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A clear understanding of the anatomy of the facial nerve, or seventh cranial nerve, is vital during head and neck surgery and for prevention and treatment of facial paralysis. There are four main components of the facial nerve, (branchial motor, special sensory, general sensory, and visceral parasympathetic) that control muscles of facial expression, taste, auricular sensation, and glandular secretion, respectively. It is important for surgeons to appreciate the complex course of the facial nerve as it travels intracranially, intratemporally and extratemporally to prevent injury to these components and identify targets for treatment. This chapter provides an overview of the anatomical course of the facial nerve, describing the anatomy and physiology as they correlate to facial nerve deficits and treatment.

Background and aims: Women with heterozygous familial hypercholesterolemia (FH) are recommended to initiate statin treatment at the same age as men (from 8 to 10 years of age). However, statins are contraindicated when pregnancy is planned, during pregnancy and breastfeeding. The aim of the study was to determine the duration of pregnancy-related off-statin periods and breastfeeding in FH women. Methods: A cross-sectional study using an anonymous online self-administered questionnaire was conducted. Women with FH were recruited through Lipid Clinics in Norway and Netherlands and national FH patient organizations. Results: 102 women with FH (n = 70 Norwegian and n = 32 Dutch) were included in the analysis. Total length of pregnancy-related off-statin periods was estimated for 80 women where data were available, and was median (min-max) 2.3 (0–14.2) years. Lost statin treatment time was estimated for 67 women where data were available, and was median (min-max) 18 (0–100)% at mean (SD) age of 31 (4.3) years at last pregnancy. More women breastfed in Norway (83%) and for longer time [8.5 [1-42] months] compared to the Netherlands [63%, p = 0.03; 3.6 (0–14) months, p < 0.001]. Eighty-six percent of the women reported need for more information on pregnancy and breastfeeding in relation to FH. Conclusions: Young FH women lose years of treatment when discontinuing statins in relation to pregnancy and breastfeeding periods and should be closely followed up to minimize the duration of these off-statin periods. Whether these periods of interrupted treatment increase the cardiovascular risk in FH women needs to be further elucidated.

Background and aims Family members who care for older adults with dementia encounter significant difficulties across many domains. There is limited research in this area; thus, the aim here is to share the actual experiences of 30 family caregivers to other family caregivers and to show how these experiences can provide help and recommendations. Methods This qualitative study of 30 family caregivers of family members aged 65 and older who died with dementia-related diagnoses used in-depth qualitative interviews conducted over a 12-month period for data collection and content analysis to understand the data. The study asked what they learned and what subsequent recommendations these caregivers had for other family caregivers taking care of an older person with dementia. Results Four primary themes emerged from the content data analysis and included the following: (1) “do not do it alone”; (2) patience, love, and kindness; (3) “ first of all, take care of yourself”; and (4) “ get educated.” Conclusions This study is unique in asking directly of family caregivers of older persons who died of dementia what they learned and what they want to share and recommend to ongoing and future family caregivers.

Family caregivers of older adults with dementia have significant challenges across many domains. While this role has been found to be burdensome on the caregiver, increasingly, though, there are also significant positive aspects reported by caregivers (known as the positive aspects of caregiving-PAC). This participatory qualitative study of 30 United States caregivers of family members age 65 and older who died with a dementia-related diagnoses used in-depth qualitative interviews and directed content analysis to understand the data. The study addressed a gap in the research literature and asked about caregiver's positive experiences during their family members' last weeks of life and investigated what this meant for the caregiver. Three primary themes were identified: (1)

Background Reduction of the aortic valve area (AVA) may lead to aortic valve stenosis with considerable impact on morbidity and mortality if not identified and treated. Lipoprotein (a) [Lp(a)] and also inflammatory biomarkers, including platelet derived biomarkers, have been considered risk factor for aortic stenosis; however, the association between Lp(a), inflammatory biomarkers and AVA among patients with familial hypercholesterolemia (FH) is not clear. Objective We aimed to investigate the relation between concentration of Lp(a), measurements of the aortic valve including velocities and valve area and circulating inflammatory biomarkers in adult FH subjects and controls. Methods In this cross-sectional study aortic valve measures were examined by cardiac ultrasound and inflammatory markers were analyzed in non-fasting blood samples. The study participants were 64 FH subjects with high (n = 29) or low (n = 35) Lp(a), and 14 healthy controls. Results Aortic valve peak velocity was higher (p = 0.02), and AVA was lower (p = 0.04) in the FH patients compared to controls; however, when performing multivariable linear regression, there were no significant differences. Furthermore, there were no significant differences between the high and low FH Lp(a) groups regarding the aortic valve. FH subjects had higher levels of platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to controls (0.003 ≤ P ≤ 0.03). This result persisted after multiple linear regression. Conclusions Middle-aged, intensively treated FH subjects have higher aortic valve velocity, lower AVA, and higher levels of the platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to healthy control subjects. The aortic valve findings were not significant after multiple linear regression, whereas the higher levels of platelet-derived markers were maintained.

Family caregivers of older persons with dementia have significant challenges across many domains. These reported problems encountered over their caregiving time are for many reasons, but what makes the caretaking difficult is complicated by both the unknown nature of the dementia disease and the dying trajectory. While there are studies, primarily from health-care professionals, of this dying process and the last few weeks of life for older persons with dementia, much less is known directly from the family caregivers’ perspectives and experiences. This qualitative study of 30 caregivers of family members aged 65 years and older who died with dementia-related diagnoses used in-depth qualitative interviews conducted over a 12-month period and directed content analysis to understand the data. The study asked what physical, behavioral, and psychological changes they observed and experienced during their family members’ last weeks of life. Three primary themes were identified around behavioral and psychological changes: (a) they become different people, (b) did not recognize caregiver, and (c) wandering and getting lost; and two primary themes identified physical decline: (a) system started shutting down and (b) drastically diminished self-sufficiency. Implications for families and professionals are reviewed and discussed.

Contains fulltext : 232514.pdf (Publisher’s version ) (Open Access) BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.

Bevacizumab is included in an increasing number of clinical trials. To find biomarkers to predict and monitor treatment response, cancer and angiogenesis relevant mutations in tumour and circulating tumour DNA (ctDNA) were investigated in 26 metastatic melanoma patients treated with bevacizumab. Patients with >1% BRAF/NRAS ctDNA at treatment start had significantly decreased progression free survival (PFS) and overall survival (OS) (PFS: p = 0.019, median 54 vs 774 days, OS: p = 0.026, median 209 vs 1064 days). Patients with >1% BRAF/NRAS ctDNA during treatment showed similar results (PFS: p = 0.002, OS: p = 0.003). ≤1% BRAF/NRAS ctDNA and normal lactate dehydrogenase (LDH) levels both significantly predicted increased response to treatment, but BRAF/NRAS ctDNA was better at predicting response compared to LDH at treatment start (OR 16.94, p = 0.032 vs OR 4.57, p = 0.190), and at predicting PFS (HR 6.76, p = 0.002) and OS (HR 6.78, p = 0.002) during therapy. ctDNA BRAF p.V600D/E/K and NRAS p.G12V/p.Q61K/L/R were better biomarkers for response prediction than TERT promoter mutations (OR 1.50, p = 0.657). Next generation sequencing showed that all patients with ≥2 mutations in angiogenesis-relevant genes had progressive disease, but did not reveal other biomarkers identifying responders. To conclude, ctDNA and LDH are useful biomarkers for both monitoring and predicting response to bevacizumab.

The aim of this study was to explore how patients with human papilloma virus (HPV)- positive head and neck cancer live with treatment and radiation induced side effects. We investigated how the treatment impacts the patients` experiences of intimacy, sexuality due to the HPV induced diagnosis. This qualitative study was conducted using semi-structured in-dept interviews and a thematic analysis. Eleven patients were included, one year or more after completing radiotherapy. The findings in this study fall into three main themes; 1) Acquiring head and neck cancer – “like an existential earthquake” 2) “Tongue kissing is over!” - Experiences of intimacy, sexuality, and an altered body and 3) Living with an HPV positive diagnosis. Oncology nurses and other health professionals must provide better information about HPV and encourage patients to address issues of intimacy and sexuality. By recognizing the need for information, we can provide better support for the patients in living with the changes after cancer treatment.

Background: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4–5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4–16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2–56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1–79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p

BackgroundSyphilitic uveitis is re-emerging alongside the systemic infection. In July 2017, an international group of uveitis-specialised ophthalmologists formed the International Ocular Syphilis Study Group to define current practice patterns.Methods103 Study Group members based in 35 countries completed a 25-item questionnaire focused on case load, clinical presentations, use and interpretation of investigations, treatment and clinical indicators of poor prognosis.ResultsMembers managed a mean of 6.1 patients with syphilitic uveitis in clinics that averaged 707 annual cases of uveitis (0.9%); 53.2% reported increasing numbers over the past decade. Patients presented to more members (40.2%) during secondary syphilis. Uveitis was usually posterior (60.8%) or pan (22.5%); complications included optic neuropathy, macular oedema and posterior synechiae. All members diagnosed syphilitic uveitis using serological tests (simultaneous or sequential testing algorithms), and 97.0% routinely checked for HIV co-infection. Cerebrospinal fluid (CSF) analysis was ordered by 90.2% of members, and 92.7% took uveitis plus Venereal Disease Research Laboratory test (VDRL) or fluorescent treponemal antibody absorption test (FTA-ABS) to indicate neurosyphilis. Patients were commonly co-managed with infectious disease physicians, and treated with penicillin for at least 10–14 days, plus corticosteroid. Features predicting poor outcome included optic neuropathy (86.3%) and initial misdiagnosis (63.7%). Reasons for delayed diagnosis were often practitioner-related. 82.5% of members tested every patient they managed with uveitis for syphilis.ConclusionThis comprehensive report by an international group of uveitis-specialised ophthalmologists provides a current approach for the management of syphilitic uveitis.

Less is known about how caregivers prepare (or not) for the death of a family member with dementia. This study's purpose was to explore how caregivers handle these dementia deaths, including identification of barriers and facilitators to preparing caregivers for the death of an elder family member dying with dementia. This qualitative, descriptive study employed a purposive sampling strategy in which the principal investigator interviewed 36 caregivers of family members age 65 and older who died from a dementia-related diagnosis. Directed content analysis was used to analyze the data. Four primary themes were identified as barriers: (1) hindrances to information; (2) barriers to hospice; (3) ineffective attempts to comfort; and (4) the nature of death with dementia. Six themes were identified as facilitators: (1) religious/spiritual beliefs; (2) caregiver initiative; (3) prior experience; (4) bearing witness to decline; (5) professionals alerting caregiver (of what to expect of impending death); and (6) culture and legacy of family caregiving. The results support an increased role of social work in addressing caregivers' awareness of impending death and helping prepare them for the death of an elder with dementia.

This exploratory study aids understanding of the experiences of baccalaureate social work students participating in an interprofessional (IP) simulation and how the simulation would inform their future practice. This study used a nonrandom purposive sample of 32 undergraduate social work students from one midwestern university who attended one of three Team STEPPS seminar training days offered during three semesters. Postseminar surveys were completed, and conventional content analysis was used to analyze data. Three themes emerged regarding the first research question of understanding students' experiences in an IP environment: (1) benefits of IP collaboration, (2) social work as a big part of the puzzle, and (3) real-life learning. Three themes emerged regarding the second research question of these students' future practice: (1) communication, (2) self-confidence, and (3) knowledge gained. The results reveal the value of participation in IP simulation activities for undergraduate social work students and support the need for continued development and implementation of such activity.

Background Reliable methods are needed to identify patients with early-stage cancer or high-grade precancerous lesions in the pancreas. Analysis of pancreatic juice to detect somatic mutations could represent one such approach. Here we investigated the concordance between mutations found in the primary tumor and pancreatic juice from the same patient. Methods Amplicon-based targeted deep sequencing was performed on samples from 21 patients with pancreatic ductal adenocarcinoma (PDAC) who had undergone Whipple’s operation. Mutation profiles were determined in formalin-fixed sections of the primary tumor and in pancreatic juice sampled from the main pancreatic duct during surgery. Results Using a cut-off of 3% for variant allele frequency, KRAS mutations were detected in 20/21 primary tumors (95%) and in 15/21 (71%) juice samples. When also considering low-frequency variants, KRAS mutations were found in 20/21 juice samples. Most juice samples exhibited multiple KRAS variants not seen in the primary tumor, and only in 11 cases (52%) did the most abundant variant of the juice correspond to the KRAS mutation detected in the tumor. TP53 mutations were found in 16 tumors (76%) and six juice samples (29%). Among the positive juice samples, only one exhibited more than a single TP53 mutation. Detection of both KRAS and TP53 mutations was fully concordant in the primary tumor and juice sample in 7/21 cases (33%). Conclusions Pancreatic juice from PDAC patients is rich in KRAS mutations often not seen in the primary tumor and possibly reflecting precancerous lesions in other regions of the pancreas. The inclusion of TP53 mutation detection and additional markers must therefore be considered for fully exploiting the clinical potential of pancreatic juice samples in early cancer detection. Electronic supplementary material The online version of this article (10.1186/s12885-018-5195-7) contains supplementary material, which is available to authorized users.

Background Maturity-onset diabetes of the young type 8 (MODY8 or CEL-MODY) is an inherited pancreatic disease characterized by chronic inflammation of the pancreas and diabetes. It is not known whether MODY8 patients have increased risk for developing pancreatic cancer. We investigated KRAS mutation load in duodenal juice from MODY8 patients, comparing with other groups of pancreatic disease. Methods Droplet digital PCR (ddPCR) was used to detect KRAS codon 12/13/61 mutations in duodenal juice sampled from 11 MODY8 patients, nine healthy subjects and 100 patients clinically investigated due to suspected pancreatic disease. Results KRAS mutations were detected in 4/11 patients with MODY8 (36%), 1/9 healthy subjects (11%), 15/44 patients with chronic pancreatitis (CP, 34%), 3/5 patients with pancreatic ductal adenocarcinoma (PDAC, 60%), 3/20 patients with acute pancreatitis (15%), 0/13 patients with other pancreatic disorders and 2/18 patients with nonpancreatic gastrointestinal disease (11%). Of the 28 positive juice samples, 25 (89%) had low-abundance mutations in codons 12/13, with a variant allele frequency (VAF) less than 1%. KRAS-positive patients with MODY8 or CP had significantly lower VAFs than patients with PDAC (Mann-Whitney U test; p = 0.041). Although the overall mutation detection rate was higher for subjects ≥50 years old (26%) than for younger subjects (15%), the difference was not statistically significant. Conclusions KRAS mutations were detectable in duodenal juice from MODY8 patients, but with low abundance and at the same frequency as in CP patients. The discriminative value of the analysis with regard to other pancreatic disease was limited.

Aim To determine the prevalence of long-term mechanical insufflation-exsufflation (MI-E) and concomitant mechanical ventilation in children with neurological conditions, with reported reasons behind the initiation of treatment. Method This was a population-based, cross-sectional study using Norwegian national registries and a questionnaire. Results In total, 114 of 19 264 children with a neurological condition had an MI-E device. Seventy-three of 103 eligible children (31 females, 42 males), median (min-max) age of 10 years 1 month (1y 5mo-17y 10mo), reported their MI-E treatment initiation. Overall, 76% reported airway clearance as the main reason to start long-term MI-E. A prophylactic use was mainly reported by children with neuromuscular disorders (NMDs). Prevalence and age at initiation differed by diagnosis. In spinal muscular atrophy and muscular dystrophies, MI-E use was reported in 34% and 7% of children, of whom 83% and 57% respectively received ventilator support. One-third of the MI-E users were children with central nervous system (CNS) conditions, such as cerebral palsy and degenerative disorders, and ventilator support was provided in 31%. The overall use of concomitant ventilatory support among the long-term MI-E users was 56%. Interpretation The prevalence of MI-E in a neuropaediatric population was 6 per 1000, with two-thirds having NMDs and one-third having conditions of the CNS. The decision to initiate MI-E in children with neurological conditions relies on clinical judgment. What this paper adds The prevalence and age at initiation of mechanical insufflation/exsufflation (MI-E) differed between diagnoses. MI-E was most commonly used in spinal muscular atrophy, where it generally coincided with ventilatory support. One-third of MI-E devices were given to children with central nervous system conditions, and one-third also received ventilatory support.

Background: Mechanical insufflation-exsufflation (MI-E) to augment cough is suggested in patients with neurological conditions at all ages when the cough is weak. The prevalence of long-term MI-E in pediatrics is unknown. Aim: To determine the prevalence of long-term MI-E use in the Norwegian neuropediatric population. Method: A population based cross-sectional study was performed. All Norwegian children equipped with a MI-E device for long-term use was identified by the units supplying technical treatment equipment for home use (4/2017). The Norwegian Patient Registry reported the children’s diagnosis, age and regional residency as well as aggregated data on children Results: In total 114 of 18861 children registered with a neurological condition in the Norwegian Patient Registry were equipped with a MI-E device for long-term use, giving a point prevalence of 6 per 1000 children, varying from 2.1 to 11.9 per 1000 children in the four health regions. The median (min-max) age was 10.7 (1.5-18) yrs. The highest prevalence was found in spinal muscular atrophy, with 24 of 76 children registered with a MI-E device (316/1000), followed by 36 of 535 children with muscular dystrophies/myopathies (67/1000). Among children with cerebral palsy 29 of 2938 had a MI-E device (9.2/1000). Conclution:MI-E was used from 1.5 yrs and was most common in children with spinal muscular atrophy. The overall prevalence of MI-E users in the Norwegian neuropediatric population varies among the four health regions.

BACKGROUND: X-linked retinitis pigmentosa (XLRP) is a hereditary retinopathy that may present with cystoid macular edema (CME). The exact cause of CME in XLRP is unknown. We describe a case report of new onset CME precipitated by travel to high altitude in an adult with XLRP, but no known prior history of CME. CASE DESCRIPTION: A 38-year-old man with XLRP caused by a hemizygous pathogenic variant in RPGR (c.372del; p.Glu125fs) reported sudden onset bilateral blurry vision 4 days after ascending to an altitude of 3,700 meters. He sought local ophthalmic care and was found to have severe bilateral CME. He was treated with topical and oral carbonic anhydrase inhibition and instructed to return to normal altitude. Follow-up imaging at normal altitude revealed that the CME was nearly completely resolved 4 days after initial presentation, and completely resolved 2 weeks after initial presentation. CONCLUSION: Vascular and metabolic changes caused by retinal degeneration in XLRP may predispose to development of CME under the hypoxic conditions experienced at high altitudes. We advise that retinal specialists treating patients with RP should caution them on traveling to high altitudes that could precipitate or exacerbate CME.

Dysregulated tyrosine kinases in myeloid/lymphoid neoplasms with eosinophilia are rare, but do occur in children. To increase awareness of this diagnosis, we present a child who was diagnosed after a 3-year disease history. The patient was initially treated according to a T-cell lymphoblastic lymphoma protocol, but genetic analyses at recurrence revealed microdeletions resulting in an in-frame fusion of ZMYM2 and FLT3. Treatment with sorafenib, an FLT3 tyrosine kinase inhibitor, rapidly resulted in significant reduction of lymphadenopathy and normalization of white blood cell and eosinophil counts. At 17 months of treatment, he remains in complete hematologic, but not molecular remission.

Pure red cell aplasia (PRCA) is a rare syndrome that only affects the erythroid lineage. It is defined by a normocytic, normochromic anemia with a marked reticulocytopenia and severe reduction or absence of erythroid precursors in the bone marrow. Treatment of primary, idiopathic PRCA is immunosuppressive therapy. Although it is rare, isolated cytogenetic abnormalities can be seen in PRCA, and abnormal karyotype is associated with poor response to immunosuppressive therapy and poor prognosis. We describe a 77-year-old male with primary, idiopathic PRCA and a deletion of chromosome 20q, del(20q), in the bone marrow cells. He was successfully treated with immunosuppressive therapy and became transfusion-independent. The same cytogenetic abnormality has also been described in a few other reports; taken together, these observations suggest that del(20q) may represent a recurrent cytogenetic abnormality in PRCA. Our case report clearly illustrates that even patients with primary PRCA and an abnormal karyotype can respond to immunosuppression and become transfusion-independent.

This is the peer reviewed version of the following article: Hardersen, R., Enebakk, T., Christiansen, D., Ludviksen, J. K., Mollnes, T. E., Lappegård, K. T. & Hovland, A. (2019). Comparison of cytokine changes in three different lipoprotein apheresis systems in an ex vivo whole blood model. Journal of Clinical Apheresis, 35(2), 104-116, which has been published in final form at https://doi.org/10.1002/jca.21765 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Introduction - Even if proprotein convertase subtilisin/kexin type 9 inhibitors have replaced lipoprotein apheresis in many patients, lipoprotein apheresis still is an important option in homozygous familial hypercholesterolemia, progressive atherosclerosis or when removal of lipoprotein(a) is indicated. Additional possible favorable effects beyond lipid lowering could include changes in the concentration of cytokines and improvement of hemorheology. Methods - We evaluated how whole blood adsorption, dextran sulfate plasma adsorption, and double filtration plasmapheresis lipoprotein apheresis systems affected cytokine concentrations, using a human whole blood ex vivo model differentiating the effect of the lipoprotein apheresis and plasma separation columns and describing temporal changes. Results - Compared to the control bag, the whole blood adsorption system reduced Interferon‐γ (IFN‐γ), IL‐8, IL‐1ra, eotaxin, tumor necrosis factor (TNF), monocyte chemoattractant protein 1 (MCP‐1), platelet derived growth factor (PDGF)‐BB, regulated on activation T cell expressed and secreted (RANTES), macrophage inflammatory protein‐1β (MIP‐1β), and IP‐10 (P P P P P Conclusion - There were marked differences in how the three systems affected total and temporal cytokine concentration changes in this in vitro model, as well as compared to former in vivo studies.

The death of an older adult with dementia often has an uncertain dying trajectory and has been referred to as "the long goodbye." Researchers have found both positive and negative outcomes of pre-death grief for caregivers of individuals with chronic illnesses. This qualitative study explored the end-of-life experiences for 36 bereaved family caregivers of older adults with dementia; focusing on understanding their experiences with pre-death grief. These caregivers shared experiences with the phenomenon of "welcoming death" and findings highlighted the primary reasons they anticipated, accepted, or wished for the death of their family member with dementia. With the overarching goal of improving bereavement outcomes and reducing feeling of guilt, inclusion of pre-death grief support services throughout the caregiving process are recommended.

AIMS Heart failure (HF) is a multifactorial disease. Current treatments target only a fraction of the putative pathophysiological pathways. In patients with HF, reduced cardiac output and congestion cause increased gut wall permeability. It has been suggested that leakage of microbial products is detrimental to the heart, at least partly through activation of systemic inflammatory pathways, which again could promote gut leakage. Whether manipulating the gut microbiota can improve cardiac function in patients with HF remains unknown. We aim to evaluate the effect of drugs targeting the gut microbiota on left ventricular function, quality of life, and functional capacity, as well as on markers of gut leakage and inflammation, in stable patients with HF with reduced ejection fraction. METHODS AND RESULTS GutHeart is a randomized, open-label, controlled trial. Four centres will randomize 150 patients with stable HF and a left ventricular ejection fraction

Summary Interleukin (IL)-6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL-6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL-6 receptor has not been examined. We therefore investigated whether SNPs in the IL-6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL-6 promoter variant rs1800975 and the IL-6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population-based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL-6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL-6R levels; the decreased IL-6R levels persisted 6 months post-transplant. In contrast, patients being homozygous for the minor allele of the IL-6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL-6R rs4845618 donor genotype showed an association with severe acute graft-versus-host disease (GVHD), whereas the donor genotype of the IL-6 SNP rs1800795 was associated with decreased survival 100 days post-transplant. Finally, the recipient genotype of the IL-6R SNP rs4329505 showed a strong association with 2-years non-relapse mortality, and this effect was also highly significant in multivariate analysis. IL-6 and IL-6R SNPs influence the clinical outcome after allogeneic stem cell transplantation.

Background and Purpose— Familial hypercholesterolemia (FH) is a common autosomal dominant disease leading to increased level of serum LDL (low-density lipoprotein) cholesterol and risk of coronary heart disease. Whether FH increases the risk of cerebrovascular disease, including ischemic stroke, is debated. Accordingly, we studied the incidence of cerebrovascular disease in a cohort of people with genetically verified FH compared with the entire Norwegian population and examined whether people in this cohort with previous cohort had increased risk of cerebrovascular disease. Methods— Incidence rates of hospitalization for cerebrovascular disease (among 3144 people with FH) and ischemic stroke (among 3166 people with FH) were estimated by linkage of FH people to Cardiovascular Disease in Norway—a nationwide database of cardiovascular disease hospitalizations (2001–2009). We calculated standardized incidence ratios and used Cox regression to estimate hazard ratios. Results— A total of 46 cases (19 women and 27 men) of cerebrovascular disease were observed in the cohort of people with FH, with no increased risk of cerebrovascular disease compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.8–1.4). Total number of ischemic strokes in the cohort of people with FH was 26 (9 women and 17 men), with no increased risk compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.7–1.5). Prior coronary heart disease significantly increased cerebrovascular disease risk in women (hazard ratio, 3.29; 95% CI, 1.20–9.00) but not in men (hazard ratio, 1.03; 95% CI, 0.45–2.37; P interaction =0.04). Conclusions— In a large cohort of genetically verified FH, risks of cerebrovascular disease and ischemic stroke were not increased compared with the total Norwegian population.

Background and aims Heart failure (HF) and atrial fibrillation/flutter (AF) are important causes of morbidity and mortality. Subjects with familial hypercholesterolemia (FH) carry a high risk of coronary artery disease (CAD) but it is not known if the risk of HF and AF is increased in FH. The present study investigated the incidence of hospitalization for HF and AF in a genetically verified FH cohort, age 25 years and older, compared to the general population. Methods Incidence rates of hospitalization for HF and AF were estimated from national registry data. Standardized incidence ratios (SIRs) were calculated. Results 4273 genotyped FH patients (51.7% women) with a total observation period of 18,300 patient years were studied. Overall, the expected number of FH patients with HF was 27.7 and the observed number of cases was 54 (SIR (95% CI) 2.0 (1.5–2.6)). The highest excess risk was observed in the age group 25–49 years, where SIRs were 3.8 (1.2–11.8) and 4.2 (2.0–8.8) in women and men, respectively. The total expected number of FH patients with AF was 39.4 while the observed number of cases was 77 (SIR 2.0 (1.6–2.4)). Among FH patients with an incident event of HF, nearly 90% had a previous diagnosis of CAD, and nearly 40% had suffered from a myocardial infarction. Conclusions We demonstrate a doubling of the risk of hospitalization for HF or AF in patients with FH. This is could have an important prognostic impact for patients and economic impact for the society.

Background: The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). Methods: In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF

Purpose Gene expression profile (GEP) testing segregates uveal melanoma (UM) into 2 main prognostic classes. It is unknown if a greater tumor regression response after iodine 125 (I 125 ) brachytherapy correlates with class 2 GEP status. The purpose of this study was to determine whether there is a significant relationship between the rate of UM height regression and GEP classification testing after I 125 plaque brachytherapy. Design Multicenter, retrospective cohort study. Participants Adult UM patients treated with I 125 plaque brachytherapy who had concurrent tumor biopsy at the time of surgery with a GEP test result from January 1, 2010 through June 30, 2014. Methods Baseline clinical data and GEP class assignments were obtained. The ultrasonographic tumor height was recorded at baseline and at 3, 6, 9, and 12 months and at the most recent final follow-up visits. Subanalysis of paired cases based on pretreatment ultrasound height was performed. Statistical analysis was performed using Wilcoxon rank-sum tests, the Fisher exact test, and Kaplan-Meier analysis. Main Outcome Measures Percentage change in tumor height from baseline. Results A total of 353 patients were included in the study. Median follow-up was 2.1 years (range, 0.5–5.3 years). Gene expression profile status was class 1 in 247 tumors (70%) and class 2 in 106 tumors (30%). Increased patient age, larger tumor dimensions, and greater tumor thickness were associated with class 2 GEP status ( P = 0.006, P P P = 0.007) and 6 months (26.8% vs. 17.1%; P = 0.007), respectively, but there was no significant difference in reduction between class 1 and 2 tumors at 9 months ( P = 0.26) and 12 months ( P = 0.57) after treatment. Class 1A and 1B tumors showed similar reduction compared with class 2 tumors ( P Conclusions Class 1 UM tumors tend to regress more rapidly than class 2 tumors in the first 6 months after plaque radiotherapy. Class 1A and 1B tumors regress at similar rates after plaque radiotherapy.

During a period of 1 month, 3 episodes of probable or actual venous air embolism occurred during hysteroscopic surgery. All patients developed the same symptoms of ventilatory and hemodynamic decompensation, beginning with a reduction in end-tidal carbon dioxide, arterial desaturation, and cyanosis on the upper trunk, and rapidly progressed to hypotension and 2 cardiac arrests. While entrainment of some air is common during hysteroscopy, life-threatening embolism is a rare but serious complication for which an anesthetist needs to be vigilant and prepared. If even a small drop in end-tidal carbon dioxide occurs, venous air embolism should be suspected and the operation should be discontinued.

Background Low-density lipoprotein (LDL) apheresis is an extracorporeal treatment modality used in high-risk coronary patients. It may, however, induce complement activation and downstream inflammation due to bio-incompatibility. Objective We explored changes in soluble inflammatory markers when changing from LDL apheresis to the novel PCSK9 inhibitor evolocumab. Methods Three patients with familial hypercholesterolemia participated. Blood samples (EDTA plasma) for complement activation and markers of inflammation were obtained before (baseline) and after LDL apheresis week at 0 and before biweekly administration of evolocumab at weeks 1, 3, 5, and 7. Complement activation was measured by ELISA and cytokines by multiplex technology. Results Complement activation products C3a and Bb were both significantly higher after LDL apheresis compared to baseline ( P = .01), returned to baseline levels before administration of evolocumab and remained low through week 7. C4d was unchanged during LDL apheresis, whereas TCC was slightly higher after apheresis compared to baseline and week 7 without statistical difference. MCP-1 was higher after LDL apheresis compared to baseline ( P = .04), returned to baseline levels before administration of evolocumab and remained low through week 7. There were minor changes for other cytokines including TNF, IFN-γ, MIP-1α, MIP-1β, with some higher and some lower after apheresis; however, none of these changes were statistically significant. Fibrinogen and CRP were lower after LDL apheresis and had returned to levels comparable to baseline at week 7, statistically significant however only for fibrinogen. Conclusions LDL apheresis activated the alternative complement system significantly as reflected by an increase in C3a and Bb. PCSK9 inhibition did not affect complement or cytokines during 7 weeks follow-up.

The purpose of this study is to determine family caregivers’ recommendations for professional health care professionals on how to help prepare them for the death of an elder with dementia. Purposive criterion sampling was employed to identify 30 bereaved caregivers of family members aged 65 and older who died with a dementia-related diagnosis. In-depth, qualitative interviews were conducted over a 12-month period, and qualitative content analysis was used to analyze the data. Three primary themes emerged: (a) Educate Caregivers, (b) Lead Caregivers, and (c) Provide a Caring and Compassionate Presence. The results highlight the importance of various health care professionals’ roles in preparing family caregivers for a death. In doing so, both the dying and their caregivers may have a better end-of-life experience with improved bereavement outcomes.

Introduction Limitations of the current reports on prognosis in ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI), are that they are based on selected samples from hospitals voluntary registries, trials and surveys and thereby lack full population coverage. In contrast to most developed countries, Sweden and the UK were for a long term, the only two countries worldwide that had continuous national clinical registries for acute coronary syndrome with mandated participation for all hospitals. This is now also the case in Norway. Of all STEMIs admitted to hospital in Norway, 77% is treated with PCI (2016). Since 2013 invasive coronary procedures is registered in The Norwegian registry for invasive cardiology (NORIC). Purpose The purpose of the current report from NORIC was to assess the mortality rates in patients treated with PCI for STEMI in Norway. Moreover we sought to assess the relationship between mortality and age at admission in this population. Methods NORIC, which is a part of the Norwegian Cardiovascular Disease Registry (NCDR), is a national person-identifiable health registry that does not require consent from the registered individual. Data were registered from 1st of January 2013 to 13th of June 2018. Results During this period 10524 patients were registered with a STEMI. The incidence is calculated for the years of 2015–2017 when the registry had full national coverage. The incidence of STEMI treated with PCI in Norway was (53 in 2015, 50 in 2016 and 52 in 2017 per 100 000). For patients younger than 80 years at admission, the mortality rates were 4.9%, 6.8% and 8.0% at 30 days, 365 days and 730 days respectively. For patients older than 80 years at admission the mortality rates were 8.3%, 15.6% and 19.0% at 30 days, 365 days and 730 days respectively. The mortality rates stratified by age are illustrated in figure 1. Survival stratified by age Conclusions Mortality in STEMI patients offered primary PCI in Norway is equal or even lower than the mortality reported from well-established national registries from UK and Sweden. This indicates a well functioning treatment strategy despite challenging geography. Age is an important determinant of mortality.

Short‐chain 3‐hydroxyacyl‐CoA dehydrogenase (SCHAD), encoded by the HADH gene, is a ubiquitously expressed mitochondrial enzyme involved in fatty acid oxidation. This protein also plays a role in insulin secretion as recessive HADH mutations cause congenital hyperinsulinism of infancy (CHI) via loss of an inhibitory interaction with glutamate dehydrogenase (GDH). Here, we present a functional evaluation of 16 SCHAD missense variants identified either in CHI patients or by high‐throughput sequencing projects in various populations. To avoid interactions with endogenously produced SCHAD protein, we assessed protein stability, subcellular localization, and GDH interaction in a SCHAD knockout HEK293 cell line constructed by CRISPR‐Cas9 methodology. We also established methods for efficient SCHAD expression and purification in E. coli, and tested enzymatic activity of the variants. Our analyses showed that rare variants of unknown significance identified in populations generally had similar properties as normal SCHAD. However, the CHI‐associated variants p.Gly34Arg, p.Ile184Phe, p.Pro258Leu, and p.Gly303Ser were unstable with low protein levels detectable when expressed in HEK293 cells. Moreover, CHI variants p.Lys136Glu, p.His170Arg, and p.Met188Val presented normal protein levels but displayed clearly impaired enzymatic activity in vitro, and their interaction with GDH appeared reduced. Our results suggest that pathogenic missense variants of SCHAD either make the protein target of a post‐translational quality control system or can impair the function of SCHAD without influencing its steady‐state protein level. We did not find any evidence that rare SCHAD missense variants observed only in the general population and not in CHI patients are functionally affected. publishedVersion

Introduction: Trisomy 8 is one of the most common cytogenetic alterations in acute myeloid leukemia (AML), with a frequency between 10% and 15%.Areas covered: The authors summarize the latest research regarding biological, translational and clinical aspects of trisomy 8 in AML.Expert opinion: Trisomy 8 can be found together with other karyotypes, although it also occurs as a sole aberration. The last decade's research has brought attention to molecular genetic alterations as strong contributors of leukemogenesis. AML with trisomy 8 seems to be associated with mutations in DNA methylation genes, spliceosome complex genes, and myeloid transcription factor genes, and these alterations probably have stronger implication for leukemic pathogenesis, treatment and hence prognosis, than the existence of trisomy 8 itself. Especially mutations in the RUNX1 and ASXL1 genes occur in high frequencies, and search for such mutations should be mandatory part of the diagnostic workup. AML with trisomy 8 is classified as intermediate-risk AML after recent European Leukemia Net (ELN) classification, and hence allogenic hematopoietic stem cell transplantation (Allo-HSCT) should be consider as consolidation therapy for this patient group.Trisomy 8 is frequently occurring in AML, although future molecular genetic workup should be performed, to optimize the diagnosis and treatment of these patients.

Postoperative handover of patients has been described as a complex work process challenged by interruptions, time pressure and a lack of supporting framework. The purpose of this study was to investigate involved personnel’s experiences with the quality of patient handovers between the operating room and the postoperative anesthesia care unit (PACU) before and after implementation of a structured tool for communication. The study was conducted in a hospital in South-eastern Norway. Personnel completed a questionnaire before (n=116) and after (n=90) implementation of the Identification-Situation-Assessment- Recommendations (ISBAR)- tool. Analysis included summative statistics, t-tests and generalized linear regression analysis. Statistical significance assumed at P&lt, 0.05.The overall impression of quality in handovers improved significantly after implementation of the ISBAR (P=0.001). Personnel’s experiences were improved in relation to that handovers followed a logical structure, available documentation was used and all relevant information was communicated (P&lt, 0.001). Moreover, personnel found it easier to establish contact at the beginning of the handover, ambiguities were resolved and documentation was more complete (P=0.001). Profession was associated with seven of the statements, relating to whether relevant information is clearly communicated, whether possible risks and complications are discussed, contact easily established, and to completeness of documentation and information. In addition, findings indicate significantly more negative experiences among receiving personnel both pre- and post-implementation.Implementation of a structured tool for communication in patient handovers, may improve quality and safety in patient handovers between the operating room and the PACU. Research is needed to define optimal patient handovers and to determine the effect of handover quality on patient outcomes.

Background Generalised anxiety disorder (GAD) is a frequent and severe anxiety disorder among older adults. GAD increases the risk of developing other disorders such as depression and coronary heart disease. Older adults with GAD exhibit a poorer response to cognitive behaviour therapy (CBT) compared to younger patients with GAD. The normal age-related cognitive decline can be a contributor to reduced treatment efficacy. One strategy for improving treatment efficacy is to combine CBT with adjunctive interventions targeted at improving cognitive functions. Physical exercise is a viable intervention in this regard. Increased levels of brain-derived neurotrophic factor may mediate improvement in cognitive function. The present study aims to investigate the proposed effects and mechanisms related to concomitant physical exercise. Methods The sample comprises 70 participants aged 60–75 years, who have GAD. Exclusion criteria comprise substance abuse and unstable medication; inability to participate in physical exercise; and conditions which precludes GAD as primary diagnosis. The interventions are individual treatment in the outpatient clinic at the local psychiatric hospital, with two experimental arms: (1) CBT + physical exercise and (2) CBT + telephone calls. The primary outcome measure is symptom reduction on the Penn State Worry Questionnaire. Other measures include questionnaires, clinical interviews, physiological, biological and neuropsychological tests. A subset of 40 participants will undergo magnetic resonance imaging (MRI). After inclusion, participants undergo baseline testing, and are subsequently randomized to a treatment condition. Participants attend five sessions of the add-on treatment in the pre-treatment phase, and move on to interim testing. After interim testing, participants attend 10 sessions of CBT in parallel with continued add-on treatment. Participants are tested post-intervention within 2 weeks of completing treatment, with follow-up testing 6 and 12 months later. Discussion This study aims to develop better treatment for GAD in older adults. Enhancing treatment response will be valuable from both individual and societal perspectives, especially taking the aging of the general population into account. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Background - Current treatment goals for familial hypercholesterolemia (FH) recommended by the European Atherosclerosis Society (EAS) are LDL-C ≤2.5 mmol/L (∼100 mg/dL) or ≤1.8 mmol/L (∼70 mg/dL) in very high-risk subjects. Objective - The objective of the present study was to investigate characteristics and treatment status in subjects with genetically verified FH followed at specialized lipid clinics in Norway. Methods - Data from treatment registries of 714 adult (>18 years) subjects with FH. Results - Fifty-seven percent were female. Mean age (SD) at last visit was 44 (16.3) years, and the subjects had been followed at a lipid clinic for 11.1 (7.9) years. Two hundred forty-five (34%) were classified as very-high-risk, and 44% of these had established coronary heart disease. Very-high-risk FH subjects more often received maximal statin dose (54% vs 33%, P < .001), ezetimibe (76% vs 48%, P < .001) or resins (23% vs 9%, P < .001), and achieved LDL-C was lower (3.2 vs 3.5 mmol/L [124 vs 135 mg/dL], P = .003) than normal-risk FH. LDL-C treatment goal was achieved in 25% and 8% of subjects with normal-risk and very-high-risk FH, respectively. Lp(a) levels were available in 599 subjects, and they were divided into 2 groups: ≥90 mg/dL (n = 96) and P < .001). Conclusion - Very few FH subjects achieve their LDL-C treatment goal. New treatment modalities are needed. Independent of LDL-C and other risk factors, high Lp(a) seem to be an important additional risk factor in genetically verified FH.

Accepted manuscript version, licensed CC BY-NC-ND 4.0. Background - Prestatin trials reported positive effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in cardiovascular disease, whereas recent studies and meta-analyses have not reproduced these results. The effect of n-3 PUFA in patients with familial hypercholesterolemia (FH), a group with particularly high risk of cardiovascular disease, is not well established. Objective - We investigated the effect of n-3 PUFA in the early stage of atherosclerosis in FH patients by evaluating in vivo (peripheral arterial tonometry [PAT]) and in vitro (plasma asymmetric dimethylarginine and E-selectin) endothelial function. Methods - This was a double-blind, placebo-controlled cross-over study with 34 FH patients on statin treatment (mean age 46.6 years). In random order, all individuals were treated for 3 months with high-dose n-3 PUFA (2 g, ×2) and 3 months placebo (olive oil, 2 g ×2), separated by a 3-month washout period. Anthropometric data, blood samples, and PAT were collected at 4 time points. Results - There were no significant changes in reactive hyperemia index measured by PAT after n-3 PUFA compared with placebo, median reactive hyperemia index after n-3 PUFA was 1.98 and after placebo 1.96 (P = .51). No significant changes were detected in the soluble endothelial marker asymmetric dimethylarginine (in 2 different assays) when comparing n-3 PUFA and placebo (P = .92 and .14, respectively). Finally, the level of E-selectin did not change significantly during the trial (P = .26). Conclusion - Addition of n-3 PUFA to standard lipid-lowering treatment in genetically verified FH patients did not affect the in vivo endothelial function or soluble endothelial markers.

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Finally version with altered title. Importance - Aortic valve stenosis (AS) is the most common valve disease. Elevated levels of low-density lipoprotein (LDL) cholesterol are a risk factor; however, lipid-lowering treatment seems not to prevent progression of AS. The importance of LDL cholesterol in the development of AS thus remains unclear. People with familial hypercholesterolemia (FH) have elevated LDL cholesterol levels from birth and until lipid-lowering treatment starts. Thus, FH may serve as a model disease to study the importance of LDL cholesterol for the development of AS. Objective - To compare the incidence of AS per year in all genetically proven patients with FH in Norway with the incidence of these diseases in the total Norwegian population of about 5 million people. Design, Setting, and Participants - This is a registry-based prospective cohort study of all Norwegian patients with FH with regard to first-time AS between 2001 and 2009. All genotyped patients with FH in Norway were compared with the total Norwegian populations through linkage with the Cardiovascular Disease in Norway project and the Norwegian Cause of Death Registry regarding occurrence of first-time AS. Data were analyzed between January 1, 2018, and December 31, 2018. Main Outcomes and Measures - Standardized incidence ratios. Results - In total, 53 cases of AS occurred among 3161 persons (1473 men [46.6%]) with FH during 18 300 person-years of follow-up. Mean age at inclusion and at time of AS were 39.9 years (range, 8-91 years) and 65 years (range, 44-88 years), respectively. Total standardized incidence ratios were 7.9 (95% CI, 6.1-10.4) for men and women combined, 8.5 (95% CI, 5.8-12.4) in women, and 7.4 (95% CI, 5.0-10.9) in men, respectively, indicating marked increased risk of AS compared with the general Norwegian population. Conclusions and Relevance - In this prospective registry study, we demonstrate a marked increase in risk of AS in persons with FH.

Background A feature of myeloproliferative neoplasia is transforming to more aggressive and malignant myeloid neoplasia, including acute myeloid leukemia. Different pathogenesis mechanisms participate in transformation, including transformation of existing potential preleukemic clones, since JAK2-mutant myeloproliferative neoplasms often transform to JAK2 wild-type acute myeloid leukemia. Case presentation Here, we present an 80 year old man with a JAK2-V617F mutant primary myelofibrosis. After 10 months the disease transform into a Philadelphia chromosome positive acute myeloid leukemia, detecting the cytogenetic aberration; t(9;22)(q34;q22) encoding the rare BCR-ABL1 fusion gene; e6a2. The patient had treatment response to tyrosine kinases, illustrating the potential benefits of such approach in treating these patients subset. Conclusion The case illustrates the potential of leukemic transformation to Philadelphia chromosome positive myeloid malignancies from potential existing preleukemic clones, and the awareness of such an evolution among patients with myeloproliferative neoplasms. Tyrosine kinases have potential effect also in patients presenting without chronic myeloid leukemia and with rare BCR-ABL1 fusion transcripts, and should probably be a part of the treatment approach.

Simple Summary We here review liquid biopsy methods and their use in the diagnostics and treatment of patients with solid cancers. More specifically, circulating tumor DNA, circulating tumor cells, and their current and future clinical applications are considered. Important factors for further integration of liquid biopsy methods in clinical practice are discussed, with a special focus on a Nordic Healthcare system. Abstract Liquid biopsies have emerged as a potential new diagnostic tool, providing detailed information relevant for characterization and treatment of solid cancers. We here present an overview of current evidence supporting the clinical relevance of liquid biopsy assessments. We also discuss the implementation of liquid biopsies in clinical studies and their current and future clinical role, with a special reference to the Nordic healthcare systems. Our considerations are restricted to the most established liquid biopsy specimens: circulating tumor DNA (ctDNA) and circulating tumor cells (CTC). Both ctDNA and CTCs have been used for prognostic stratification, treatment choices, and treatment monitoring in solid cancers. Several recent publications also support the role of ctDNA in early cancer detection. ctDNA seems to provide more robust clinically relevant information in general, whereas CTCs have the potential to answer more basic questions related to cancer biology and metastasis. Epidermal growth factor receptor-directed treatment of non-small-cell lung cancer represents a clinical setting where ctDNA already has entered the clinic. The role of liquid biopsies in treatment decisions, standardization of methods, diagnostic performance and the need for further research, as well as cost and regulatory issues were identified as factors that influence further integration in the clinic. In conclusion, substantial evidence supports the clinical utility of liquid biopsies in cancer diagnostics, but further research is still required for a more general application in clinical practice.

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders resulting from deficiency of enzymes essential for the synthesis of cortisol. Disease of the adrenal cortex, but there may be involvement adrenomedullary. Cortisol and epinephrine are directly related to the individual’s stress response. Lower values of epinephrine in children with congenital adrenal yperplasia could be related to increased clinical complications and hospitalizations rate. We evaluated the serum values of metanephrines and normetanephrines in children and adolescents with classic congenital adrenal hyperplasia and primary hypothyroidism and possible correlations with disease and hospitalizations. Cross-sectional study involved 29 patients (10 simple virilizing and 19 salt-wasting), and control group of 28 patients with primary hypothyroidism (10 overt and 18 subclinical). There were no differences in age (p = 0.24) and metanephrine (p = 0.34) or normetanephrine values (p = 0.85) between groups.Hospitalization rate was higher in the cases than in the controls (51 x 12).We conclude the serum values of metanephrine and normetanephrine in patients with congenital adrenal hyperplasia were within the normal values of reference, with no significant difference of group with primary hypothiroidism. The number of hospitalizations in the case was high in relation to the control, mainly in salt-wasting.

Background Guided Internet-based cognitive behavioural therapy (ICBT) is a recommended treatment for panic disorder promising to increase treatment availability, but there are some concerns regarding adherence, including adherence to the in vivo exposure given as home assignments. The aim of this study was to assess the feasibility of combining ICBT with physical exercise with the aim of improving adherence and treatment response to ICBT. Method 12 participants were included via routine clinical practice to an open pre- post trial of feasibility using ICBT and an aerobe exercise protocol. We used a mixed model design investigating multiple areas of adherence, participants’ experience and clinical outcome. Results 90.9% of the participants was considered completers in the ICBT program and the average adherence to the physical exercise was 93.1%. The experience of participating was summarized as “Hard work but worth it”. Clinical outcomes effect sizes (d) ranged from 2.79 (panic severity) to .64 (Beck's anxiety index). Conclusion The sum results on adherence, qualitative and quantitative data all suggest that augmenting ICBT with an aerobic exercise protocol is feasible. We conclude that further research is warranted.

Background Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. Methods We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. Results At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P