Pulmonary embolism in menopausal hormone therapy: a population-based register study.

OBJECTIVE: Oral but not transdermal menopausal hormone therapy (MHT) increases the risk of venous thromboembolism. There is no evidence regarding the risk of the serious complication pulmonary embolism (PE). The aim was to investigate the risk of PE in women using MHT depending on administration route, type of progestin and treatment duration. METHOD: The population-based case-control study covered 1,771,253 women aged 40-69 years, during 2006-2015. Diagnoses of PE (n = 13,974) and drug dispensations were received from national validated registers. RESULTS: Current MHT users had a higher risk of PE than non-users (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.05-1.26). First ever users had the highest risk (OR 2.07, 95% CI 1.23-3.50). Transdermal administration was not associated with increased risk of PE. The OR was slightly but non-significantly higher with estrogen combined with medroxyprogesterone acetate than with norethisterone acetate. DISCUSSION: The risk of PE was significantly increased in users of oral but not transdermal MHT, with the highest risk in first ever users of oral estrogen combined with medroxyprogesterone acetate. The risk was considerably lower in women with recurrent treatment, probably because of the healthy user effect. CONCLUSION: PE was most common close to initiation of oral treatment. Transdermal MHT did not increase the risk of PE.

Genetic influences on central and peripheral nervous system activity during fear conditioning.

Fear conditioning is an evolutionarily conserved type of learning serving as a model for the acquisition of situationally induced anxiety. Brain function supporting fear conditioning may be genetically influenced, which in part could explain genetic susceptibility for anxiety following stress exposure. Using a classical twin design and functional magnetic resonance imaging, we evaluated genetic influences (h2) on brain activity and standard autonomic measures during fear conditioning. We found an additive genetic influence on mean brain activation (h2 = 0.34) and autonomic responses (h2 = 0.24) during fear learning. The experiment also allowed estimation of the genetic influence on brain activation during safety learning (h2 = 0.55). The mean safety, but not fear, related brain activation was genetically correlated with autonomic responses. We conclude that fear and safety learning processes, both involved in anxiety development, are moderately genetically influenced as expressed both in the brain and the body.

The health promoting conversations intervention for families with a critically ill relative: A pilot study.

BACKGROUND: After intensive care unit treatment, patients often have prolonged impairments that affect their physical, cognitive and mental health. Family members can face overwhelming and emotionally challenging situations and their concerns and needs must be addressed. OBJECTIVE: We investigated the outcomes of pilot randomised control trial, a nurse-led family intervention, Health Promoting Conversations, which focused on family functioning and wellbeing in families with a critically ill member. STUDY DESIGN: This randomised controlled pilot study used a pre-test, post-test design with intervention and control groups to investigate the outcomes of the nurse-led intervention in 17 families. OUTCOME MEASURES: The Health Promoting Conversations intervention was evaluated using validated instruments that measure family functioning and family wellbeing: the General Functioning sub-scale from the McMaster Family Assessment Device; the Family Sense of Coherence, the Herth Hope Index, and the Medical Outcome Short-Form Health Survey. Descriptive and analytical statistical methods were used to analyse the data. RESULTS: After 12 months, the intervention group reported better family functioning than the control group. The intervention group also had better social functioning and mental health after 12 months. CONCLUSION: This intervention may improve family wellbeing by improving family function, reducing stress, and promoting better mental health.

Diffusion tensor imaging and tractography of the white matter in normal aging: The rate-of-change differs between segments within tracts.

Knowledge concerning the normal aging of cerebral white matter will improve our understanding of abnormal changes in neurodegenerative diseases. The microstructural basis of white matter maturation and aging can be investigated using diffusion tensor imaging (DTI). Generally, diffusion anisotropy increases during childhood and adolescence followed by a decline in middle age. However, this process is subject to spatial variations between tracts. The aim of this study was to investigate to what extent age-related variations also occur within tracts. DTI parameters were compared between segments of two white matter tracts, the cingulate bundle (CB) and the inferior fronto-occipital fasciculus (IFO), in 257 healthy individuals between 13 and 84years of age. Segments of the CB and the IFO were extracted and parameters for each segment were averaged across the hemispheres. The data was analysed as a function of age. Results show that age-related changes differ both between and within individual tracts. Different age trajectories were observed in all segments of the analysed tracts for all DTI parameters. In conclusion, aging does not affect white matter tracts uniformly but is regionally specific; both between and within white matter tracts.

Deaths caused by injury among people of working age (18-64) are decreasing, while those among older people (64+) are increasing.

BACKGROUND: Injury is an important cause of death in all age groups worldwide, and contributes to many losses of human and economic resources. Currently, we know a few data about mortality from injury, particularly among the working population. The aim of the present study was to examine death from injury over a period of 14 years (1999-2012) using the Swedish Cause of Death Registry (CDR) and the National Patient Registry, which have complete national coverage. METHOD: CDR was used to identify injury-related deaths among adults (18 years or over) during the years 1999-2012. ICD-10 diagnoses from V01 to X39 were included. The significance of changes over time was analyzed by linear regression. RESULTS: The incidence of prehospital death decreased significantly (coefficient -0.22, r 2 = 0.30; p = 0.041) during the study period, while that of deaths in hospital increased significantly (coefficient 0.20, r 2 = 0.75; p < 0.001). Mortality/100,000 person-years in the working age group (18-64 years) decreased significantly (coefficient -0.40, r 2 = 0.37; p = 0.020), mainly as a result of decrease in traffic-related deaths (coefficient -0.34, r 2 = 0.85; p < 0.001). The incidence of deaths from injury among elderly (65 years and older) patients increased because of the increase in falls (coefficient 1.71, r 2 = 0.84; p < 0.001) and poisoning (coefficient 0.13, r 2 = 0.69; p < 0.001). CONCLUSION: The epidemiology of injury in Sweden has changed during recent years in that mortality from injury has declined in the working age group and increased among those people 64 years old and over.

Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study.

The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [11C]GR205171.

The neurokinin-1 (NK1) receptor is abundantly expressed in the fear circuitry of the brain, including the amygdala, where it modulates stress and anxiety. Despite its proposed involvement in psychopathology, only a few studies of NK1 receptor availability in human subjects with anxiety disorders exist. Here, we compared NK1 receptor availability in patients with social anxiety disorder (SAD; n = 17) and healthy controls (n = 17) using positron emission tomography and the radiotracer [11C]GR205171. The Patlak Graphical plot using a cerebellar reference region was used to model the influx parameter, Ki measuring NK1 receptor availability. Voxel-wise statistical parametric mapping analyses revealed increased NK1 receptor availability specifically in the right amygdala in SAD patients relative to controls. Thus, we demonstrate that exaggerated social anxiety is related to enhanced NK1 receptor availability in the amygdala. This finding supports the contribution of NK1 receptors not only in animal models of stress and anxiety but also in humans with anxiety disorders.

Association between amygdala reactivity and a dopamine transporter gene polymorphism.

Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [(15)O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.

Genetic variations of NLRP1: susceptibility in psoriasis.

BACKGROUND: NACHT, LRR and PYD domain-containing protein (NLRP)1 is part of the inflammasome multiprotein complex involved in the production of interleukin (IL)-1ß and IL-18, two cytokines strongly implicated in psoriasis pathogenesis. Genetic variations in NLRP1 are associated with a predisposition for chronic inflammatory conditions. OBJECTIVES: The aim of the study was to investigate the role of genetic variation in the NLRP1 inflammasome in psoriasis susceptibility. MATERIAL AND METHODS: Four haplotype-tagging single-nucleotide polymorphisms (SNPs) (rs6502867, rs8079034, rs878329 and rs12150220) were investigated by TaqMan allelic discrimination in a patient sample comprising 1847 individuals from 478 families and 802 healthy controls. RESULTS: Using the transmission disequilibrium test, a significant increase in the transmission of the NLRP1 rs8079034C and rs878329C alleles to patients with psoriasis was demonstrated (P = 0·006 and P = 0·033, respectively). Furthermore, homozygosity for the rs878329C allele correlated with a younger age of onset. We also observed an increase in the expression of NLRP1 mRNA in the peripheral blood cells of patients with psoriasis. This was accompanied by a higher level of circulating IL-18 and appeared to be associated with the rs878329C allele. CONCLUSIONS: Our data support the involvement of NLRP1 and the NLRP1 inflammasome in psoriasis susceptibility and further support the role of innate immunity in psoriasis.

What determines immediate use of invasive ventilation in patients with COPD?

BACKGROUND: The choice between non-invasive ventilation (NIV) and invasive ventilation in patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) may be irrational. The aim of this study was to examine those patient characteristics, and circumstances deemed important in the choice made between NIV and invasive ventilation in the intensive care unit (ICU). METHODS: We first examined 95 admissions of AECOPD patients on nine ICUs and identified variables associated with invasive ventilation. Thereafter, a questionnaire was sent to ICU personnel to study the relative importance of different factors with a possible influence on the decision to use invasive ventilation at once. RESULTS: Univariable analysis showed that increasing age [odds ratio (OR) 1.06 per year] and increasing body mass index (BMI) (OR 1.11 per kg/m(2) ) were associated with immediate invasive ventilation, while there was no such association with arterial blood gases or breath rate. BMI was the only factor that remained associated with immediate invasive ventilation in the multivariable analysis [OR 1.12 (95% confidence interval 1.03-1.23) kg/m(2) ]. Ranking of responses to the questionnaire showed that consciousness, respiratory symptoms and blood gases were powerful factors determining invasive ventilation, whereas high BMI and age were ranked low. Non-patient-related factors were also deemed important (physician in charge, presence of guidelines, ICU workload). CONCLUSION: Factors other than those deemed most important in guidelines appear to have an inappropriate influence on the choice between NIV and immediate intubation in AECOPD in the ICU. These factors must be identified to further increase the appropriate use of NIV.

Long term health-related quality of life after burns is strongly dependent on pre-existing disease and psychosocial issues and less due to the burn itself.

BACKGROUND: Health-related quality of life (HRQoL) is reduced after a burn, and is affected by coexisting conditions. The aims of the investigation were to examine and describe effects of coexisting disease on HRQoL, and to quantify the proportion of burned people whose HRQoL was below that of a reference group matched for age, gender, and coexisting conditions. METHOD: A nationwide study covering 9 years and examined HRQoL 12 and 24 months after the burn with the SF-36 questionnaire. The reference group was from the referral area of one of the hospitals. RESULTS: The HRQoL of the burned patients was below that of the reference group mainly in the mental dimensions, and only single patients were affected in the physical dimensions. The factor that significantly affected most HRQoL dimensions (n=6) after the burn was unemployment, whereas only smaller effects could be attributed directly to the burn. CONCLUSION: Poor HRQoL was recorded for only a small number of patients, and the decline were mostly in the mental dimensions when compared with a group adjusted for age, gender, and coexisting conditions. Factors other than the burn itself, such as mainly unemployment and pre-existing disease, were most important for the long term HRQoL experience in these patients.

Quantifying the potential for dose reduction with visual grading regression.

OBJECTIVES: To propose a method to study the effect of exposure settings on image quality and to estimate the potential for dose reduction when introducing dose-reducing measures. METHODS: Using the framework of visual grading regression (VGR), a log(mAs) term is included in the ordinal logistic regression equation, so that the effect of reducing the dose can be quantitatively related to the effect of adding post-processing. In the ordinal logistic regression, patient and observer identity are treated as random effects using generalised linear latent and mixed models. The potential dose reduction is then estimated from the regression coefficients. The method was applied in a single-image study of coronary CT angiography (CTA) to evaluate two-dimensional (2D) adaptive filters, and in an image-pair study of abdominal CT to evaluate 2D and three-dimensional (3D) adaptive filters. RESULTS: For five image quality criteria in coronary CTA, dose reductions of 16-26% were predicted when adding 2D filtering. Using five image quality criteria for abdominal CT, it was estimated that 2D filtering permits doses were reduced by 32-41%, and 3D filtering by 42-51%. CONCLUSIONS: VGR including a log(mAs) term can be used for predictions of potential dose reduction that may be useful for guiding researchers in designing subsequent studies evaluating diagnostic value. With appropriate statistical analysis, it is possible to obtain direct numerical estimates of the dose-reducing potential of novel acquisition, reconstruction or post-processing techniques.

Quantifying the potential for dose reduction with visual grading regression.

Objectives To propose a method to study the effect of exposure settings on image quality and to estimate the potential for dose reduction when introducing dose-reducing measures. Methods Using the framework of visual grading regression (VGR), a log(mAs) term is included in the ordinal logistic regression equation, so that the effect of reducing the dose can be quantitatively related to the effect of adding post-processing. In the ordinal logistic regression, patient and observer identity are treated as random effects using generalised linear latent and mixed models. The potential dose reduction is then estimated from the regression coefficients. The method was applied in a single-image study of coronary CT angiography (CTA) to evaluate two-dimensional (2D) adaptive filters, and in an image-pair study of abdominal CT to evaluate 2D and three-dimensional (3D) adaptive filters. Results For five image quality criteria in coronary CTA, dose reductions of 16-26% were predicted when adding 2D filtering. Using five image quality criteria for abdominal CT, it was estimated that 2D filtering permits doses were reduced by 32-41%, and 3D filtering by 42-51%. Conclusions VGR including a log(mAs) term can be used for predictions of potential dose reduction that may be useful for guiding researchers in designing subsequent studies evaluating diagnostic value. With appropriate statistical analysis, it is possible to obtain direct numerical estimates of the dose-reducing potential of novel acquisition, reconstruction or post-processing techniques.

Human fear reconsolidation and allelic differences in serotonergic and dopaminergic genes.

Fear memory persistence, central for the development and maintenance of anxiety disorders, is partially genetically controlled. Recently, consolidation and reconsolidation processes have been reported to affect fear memory stability and integrity. This study explored the impact of reconsolidation processes and genetic make-up on fear reacquisition by manipulating reconsolidation, using extinction performed outside or inside a reconsolidation interval. Reacquisition measured by skin conductance responses was stronger in individuals that extinguished outside (6 h) than inside (10 min) the reconsolidation interval. However, the effect was predominantly present in val/val homozygotes of the functional val158met polymorphism of the catechol O-methyltransferase (COMT) enzyme and in short-allele carriers of the serotonin-transporter length 5-HTTLPR polymorphism. These results demonstrate that reconsolidation of human fear memory is influenced by dopamine and serotonin-related genes.

Impact of stress coping capacity on recovery from abdominal hysterectomy in a fast-track programme: a prospective longitudinal study.

OBJECTIVE: To evaluate the effect of stress coping capacity in combination with mode of anaesthesia on postoperative recovery in fast-track abdominal hysterectomy. DESIGN: Prospective longitudinal study. SETTING: Five hospitals in the south-east of Sweden. POPULATION: A cohort of 162 women undergoing fast-track abdominal hysterectomy for benign conditions. METHODS: Self-administered questionnaires, the Stress Coping Inventory (SCI) and the Swedish Postoperative Symptom Questionnaire (SPSQ), and clinical information were collected prospectively. Stress coping capacity was categorised as high or low according to the summed score of the SCI. Comparisons of effect variables were adjusted using a propensity score-matching model. MAIN OUTCOME MEASURES: Associations between stress coping capacity and hospital stay, sick leave, use of analgesic and self-reported postoperative symptoms. RESULTS: Women with high stress coping capacity had a significantly shorter sick leave, experienced postoperative symptoms significantly less often, and with lower intensity, than women with low stress coping capacity. With the exception of symptom intensity, these findings were related to having had the operation under spinal anaesthesia as opposed to general anaesthesia. Hospital stay, use of analgesics and abdominal pain were not related to stress coping capacity. CONCLUSIONS: In patients for whom spinal anaesthesia was applied, high stress coping seems to be a quality that helps patients manage the burden of surgery. It is desirable for the individual, as well as for the healthcare system, to enhance recovery by using intervention programmes designed to improve or manage stress coping, particularly for individuals with low stress coping capacity. This recommendation merits further investigation.

In type 2 diabetes, randomisation to advice to follow a low-carbohydrate diet transiently improves glycaemic control compared with advice to follow a low-fat diet producing a similar weight loss.

AIMS/HYPOTHESIS: The study aimed to compare the effects of a 2 year intervention with a low-fat diet (LFD) or a low-carbohydrate diet (LCD), based on four group meetings to achieve compliance. METHODS: This was a prospective randomised parallel trial involving 61 adults with type 2 diabetes consecutively recruited in primary care and randomised by drawing ballots. Patients that did not speak Swedish could not be recruited. The primary outcomes in this non-blinded study were weight and HbA(1c). Patients on the LFD aimed for 55-60 energy per cent (E%) and those on LCD for 20 E% from carbohydrate. RESULTS: The mean BMI and HbA(1c) of the participants were 32.7 ± 5.4 kg/m(2) and 57.0 ± 9.2 mmol/mol, respectively. No patients were lost to follow-up. Weight loss did not differ between groups and was maximal at 6 months: LFD -3.99 ± 4.1 kg (n=31); LCD -4.31 ± 3.6 kg (n=30); p < 0.001 within groups. At 24 months, patients on the LFD had lost -2.97 ± 4.9 kg and those on LCD -2.34 ± 5.1 kg compared with baseline (p = 0.002 and p = 0.020 within groups, respectively). HbA(1c) fell in the LCD group only (LCD at 6 months -4.8 ± 8.3 mmol/mol, p = 0.004, at 12 months -2.2 ± 7.7 mmol/mol, p = 0.12; LFD at 6 months -0.9 ± 8.8 mmol/mol, p = 0.56). At 6 months, HDL-cholesterol had increased with the LCD (from 1.13 ± 0.33 mmol/l to 1.25 ± 0.47 mmol/l, p = 0.018) while LDL-cholesterol did not differ between groups. Insulin doses were reduced in the LCD group (0 months, LCD 42 ± 65 E, LFD 39 ± 51 E; 6 months, LCD 30 ± 47 E, LFD 38 ± 48 E; p = 0.046 for between-group change). CONCLUSIONS/INTERPRETATION: Weight changes did not differ between the diet groups, while insulin doses were reduced significantly more with the LCD at 6 months, when compliance was good. Thus, aiming for 20% of energy intake from carbohydrates is safe with respect to cardiovascular risk compared with the traditional LFD and this approach could constitute a treatment alternative. TRIAL REGISTRATION: ClinicalTrials.gov NCT01005498 FUNDING: University Hospital of Linköping Research Funds, Linköping University, the County Council of Östergötland, and the Diabetes Research Centre of Linköping University.

Visual grading regression: analysing data from visual grading experiments with regression models.

For visual grading experiments, which are an easy and increasingly popular way of studying image quality, hitherto used data analysis methods are often inadequate. Visual grading analysis makes assumptions that are not statistically appropriate for ordinal data, and visual grading characteristic curves are difficult to apply in more complex experimental designs. The approach proposed in this paper, visual grading regression (VGR), consists of an established statistical technique, ordinal logistic regression, applied to data from single-image and image-pair experiments with visual grading scores selected on an ordinal scale. The approach is applicable for situations in which, for example, the effects of the choice of imaging equipment and post-processing method are to be studied simultaneously, while controlling for potentially confounding variables such as patient and observer identity. The analysis can be performed with standard statistical software packages using straightforward coding of the data. We conclude that the proposed statistical technique is useful in a wide range of visual grading studies.