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Purpose One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the potential to improve breast cancer mortality and morbidity. Anti-estrogens, which may be associated with severe side-effects, can be used for prevention of breast cancer in women with high risk of the disease per se. However, no preventive therapy targeting dense breasts is currently available. Inflammation is a hallmark of cancer. Although the biological mechanisms involved in the increased risk of cancer in dense breasts is not yet fully understood, high mammographic density has been associated with increased inflammation. We investigated whether low-dose acetylsalicylic acid (ASA) affects local breast tissue inflammation and/or structural and dynamic changes in dense breasts. Methods Postmenopausal women with mammographic dense breasts on their regular mammography screen were identified. A total of 53 women were randomized to receive ASA 160 mg/day or no treatment for 6 months. Magnetic resonance imaging (MRI) was performed before and after 6 months for a sophisticated and continuous measure breast density by calculating lean tissue fraction (LTF). Additionally, dynamic quantifications including tissue perfusion were performed. Microdialysis for sampling of proteins in vivo from breasts and abdominal subcutaneous fat, as a measure of systemic effects, before and after 6 months were performed. A panel of 92 inflammatory proteins were quantified in the microdialysates using proximity extension assay. Results After correction for false discovery rate, 20 of the 92 inflammatory proteins were significantly decreased in breast tissue after ASA treatment, whereas no systemic effects were detected. In the no-treatment group, protein levels were unaffected. Breast density, measured by LTF on MRI, were unaffected in both groups. ASA significantly decreased the perfusion rate. The perfusion rate correlated positively with local breast tissue concentration of VEGF. Conclusions ASA may shape the local breast tissue microenvironment into an anti-tumorigenic state. Trials investigating the effects of low-dose ASA and risk of primary breast cancer among postmenopausal women with maintained high mammographic density are warranted. Trial registration EudraCT: 2017-000317-22.

OBJECTIVE The apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for dementia and Alzheimer’s disease (AD), but the underlying mechanism for the increased risk is not well understood. Cerebral small vessel disease (SVD) is prevalent among patients with cognitive impairment and is thought to play an important role in the pathophysiology of dementia. We aimed to investigate the association between the APOE ε genotype and magnetic resonance imaging (MRI) markers of SVD in a memory clinic population. MATERIAL AND METHODS This is a cross-sectional study with a total of 520 patients undergoing dementia investigation, including an MRI brain scan and APOE genotyping in all patients enrolled, and cerebrospinal fluid (CSF) analysis for routine AD biomarkers in 399 patients. MR images were assessed for markers of SVD: cerebral microbleeds, cortical superficial siderosis, intracerebral haemorrhage, white matter hyperintensities, lacunar infarcts and enlarged perivascular spaces. RESULTS APOE ε4 carriers with AD had a higher number of cerebral microbleeds when looking at all brain regions and lobar brain regions (P<0.001). A lower number of cerebral microbleeds were seen in APOE ε2 (P<0.05), ε3 and ε3/3 carriers (P<0.001) when looking at all brain regions. A higher number of cerebral microbleeds in deep and infratentorial regions were seen in APOE ε2 and ε3 (P<0.05). In APOE ε4/4 carriers, cerebral microbleeds, cortical superficial siderosis, white matter hyperintensities and enlarged perivascular spaces were associated with lower levels of CSF amyloid β (Aβ) 42 in the whole cohort, and in individuals with AD and mild cognitive impairment (P<0.05). CONCLUSION APOE ε4 is associated with MRI markers of SVD related to amyloid pathology, specifically cerebral microbleeds and Aβ42 plaque formation in the brain, as reflected by decreased CSF Aβ42 levels, whereas APOE ε3 and ε2 are associated with markers of hypertensive arteriopathy, as reflected by the association with cerebral microbleeds in deep and infratentorial brain regions.

Background Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer’s disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion. Methods Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day. Results All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable. Conclusions The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD. Trial registration ClinicalTrials.gov identifier: NCT01163825 . Registered on 14 Jul 2010.

Background Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis. Methods We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts. Results Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2 , known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. Conclusions Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.

Background Health care systems in Finland, Norway and Sweden share many similarities, e.g. full-coverage and tax-financed, with predominately public sector hospitals. Despite similarities, there are differences in the working situations for RNs within these Nordic countries. The aim of this study was to analyze associations between RNs’ patient workload and level of involvement in direct patient care, their job satisfaction and intention to leave in these countries. Methods A workforce survey was conducted through RN4CAST, an EU 7th framework project. The survey included 118 items derived from validated instruments or tested in prior research. Responses from 1133 RNs at 32 Finnish hospitals, 3752 RNs at 35 Norwegian hospitals, and 11 015 RNs at 71 Swedish hospitals comprise the database, which was analyzed using logistic and odds ratio regressions analyses. Results We found statistically significant differences in RNs’ level of involvement in direct patient care (p < 0.001, Sweden compared to Norway and Finland), in patient workload and in number of patients needing ADL assistance and surveillance. A U-formed relationship was found between level of involvement in direct patient care and intention to leave in Sweden, and more satisfaction among RNs in roles with more direct patient care (OR = 1.16, 1.02 ≤ CI 95%  ≤ 1.32). Nearly half the Finnish sample report intention to leave, with significantly lower levels in Norway and Sweden (p < 0.001). Patient workload is associated with job satisfaction and intention to leave to some degree in all countries, i.e. greater patient workload, less job satisfaction and greater intention to leave. Conclusions This study suggests that more attention paid to patient mix, workload and role of RNs in patient care might potentially diminish intention to leave and increase job satisfaction in these Nordic countries.

Background In the context of monitoring dogs, usually, accelerometers have been used to measure the dog’s movement activity. Here, we study another application of the accelerometers (and gyroscopes)—seismocardiography (SCG) and gyrocardiography (GCG)—to monitor the dog’s heart. Together, 3-axis SCG and 3-axis GCG constitute of 6-axis mechanocardiography (MCG), which is inbuilt to most modern smartphones. Thus, the objective of this study is to assess the feasibility of using a smartphone-only solution to studying dog’s heart. Methods A clinical trial (CT) was conducted at the University Small Animal Hospital, University of Helsinki, Finland. 14 dogs (3 breeds) including 18 measurements (about one half of all) where the dog’s status was such that it was still and not panting were further selected for the heart rate (HR) analysis (each signal with a duration of 1 min). The measurement device in the CT was a custom Holter monitor including synchronized 6-axis MCG and ECG. In addition, 16 dogs (9 breeds, one mixed-breed) were measured at home settings by the dog owners themselves using Sony Xperia Android smartphone sensor to further validate the applicability of the method. Results The developed algorithm was able to select 10 good-quality signals from the 18 CT measurements, and for 7 of these, the automated algorithm was able to detect HR with deviation below or equal to 5 bpm (compared to ECG). Further visual analysis verified that, for approximately half of the dogs, the signal quality at home environment was sufficient for HR extraction at least in some signal locations, while the motion artifacts due to dog’s movements are the main challenges of the method. Conclusion With improved data analysis techniques for managing noisy measurements, the proposed approach could be useful in home use. The advantage of the method is that it can operate as a stand-alone application without requiring any extra equipment (such as smart collar or ECG patch).

Serum triglyceride concentrations increase in dogs with obesity, which is typically assessed by body condition score (BCS), however little is known about changes that take place in non-obese dogs in overweight condition. Further, the associations of triglyceride levels with other markers of energy homeostasis are poorly characterised in healthy animals. The present study aimed to evaluate associations between both BCS and triglyceride concentrations with other markers of lipid and glucose metabolism in healthy, non-obese dogs, as well as to assess whether these markers change significantly in non-obese dogs with overweight as compared to their lean counterparts. Serum concentrations of cholesterol, free fatty acids, triglycerides, insulin, glucose and fructosamine were measured in 532 healthy, client-owned dogs, assigned either to ‘lean’ (BCS: 3–5) or ‘overweight’ (BCS: 6–7) categories. Generalised linear mixed models were used to assess associations between BCS categories, triglyceride concentrations and other variables, correcting for the effect of breed. Compared with lean dogs, overweight dogs had a greater serum cholesterol concentration (95% CI, 5.3–6.2 mmol/L or 205–237 mg/dL versus 5.1–5.4 mmol/L or 198–210 mg/dL, p  = 0.0032), insulin concentration (95% CI, 17.5–22.1 μU/ml versus 16.7–18.0 μU/ml, p  = 0.0374) and were older (95% CI, 4.0–5.3 versus 3.4–3.7 years, p  = 0.0005). Triglyceride concentrations were positively associated with fructosamine ( r 2  = 0.31, p  = 0.0012), cholesterol ( r 2  = 0.25, p  < 0.0001), insulin ( r 2  = 0.14, p  = 0.0030) and glucose ( r 2  = 0.10, p  = 0.0014) concentrations, and negatively associated with free fatty acid concentrations ( r 2  = 0.11, p  < 0.0001). However, there was no association between triglyceride concentrations and age. In conclusion, both BCS and triglyceride concentrations were associated with other markers of glucose and lipid metabolism in non-obese healthy dogs, amongst which those with overweight showed metabolic changes as compared to their lean counterparts. Triglyceride concentrations were associated with an increase in insulin and fructosamine concentrations that might reflect an early-phase impairment in glucose tolerance which, surprisingly, was concurrent with lower basal free fatty acid concentrations.

Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

The discriminative ability of established diagnostic criteria for MRI of the breast is assessed, and their relative relevance using artificial neural networks (ANNs) is determined. A total of 89 women with 105 histopathologically verified breast lesions (73 invasive cancers, 2 in situ cancers, and 30 benign lesions) were included in this study. A T1-weighted 3D FLASH sequence was acquired before and seven times after the intravenous administration of gadopentetate dimeglumine at a dose of 0.2 mmol/kg body weight. ANN models were built to test the discriminative ability of kinetic, morphologic, and combined MR features. The subjects were randomly divided into two parts: a training set of 59 lesions and a verification set of 46 lesions. The training set was used for learning, and the performance of each model was evaluated on the verification set by measuring the area under the ROC curve (Az). An optimally minimized model was constructed using the most relevant input variables that were determined by the automatic relevance determination (ARD) method. ANN models were compared with the performance of a human reader. Margin type, time-to-peak enhancement, and washout ratio showed the highest discriminative ability among diagnostic criteria and comprised the minimized model. Compared with the expert radiologist (Az = 0.799), using the same prediction scale, the minimized ANN model performed best (Az = 0.771), followed by the best kinetic (Az = 0.743), the maximized (Az = 0.727), and the morphologic model (Az = 0.678). The performance of a neural network prediction model is comparable to that of an expert radiologist. A neurostatistical approach is preferred for the analysis of diagnostic criteria when many parameters are involved and complex nonlinear relationships exist in the data set.

The purpose is to introduce a method for accurately and objectively evaluating volume and mean intratendinous signal within the Achilles tendon using MRI. We prospectively studied MRI from 33 patients with chronic Achilles tendinosis (20 males and 13 females) with a median age of 52 years (range 29–70). In all patients, both Achilles tendons were investigated with T1‐WI as well as PD‐WI MRI. Thus, 66 Achilles tendons were evaluated in the study. Tendon volume and mean intratendinous signal were evaluated using a computerized 3‐D seed‐growing technique. In general, the computerized 3‐D seed‐growing technique resulted in an excellent overall observer reliability of the MRI‐measurements. The reliability ( R ) for tendon volume measurements was highest for the T1‐WI sequence ( R =97.9%). For the mean intratendinous signal, the PD‐WI sequence showed the highest reliability ( R =88.1%). The same pattern was present when we studied the coefficient of variation (CV). For the CV, lower figures indicate more reliable estimates. CV was 4.9% for tendon volume and 8.9% for mean intratendinous signal. In conclusion, it could be said that a computerized 3‐D seed‐growing technique to monitor and evaluate the volume of the Achilles tendon and mean intratendinous signal, using MRI, shows an overall excellent reliability regarding inter‐ as well as intra‐observer reliability.