperative management of urinary catheters and, second, to identify the optimal time of suprapubic bladder catheter removal in regard to the removal of the epidural catheter.MethodsWe sent a questionnaire to 102 German hospitals and analyzed the 83 received answers to evaluate the current handling of bladder drainage and epidural catheters. Then, we conducted a retrospective study including 501 patients, who received an epidural and suprapubic catheter after abdominal surgery at the University Hospital Würzburg. We divided the patients into three groups according to the point in time of suprapubic bladder drainage removal in regard to the removal of the epidural catheter and analyzed the onset of a UTI.ResultsOur survey showed that in almost all hospitals (98.8%), patients received an epidural catheter and a bladder drainage after abdominal surgery. The point in time of urinary catheter removal was equally distributed between before, simultaneously and after the removal of the epidural catheter (respectively: ~28-29%). The retrospective study showed a catheter-associated UTI in 6.7%. Women were affected significantly more often than men (10,7% versus 2,5%, pConclusionThe point in time of suprapubic bladder drainage removal in relation to the removal of the epidural catheter does not seem to correlate with the rate of UTIs. The current handling in Germany is inhomogeneous, so further studies to standardize treatment are recommended.

The degree of gene flow within and among populations, i.e. genetic population connectivity, may closely track demographic population connectivity. Alternatively, the rate of gene flow may change relative to the rate of dispersal. In this study, we explored the relationship between genetic and demographic population connectivity using the Scandinavian brown bear as model species, due to its pronounced male dispersal and female philopatry. Thus, we expected that females would shape genetic structure locally, whereas males would act as genetic mediators among regions. To test this, we used eight validated microsatellite markers on 1531 individuals sampled noninvasively during country-wide genetic population monitoring in Sweden and Norway from 2006 to 2013. First, we determined sex-specific genetic structure and substructure across the study area. Second, we compared genetic differentiation, migration/gene flow patterns, and spatial autocorrelation results between the sexes both within and among genetic clusters and geographic regions. Our results indicated that demographic connectivity was not a reliable indicator of genetic connectivity. Among regions, we found no consistent difference in long-term gene flow and estimated current migration rates between males and females. Within regions/genetic clusters, only females consistently displayed significant positive spatial autocorrelation, indicating male-biased small-scale dispersal. In one cluster, however, males showed a dispersal pattern similar to females. The Scandinavian brown bear population has experienced substantial recovery over the last decades; however, our results did not show any changes in its large-scale population structure compared to previous studies, suggesting that an increase in population size and dispersal of individuals does not necessary lead to increased genetic connectivity. Thus, we conclude that both genetic and demographic connectivity should be estimated, so as not to make false assumptions about the reality of wildlife populations.

We explored the assembly of intestinal microbiota in healthy male participants during the randomized crossover design of run-in (5 day) and experimental phases (21-day normoxic bed rest (NBR), hypoxic bed rest (HBR) and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, with balanced fluid and dietary intakes, controlled circadian rhythm, microbial ambiental burden and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4000 m simulated altitude), respectively. A number of parameters linked to intestinal environment such as defecation frequency, intestinal electrical conductivity (IEC), sterol and polyphenol content and diversity, indole, aromaticity and spectral characteristics of dissolved organic matter (DOM) were measured (64 variables). The structure and diversity of bacterial microbial community was assessed using 16S rRNA amplicon sequencing. Inactivity negatively affected frequency of defecation and in combination with hypoxia increased IEC (p < 0.05). In contrast, sterol and polyphenol diversity and content, various characteristics of DOM and aromatic compounds, the structure and diversity of bacterial microbial community were not significantly affected over time. A new in-house PlanHab database was established to integrate all measured variables on host physiology, diet, experiment, immune and metabolic markers (n = 231). The observed progressive decrease in defecation frequency and concomitant increase in IEC suggested that the transition from healthy physiological state towards the developed symptoms of low magnitude obesity-related syndromes was dose dependent on the extent of time spent in inactivity and preceded or took place in absence of significant rearrangements in bacterial microbial community. Species B. thetaiotamicron, B. fragilis, B. dorei and other Bacteroides with reported relevance for dysbiotic medical conditions were significantly enriched in HBR, characterized with most severe inflammation symptoms, indicating a shift towards host mucin degradation and proinflammatory immune crosstalk.

Developing patient derived models from individual tumors that capture the biological heterogeneity and mutation landscape in advanced prostate cancer is challenging, but essential for understanding tumor progression and delivery of personalized therapy in metastatic castrate resistant prostate cancer stage. To demonstrate the feasibility of developing patient derived xenograft models in this stage, we present a case study wherein xenografts were derived from cancer metastases in a patient progressing on androgen deprivation therapy and prior to initiating pre-chemotherapy enzalutamide treatment. Tissue biopsies from a metastatic rib lesion were obtained for sequencing before and after initiating enzalutamide treatment over a twelve-week period and also implanted subcutaneously as well as under the renal capsule in immuno-deficient mice. The genome and transcriptome landscapes of xenografts and the original patient tumor tissues were compared by performing whole exome and transcriptome sequencing of the metastatic tumor tissues and the xenografts at both time points. After comparing the somatic mutations, copy number variations, gene fusions and gene expression we found that the patient's genomic and transcriptomic alterations were preserved in the patient derived xenografts with high fidelity. These xenograft models provide an opportunity for predicting efficacy of existing and potentially novel drugs that is based on individual metastatic tumor expression signature and molecular pharmacology for delivery of precision medicine.

Both exposure to hypoxia and exercise training have the potential to modulate appetite and induce beneficial metabolic adaptations. The purpose of this study was to determine whether daily moderate exercise training performed during a 10-day exposure to normobaric hypoxia alters hormonal appetite regulation and augments metabolic health.Fourteen healthy, male participants underwent a 10-day hypoxic confinement at ∼ 4000 m simulated altitude (FIO2 = 0.139 ± 0.003%) either combined with daily moderate intensity exercise (Exercise group; N = 8, Age = 25.8 ± 2.4 yrs, BMI = 22.9 ± 1.2 kg · m(-2)) or without any exercise (Sedentary group; N = 6 Age = 24.8 ± 3.1 yrs, BMI = 22.3 ± 2.5 kg · m(-2)). A meal tolerance test was performed before (Pre) and after the confinement (Post) to quantify fasting and postp randial concentrations of selected appetite-related hormones and metabolic risk markers. 13C-Glucose was dissolved in the test meal and 13CO2 determined in breath samples. Perceived appetite ratings were obtained throughout the meal tolerance tests.While body mass decreased in both groups (-1.4 kg; p = 0.01) following the confinement, whole body fat mass was only reduced in the Exercise group (-1.5 kg; p = 0.01). At Post, postprandial serum insulin was reduced in the Sedentary group (-49%; p = 0.01) and postprandial plasma glucose in the Exercise group (-19%; p = 0.03). Fasting serum total cholesterol levels were reduced (-12%; p = 0.01) at Post in the Exercise group only, secondary to low-density lipoprotein cholesterol reduction (-16%; p = 0.01). No differences between groups or testing periods were noted in fasting and/or postprandial concentrations of total ghrelin, peptide YY, and glucagon-like peptide-1, leptin, adiponectin, expired 13CO2 as well as perceived appetite ratings (p>0.05).These findings suggest that performing daily moderate intensity exercise training during continuous hypoxic exposure does not alter hormonal appetite regulation but can improve the lipid profile in healthy young males.

Large carnivores were persecuted to near extinction during the last centuries, but have now recovered in some countries. It has been proposed earlier that the recovery of the Northern European brown bear is supported by migration from Russia. We tested this hypothesis by obtaining for the first time continuous sampling of the whole Finnish bear population, which is located centrally between the Russian and Scandinavian bear populations. The Finnish population is assumed to experience high gene flow from Russian Karelia. If so, no or a low degree of genetic differentiation between Finnish and Russian bears could be expected. We have genotyped bears extensively from all over Finland using 12 validated microsatellite markers and compared their genetic composition to bears from Russian Karelia, Sweden, and Norway. Our fine masked investigation identified two overlapping genetic clusters structured by isolation-by-distance in Finland (pairwise FST = 0.025). One cluster included Russian bears, and migration analyses showed a high number of migrants from Russia into Finland, providing evidence of eastern gene flow as an important driver during recovery. In comparison, both clusters excluded bears from Sweden and Norway, and we found no migrants from Finland in either country, indicating that eastern gene flow was probably not important for the population recovery in Scandinavia. Our analyses on different spatial scales suggest a continuous bear population in Finland and Russian Karelia, separated from Scandinavia.