Inotropes and mortality in patients with cardiogenic shock: an instrumental variable analysis from the SWEDEHEART registry.

BACKGROUND: The use of inotropic agents in treating cardiogenic shock (CS) remains controversial. This study investigates the effect of inotropes on 30-day mortality in CS patients using data from the SWEDEHEART registry (The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies). METHODS: Data were sourced from the national SWEDEHEART registry for all CS patients in Sweden from 2000 to 2022. The primary endpoint was 30-day all-cause mortality. We employed multilevel Cox proportional-hazards regression with instrumental variable and inverse probability weighting propensity score to adjust for confounders. The treatment-preference instrument was the quintile of preference for inotrope use at the treating hospital. RESULTS: A total of 16 214 patients (60.5% men, 39.5% women) were included; 23.5% had diabetes, 10.2% had a previous myocardial infarction (MI), and 13.8% had previous heart failure (HF). The median age was 70 years (IQR; 19), with 66.4% over 70. Acute coronary syndrome (ACS) caused CS in 82.9%. Inotropes were administered to 43.8% of patients, while 56.2% did not receive them. There were 7 875 (48.1%) deaths. Patients treated with inotropes were, on average, two years younger and more likely to have ACS, while those not treated had more previous MI and were less likely to undergo PCI. The number of CS cases decreased by 12% per year (Ptrend < 0.001), and inotrope use increased by 5% per year (Ptrend < 0.001). Unadjusted mortality in CS rose by 2% per calendar year (Ptrend < 0.001). Inotropes were associated with higher mortality (adjusted HR 1.72; 95% CI 1.26-2.35; P = 0.001), with significant interactions between inotrope treatment, age, and diagnosis (Pinteraction < 0.001 and Pinteraction = 0.018). CONCLUSIONS: In this observational study, inotropes were linked to higher mortality in CS patients, particularly those younger than 70. While CS cases decreased, inotrope use and mortality increased in Sweden.

Impact of Lipidic Plaque on In-Stent and Stent Edge-Related Events After PCI in Myocardial Infarction: A PROSPECT II Substudy.

BACKGROUND: Lipid content in untreated nonobstructive coronary artery lesions is associated with adverse clinical outcomes, and residual in-stent or stent edge lipid may worsen outcomes after percutaneous coronary intervention (PCI). METHODS: Near-infrared spectroscopy-intravascular ultrasound was performed before and after PCI in patients with myocardial infarction. We evaluated the impact of lipid assessed by near-infrared spectroscopy (maximal lipid core burden index over 4 mm [maxLCBI4mm]) along with intravascular ultrasound information including residual plaque burden on in-stent or edge-related major adverse cardiac events (MACE) in de novo PCI-treated culprit coronary artery lesions. The primary end point was culprit lesion-related MACE (CL-MACE), defined as cardiac death, myocardial infarction, or unstable or progressive angina either requiring revascularization or with rapid lesion progression and classified as in-stent or stent edge-related. RESULTS: During a median follow-up of 3.8 years, 25 CL-MACE (11 stent edge-related, 13 in-stent, and 1 in-lesion without a stent) occurred in 1041 PCI-treated lesions in 768 patients. Pre-PCI or post-PCI measures of lipid content were not related to in-stent CL-MACE. However, stent edge-related CL-MACE was increased if both the post-PCI stent edge maxLCBI4mm was greater than the upper quartile (108.7) and the stent edge plaque burden was >50% (adjusted odds ratio, 4.11 [95% CI, 1.12-15.2]; P=0.03). CONCLUSIONS: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), CL stent implantation leaving behind greater stent edge-related lipid and uncovered plaque burden was associated with an increased risk of stent edge-related CL-MACE during follow-up. In contrast, CL lipid content was not related to in-stent CL-MACE. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02171065.

The Effect of Whole-Diet Interventions on Memory and Cognitive Function in Healthy Older Adults - A Systematic Review.

An increasing number of cross-sectional studies suggests that diet may impact memory and cognition in healthy older adults. However, randomized controlled trials investigating the effects of whole-diet interventions on memory and cognition in healthy older adults are rather rare, and conflicting results are often reported. Therefore, a systematic review was conducted to compile the current evidence regarding the potential effects of whole-diet interventions on 1) memory and 2) other cognitive outcomes in older adults. Studies that reported on randomized controlled trials with dietary interventions in healthy older adults (≥60 y) were included. Studies utilizing supplements, single food items, or trials in specific patient groups (i.e., neurodegenerative diagnoses) were excluded. For the 23 included articles, the main outcomes examined fell into 1 or more of the following categories: cognitive task-based outcomes related to memory, other cognitive task-based outcomes, and additional outcomes related to cognitive function or disease risk. Three of the studies that investigated dietary interventions alone and 2 multidomain studies showed positive effects on memory function, whereas 5 multidomain interventions and 1 intervention that focused on diet alone showed positive effects on other cognitive outcomes. The effect of randomized, controlled whole-diet interventions on memory and cognitive function in healthy older adults is modest and inconclusive, highlighting the need for more well-designed, sufficiently powered studies. Furthermore, the potential mechanisms by which diet impacts cognition in healthy aging need to be elucidated. This systematic review is registered in PROSPERO as CRD42022329759.

Early symptom improvement and other clinical predictors of response to repetitive transcranial magnetic stimulation for depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a rapidly emerging treatment for depression, but outcome prediction is still a challenge. This study aimed to identify predictors of response to rTMS among baseline clinical factors and early symptomatic improvements. METHODS: This cohort study comprised 136 patients with a unipolar or bipolar depressive episode referred for clinical intermittent theta-burst stimulation or right-sided 1 Hz rTMS at the Uppsala Brain Stimulation Unit. The co-primary outcomes used for logistic regression were response, defined as ≥50 % reduction of Montgomery and Åsberg Depression Rating Scale Self-assessment (MADRS-S) total score, and 1-2 points on the Clinical Global Impression Improvement (CGI-I) scale. Early improvement was defined as ≥20 % reduction in the MADRS-S total score, or ≥ 1 point reduction in each MADRS-S item, after two weeks of treatment. RESULTS: The response rates were 21 % for MADRS-S and 45 % for CGI-I. A depressive episode >24 months had lower odds for MADRS-S response compared to ≤12 months. Early improvement of the MADRS-S total score predicted CGI-I response (95 % CI = 1.35-9.47, p = 0.011), Initiative6 predicted MADRS-S response (95 % CI = 1.08-9.05, p = 0.035), and Emotional involvement7 predicted CGI-I response (95 % CI = 1.03-8.66, p = 0.044). LIMITATIONS: No adjustment for concurrent medication. CONCLUSIONS: A depressive episode ≤12 months and early improvement in overall depressive symptoms, as well as the individual items, Initiative6 and Emotional involvement7, predicted subsequent rTMS response in a naturalistic sample of depressed patients. This could facilitate the early identification of patients who will benefit from further rTMS sessions.

Hemiplegic (unilateral) cerebral palsy in northern Stockholm: Intellectual disability and epilepsy.

PURPOSE: The purpose of this study was to describe intellectual disability and its association with epilepsy and brain imaging, in a population-based group of children with hemiplegic (unilateral) cerebral palsy, previously investigated and published in 2020. MATERIALS AND METHODS: Forty-seven children of school age in northern Stockholm, fulfilling the Surveillance of Cerebral Palsy in Europe-criteria of hemiplegic (unilateral spastic) cerebral palsy, were invited to participate in the study. Twenty-one children consented to participate. A WISC (Wechsler Intelligence Scale for Children)-test was performed by an experienced psychologist. RESULTS: In the study population of twenty-one children, 57 % (n 12) displayed uneven cognitive profiles, 38 % (n 8) intellectual disability and 62 % (n 13) had a normal IQ. 43 % (n 9) developed epilepsy. Children with extensive brain lesions had more severe intellectual disability. CONCLUSIONS: In this study intellectual disability and/or epilepsy were associated with the type and extent of the underlying brain lesion. Intellectual disability and uneven cognitive profiles were common. We therefore recommend individual cognitive assessment to ensure an optimal school start.

Exploring brain plasticity in developmental dyslexia through implicit sequence learning.

Developmental dyslexia (DD) is defined as difficulties in learning to read even with normal intelligence and adequate educational guidance. Deficits in implicit sequence learning (ISL) abilities have been reported in children with DD. We investigated brain plasticity in a group of 17 children with DD, compared with 18 typically developing (TD) children, after two sessions of training on a serial reaction time (SRT) task with a 24-h interval. Our outcome measures for the task were: a sequence-specific implicit learning measure (ISL), entailing implicit recognition and learning of sequential associations; and a general visuomotor skill learning measure (GSL). Gray matter volume (GMV) increased, and white matter volume (WMV) decreased from day 1 to day 2 in cerebellar areas regardless of group. A moderating effect of group was found on the correlation between WMV underlying the left precentral gyrus at day 2 and the change in ISL performance, suggesting the use of different underlying learning mechanisms in DD and TD children during the ISL task. Moreover, DD had larger WMV in the posterior thalamic radiation compared with TD, supporting previous reports of atypical development of this structure in DD. Further studies with larger sample sizes are warranted to validate these results.

Adolescent Girls' Musculoskeletal Pain is More Affected by Insomnia Than Boys, and Through Different Psychological Pathways.

Prior research has established that insomnia is predictive of pain in adolescents and that psychological mechanisms have a crucial role in this relationship. Adolescent girls report more insomnia and pain than boys, yet little is known of gender differences in how insomnia influences pain. This study assessed gender differences in levels and trajectories of insomnia and pain during adolescence, and whether rumination and negative mood mediated the effect of insomnia on pain. Longitudinal survey data measured on 5 annual occasions (Nbaseline = 2,767) were analyzed in a multigroup longitudinal serial mediation model. A final model was generated with insomnia as the predictor, rumination and depressed mood as mediators, pain as the outcome, and gender as the grouping variable. The results showed that insomnia predicted pain in adolescents, with an effect 3.5 times larger in girls than boys. Depressed mood was the main mediator in boys. In girls, rumination was the only significant mediator. There were significant gender differences in the effects of insomnia on rumination and pain, and in the effects of rumination on depressed mood and pain, with stronger effects in girls. These results highlight that girls and boys should be considered separately when studying the relationship between insomnia and pain. PERSPECTIVE: Levels of insomnia and pain are progressively higher in adolescent girls than boys, across adolescence. The predictive strength of insomnia symptoms for future pain is 3.5 times greater in girls, with distinct gender-specific underlying pathways: rumination partially mediates this effect in girls, while depressed mood does so in boys.

Non-invasive PET imaging of liver fibrogenesis using a RESCA-conjugated Affibody molecule.

Non-invasive assessment of fibrogenic activity, rather than fibrotic scars, could significantly improve the management of fibrotic diseases and the development of anti-fibrotic drugs. This study explores the potential of an Affibody molecule (Z09591) labeled with the Al(18)F-restrained complexing agent (RESCA) method as a tracer for the non-invasive detection of fibrogenic cells. Z09591 was functionalized with the RESCA chelator for direct labeling with [18F]AlF. In vivo positron emission tomography/magnetic resonance imaging scans on U-87 tumor-bearing mice exhibited high selectivity of the resulting radiotracer, [18F]AlF-RESCA-Z09591, for platelet-derived growth factor receptor ß (PDGFRß), with minimal non-specific background uptake. Evaluation in a mouse model with carbon tetrachloride-induced fibrotic liver followed by a disease regression phase, revealed the radiotracer's high affinity and specificity for fibrogenic cells in fibrotic livers (standardized uptake value [SUV] 0.43 ± 0.05), with uptake decreasing during recovery (SUV 0.29 ± 0.03) (p < 0.0001). [18F]AlF-RESCA-Z09591 accurately detects PDGFRß, offering non-invasive assessment of fibrogenic cells and promising applications in precise liver fibrogenesis diagnosis, potentially contributing significantly to anti-fibrotic drug development.

Encoding-related Brain Activity Predicts Subsequent Trial-level Control of Proactive Interference in Working Memory.

Proactive interference (PI) appears when familiar information interferes with newly acquired information and is a major cause of forgetting in working memory. It has been proposed that encoding of item-context associations might help mitigate familiarity-based PI. Here, we investigate whether encoding-related brain activation could predict subsequent level of PI at retrieval using trial-specific parametric modulation. Participants were scanned with event-related fMRI while performing a 2-back working memory task with embedded 3-back lures designed to induce PI. We found that the ability to control interference in working memory was modulated by level of activation in the left inferior frontal gyrus, left hippocampus, and bilateral caudate nucleus during encoding. These results provide insight to the processes underlying control of PI in working memory and suggest that encoding of temporal context details support subsequent interference control.

Noninvasive PET Detection of CD69-Positive Immune Cells Before Signs of Clinical Disease in Inflammatory Arthritis.

Rheumatoid arthritis (RA) is the most common inflammatory joint disease, and early diagnosis is key for effective disease management. CD69 is one of the earliest cell surface markers seen at the surface of activated immune cells, and CD69 is upregulated in synovial tissue in patients with active RA. In this study, we evaluated the performance of a CD69-targeting PET agent, [68Ga]Ga-DOTA-ZCAM241, for early disease detection in a model of inflammatory arthritis. Methods: A model of inflammatory arthritis was induced by transferring splenocytes from KRN T-cell receptor transgenic B6 mice into T-cell-deficient I-Ag7 major histocompatibility complex class II-expressing recipient mice. The mice were examined longitudinally by [68Ga]Ga-DOTA-ZCAM241 PET/CT before and 3, 7, and 12 d after induction of arthritis. Disease progression was monitored by clinical parameters, including measuring body weight and scoring the swelling of the paws. The uptake of [68Ga]Ga-DOTA-ZCAM241 in the paws was analyzed and expressed as SUVmean Tissue biopsy samples were analyzed for CD69 expression by flow cytometry or immunostaining for a histologic correlate. A second group of mice was examined by a nonbinding, size-matched Affibody molecule as the control. Results: Clinical symptoms appeared 5-7 d after induction of arthritis. The uptake of [68Ga]Ga-DOTA-ZCAM241 in the joints was negligible at baseline but increased gradually after disease induction. An elevated PET signal was found on day 3, before the appearance of clinical symptoms. The uptake of [68Ga]Ga-DOTA-ZCAM241 correlated with the clinical score and disease severity. The presence of CD69-positive cells in the joints and lymph nodes was confirmed by flow cytometry and immunostaining. The uptake of the nonbinding tracer that was the negative control also increased gradually with disease progression, although to a lesser extent than with [68Ga]Ga-DOTA-ZCAM241 Conclusion: The uptake of [68Ga]Ga-DOTA-ZCAM241 in the inflamed joints preceded the clinical symptoms in the KRN T-cell transfer model of inflammatory arthritis, in accordance with immunostaining for CD69. [68Ga]Ga-DOTA-ZCAM241 is thus a promising PET imaging marker of activated immune cells in tissue during RA onset.

Frontotemporal contributions to social and non-social semantic judgements.

Semantic judgements involve the use of general knowledge about the world in specific situations. Such judgements are typically associated with activity in a number of brain regions that include the left inferior frontal gyrus (IFG). However, previous studies showed activity in brain regions associated with mentalizing, including the right temporoparietal junction (TPJ), in semantic judgements that involved social knowledge. The aim of the present study was to investigate if social and non-social semantic judgements are dissociated using a combination of fMRI and repetitive TMS. To study this, we asked participants to estimate the percentage of exemplars in a given category that shared a specified attribute. Categories could be either social (i.e., stereotypes) or non-social (i.e., object categories). As expected, fMRI results (n = 26) showed enhanced activity in the left IFG that was specific to non-social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation (n = 19) to this brain region specifically disrupted non-social semantic judgements. Also as expected, the right TPJ showed enhanced activity to social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation to this brain region specifically disrupted social semantic judgements. It is possible that the causal networks involved in social and non-social semantic judgements may be more complex than expected.

GABAA Receptor Availability in Relation to Cortical Excitability in Depressed and Healthy: A Positron Emission Tomography and Transcranial Magnetic Stimulation Study.

INTRODUCTION: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABAA receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls. METHODS: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [11C]flumazenil positron emission tomography to assess GABAA receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABAA receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABAA receptor activity, long-interval intracortical inhibition representing GABAB receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability. RESULTS: No significant differences in baseline GABAA receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABAA receptor availability and TMS outcomes. Changes in GABAA receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT. CONCLUSION: We found that a change in GABAA receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.

Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells.

BACKGROUND: Beta-cell replacement methods such as transplantation of isolated donor islets have been proposed as a curative treatment of type 1 diabetes, but widespread application is challenging due to shortages of donor tissue and the need for continuous immunosuppressive treatments. Stem-cell-derived islets have been suggested as an alternative source of beta cells, but face transplantation protocols optimization difficulties, mainly due to a lack of available methods and markers to directly monitor grafts survival, as well as their localization and function. Molecular imaging techniques and particularly positron emission tomography has been suggested as a tool for monitoring the fate of islets after clinical transplantation. The integral membrane protein DGCR2 has been demonstrated to be a potential pancreatic islet biomarker, with specific expression on insulin-positive human embryonic stem-cell-derived pancreatic progenitor cells. The candidate Affibody molecule ZDGCR2:AM106 was radiolabeled with fluorine-18 using a novel click chemistry-based approach. The resulting positron emission tomography tracer [18F]ZDGCR2:AM106 was evaluated for binding to recombinant human DGCR2 and cryosections of stem-cell-derived islets, as well as in vivo using an immune-deficient mouse model transplanted with stem-cell-derived islets. Biodistribution of the [18F]ZDGCR2:AM106 was also assessed in healthy rats and pigs. RESULTS: [18F]ZDGCR2:AM106 was successfully synthesized with high radiochemical purity and yield via a pretargeting approach. [18F]ZDGCR2:AM106 retained binding to recombinant human DCGR2 as well as to cryosectioned stem-cell-derived islets, but in vivo binding to native pancreatic tissue in both rat and pig was low. However, in vivo uptake of [18F]ZDGCR2:AM106 in stem-cell-derived islets transplanted in the immunodeficient mice was observed, albeit only within the early imaging frames after injection of the radiotracer. CONCLUSION: Targeting of DGCR2 is a promising approach for in vivo detection of stem-cell-derived islets grafts by molecular imaging. The synthesis of [18F]ZDGCR2:AM106 was successfully performed via a pretargeting method to label a site-specific covalently bonded fluorine-18 to the Affibody molecule. However, the rapid washout of [18F]ZDGCR2:AM106 from the stem-cell-derived islets graft indicates that dissociation kinetics can be improved. Further studies using alternative binders of similar classes with improved binding potential are warranted.

Externalizing Behaviors and Alzheimer's Disease and Any Dementia: A Multigeneration Cohort Study in Sweden.

Background and Objectives: We examined the extent to which externalizing behaviors such as violent and nonviolent criminal behavior, and substance use disorders (SUD) are associate with the onset of Alzheimer's disease (AD) and any dementia in prior generations. Research Design and Methods: A nationwide cohort of 2,463,033 individuals born between 1973 and 1997 (index persons) were linked to their biological relatives (parents, grandparents, and uncles/aunts) using Swedish national registers. Cox regression models were used to examine the association between each measure of externalizing behaviors with AD and any dementia in each of the relative cohorts. Results: Parents of index persons with externalizing behaviors had an increased risk for AD compared with parents of index persons without externalizing behaviors-nonviolent criminal behavior: Hazard Ratio (HR) = 1.16, 95% Confidence Intervals (CI) 1.10-1.22; violent criminal behavior: HR = 1.32 (95% CI: 1.19-1.45); SUD: HR = 1.28 (95% CI: 1.17, 1.40). The associations attenuated with decreasing familial relatedness. Relatives of individuals with externalizing behaviors compared with relatives of individuals without, showed an increased risk of having both early-onset and late-onset AD but the strength of the associations was higher for early-onset AD than for late-onset AD. A similar pattern of results was observed for the association with any dementia. Discussion and Implications: Externalizing behaviors are associated with AD and any dementia in prior generations. The associations were stronger for parents in comparison with grandparents and uncles/aunts, suggesting shared familial risks between conditions. This warrants further studies examining common genetic and family-wide environmental factors that may contribute to identifying common underlying mechanisms to the development of externalizing behaviors, AD, and any dementia.

Optimal timing of influenza vaccination among patients with acute myocardial infarction - Findings from the IAMI trial.

Influenza vaccination reduces the risk of adverse cardiovascular events.The IAMI trial randomly assigned 2571 patients with acute myocardial infarction (AMI) to receive influenza vaccine or saline placebo during their index hospital admission. It was conducted at 30 centers in 8 countries from October 1, 2016 to March 1, 2020. In this post-hoc exploratory sub-study, we compare the trial outcomes in patients receiving early season vaccination (n = 1188) and late season vaccination (n = 1344).The primary endpoint wasthe composite of all-cause death, myocardial infarction (MI), or stent thrombosis at 12 months. Thecumulative incidence of the primary and key secondary endpoints by randomized treatment and early or late vaccination was estimated using the Kaplan-Meier method. In the early vaccinated group, the primary composite endpoint occurred in 36 participants (6.0%) assigned to influenza vaccine and 49 (8.4%) assigned to placebo (HR 0.69; 95% CI 0.45 to 1.07), compared to 31 participants (4.7%) assigned to influenza vaccine and 42 (6.2%) assigned to placebo (HR 0.74; 95% CI 0.47 to 1.18) in the late vaccinated group (P = 0.848 for interaction on HR scale at 1 year). We observed similar estimates for the key secondary endpoints of all-cause death and CV death. There was no statistically significant difference in vaccine effectiveness against adverse cardiovascular events by timing of vaccination. The effect of vaccination on all-cause death at one year was more pronounced in the group receiving early vaccination (HR 0.50; 95% CI, 0.29 to 0.86) compared late vaccination group (HR 0.75; 35% CI, 0.40 to 1.40) but there was no statistically significant difference between these groups (Interaction P = 0.335). In conclusion,there is insufficient evidence from the trial to establish whether there is a difference in efficacy between early and late vaccinationbut regardless of vaccination timing we strongly recommend influenza vaccination in all patients with cardiovascular diseases.

Accelerometer derived physical activity and subclinical coronary and carotid atherosclerosis: cross-sectional analyses in 22 703 middle-aged men and women in the SCAPIS study.

OBJECTIVES: The aim included investigation of the associations between sedentary (SED), low-intensity physical activity (LIPA), moderate-to-vigorous intensity PA (MVPA) and the prevalence of subclinical atherosclerosis in both coronaries and carotids and the estimated difference in prevalence by theoretical reallocation of time in different PA behaviours. DESIGN: Cross-sectional. SETTING: Multisite study at university hospitals. PARTICIPANTS: A total of 22 670 participants without cardiovascular disease (51% women, 57.4 years, SD 4.3) from the population-based Swedish CArdioPulmonary bioImage study were included. SED, LIPA and MVPA were assessed by hip-worn accelerometer. PRIMARY AND SECONDARY OUTCOMES: Any and significant subclinical coronary atherosclerosis (CA), Coronary Artery Calcium Score (CACS) and carotid atherosclerosis (CarA) were derived from imaging data from coronary CT angiography and carotid ultrasound. RESULTS: High daily SED (>70% ≈10.5 hours/day) associated with a higher OR 1.44 (95% CI 1.09 to 1.91), for significant CA, and with lower OR 0.77 (95% CI 0.63 to 0.95), for significant CarA. High LIPA (>55% ≈8 hours/day) associated with lower OR for significant CA 0.70 (95% CI 0.51 to 0.96), and CACS, 0.71 (95% CI 0.51 to 0.97), but with higher OR for CarA 1.41 (95% CI 1.12 to 1.76). MVPA above reference level, >2% ≈20 min/day, associated with lower OR for significant CA (OR range 0.61-0.67), CACS (OR range 0.71-0.75) and CarA (OR range 0.72-0.79). Theoretical replacement of 30 min of SED into an equal amount of MVPA associated with lower OR for significant CA, especially in participants with high SED 0.84 (95% CI 0.76 to 0.96) or low MVPA 0.51 (0.36 to 0.73). CONCLUSIONS: MVPA was associated with a lower risk for significant atherosclerosis in both coronaries and carotids, while the association varied in strength and direction for SED and LIPA, respectively. If causal, clinical implications include avoiding high levels of daily SED and low levels of MVPA to reduce the risk of developing significant subclinical atherosclerosis.

Imaging of fibrogenesis in the liver by [18F]TZ-Z09591, an Affibody molecule targeting platelet derived growth factor receptor ß.

BACKGROUND: Platelet-derived growth factor receptor beta (PDGFRß) is a receptor overexpressed on activated hepatic stellate cells (aHSCs). Positron emission tomography (PET) imaging of PDGFRß could potentially allow the quantification of fibrogenesis in fibrotic livers. This study aims to evaluate a fluorine-18 radiolabeled Affibody molecule ([18F]TZ-Z09591) as a PET tracer for imaging liver fibrogenesis. RESULTS: In vitro specificity studies demonstrated that the trans-Cyclooctenes (TCO) conjugated Z09591 Affibody molecule had a picomolar affinity for human PDGFRß. Biodistribution performed on healthy rats showed rapid clearance of [18F]TZ-Z09591 through the kidneys and low liver background uptake. Autoradiography (ARG) studies on fibrotic livers from mice or humans correlated with histopathology results. Ex vivo biodistribution and ARG revealed that [18F]TZ-Z09591 binding in the liver was increased in fibrotic livers (p = 0.02) and corresponded to binding in fibrotic scars. CONCLUSIONS: Our study highlights [18F]TZ-Z09591 as a specific tracer for fibrogenic cells in the fibrotic liver, thus offering the potential to assess fibrogenesis clearly.

Hub architecture of the human structural connectome: Links to aging and processing speed.

The human structural brain network, or connectome, has a rich-club organization with a small number of brain regions showing high network connectivity, called hubs. Hubs are centrally located in the network, energy costly, and critical for human cognition. Aging has been associated with changes in brain structure, function, and cognitive decline, such as processing speed. At a molecular level, the aging process is a progressive accumulation of oxidative damage, which leads to subsequent energy depletion in the neuron and causes cell death. However, it is still unclear how age affects hub connections in the human connectome. The current study aims to address this research gap by constructing structural connectome using fiber bundle capacity (FBC). FBC is derived from Constrained Spherical Deconvolution (CSD) modeling of white-matter fiber bundles, which represents the capacity of a fiber bundle to transfer information. Compared to the raw number of streamlines, FBC is less bias for quantifying connection strength within biological pathways. We found that hubs exhibit longer-distance connections and higher metabolic rates compared to peripheral brain regions, suggesting that hubs are biologically costly. Although the landscape of structural hubs was relatively age-invariant, there were wide-spread age effects on FBC in the connectome. Critically, these age effects were larger in connections within hub compared to peripheral brain connections. These findings were supported by both a cross-sectional sample with wide age-range (N = 137) and a longitudinal sample across 5 years (N = 83). Moreover, our results demonstrated that associations between FBC and processing speed were more concentrated in hub connections than chance level, and FBC in hub connections mediated the age-effects on processing speed. Overall, our findings indicate that structural connections of hubs, which demonstrate greater energy demands, are particular vulnerable to aging. The vulnerability may contribute to age-related impairments in processing speed among older adults.

PCI or CABG for left main coronary artery disease: the SWEDEHEART registry.

AIMS: An observational nationwide all-comers prospective register study to analyse outcomes after coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in unprotected left main coronary artery (LMCA) disease. METHODS AND RESULTS: All patients undergoing coronary angiography in Sweden are registered in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Between 01/01/2005 and 12/31/2015, 11 137 patients with LMCA disease underwent CABG (n = 9364) or PCI (n = 1773). Patients with previous CABG, ST-elevation myocardial infarction (MI) or cardiac shock were excluded. Death, MI, stroke, and new revascularization during follow-up until 12/31/2015 were identified using national registries. Cox regression with inverse probability weighting (IPW) and an instrumental variable (IV), administrative region, were used. Patients undergoing PCI were older, had higher prevalence of comorbidity but lower prevalence of three-vessel disease. PCI patients had higher mortality than CABG patients after adjustments for known cofounders with IPW analysis (hazard ratio [HR] 2.0 [95% confidence interval (CI) 1.5-2.7]) and known/unknown confounders with IV analysis (HR 1.5 [95% CI 1.1-2.0]). PCI was associated with higher incidence of major adverse cardiovascular and cerebrovascular events (MACCE; death, MI, stroke, or new revascularization) than CABG, with IV analysis (HR 2.8 [95% CI 1.8-4.5]). There was a quantitative interaction for diabetic status regarding mortality (P = 0.014) translating into 3.6 years (95% CI 3.3-4.0) longer median survival time favouring CABG in patients with diabetes. CONCLUSION: In this non-randomized study, CABG in patients with LMCA disease was associated with lower mortality and fewer MACCE compared to PCI after multivariable adjustment for known and unknown confounders.