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Objective: To evaluate the effects of adding individually tailored interventions to a standard treatment in patients with stress-related exhaustion disorder, with regard to sick-leave days and symptoms of burnout. The study design was a 2-armed randomized controlled intervention, with follow-up after 15 months. Data were obtained from patients referred to the Institute of Stress Medicine, and were collected between 2011 and 2014 in western Sweden. Methods: Inclusion criteria were scoring above cut-off in at least 1 of 4 dimensions; mental and physical exhaustion, disturbed sleep, reduced cognitive function and perceived poor self-esteem. The total study population comprised 142 patients (112 females, 30 males) allocated through block randomization to either the intervention group (n = 71) or the control group (n = 71). The intervention group received 1–4 individually tailored interventions (physical activity, cognitive behaviour therapy for insomnia, computerized memory training, cognitive behavioural therapy for self-esteem), based on the results of screening assessments. The interventions were additional to a standard treatment. The control group received solely the standard treatment. The primary outcome measure was the proportion of participants not sicklisted at the 15-month follow-up. Results: At the 15-month follow-up, 30% of subjects in the intervention group and 34% in the control group had 0% sick-listed (p = 0.58). No change between baseline and follow-up was seen in 42% of the intervention group and 39% of the control group, while an increased sick-leave rate was seen in 1% of the intervention group and 4% of the control group. However, no statistically significant difference was seen between groups. Conclusion: Adding individually tailored interventions to a standard treatment in patients with stress-related exhaustion did not reduce sick-leave days or burnout symptoms. LAY ABSTRACT The aim of this randomized controlled study was to investigate whether individually tailored interventions, added to a standard treatment for patients diagnosed with stress-related exhaustion, could reduce sick-leave and symptoms of burnout more in the intervention group than in a control group. Patients were allocated randomly into either the intervention group or a control group. To be included in the study patients had to score above cut-off in 1 or more of the core dimensions characterizing stress-related exhaustion, mental and physical exhaustion, disturbed sleep, cognitive decline, or perceived poor self-esteem. Patients assigned to the intervention group received additional interventions as well as a standard treatment, while the control group received only standard treatment. The results showed no major differences between the intervention group and the control group, with respect to either sick-leave and symptoms of burnout at the 15-month follow-up. The clinical implication from this study is that individually tailored interventions added to the standard treatment are inefficient in reducing both sick-leave days and burden of disease in this patient group, and should be accompanied by interventions targeting the workplace and the work organization level.

The neonatal immune system is distinct from the immune system of older individuals rendering neonates vulnerable to infections and poor responders to vaccination. Adjuvants can be used as tools to enhance immune responses to co-administered antigens. Antibody (Ab) persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow, and transient Ab responses in early life have been associated with decreased survival of plasma cells, possibly due to lack of survival factors. Various cells can secrete these factors and which cells are the main producers is still up for debate, especially in early life where this has not been fully addressed. The receptor BCMA and its ligand APRIL have been shown to be important in the maintenance of plasma cells and Abs. Herein, we assessed age-dependent maturation of a broad range of bone marrow accessory cells and their expression of the survival factors APRIL and IL-6. Furthermore, we performed a comparative analysis of the potential of 5 different adjuvants; LT-K63, mmCT, MF59, IC31 and alum, to enhance expression of survival factors and BCMA following immunization of neonatal mice with tetanus toxoid (TT) vaccine. We found that APRIL expression was reduced in the bone marrow of young mice whereas IL-6 expression was higher. Eosinophils, macrophages, megakaryocytes, monocytes and lymphocytes were important secretors of survival factors in early life but undefined cells also constituted a large fraction of secretors. Immunization and adjuvants enhanced APRIL expression but decreased IL-6 expression in bone marrow cells early after immunization. Furthermore, neonatal immunization with adjuvants enhanced the proportion of plasmablasts and plasma cells that expressed BCMA both in spleen and bone marrow. Enhanced BCMA expression correlated with enhanced vaccine-specific humoral responses, even though the effect of alum on BCMA was less pronounced than those of the other adjuvants at later time points. We propose that low APRIL expression in bone marrow as well as low BCMA expression of plasmablasts/plasma cells in early life together cause transient Ab responses and could represent targets to be triggered by vaccine adjuvants to induce persistent humoral immune responses in this age group.

Abstract Background Exhaustion disorder (ED) is a common cause of sick leave in Sweden, and patients often have long-lasting symptoms and reduced work capacity. The aim of this study was to explore whether patients with ED had made any changes in their work situation from the period of treatment and up to 7 years later. Methods In this cross-sectional study, patients diagnosed with ED at a specialist outpatient clinic were followed up after 7 years (n = 217). They received questionnaires at baseline covering sex, age, marital status, level of education, and symptoms of burnout, depression, and anxiety measured with the Shirom-Melamed Burnout Questionnaire and the Hospital Anxiety and Depression Scale. After 7 years, they were sent a follow-up questionnaire asking about their work situation and work-related stressors both before they fell sick and at the 7-year follow-up. There were three questions on work situation (change of workplace, change of work tasks, and change of working hours), and 155 patients responded to all three. Results After 7 years, the majority of the patients (63%; n = 98/155) reported that they had made some kind of change at work. Women were more likely than men to report decreased working hours (p = 0.001), and work-related stressors such as conflicts at work, reorganization, deficient leadership, and general discontent with the work situation were significantly more common at baseline in the group who had made changes at work. Patients who made no changes at work experienced more work-related stress due to quantitative demands in the 7-year follow-up. Conclusion The majority of the patients with ED made some kind of change in their work situation, and gender differences were found for changes of work tasks and working hours. Work-related stressors might be decisive for making changes at work.

Eiriksdottir et al. use a temporal proteomic dataset from over 22,000 Icelandic individuals to identify predictors and predict all-cause mortality. Their findings suggest that the plasma proteome may be of value in general health screening for risk of death.

The concentration of SARS-CoV-2 changes during an individual’s infection, and mutations accumulate as viruses are transmitted between people. Here, the authors use data from Iceland to demonstrate how this information can be exploited at the population-level to determine the phase of the epidemic.

Erna Ivarsdottir et al. report a genome-wide association meta-analysis for age-related hearing loss in the Icelandic and UK populations. They identify 21 novel variants, 13 of which are rare, and reveal a genetic correlation between age-related hearing loss and tinnitus.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic with unprecedented economic and societal impact. Currently, several vaccines are available and multitudes of antiviral treatments have been proposed and tested. Although many of the vaccines show clinical efficacy, they are not equally accessible worldwide. Additionally, due to the continuous emergence of new variants and generally short duration of immunity, the development of effective antiviral treatments remains of the utmost importance. Since the emergence of SARS-CoV-2, substantial efforts have been undertaken to repurpose existing drugs for accelerated clinical testing and emergency use authorizations. However, drug-repurposing studies using cellular assays often identify hits that later prove ineffective clinically, highlighting the need for more complex screening models. To this end, we evaluated the activity of single compounds that have either been tested clinically or already undergone extensive preclinical profiling, using a standardized in vitro model of human nasal epithelium. Furthermore, we also evaluated drug combinations based on a sub-maximal concentration of molnupiravir. We report the antiviral activity of 95 single compounds and 30 combinations. We show that only a few single agents are highly effective in inhibiting SARS-CoV-2 replication while selected drug combinations containing 10 µM molnupiravir boosted antiviral activity compared to single compound treatment. These data indicate that molnupiravir-based combinations are worthy of further consideration as potential treatment strategies against coronavirus disease 2019 (COVID-19).

BackgroundCholinergic drugs are the most commonly used drugs for the treatment of Alzheimer’s disease (AD). Therefore, a better understanding of the cholinergic system and its relation to both AD-related biomarkers and cognitive functions is of high importance.ObjectivesTo evaluate the relationships of cerebrospinal fluid (CSF) cholinergic enzymes with markers of amyloidosis, neurodegeneration, neurofibrillary tangles, inflammation and performance on verbal episodic memory in a memory clinic cohort.MethodsIn this cross-sectional study, 46 cholinergic drug-free subjects (median age = 71, 54% female, median MMSE = 28) were recruited from an Icelandic memory clinic cohort targeting early stages of cognitive impairment. Enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was measured in CSF as well as levels of amyloid-β1–42 (Aβ42), phosphorylated tau (P-tau), total-tau (T-tau), neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B), and glial fibrillary acidic protein (GFAP). Verbal episodic memory was assessed with the Rey Auditory Verbal Learning (RAVLT) and Story tests.ResultsNo significant relationships were found between CSF Aβ42 levels and AChE or BuChE activity (p > 0.05). In contrast, T-tau (r = 0.46, p = 0.001) and P-tau (r = 0.45, p = 0.002) levels correlated significantly with AChE activity. Although neurodegeneration markers T-tau and NFL did correlate with each other (r = 0.59, p < 0.001), NFL did not correlate with AChE (r = 0.25, p = 0.09) or BuChE (r = 0.27, p = 0.06). Inflammation markers S100B and YKL-40 both correlated significantly with AChE (S100B: r = 0.43, p = 0.003; YKL-40: r = 0.32, p = 0.03) and BuChE (S100B: r = 0.47, p < 0.001; YKL-40: r = 0.38, p = 0.009) activity. A weak correlation was detected between AChE activity and the composite score reflecting verbal episodic memory (r = −0.34, p = 0.02). LASSO regression analyses with a stability approach were performed for the selection of a set of measures best predicting cholinergic activity and verbal episodic memory score. S100B was the predictor with the highest model selection frequency for both AChE (68%) and BuChE (73%) activity. Age (91%) was the most reliable predictor for verbal episodic memory, with selection frequency of both cholinergic enzymes below 10%.ConclusionsResults indicate a relationship between higher activity of the ACh-degrading cholinergic enzymes with increased neurodegeneration, neurofibrillary tangles and inflammation in the stages of pre- and early symptomatic dementia, independent of CSF Aβ42 levels.

Abstract Muscle synergies are hypothesized to reflect connections among motoneurons in the spinal cord activated by central commands and sensory feedback. Robotic rehabilitation of upper limb in post-stroke subjects has shown promising results in terms of improvement of arm function and motor control achieved by reassembling muscle synergies into a set more similar to that of healthy people. However, in stroke survivors the potentially neurophysiological changes induced by robot-mediated learning versus usual care have not yet been investigated. We quantified upper limb motor deficits and the changes induced by rehabilitation in 32 post-stroke subjects through the movement analysis of two virtual untrained tasks of object placing and pronation. The sample analyzed in this study is part of a larger bi-center study and included all subjects who underwent kinematic analysis and were randomized into robot and usual care groups. Post-stroke subjects who followed robotic rehabilitation showed larger improvements in axial-to-proximal muscle synergies with respect to those who underwent usual care. This was associated to a significant improvement of the proximal kinematics. Both treatments had negative effects in muscle synergies controlling the distal district. This study supports the definition of new rehabilitative treatments for improving the neurophysiological recovery after stroke.

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women.

Abstract Bell’s palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4–14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell’s palsy (rs9357446-A; P = 6.79 × 10−23, OR = 1.23; N cases = 4714, N controls = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10−11, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.

Background: People with chronic neurological diseases, such as Parkinson’s Disease (PD) and Multiple Sclerosis (MS), often present postural disorders and a high risk of falling. When difficulties in achieving outpatient rehabilitation services occur, a solution to guarantee the continuity of care may be telerehabilitation. This study intends to expand the scope of our previously published research on the impact of telerehabilitation on quality of life in an MS sample, testing the impact of this type of intervention in a larger sample of neurological patients also including PD individuals on postural balance. Methods: We included 60 participants with MS and 72 with PD. All enrolled subjects were randomized into two groups: 65 in the intervention group and 67 in the control group. Both treatments lasted 30–40 sessions (5 days/week, 6–8 weeks). Motor, cognitive, and participation outcomes were registered before and after the treatments. Results: All participants improved the outcomes at the end of the treatments. The study’s primary outcome (Mini-BESTest) registered a greater significant improvement in the telerehabilitation group than in the control group. Conclusions: Our results demonstrated that non-immersive virtual reality telerehabilitation is well tolerated and positively affects static and dynamic balance and gait in people with PD and MS.

Winter storage of seedlings in freezers reduces the amount of heat sum available for growth in the following growing season compared to seedlings stored outdoors. To test the effects of a reduced growing period on the autumn frost hardiness of the six species most used in Icelandic afforestation, seedlings were stored outdoors or in a freezer during winter. In spring, the seedlings were planted on 24 May, 7 June, 21 June, and 5 July, and the frost hardiness of all treatments was tested on 12 and 26 September. In general, the probability of freezing damage increased with a later planting date, with outdoor-stored seedlings having the lowest probability of damage. The timing of frost events was of great importance; the later the freezing date, the less damage was observed. Growth cessation occurred at different times for each species, and they responded differently to the reduced heat sum. Lodgepole pine and birch accumulated the most frost hardiness in September. Sitka spruce had less autumn frost hardiness than Lutz spruce. Hybrid larch accumulated less frost hardiness than Russian larch and was most sensitive to the reduced heat sum. The results can be used to determine which species should be prioritised in frozen storage with regard to Iceland's short growing season. [ABSTRACT FROM AUTHOR]

Objectives To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. Methods We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short- and long-term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. Results No individual SNP reached genome-wide significance (P  < 5 × 10−8), either for persistence at 1 year or at 3 years. The RA PRS was not significantly associated with MTX treatment persistence at 1 year [relative risk (RR) = 0.98 (0.96–1.01)] or at 3 years [RR = 0.96 (0.93–1.00)]. The heritability of MTX treatment persistence was estimated to be 0.45 (0.15–0.75) at 1 year and 0.14 (0–0.40) at 3 years. The results in seropositive RA were comparable with those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. Conclusion Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, MTX monotherapy persistence was lower in patients with a greater genetic disposition, per the PRS, towards RA. [ABSTRACT FROM AUTHOR]

Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

The original version of the acknowledgement unfortunately contained a mistake.

Introduction Breast cancer is still the most common malignancy among women worldwide. The Prospective Breast Cancer Biobank (PBCB) collects blood and urine from patients with breast cancer every 6 or 12 months for 11 years from 2011 to 2030 at two university hospitals in Western Norway. The project aims to identify new biomarkers that enable detection of systemic recurrences at the molecular level. As blood represents the biological interface between the primary tumour, the microenvironment and distant metastases, liquid biopsies represent the ideal medium to monitor the patient‘s cancer biology for identification of patients at high risk of relapse and for early detection systemic relapse.Including patient-reported outcome measures (PROMs) allows for a vast number of possibilities to compare PROM data with biological information, enabling the study of fatigue and Quality of Life in patients with breast cancer.Methods and analysis A total of 1455 patients with early-stage breast cancer are enrolled in the PBCB study, which has a one-armed prospective observational design. Participants consent to contribute liquid biopsies (i.e., peripheral blood and urine samples) every 6 or 12 months for 11 years. The liquid biopsies are the basis for detection of circulating tumour cells, circulating tumour DNA (ctDNA), exosomal micro-RNA (miRNA), miRNA in Tumour Educated Platelet and metabolomic profiles. In addition, participants respond to 10 PROM questionnaires collected annually. Moreover, a control group comprising 200 women without cancer aged 25–70 years will provide the same data.Ethics and dissemination The general research biobank PBCB was approved by the Ministry of Health and Care Services in 2007, by the Regional Ethics Committee (REK) in 2010 (#2010/1957). The PROM (#2011/2161) and the biomarker study PerMoBreCan (#2015/2010) were approved by REK in 2011 and 2015 respectively. Results will be published in international peer reviewed journals. Deidentified data will be accessible on request.Trial registration number NCT04488614.