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Abstract Background We sought to analyze, in well-defined clinical setting, the first 100 patients treated at the intraoperative MRI (iMRI) hybrid surgical theatre at our facility in a population-based setting to evaluate which pathologies are best approached with iMRI assisted surgeries, as this is not yet clearly defined. Methods Patients undergoing surgery in the 3T iMRI hybrid surgical theatre at our neurosurgical department between December 2017 to May 2021 were included after informed consent. Demographic, clinical, surgical, histological, radiological and outcome parameters, as well as variables related to iMRI, were retrospectively collected and analyzed. Patients were subdivided into adult and pediatric cohorts. Results Various neurosurgical procedures were performed; resection of tumors and epileptic foci, endoscopic skull base procedures including pituitary lesions, deep brain stimulation (DBS) and laser interstitial thermal therapy (LITT). In total, 41 patients were pediatric. An iMRI scan was carried out in 96% of cases and led to continuation of surgery in 50% of cases, mainly due to visualized remaining pathological tissue (95.2%). Median time to iMRI from intubation was 280 min and median total duration of surgery was 445 min. The majority of patients experienced no postoperative complications (70%), 13 patients suffered permanent postoperative deficits, predominantly visual. Conclusion Herein, we demonstrate the first 100 patients undergoing neurosurgery aided by iMRI at our facility since introduction. Indications for surgery differed between pediatric and adult patients. The iMRI was utilized for tumor surgeries, particularly adult low-grade gliomas and pediatric tumors, as well as for epilepsy surgery and DBS. In this heterogenous population, iMRI led to continuation of surgery in 50%. To establish the benefit in maximizing the extent of resection in these brain pathologies future studies are recommended. Clinical trial number Not applicable.

Abstract Background Takotsubo syndrome (TTS) is an acute heart failure syndrome with symptoms similar to acute myocardial infarction. TTS is often triggered by acute emotional or physical stress and is a significant cause of morbidity and mortality. Predictors of mortality in patients with TS are not well understood, and there is a need to identify high-risk patients and tailor treatment accordingly. This study aimed to assess the importance of various clinical factors in predicting 30-day mortality in TTS patients using a machine learning algorithm. Methods We analyzed data from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR) for all patients with TTS in Sweden between 2015 and 2022. Gradient boosting was used to assess the relative importance of variables in predicting 30-day mortality in TTS patients. Results Of 3,180 patients hospitalized with TTS, 76.0% were women. The median age was 71.0 years (interquartile range 62–77). The crude all-cause mortality rate was 3.2% at 30 days. Machine learning algorithms by gradient boosting identified treating hospitals as the most important predictor of 30-day mortality. This factor was followed in significance by the clinical indication for angiography, creatinine level, Killip class, and age. Other less important factors included weight, height, and certain medical conditions such as hyperlipidemia and smoking status. Conclusions Using machine learning with gradient boosting, we analyzed all Swedish patients diagnosed with TTS over seven years and found that the treating hospital was the most significant predictor of 30-day mortality.

Abstract Background The health center where this study was performed the management wanted to test whether a sick leave team provided the physicians with better conditions for the task of assessing sick leave. The goals were to ensure the quality of the assessment of patients with sick leave needs and to improve the work environment. The aim of this study was to take part in the staff's experiences of having access to and working in sick leave teams and how the working method affected the number of sick leave patients and sick leave pattern. Methods A mixture of qualitative and quantitative methods. Two focus groups were conducted with a total of 11 participants. The head of the health center formed the focus groups, which consisted of 6 doctors, 3 district nurses, 1 rehab coordinator and 1 psychologist. Aggregated sick leave data for full-time and part-time sick leave of more than 90, 180 and 360 days, respectively, were obtained and compiled at project start and end, and from the corresponding period 18 months before project start. Results The introduction of sick leave teams with physicians and rehabilitation coordinator for patients who turn to the health center for mental illness and / or musculoskeletal problems emerged three main categories from the analysis of the focus group discussions: working environment, clear roles and in-depth competence. The total number of people who were on sick leave more than 365 days decreased by 27% between start and the end of the project, and the proportion of women increased by 11%. Conclusions The study shows that the complex task of sick leave can be perceived as positive by physicians with the support of teamwork. The working method is similar to that applied in occupational health care, where the physician is not alone with this task. This can also be a way to make primary care a more attractive workplace.

Abstract Background Fatty degeneration of thymus (or thymus involution) has long been considered a normal ageing process. However, there is emerging evidence that thymic involution is linked to T cell aging, chronic inflammation and increased morbidity. Other factors, aside from chronological age, have been proposed to affect the involution rate. In the present study, we investigated the imaging characteristics of thymus on computed tomography (CT) in a Swedish middle-aged population. The major aims were to establish the prevalence of fatty degeneration of thymus and to determine its associations with demographic, lifestyle and clinical factors, as well as inflammation, T cell differentiation and thymic output. Results In total, 1 048 randomly invited individuals (aged 50–64 years, 49% females) were included and thoroughly characterized. CT evaluation of thymus included measurements of attenuation, size and a 4-point scoring system, with scale 0–3 based on the ratio of fat and soft tissue. A majority, 615 (59%) showed complete fatty degeneration, 259 (25%) predominantly fatty attenuation, 105 (10%) half fatty and half soft-tissue attenuation, while 69 (6.6%) presented with a solid thymic gland with predominantly soft-tissue attenuation. Age, male sex, high BMI, abdominal obesity and low dietary intake of fiber were independently associated with complete fatty degeneration of thymus. Also, fatty degeneration of thymus as well as low CT attenuation values were independently related to lower proportion of naïve CD8+ T cells, which in turn was related to lower thymic output, assessed by T-cell receptor excision circle (TREC) levels. Conclusion Among Swedish middle-aged subjects, nearly two-thirds showed complete fatty degeneration of thymus on CT. This was linked to depletion of naïve CD8+ T cells indicating that CT scans of thymus might be used to estimate immunological aging. Furthermore, our findings support the intriguing concept that obesity as well as low fiber intake contribute to immunological aging, thereby raising the possibility of preventive strategies.

Abstract Helminth/tuberculosis (TB)-coinfection can reduce cell-mediated immunity against Mycobacterium tuberculosis (Mtb) and increase disease severity, although the effects are highly helminth species dependent. Mtb have long been ranked as the number one single infectious agent claiming the most lives. The only licensed vaccine for TB (BCG) offers highly variable protection against TB, and almost no protection against transmission of Mtb. In recent few years the identification of naturally occurring antibodies in humans that are protective during Mtb infection has reignited the interest in adaptive humoral immunity against TB and its possible implementation in novel TB vaccine design. The effects of helminth/TB coinfection on the humoral response against Mtb during active pulmonary TB are however still unclear, and specifically the effect by globally prevalent helminth species such as Ascaris lumbricoides, Strongyloides stercoralis, Ancylostoma duodenale, Trichuris trichiura. Plasma samples from smear positive TB patients were used to measure both total and Mtb-specific antibody responses in a Peruvian endemic setting where these helminths are dominating. Mtb-specific antibodies were detected by a novel approach coating ELISA-plates with a Mtb cell-membrane fraction (CDC1551) that contains a broad range of Mtb surface proteins. Compared to controls without helminths or TB, helminth/TB coinfected patients had high levels of Mtb-specific IgG (including an IgG1 and IgG2 subclass response) and IgM, which were similarly increased in TB patients without helminth infection. These data, indicate that helminth/TB coinfected have a sustained humoral response against Mtb at the level of active TB only. More studies on the species-specific impact of helminths on the adaptive humoral response against Mtb using a larger sample size, and in relation to TB disease severity, are needed.

Abstract Background One of the COVID-19 pandemic consequences that has affected families the most is school lockdowns. Some studies have shown that distance learning has been especially challenging for families with a child with neurodevelopmental disorders such as ADHD or ASD. However, previous studies have not taken the heterogeneity of these disorders into account. The aim of the present study was therefore to investigate differences between families with a child with ADHD, ASD, or both conditions, and to examine the role of underlying deficits in executive functioning (EF) in both children and parents in relation to negative and positive effects of distance learning. Methods Survey data assessing both negative and positive experiences of distance learning were collected from parents with a child aged 5–19 years in seven Western European countries: the UK, Germany, Spain, Sweden, the Netherlands, Italy, and Belgium. Altogether, the study included 1010 families with a child with ADHD and/or ASD and an equally large comparison group of families with a child without mental health problems. We included measures of three different types of negative effects (i.e., effects on the child, effects on the parent, and lack of support from school) and positive effects on the family. Results Results confirmed that families with a child with ADHD, ASD or a combination of ADHD and ASD showed higher levels of both negative and positive effects of distance learning than the comparison group. However, few differences were found between the clinical groups. Group differences were more pronounced for older compared to younger children. Regarding the role of both ADHD/ASD diagnosis and EF deficits, primarily children’s EF deficits contributed to high levels of negative effects. Parent EF deficits did not contribute significantly beyond the influence of child EF deficits. Families of children with ADHD/ASD without EF deficits experienced the highest levels of positive effects. Conclusions School closings during COVID-19 have a major impact on children with EF problems, including children with neurodevelopmental disorders. The present study emphasizes that schools should not focus primarily on whether a student has a neurodevelopmental disorder, but rather provide support based on the student’s individual profile of underlying neuropsychological deficits.

Abstract Background Subarctic regions are particularly vulnerable to climate change, yet little is known about nutrient availability and biodiversity of their cave ecosystems. Such knowledge is crucial for predicting the vulnerability of these ecosystems to consequences of climate change. Thus, to improve our understanding of life in these habitats, we characterized environmental variables, as well as bacterial and invertebrate communities of six subarctic caves in Northern Norway. Results Only a minuscule diversity of surface-adapted invertebrates were found in these caves. However, the bacterial communities in caves were compositionally different, more diverse and more complex than the nutrient-richer surface soil. Cave soil microbiomes were less variable between caves than between surface communities in the same area, suggesting that the stable cave environments with tougher conditions drive the uniform microbial communities. We also observed only a small proportion of cave bacterial genera originating from the surface, indicating unique cave-adapted microbial communities. Increased diversity within caves may stem from higher niche specialization and levels of interdependencies for nutrient cycling among bacterial taxa in these oligotrophic environments. Conclusions Taken together this suggest that environmental changes, e.g., faster melting of snow as a result of global warming that could alter nutrient influx, can have a detrimental impact on interactions and dependencies of these complex communities. This comparative exploration of cave and surface microbiomes also lays the foundation to further investigate the long-term environmental variables that shape the biodiversity of these vulnerable ecosystems.

Abstract Background There are currently no approved medications for impaired social cognition and function, core symptoms of autism spectrum disorder. We describe marked improvement of these symptoms with long-term low-dose administration of the partial µ-opioid agonist buprenorphine. We discuss these observations in the context of a role for endogenous opioid systems in social attachment, and theories integrating those findings mechanistically with autism spectrum disorder. Case presentation M, a 43-year-old Caucasian male, is medically healthy. Despite social difficulties since childhood, he completed high school with better-than-average grades, but failed university education. A psychiatric evaluation in his twenties diagnosed attention deficit hyperactivity disorder but also noted symptoms of coexisting autism spectrum disorder. M accidentally came across buprenorphine in his late twenties and experienced progressively improved social functioning on a low daily dosage (0.5–1.0 mg/day), an effect maintained for 15 years. He lived independently and maintained a part-time occupation. After abrupt discontinuation of treatment, his autistic symptoms returned, and function deteriorated. Following evaluation by our team, buprenorphine was resumed, with gradual return to prior level of functioning. An attempt to formally evaluate M both on and off medication was agreed with him and approved by the Swedish Ethics Authority, but medication had to be resumed when the patient worsened following discontinuation. Conclusions According to the µ-opioid receptor balance model, both excessive and deficient μ-receptor activity may negatively influence social behavior, and accordingly both opioid agonist and opioid antagonist treatment may be able to improve social functioning, depending on an individual’s opioid tone before treatment. Our case report is consistent with these hypotheses, and given the extensive unmet medical needs in individuals with autism spectrum disorders, randomized controlled trial appears warranted.

Abstract Background In 2015 a study of isolated lateral malleolar fractures (AO/OTA44-B1) treated at Sahlgrenska University hospital (SU) during two consecutive years revealed large-scale variation in the choice of treatment and planned follow-up. The study resulted in the development of a structured treatment algorithm (TA) for ankle fractures. We investigated the effects of this well-implemented TA on the classification, treatment and follow-up of lateral malleolar fractures. Methods The current study is an uncontrolled, non-randomized, retrospective before-and-after study comparing a group of AO/OTA44-B1 fractures treated at SU before the introduction of the TA for ankle fractures (1 April 2012 to 31 March 2014) with a group treated after the introduction of the TA (1 September 2017 to 31 August 2019). Results In all the studied parameters regarding treatment for AO/OTA44-B1 fractures, a statistically significant change was seen after the introduction of the TA. Surgical treatment reduced from 32% (95% CI 27.5 – 36.5) pre-TA to 10% (95% CI 6.9 – 13.1) post-TA, while the number of patients permitted full weight-bearing increased from 41% (95% CI 36.3 – 45.7) to 84% (95% CI 80.1 – 87.9). Conclusions A thoroughly implemented treatment algorithm can reduce the number of surgical treatments for stable ankle fractures. The current study demonstrates that a structured treatment algorithm can standardize the management of ankle fractures and make decisions less dependent on the surgeon’s discretion.

Abstract Background The increasing prevalence of type 2 diabetes worldwide is a major global public health concern. Prediabetes is a reversible condition and is seen as the critical phase for the prevention of type 2 diabetes. The aim of this study is to identify and synthesize current evidence on the perceived barriers and facilitators of lifestyle change among people with prediabetes in terms of both initial change and lifestyle change maintenance. Methods A systematic literature search in six bibliographic databases was conducted in April 2021. Potential studies were assessed for eligibility based on pre-set criteria. Quality appraisal was done on the included studies, and the thematic synthesis approach was applied to synthesize and analyse the data from the included studies. Results Twenty primary studies were included, containing the experiences of 552 individuals. Thirteen studies reported participants perceived facilitators and barriers of lifestyle change when taking part in community-based lifestyle intervention programs, while seven studies reported on perceived facilitators and barriers of lifestyle change through consultations with health care professionals (no intervention involved). Three analytical themes illuminating perceived barriers and facilitators for lifestyle change were identified: 1) the individual’s evaluation of the importance of initiating lifestyle change, 2) the second theme was strategies and coping mechanisms for maintaining lifestyle changes and 3) the last theme was the significance of supportive relations and environments in initiating and maintaining lifestyle change. Conclusion Awareness of prediabetes and the perception of its related risks affects the motivation for lifestyle change in people at risk of type 2 diabetes; but this does not necessarily lead to lifestyle changes. Facilitators and barriers of lifestyle change are found to be in a complex interplay within multiple ecological levels, including the interpersonal, intrapersonal, environmental and policy level. An integrated understanding and analysis of the perceived barriers and facilitators of lifestyle change might inform people with prediabetes, healthcare professionals, and policy makers in terms of the need for psychological, social, and environmental support for this population.

Highlights The New Urban Science leverages digital tools and techniques to develop new knowledge that can inform urban development processes. Interdisciplinary and transdisciplinary approaches are critical to expanding and enhancing digital modes of urban scientific knowledge production. An expansive approach to the New Urban Science can be used to develop urban transformative capacity by fostering communities of learning to leverage the commonalities and differences between and within cities.

Abstract Background The use of alcohol and illicit drugs during adolescence can lead to serious short- and long-term health related consequences. Despite a global trend of decreased substance use, in particular alcohol, among adolescents, evidence suggests excessive use of substances by young people in socioeconomically affluent areas. To prevent substance use-related harm, we need in-depth knowledge about the reasons for substance use in this group and how they perceive various prevention interventions. The aim of the current study was to explore motives for using or abstaining from using substances among students in affluent areas as well as their attitudes to, and suggestions for, substance use prevention. Methods Twenty high school students (age 15–19 years) in a Swedish affluent municipality were recruited through purposive sampling to take part in semi-structured interviews. Qualitative content analysis of transcribed interviews was performed. Results The most prominent motive for substance use appears to be a desire to feel a part of the social milieu and to have high social status within the peer group. Motives for abstaining included academic ambitions, activities requiring sobriety and parental influence. Students reported universal information-based prevention to be irrelevant and hesitation to use selective prevention interventions due to fear of being reported to authorities. Suggested universal prevention concerned reliable information from credible sources, stricter substance control measures for those providing substances, parental involvement, and social leisure activities without substance use. Suggested selective prevention included guaranteed confidentiality and non-judging encounters when seeking help. Conclusions Future research on substance use prevention targeting students in affluent areas should take into account the social milieu and with advantage pay attention to students’ suggestions on credible prevention information, stricter control measures for substance providers, parental involvement, substance-free leisure, and confidential ways to seek help with a non-judging approach from adults.

Abstract Background The development of routines regarding medication is important to avoid medication-related harm. Medication review and medication reports have earlier been found to be effective, but their implementation is not always successful. The aim of this study was to evaluate the introduction of medication review/medication report in hospital and primary care, in terms of perceptions of the implementation strategy, adoption and sustainability, in one Swedish county. Methods The study included 105 clinics. Data was collected from interviews with managers immediately after implementation, survey data and registry data collected five years later. Quantitative data was analysed using non-parametric statistical tests. Open-ended questions were analysed with qualitative methods. Results The implementation activities were found satisfying, and managers were satisfied with their own influence over the process. After five years medication review and medication reports were reported mainly implemented by the managers. Facilitating factors reported were routines, staff influence, dedication, reminders, and a stable workforce, while hindering factors reported were organizational factors, less commitment and flaws in reporting. Registry data showed that performance of medication review was very limited in primary care. In hospital care medication review was registered in about one fifth of the patients, while medication reports, only relevant for hospital care, was registered in half of the patients. Conclusions The managers’ perceptions of the implementation process were mainly positive, and they found the new practices of medication review/medication report implemented. Implementation success, however, was not supported by registry data, showing the need for reliable outcome measures for implementation.

Abstract Background The combined effect of sarcopenia and obesity, i.e., sarcopenic obesity, has been associated with disability and worse outcomes in older adults, but results are conflicting. The objectives of this study were to describe the prevalence of sarcopenic obesity (SO) in older adults, and to examine how the risk of mortality is associated with SO and its various components. Methods Data were obtained from two Swedish population studies, the Gothenburg H70 Birth Cohort Studies of 521 women and men at the age of 75, and the Uppsala Longitudinal Study of Adult Men (ULSAM), which included 288 men aged 87 years. Sarcopenia was defined using the recently updated EWGSOP2 definition. Obesity was defined by any of three established definitions: body mass index ≥30 kg/m2, fat mass > 30%/ > 42% or waist circumference ≥ 88 cm/≥102 cm for women and men, respectively. The Kaplan-Meier survival curve and the Cox proportional hazard model were used for 10-year and 4-year survival analyses in the H70 and ULSAM cohorts, respectively. Results SO was observed in 4% of the women and 11% of the men in the H70 cohort, and in 10% of the ULSAM male cohort. The 75-year-old women with SO had a higher risk (HR 3.25, 95% confidence interval (1.2–8.9)) of dying within 10 years compared to those with a “normal” phenotype. A potential similar association with mortality among the 75-year-old men was not statistically significant. In the older men aged 87 years, obesity was associated with increased survival. Conclusions SO was observed in 4–11% of community-dwelling older adults. In 75-year-old women SO appeared to associate with an increased risk of dying within 10 years. In 87-year-old men, the results indicated that obesity without sarcopenia was related to a survival benefit over a four-year period.

Abstract Background The study is part of a randomised controlled trial with the overall aim to evaluate if use of the Work Stress Questionnaire (WSQ), combined with feedback at consultation, can be used by healthcare professionals in primary health care to prevent sickness absence. The specific aim of the present study was to investigate whether there were differences in pharmacy dispensing of prescription medications between the intervention group and the control group. Methods The study was a randomized controlled trial. Non-sick-listed employed women and men, aged 18 to 64 years, seeking care at primary health care centres (PHCCs) were eligible participants. The intervention included early identification of work-related stress by the WSQ, general practitioner (GP) training and GP feedback at consultation. Pharmacy dispensing data from the Swedish Prescription Drug Register for a period of 12 months following the intervention was used. Primary outcomes were the number of different medications used, type of medication and number of prescribing clinics. Data was analysed using Mann Whitney U tests and chi-square tests. Results The study population included 271 individuals (132 in the intervention group and 139 in the control group). The number of different medications used per individual did not differ significantly between the control group (median 4.0) and the intervention group (median 4.0, p-value 0.076). The proportion of individuals who collected more than 10 different medications was higher in the control group than in the intervention group (15.8% versus 4.5%, p = 0.002). In addition, the proportion of individuals filling prescriptions issued from more than three different clinics was higher in the control group than in the intervention group (17.3% versus 6.8%, p = 0.007). Conclusion Systematic use of the WSQ combined with training of GPs and feedback at consultation may affect certain aspects of pharmacological treatment in primary health care patients. In this randomised control trial, analysis of pharmacy dispensing data show that patients in the intervention group had less polypharmacy and filled prescriptions issued from a smaller number of different clinics. Trial registration ClinicalTrials.gov . Identifier: NCT02480855 . Registered 20 May 2015.

Abstract Background Stiffness and pain from arthrofibrosis following total knee arthroplasty (TKA) is a challenging problem, and investigating methods to prevent or reduce the incidence of postoperative arthrofibrosis is critical. Studies have shown that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are efficacious at preventing fibrotic disorders in the lungs, liver, kidneys, and eyes. Our aim was to determine if ACEI or ARB use postoperatively reduces the incidence of arthrofibrosis in TKA patients. Methods In a retrospective review, we analyzed 141 consecutive TKAs performed at a single institution by a single surgeon from December 2010 to December 2014. Range of motion (ROM) in patients already taking ACEI, ARB, or neither medication was compared. Independent variables recorded were gender, age, BMI, presence of diabetes or preoperative opioid or statin use, preoperative ROM, and use of ACEIs or ARBs. Dependent variables recorded were postoperative knee flexion, extension, and total arc of motion. The primary outcome variable was success or failure of achieving 118o total arc of motion postoperatively, based on a study that found significant compromise of function in TKA patients who failed to obtain this goal. Secondary endpoints were postoperative knee flexion, extension, and total arc of motion. Results The use of neither ACEIs nor ARBs showed a significant difference in attaining greater than 118° of motion postoperatively compared to controls at 6 months. Significant predictors of obtaining > 118° motion were BMI (p

Abstract Background The genetic origins of Uralic speakers from across a vast territory in the temperate zone of North Eurasia have remained elusive. Previous studies have shown contrasting proportions of Eastern and Western Eurasian ancestry in their mitochondrial and Y chromosomal gene pools. While the maternal lineages reflect by and large the geographic background of a given Uralic-speaking population, the frequency of Y chromosomes of Eastern Eurasian origin is distinctively high among European Uralic speakers. The autosomal variation of Uralic speakers, however, has not yet been studied comprehensively. Results Here, we present a genome-wide analysis of 15 Uralic-speaking populations which cover all main groups of the linguistic family. We show that contemporary Uralic speakers are genetically very similar to their local geographical neighbours. However, when studying relationships among geographically distant populations, we find that most of the Uralic speakers and some of their neighbours share a genetic component of possibly Siberian origin. Additionally, we show that most Uralic speakers share significantly more genomic segments identity-by-descent with each other than with geographically equidistant speakers of other languages. We find that correlated genome-wide genetic and lexical distances among Uralic speakers suggest co-dispersion of genes and languages. Yet, we do not find long-range genetic ties between Estonians and Hungarians with their linguistic sisters that would distinguish them from their non-Uralic-speaking neighbours. Conclusions We show that most Uralic speakers share a distinct ancestry component of likely Siberian origin, which suggests that the spread of Uralic languages involved at least some demic component.

Abstract Background Genotoxicity is an important toxicological endpoint due to the link to diseases such as cancer. Therefore, an increased understanding regarding genotoxicity and underlying mechanisms is needed for assessing the risk with exposure to nanoparticles (NPs). The aim of this study was to perform an in-depth investigation regarding the genotoxicity of well-characterized Ni and NiO NPs in human bronchial epithelial BEAS-2B cells and to discern possible mechanisms. Comparisons were made with NiCl2 in order to elucidate effects of ionic Ni. Methods BEAS-2B cells were exposed to Ni and NiO NPs, as well as NiCl2, and uptake and cellular dose were investigated by transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS). The NPs were characterized in terms of surface composition (X-ray photoelectron spectroscopy), agglomeration (photon cross correlation spectroscopy) and nickel release in cell medium (ICP-MS). Cell death (necrosis/apoptosis) was investigated by Annexin V-FITC/PI staining and genotoxicity by cytokinesis-block micronucleus (cytome) assay (OECD 487), chromosomal aberration (OECD 473) and comet assay. The involvement of intracellular reactive oxygen species (ROS) and calcium was explored using the fluorescent probes, DCFH-DA and Fluo-4. Results NPs were efficiently taken up by the BEAS-2B cells. In contrast, no or minor uptake was observed for ionic Ni from NiCl2. Despite differences in uptake, all exposures (NiO, Ni NPs and NiCl2) caused chromosomal damage. Furthermore, NiO NPs were most potent in causing DNA strand breaks and generating intracellular ROS. An increase in intracellular calcium was observed and modulation of intracellular calcium by using inhibitors and chelators clearly prevented the chromosomal damage. Chelation of iron also protected against induced damage, particularly for NiO and NiCl2. Conclusions This study has revealed chromosomal damage by Ni and NiO NPs as well as Ni ionic species and provides novel evidence for a calcium-dependent mechanism of cyto- and genotoxicity.

Abstract Background Human induced pluripotent stem cells-derived myogenic progenitors develop functional and ultrastructural features typical of skeletal muscle when differentiated in culture. Besides disease-modeling, such a system can be used to clarify basic aspects of human skeletal muscle development. In the present study, we focus on the development of the excitation-contraction (E-C) coupling, a process that is essential both in muscle physiology and as a tool to differentiate between the skeletal and cardiac muscle. The occurrence and maturation of E-C coupling structures (Sarcoplasmic Reticulum-Transverse Tubule (SR-TT) junctions), key molecular components, and Ca2+ signaling were examined, along with myofibrillogenesis. Methods Pax7+-myogenic progenitors were differentiated in culture, and developmental changes were examined from a few days up to several weeks. Ion channels directly involved in the skeletal muscle E-C coupling (RyR1 and Cav1.1 voltage-gated Ca2+ channels) were labeled using indirect immunofluorescence. Ultrastructural changes of differentiating cells were visualized by transmission electron microscopy. On the functional side, depolarization-induced intracellular Ca2+ transients mediating E-C coupling were recorded using Fura-2 ratiometric Ca2+ imaging, and myocyte contraction was captured by digital photomicrography. Results We show that the E-C coupling machinery occurs and operates within a few days post-differentiation, as soon as the myofilaments align. However, Ca2+ transients become effective in triggering myocyte contraction after 1 week of differentiation, when nascent myofibrils show alternate A-I bands. At later stages, myofibrils become fully organized into adult-like sarcomeres but SR-TT junctions do not reach their triadic structure and typical A-I location. This is mirrored by the absence of cross-striated distribution pattern of both RyR1 and Cav1.1 channels. Conclusions The E-C coupling machinery occurs and operates within the first week of muscle cells differentiation. However, while early development of SR-TT junctions is coordinated with that of nascent myofibrils, their respective maturation is not. Formation of typical triads requires other factors/conditions, and this should be taken into account when using in-vitro models to explore skeletal muscle diseases, especially those affecting E-C coupling.

Abstract Background Alcohol-related problems at professional sporting events are of increasing concern and alarming reports are often reported in international media. Although alcohol consumption increases the risk for interpersonal violence, it is viewed as a focal element of large football events. Sweden has a long tradition of high public support for strict alcohol-control policies. However, little is known about public opinions on alcohol intoxication and the support for interventions to decrease intoxication at football events. The current study explored the public opinion towards alcohol use, intoxication and alcohol policies at professional football matches in Sweden. Methods A cross-sectional design was utilized and a random general population sample of 3503 adult Swedish residents was asked to participate in a web survey during 2016 (response rate 68%). Results In total, 26% of the respondents supported alcohol sales at football events. Over 90% reported that obviously intoxicated spectators should be denied entrance or evicted from arenas. The support for regulations limiting alcohol availability varied with background factors such as gender, alcohol use and frequency of football event attendance. Conclusions There is a strong public consensus for strategies and policies to reduce alcohol sales and intoxication levels at football matches. This public support has implications for our preventive efforts and will facilitate the implementation of strategies and policy changes.

Abstract Background General Practitioners {GP} in Sweden prescribe more than 50% of all prescriptions. Scientific knowledge on the opinions of GPs regarding drug information has been sparse. Such knowledge could be valuable when designing evidence-based drug information to GPs. GPs' opinions on public- and industry-provided drug information are presented in this article. Methods A cross-sectional study using a questionnaire was answered by 368 GPs at 97 primary-health care centres {PHCC}. The centres were invited to participate by eight out of 29 drug and therapeutic committees {DTCs}. A multilevel model was used to analyse associations between opinions of GPs regarding drug information and whether the GPs worked in public sector or in a private enterprise, their age, sex, and work experience. PHCC and geographical area were included as random effects. Results About 85% of the GPs perceived they received too much information from the industry, that the quality of public information was high and useful, and that the main task of public authorities was to increase the GPs' knowledge of drugs. Female GPs valued information from public authorities to a much greater extent than male GPs. Out of the GPs, 93% considered the main task of the industry was to promote sales. Differences between the GPs' opinions between PHCCs were generally more visible than differences between areas. Conclusions Some kind of incentives could be considered for PHCCs that actively reduce drug promotion from the industry. That female GPs valued information from public authorities to a much greater extent than male GPs should be taken into consideration when designing evidence-based drug information from public authorities to make implementation easier.

Abstract Background Dogs were an important element in many native American cultures at the time Europeans arrived. Although previous ancient DNA studies revealed the existence of unique native American mitochondrial sequences, these have not been found in modern dogs, mainly purebred, studied so far. Results We identified many previously undescribed mitochondrial control region sequences in 400 dogs from rural and isolated areas as well as street dogs from across the Americas. However, sequences of native American origin proved to be exceedingly rare, and we estimate that the native population contributed only a minor fraction of the gene pool that constitutes the modern population. Conclusions The high number of previously unidentified haplotypes in our sample suggests that a lot of unsampled genetic variation exists in non-breed dogs. Our results also suggest that the arrival of European colonists to the Americas may have led to an extensive replacement of the native American dog population by the dogs of the invaders.

Abstract Background Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer. Methods Statistical analysis was performed using multipoint parametric and nonparametric linkage. Results Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1). Conclusion The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.

Abstract Background HMG-CoA reductase inhibitors, statins, are widely prescribed to lower cholesterol. High doses of orally administered simvastatin has previously been shown to improve fracture healing in a mouse femur fracture model. In this study, simvastatin was administered either subcutaneously or directly to the fracture area, with the goal of stimulating fracture repair at acceptable doses. Methods Femur fractures were produced in 70 mature male Balb-C mice and stabilized with marrow-nailing. Three experiments were performed. Firstly, 20 mice received subcutaneous injections of either simvastatin (20 mg) or vehicle. Secondly, 30 mice were divided into three groups of 10 mice receiving continuous subcutaneous delivery of the vehicle substance, the vehicle with 5 mg or with 10 mg of simvastatin per kg bodyweight per day. Finally, in 20 mice, a silicone tube was led from an osmotic mini-pump to the fracture area. In this way, 10 mice received an approximate local dose of simvastatin of 0.1 mg per kg per day for the duration of the experiment and 10 mice received the vehicle compound. All treatments lasted until the end of the experiment. Bilateral femurs were harvested 14 days post-operative. Biomechanical tests were performed by way of three-point bending. Data was analysed with ANOVA, Scheffé's post-hoc test and Student's unpaired t-test. Results With daily simvastatin injections, no effects could be demonstrated for any of the parameters examined. Continuous systemic delivery resulted in a 160% larger force at failure. Continuous local delivery of simvastatin resulted in a 170% larger force at failure as well as a twofold larger energy uptake. Conclusion This study found a dramatic positive effect on biomechanical parameters of fracture healing by simvastatin treatment directly applied to the fracture area.

Abstract Background Positive attitudes towards prisoners are important in securing the effectiveness of various correctional rehabilitation programs and the successful reintegration of prisoners after release. We wanted to investigate the attitudes towards prisoners among prison inmates, prison employees and college students. Methods The Attitudes Toward Prisoners scale was completed by 298 inmates in 4 Norwegian prisons, 387 employees working in the same prisons, and 183 college students. In addition, all respondents were asked a number of general questions about prisoners, crime and punishment. Results The study groups differed significantly in their attitudes towards prisoners, as measured by the Attitudes Toward Prisoners scale, with prison inmates holding the most positive attitudes. Prison officers held more negative attitudes than other prison employees. Prison employees working in female-only facilities held more positive attitudes than those working in male-only facilities. Students differed significantly in their attitudes, with those studying business economics holding more negative attitudes than those studying nursing. A number of strong correlations emerged between negative attitudes towards prisoners and more pessimistic and punitive answers on general questions about prisoners, crime and punishment. Conclusion The attitudes towards prisoners differed markedly among the groups investigated. The findings could have important implications, particularly for the preventive work carried out in our prisons. Whether attitudes toward prisoners can be influenced by educational programs and the dispersion of factual information needs to be investigated.