PURPOSE: To report the experience of a percutaneous closure device used for transfemoral transcatheter aortic valve implantation (TAVI) in an unselected patient and operator population.

MATERIALS AND METHODS: Eighty-two consecutive patients (32 women, 50 men) who underwent transfemoral TAVI between September 2009 and February 2014 at our hospital were retrospectively reviewed for percutaneous closure device (PCD) failure, vascular complications, and bleeding. The diameter and calcification of the common femoral artery (CFA) and the thickness of the subcutaneous fat layer in the groin were assessed on computed tomography images.

RESULTS: The incidences of PCD failure and minor and major vascular complications were 19.5 % (n = 16/82), 19.5 % (n = 16/82), and 7 % (n = 6/82) respectively. 8.5 % (n = 7/82) had a minor perioperative bleeding, 6 % (n = 5/82) had a major bleeding, and none had any life-threatening bleeding. When PCD failed, haemostasis was obtained with fascia suturing, covered stent placement, or with surgical cutdown. Thirty-day mortality and 1-year all-cause mortality were 8.5 % (n = 7/82) and 19.5 % (n = 16/82), respectively. In a multiple regression analysis, the CFA diameter and the presence of severe calcification were independently related to PCD failure (correlation coefficient = -0.24, p = 0.027 and correlation coefficient = 0.23, p = 0.036, respectively).

CONCLUSION: PCD failure was related to a small CFA diameter and to a severely calcified CFA. Failure could largely be managed with minimally invasive techniques such as covered stents or fascia suturing.

Background: Portomesenteric vein thrombosis may be life-threatening due to bowel ischemia caused by venous stasis, or variceal bleeding caused by portal hypertension. Purpose: To evaluate the effectiveness and safety of recanalization combined with transjugular intrahepatic portosystemic shunt in acute and chronic portomesenteric vein thrombosis in patients with and without liver cirrhosis. Material and Methods: 21 consecutive patients (5 women, 16 men; mean 48 years) with portomesenteric vein thrombosis (8 acute, 13 chronic) treated at the Interventional Radiology department between March 2014 and September 2018 were retrospectively reviewed. The main portal vein was completely obliterated and the portomesenteric vein thrombosis extended into the superior mesenteric vein in all patients. The portomesenteric vein thromboses were recanalized transhepatically, a transjugular intrahepatic portosystemic shunt was inserted, thrombectomy was performed in acute portomesenteric vein thrombosis, and angioplasty with or without additional stenting was performed in chronic portomesenteric vein thrombosis. Results: Recanalization was successful in 8/8 patients (100%) with acute portomesenteric vein thrombosis, and in 11/13 patients (85%) with chronic portomesenteric vein thrombosis. In 12 patients, blood flow was restored in one session. Several sessions were more frequently needed in patients with acute portomesenteric vein thrombosis compared to those with chronic portomesenteric vein thrombosis (p = 0.003). Re-occlusion occurred and was recanalized in 10/19 patients and was more frequent in patients with chronic (n = 8/11) than on those with acute (n = 2/8) portomesenteric vein thrombosis (p = 0.04). Adverse events occurred in five patients. There was no 30-day mortality. Conclusion: Recanalization and insertion of a transjugular intrahepatic portosystemic shunt is safe and effective in patients with acute and chronic portomesenteric vein thrombosis with or without cirrhosis. Recanalization was more likely to stay patent in acute compared with chronic portomesenteric vein thrombosis.

BACKGROUND: Individuals with unrecognized myocardial infarctions (UMIs) detected with cardiovascular magnetic resonance (CMR) constitute a recently defined group whose prognosis has not been fully evaluated. However, increasing evidence indicate that these individuals may be at considerable cardiovascular risk. The aim of the present study was to investigate the prognostic impact of CMR detected UMIs for major adverse cardiac events (MACE) in community living elderly individuals.

METHODS: Late gadolinium enhancement CMR was performed in 248 randomly chosen 70-year-olds. Individuals with myocardial infarction (MI) scars, with or without a hospital diagnosis of MI were classified as recognized MI (RMI) or UMI, respectively. Medical records and death certificates were scrutinized. MACE was defined as cardiac death, non-fatal MI, a new diagnosis of angina pectoris, or symptom-driven coronary artery revascularization.

RESULTS: During follow-up (mean 11 years) MACE occurred in 10 % (n = 18/182) of the individuals without MI scars, in 20 % (n = 11/55) of the individuals with UMI, and in 45 % (n = 5/11) of the individuals with RMI, with a significant difference between the UMI group and the group without MI scars (p = 0.045), and between the RMI group and the group without MI scars (p = 0.0004). Cardiac death and/or non-fatal MI occurred in 15, 5, and 3 of the individuals in the NoMI, UMI, and RMI group respectively. Hazards ratios for MACE adjusted for risk factors and sex were 2.55 (95 % CI 1.20-5.42; p = 0.015) for UMI and 3.28 (95 % CI1.16-9.22; p = 0.025) for RMI.

CONCLUSIONS: The presence of a CMR detected UMI entailed a more than double risk for MACE in community living 70-year-old individuals.

Simple Summary This article reviews the value of Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in evaluating female pelvic cancers. It also provides a comparative analysis of PET/MRI with other imaging modalities in the context of female pelvic malignancies and outlines their respective strengths and limitations. The aim of this narrative review is to introduce to clinicians up and coming technology and how it may be valuable to their assessment of female pelvic cancers.Abstract The diagnosis, treatment, and management of gynecologic malignancies benefit from both positron emission tomography/computed tomography (PET/CT) and MRI. PET/CT provides important information on the local extent of disease as well as diffuse metastatic involvement. MRI offers soft tissue delineation and loco-regional disease involvement. The combination of these two technologies is key in diagnosis, treatment planning, and evaluating treatment response in gynecological malignancies. This review aims to assess the performance of PET/MRI in gynecologic cancer patients and outlines the technical challenges and clinical advantages of PET/MR systems when specifically applied to gynecologic malignancies.

Kidney injury is a major cause of morbidity and mortality throughout the world, leading to substantial individual suffering and to a heavy financial burden for the society. A large number of common conditions such as diabetes, hypertension, autoimmune diseases and infections are highly associated with kidney injury. Disturbances in renal perfusion and oxygenation are believed to be involved in the pathogenesis of kidney injury and are therefore of interest to investigate closely. Studies to further the understanding of kidney injury have previously most often involved invasive procedures or ionizing radiation which have limited studies in humans due to ethical reasons. Hence there is a need to explore and implement noninvasive, nonionizing techniques to carry out human studies of renal physiology in health and disease. This thesis aimed to do so using a number of novel, noninvasive magnetic resonance imaging (MRI) techniques. 

In the first study of this thesis, we scanned the kidneys of healthy volunteers with noninvasive MRI and found significant differences between the renal cortex, inner and outer medulla regarding blood flow, oxygenation, water diffusion and tissue characteristics. In the second study we scanned the kidneys with MRI and collected urine from healthy volunteers every fourth hour for 24 hours and found circadian variations for total renal blood flow as well as for a number of urinary parameters. Renal oxygenation was stable with only small diurnal variations. In the third study we implemented the MRI techniques used in study 1 and 2 and one additional MRI technique in COVID-19 patients admitted to the intensive care unit for severe respiratory failure, with and without acute kidney injury (AKI). We found significantly reduced total renal blood flow as well as  cortical and medullary perfusion in patients with AKI compared to patients without AKI. No significant difference was found between the two groups regarding renal oxygenation, water diffusion or tissue characteristics. In the fourth study we used the same MRI techniques as in study 3 to follow up patients previously treated for severe COVID-19 without and with different degrees of AKI. We found significantly reduced apparent diffusion coefficient (ADC) and total renal blood flow in patients that had high grade AKI compared to patients that did not have AKI during hospitalization for COVID-19. No significant difference regarding oxygenation was found between the groups.

In conclusion, this thesis shows that it is possible to use multiparametric noninvasive MRI for renal studies in clinical practice. 

Circadian regulation of kidney function is involved in maintaining whole body homeostasis, and dysfunctional circadian rhythm can potentially be involved in disease development. Magnetic resonance imaging (MRI) provides reliable and reproducible repetitive estimates of kidney function noninvasively without the risk of adverse events associated with contrast agents and ionizing radiation. The purpose of this study was to estimate circadian variations in kidney function in healthy human subjects with MRI and to relate the findings to urinary excretions of electrolytes and markers of kidney function. Phase-contrast imaging, arterial spin labeling, and blood oxygen level-dependent transverse relaxation rate (R₂*) mapping were used to assess total renal blood flow and regional perfusion as well as intrarenal oxygenation in eight female and eight male healthy volunteers every fourth hour during a 24-h period. Parallel with MRI scans, standard urinary and plasma parameters were quantified. Significant circadian variations of total renal blood flow were found over 24 h, with increasing flow from noon to midnight and decreasing flow during the night. In contrast, no circadian variation in intrarenal oxygenation was detected. Urinary excretions of electrolytes, osmotically active particles, creatinine, and urea all displayed circadian variations, peaking during the afternoon and evening hours. In conclusion, total renal blood flow and kidney function, as estimated from excretion of electrolytes and waste products, display profound circadian variations, whereas intrarenal oxygenation displays significantly less circadian variation.

Non-invasive methods of magnetic resonance imaging (MRI) can quantify parameters of kidney function. The main purpose of this study was to determine baseline values of such parameters in healthy volunteers. In 28 healthy volunteers (15 females, 13 males), Arterial Spin Labeling (ASL) to estimate regional renal perfusion, Blood Oxygen Level Dependent (BOLD) transverse relaxation rate (R₂*) to estimate oxygenation, and Apparent Diffusion Coefficient (ADC), true diffusion (D) and longitudinal relaxation time (T₁) to estimate tissue properties were determined bilaterally in the cortex, outer and inner medulla. Additionally, phase contrast (PC) MRI was applied in the renal arteries to quantify total renal blood flow. The results demonstrated profound gradients of perfusion, ADC and D with highest values in the kidney cortex and a decrease towards the inner medulla. R₂* and T₁ were lowest in kidney cortex and increased towards the inner medulla. Total renal blood flow correlated with body surface area, body mass index and renal volume. Similar patterns in all investigated parameters were observed in females and males. In conclusion, non-invasive MRI provides useful tools to evaluate intra renal differences in blood flow, perfusion, diffusion, oxygenation and structural properties of the kidney tissue. As such, this experimental approach has the potential to advance our current understanding regarding normal physiology and the pathological processes associated with acute and chronic kidney disease.

Severe Corona virus disease 2019 (COVID-19) with acute kidney injury (AKI) increases the risk of developing chronic kidney disease (CKD). In the present study we aimed to investigate the effects of severe COVID-19 on renal blood flow, perfusion, oxygenation and tissue characteristics in recovered patients using noninvasive multiparametric magnetic resonance imaging (MRI). Twenty-two patients, previously treated in the intensive care unit for COVID-19 were stratified depending on their degree of AKI during hospitalization. Patients without AKI were matched with those with AKI grade 1 and AKI grade 3 regarding age, sex, height, weight, body surface area (BSA) and body mass index (BMI). All patients had a normal measurement of creatinine within two years before hospitalization. An MRI scan was conducted 21±6 weeks after the first day of intensive care. Cortical and medullary apparent diffusion coefficients (ADC) were significantly lower in the ´AKI grade 3´group compared to the ´no AKI´ group, 1.83±0.11 vs 2.16±0.13 x 10-3 mm2/s (p=0.001) for cortex and 1.84±0.04 vs 2.09±0.13 x 10-3 mm2/s (p=0.007) for medulla. Also, total renal blood flow (tRBF) and global perfusion were significantly lower in the ´AKI grade 3´ group compared to the ´no AKI´ group. No differences regarding renal oxygenation, T1 or T2 were found. 

We conclude that patients treated for severe COVID-19 with high grade AKI, show decreased cortical and medullary ADC and reduced total renal blood flow and global perfusion compared to similar patients without AKI at follow up approximately five months after intensive care. These findings might indicate incipient development of renal fibrosis. 

Neuroendocrine tumours (NETs) can arise in different locations in the body, and may give rise to hormonal symptoms, which amongst other factors may affect patients' health-related quality of life (HRQoL). Up to four cycles of peptide receptor radionuclide therapy (PRRT) have been shown effective for symptom alleviation and prolonging progression-free survival. The aim of this study was to assess the patient's perspective regarding changes in their HRQoL during PRRT. HRQoL was assessed using the questionnaires for cancer in general, EORTC QLQ-C30, and the gastrointestinal NET-specifically EORTC QLQ-GINET21. Patients with NET (n = 204) rated their HRQoL before PRRT cycles one and four. The medical records of patients were reviewed and their HRQoL was compared to a matched reference population (n = 4910). HRQoL was found to improve during PRRT in aspects of global quality of life; role, social, and emotional functioning, and multiple symptom relief. Potential risk groups for worse HRQoL during PRRT were patients with overweight (BMI >25) who completed four cycles of PRRT and older patients (>65 years old). In conclusion, we found that PRRT improves HRQoL in patients with NETs. The results of this study may be used to improve person-centred care.

BACKGROUND:

Weight loss before laparoscopic Roux-en-Y gastric bypass (LRYGB) is desirable, because it can reduce liver volume and thereby facilitate the procedure. The optimal duration of a low-calorie diet (LCD) has not been established. The objective of this study was to assess changes in liver volume and body composition during 4 weeks of LCD.

METHODS:

Ten women (aged 43±8.9 years, 114±12.1 kg, and body mass index 42±2.6 kg/m²) were examined on days 0, 3, 7, 14, and 28 after commencing the LCD. At each evaluation, body composition was assessed through bioelectric impedance analysis, and liver volume and intrahepatic fat content were assessed by magnetic resonance imaging. Serum and urine samples were obtained. Questionnaires regarding quality of life and LCD-related symptoms were administered.

RESULTS:

In total, mean weight decreased by 7.4±1.2 kg (range 5.7-9.1 kg), and 71% of the weight loss consisted of fat mass according to bioelectric impedance analysis. From day 0 to day 3, the weight loss (2.0 kg) consisted mainly of water. Liver volume decreased by 18%±6.2%, from 2.1 to 1.7 liters (P<.01), during the first 2 weeks with no further change thereafter. A continuous 51%±16% decrease was seen in intrahepatic fat content. Systolic blood pressure, insulin, and lipids improved, while liver enzymes, glucose levels, and quality of life were unaffected.

CONCLUSION:

A significant decrease in liver volume (18%) occurred during the first 2 weeks of LCD treatment, and intrahepatic fat gradually decreased throughout the study period. A preoperative 2-week LCD treatment seems sufficient in similar patients.

Aim: To give a detailed description of the long-term outcome of a cohort of children with glioneuronal tumors regarding pre-and postsurgical factors, including "dual" and "double" pathology, seizure freedom, and psychosocial outcome.

Methods: During a fifteen-year period (1995-2009), all patients (age 0-17.99 years) with a glioneuronal brain tumor diagnosed and treated at Uppsala University Children's Hospital were identified from the National Brain Tumor Registry and the National Epilepsy Surgery Registry. Hospital medical records were reviewed and neuroradiological and neuropathological findings were re-evaluated. A cross-sectional long-term follow-up prospective evaluation, including an interview, neurologic examination, and electroencephalogram, was accomplished in patients accepting participants in the study.

Results: A total of 25 out of 28 (89%) eligible patientswere included. The M: F ratiowas 1.5: 1. Mean follow-up time after surgery was 12.1 years (range 5.0-19.3). Twenty patients were adults (N18 years) at follow-up. Seizure freedomwas achieved in 64%. Gross total resection (GTR) was the only preoperative factor significantly correlating to seizure freedom (p= 0.027). Thirty-eight percent were at some time postoperatively admitted for a psychiatric evaluation. There was a trend towards both higher educational level and employment status in adults who became seizure free.

Conclusion: Long-termoutcome is good regarding seizure freedom if GTR can be achieved, but late seizure recurrence can occur. "Dual" and "double" pathology is uncommon and does not influence seizure outcome. Obtaining seizure freedomseems to be important for psychosocial outcome, but there is a risk for psychiatric comorbidities and long-term follow-up by a multi-professional team is advisable.

Human epidermal growth factor receptor 2 (HER2) is a major prognostic and predictive marker overexpressed in 15-20% of breast cancers. The diagnostic reference standard for selecting patients for HER2-targeted therapy is based on the analysis of tumor biopsies. Previously patients were defined as HER2-positive or -negative; however, with the approval of novel treatment options, specifically the antibody-drug conjugate trastuzumab deruxtecan, many breast cancer patients with tumors expressing low levels of HER2 have become eligible for HER2-targeted therapy. Such patients will need to be reliably identified by suitable diagnostic methods. Biopsy-based diagnostics are invasive, and repeat biopsies are not always feasible. They cannot visualize the heterogeneity of HER2 expression, leading to a substantial number of misdiagnosed patients. An alternative and highly accurate diagnostic method is molecular imaging with radiotracers. In the case of HER2, various studies demonstrate the clinical utility and feasibility of such approaches. Radiotracers based on Affibody((R)) molecules, small, engineered affinity proteins with a size of similar to 6.5 kDa, are clinically validated molecules with favorable characteristics for imaging. In this article, we summarize the HER2-targeted therapeutic landscape, describe our experience with imaging diagnostics for HER2, and review the currently available clinical data on HER2-Affibody-based molecular imaging as a novel diagnostic tool in breast cancer and beyond.

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.

BACKGROUND: A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors.

MATERIAL AND METHODS: This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing.

RESULTS AND CONCLUSION: Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.

Introduction Breathlessness is common in the population, especially in women and associated with adverse health outcomes. Obesity (body mass index (BMI) >30 kg/m²) is rapidly increasing globally and its impact on breathlessness is unclear.

Methods This population-based study aimed primarily to evaluate the association of current BMI and self-reported change in BMI since age 20 with breathlessness (modified Research Council score ≥1) in the middle-aged population. Secondary aims were to evaluate factors that contribute to breathlessness in obesity, including the interaction with spirometric lung volume and sex.

Results We included 13 437 individuals; mean age 57.5 years; 52.5% women; mean BMI 26.8 (SD 4.3); mean BMI increase since age 20 was 5.0 kg/m²; and 1283 (9.6%) reported breathlessness. Obesity was strongly associated with increased breathlessness, OR 3.54 (95% CI, 3.03 to 4.13) independent of age, sex, smoking, airflow obstruction, exercise level and the presence of comorbidities. The association between BMI and breathlessness was modified by lung volume; the increase in breathlessness prevalence with higher BMI was steeper for individuals with lower forced vital capacity (FVC). The higher breathlessness prevalence in obese women than men (27.4% vs 12.5%; p<0.001) was related to their lower FVC. Irrespective of current BMI and confounders, individuals who had increased in BMI since age 20 had more breathlessness.

Conclusion Breathlessness is independently associated with obesity and with weight gain in adult life, and the association is stronger for individuals with lower lung volumes.

Imaging has become an important aspect of medicine, enabling visualization of internals in a non-invasive manner. The rapid advancement and adoption of imaging techniques have led to a demand for tools able to take advantage of the information that is produced. Medical image analysis aims to extract relevant information from acquired images to aid diagnostics in healthcare and increase the understanding within medical research. The main subject of this thesis, image registration, is a widely used tool in image analysis that can be employed to find a spatial transformation aligning a set of images. One application, that is described in detail in this thesis, is the use of image registration for large-scale analysis of whole-body images through the utilization of the correspondences defined by the resulting transformations. To produce detailed results, the correspondences, i.e. transformations, need to be of high resolution and the quality of the result has a direct impact on the quality of the analysis. Also, this type of application aims to analyze large cohorts and the value of a registration method is not only weighted by its ability to produce an accurate result but also by its efficiency. This thesis presents two contributions on the subject; a new method for efficient image registration with the ability to produce dense deformable transformations, and the application of the presented method in large-scale analysis of a whole-body dataset acquired using an integrated positron emission tomography (PET) and magnetic resonance imaging (MRI) system. In this thesis, it is shown that efficient and detailed image registration can be performed by employing graph cuts and a heuristic where the optimization is performed on subregions of the image. The performance can be improved further by the efficient utilization of a graphics processing unit (GPU). It is also shown that the method can be employed to produce a model on health based on a PET-MRI dataset which can be utilized to automatically detect pathology in the imaging.

Whole-body imaging presents a variety of interesting applications and combining these information rich images with image registration enables detailed large scale analysis. Whole-body image registration, with the large variability present in human anatomy, introduces a range of challenges that need to be dealt with. This paper aims to present two new extensions to a previously published registration method based on compositive updates and voxel-wise regularization. The new extensions are evaluated against a previously presented pipeline for whole-body registration and a learning-based approach using the Voxel Morph framework. The methods are evaluated on Dice overlap, smoothness of produced displacement fields, and the inverse consistency error. The presented extensions are shown to improve upon previous method both in terms of computation time and registration quality. The voxel-wise regularization produces a mean Dice overlap of 0.828 for the 10 segmented regions and a mean computation time of 320 seconds per subject. The learning-based approach had an inference time of only 3 seconds but a training time of 16 hours per reference subject. This approach produced a mean Dice overlap of only 0.797 but it was shown that the issues in overlap score were limited to the kidneys. In conclusion, both the extensions and VoxelMorph has presented great promise for the task of whole-body registration compared to previous method. However, the choice of method will be highly dependent upon the task. VoxelMorph provides results of lower quality and reduced flexibility but a computation time of only a few seconds.

Deformable image registration is a fundamental problem in medical image analysis, with applications such as longitudinal studies, population modeling, and atlas-based image segmentation. Registration is often phrased as an optimization problem, i.e., finding a deformation field that is optimal according to a given objective function. Discrete, combinatorial, optimization techniques have successfully been employed to solve the resulting optimization problem. Specifically, optimization based on α-expansion with minimal graph cuts has been proposed as a powerful tool for image registration. The high computational cost of the graph-cut based optimization approach, however, limits the utility of this approach for registration of large volume images. Here, we propose to accelerate graph-cut based deformable registration by dividing the image into overlapping sub-regions and restricting the α-expansion moves to a single sub-region at a time. We demonstrate empirically that this approach can achieve a large reduction in computation time - from days to minutes - with only a small penalty in terms of solution quality. The reduction in computation time provided by the proposed method makes graph-cut based deformable registration viable for large volume images. Graph-cut based image registration has previously been shown to produce excellent results, but the high computational cost has hindered the adoption of the method for registration of large medical volume images. Our proposed method lifts this restriction, requiring only a small fraction of the computational cost to produce results of comparable quality.

Purpose: Image registration is an important aspect of medical image analysis and a key component in many analysis concepts. Applications include fusion of multimodal images, multi-atlas segmentation, and whole-body analysis. Deformable image registration is often computationally expensive, and the need for efficient registration methods is highlighted by the emergence of large-scale image databases, e.g., the UK Biobank, providing imaging from 100 000 participants.

Approach: We present a heterogeneous computing approach, utilizing both the CPU and the GPU, to accelerate a previously proposed image registration method. The parallelizable task of computing the matching criterion is offloaded to the GPU, where it can be computed efficiently, while the more complex optimization task is performed on the CPU. To lessen the impact of data synchronization between the CPU and GPU we propose a pipeline model, effectively overlapping computational tasks with data synchronization. The performance is evaluated on a brain labeling task and compared with a CPU implementation of the same method and the popular Advanced Normalization Tools (ANTs) software.

Results: The proposed method presents a speed-up by a factor of 4 and 8 against the CPU implementation and the ANTs software respectively. A significant improvement in labeling quality was also observed, with measured mean Dice overlaps of 0.712 and 0.701 for our method and ANTs respectively.

Conclusions: We showed that the proposed method compares favorably to the ANTs software yielding both a significant speed-up and an improvement in labeling quality. The registration method together with the proposed parallelization strategy is implemented as an open-source software package, deform.

Purpose: Image registration is an important aspect of medical image analysis and a key component in many analysis concepts. Applications include fusion of multimodal images, multi-atlas segmentation, and whole-body analysis. Deformable image registration is often computationally expensive, and the need for efficient registration methods is highlighted by the emergence of large-scale image databases, e.g., the UK Biobank, providing imaging from 100,000 participants. Approach: We present a heterogeneous computing approach, utilizing both the CPU and the graphics processing unit (GPU), to accelerate a previously proposed image registration method. The parallelizable task of computing the matching criterion is offloaded to the GPU, where it can be computed efficiently, while the more complex optimization task is performed on the CPU. To lessen the impact of data synchronization between the CPU and GPU, we propose a pipeline model, effectively overlapping computational tasks with data synchronization. The performance is evaluated on a brain labeling task and compared with a CPU implementation of the same method and the popular advanced normalization tools (ANTs) software. Results: The proposed method presents a speed-up by factors of 4 and 8 against the CPU implementation and the ANTs software, respectively. A significant improvement in labeling quality was also observed, with measured mean Dice overlaps of 0.712 and 0.701 for our method and ANTs, respectively. Conclusions: We showed that the proposed method compares favorably to the ANTs software yielding both a significant speed-up and an improvement in labeling quality. The registration method together with the proposed parallelization strategy is implemented as an open-source software package, deform.

Background

Prolonged seizures generate cerebral hypoxia and increased intracranial pressure, resulting in an increased risk of neurological deterioration, increased long-term morbidity, and shorter survival. Seizures should be recognized early and treated promptly.

The aim of the study was to investigate the occurrence of postoperative seizures in patients undergoing craniotomy for primary brain tumors and to determine if non-convulsive seizures could explain some of the postoperative neurological deterioration that may occur after surgery.

Methods

A single-center prospective study of 100 patients with suspected glioma. Participants were studied with EEG and video recording for at least 24 h after surgery.

Results

Seven patients (7%) displayed seizure activity on EEG recording within 24 h after surgery and another two patients (2%) developed late seizures. One of the patients with early seizures also developed late seizures. In five patients (5%), there were non-convulsive seizures. Four of these patients had a combination of clinically overt and non-convulsive seizures and in one patient, all seizures were non-convulsive. The non-convulsive seizures accounted for the majority of total seizure time in those patients. Non-convulsive seizures could not explain six cases of unexpected postoperative neurological deterioration. Postoperative ischemic lesions were more common in patients with early postoperative seizures.

Conclusions

Early seizures, including non-convulsive, occurred in 7% of our patients. Within this group, non-convulsive seizure activity had longer durations than clinically overt seizures, but only 1% of patients had exclusively non-convulsive seizures. Seizures were not associated with unexpected neurological deterioration.

A 30-year-old man presented with minute-long episodes of vertigo and severe autophony. CVEMP showed a decreased threshold when testing the left side, potentially indicating SSCD. A subsequent MRI demonstrated a multi-lobulated, cystic mass in the temporal bone and the radiological diagnosis at that time was ELST. Tumor excision was performed, and microscopic examination of the excised material revealed fibrovascular tissue without signs of papillary or cystic projections. The conclusion of the histological assessment rendered a diagnosis of angiofibroma. We were unable to find a previous report of ENA originating around the endolymphatic sac.

BACKGROUND: Overeating different dietary fatty acids influence the amount of liver fat stored during weight gain, however, the mechanisms responsible are unclear. We aimed to identify non-lipid metabolites that may differentiate between saturated (SFA) and polyunsaturated fatty acid (PUFA) overfeeding using a non-targeted metabolomic approach. We also investigated the possible relationships between plasma metabolites and body fat accumulation.

METHODS: In a randomized study (LIPOGAIN study), n=39 healthy individuals were overfed with muffins containing SFA or PUFA. Plasma samples were precipitated with cold acetonitrile and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Pattern recognition techniques were used to overview the data, identify variables contributing to group classification and to correlate metabolites with fat accumulation.

RESULTS: We previously reported that SFA causes a greater accumulation of liver fat, visceral fat and total body fat, whereas lean tissue levels increases less compared with PUFA, despite comparable weight gain. In this study, lactate and acetate were identified as important contributors to group classification between SFA and PUFA (P<0.05). Furthermore, the fat depots (total body fat, visceral adipose tissue and liver fat) and lean tissue correlated (P(corr)>0.5) all with two or more metabolites (for example, branched amino acids, alanine, acetate and lactate). The metabolite composition differed in a manner that may indicate higher insulin sensitivity after a diet with PUFA compared with SFA, but this needs to be confirmed in future studies.

CONCLUSION: A non-lipid metabolic profiling approach only identified a few metabolites that differentiated between SFA and PUFA overfeeding. Whether these metabolite changes are involved in depot-specific fat storage and increased lean tissue mass during overeating needs further investigation.

Background: Even though different subtypes of spontaneous ICH are frequently linked to a poor prognosis, their causes, pathological features, and prognoses vary. Atypical intracerebral hemorrhage is the subtype of spontaneous ICH that usually occurs due to an underlying localized vascular lesion. It is unrelated to systemic vascular risk factors, mostly affects children and young adults and is associated with a relatively good outcome. This fact should be considered when planning the evaluation and treatment. Investigating the cause of this subtype is fundamental to providing optimal management. However, if resources do not allow completing the investigations, the cause will be more difficult to discover. Treatment decisions will be made under stress to save the patient's life, especially with rapidly deteriorating patients. Methods: We described three cases of spontaneous ICH without systemic risk factors where the bleeding source could not be determined before surgery due to a lack of resources, preventing preoperative vascular investigation. Knowing that the atypical ICH has a distinct identity, regarding etiology and prognosis, encouraged the surgeons to resort to early surgical decompression as an alternative plan. We reviewed the literature searching for supporting evidence. Results: The results of treatment of the presented cases were satisfactory. The lack of reported similar cases was brought to light by a literature analysis that sought to provide backing for the proposed management strategy. In the end, we supplied two graphic organizers to help readers remember the different types and treatment of hemorrhagic stroke. Conclusion: There isn't enough evidence to show that there are other ways to treat atypical intracerebral haemorrhage when resources are limited. The presented cases highlight the importance of decisionmaking in resource-constrained situations when patient outcomes can be improved.

Background

Ground glass opacity (GGO) is the main HRCT feature representing alveolitis in systemic sclerosis-associated interstitial lung disease (SSc-ILD), but may also represent other conditions such as atelectasis or edema. It is unclear how much this is affected by the HRCT scan protocol used. We aimed to compare the performance of three different HRCT protocols to evaluate the degree of SSc-ILD related changes.

Methods

Eleven patients with SSc underwent chest HRCT scan by three different protocols: First, a supine scan after lying down for 15 minutes, then two scans in alternating order: A prone position scan, and a supine position scan after performing 10 deep breaths using a positive expiratory pressure (PEP) device. The HRCT scans were evaluated by the Warrick score system for ILD-related findings.

Results

The three HRCT protocols were compared and resulted in different mean (95% CI) Warrick scores: 9.4 (5.3–13.4) in supine after rest; 7.5 (95% CI 3.8–11.1) in prone and 7.6 (95% CI 4.2–11.1) in supine after PEP. When comparing supine after rest to prone and supine after PEP, the latter two scans had a significantly lower score (p = 0.001 for both comparisons). In all cases, only sub-scores for ground glass opacities differed, while sub-scores for fibrosis-related changes did not change.

Conclusions

Different HRCT scan protocols significantly altered the Warrick severity score for SSc-ILD findings, primarily because of changes in ground glass opacities. These differences may be clinically meaningful.

Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback is used as a tool to gain voluntary control of activity in various brain regions. Little emphasis has been put on the influence of cognitive and personality traits on neurofeedback efficacy and baseline activity. Here, we assessed the effect of individual pain coping on rt-fMRI neurofeedback during heat-induced pain. Twenty-eight healthy subjects completed the Coping Strategies Questionnaire (CSQ) prior to scanning. The first part of the fMRI experiment identified target regions using painful heat stimulation. Then, subjects were asked to down-regulate the pain target brain region during four neurofeedback runs with painful heat stimulation. Functional MRI analysis included correlation analysis between fMRI activation and pain ratings as well as CSQ ratings. At the behavioral level, the active pain coping (first principal component of CSQ) was correlated with pain ratings during neurofeedback. Concerning neuroimaging, pain sensitive regions were negatively correlated with pain coping. During neurofeedback, the pain coping was positively correlated with activation in the anterior cingulate cortex, prefrontal cortex, hippocampus and visual cortex. Thermode temperature was negatively correlated with anterior insula and dorsolateral prefrontal cortex activation. In conclusion, self-reported pain coping mechanisms and pain sensitivity are a source of variance during rt-fMRI neurofeedback possibly explaining variations in regulation success. In particular, active coping seems to be associated with successful pain regulation.

The emerging technique of real-time fMRI neurofeedback trains individuals to regulate their own brain activity via feedback from an fMRI measure of neural activity. Optimum feedback presentation has yet to be determined, particularly when working with clinical populations. To this end, we compared continuous against intermittent feedback in subjects with tinnitus.

Fourteen participants with tinnitus completed the whole experiment consisting of nine runs (3 runs × 3 days). Prior to the neurofeedback, the target region was localized within the auditory cortex using auditory stimulation (1 kHz tone pulsating at 6 Hz) in an ON-OFF block design. During neurofeedback runs, participants received either continuous (n = 7, age 46.84 ± 12.01, Tinnitus Functional Index (TFI) 49.43 ± 15.70) or intermittent feedback (only after the regulation block) (n = 7, age 47.42 ± 12.39, TFI 49.82 ± 20.28). Participants were asked to decrease auditory cortex activity that was presented to them by a moving bar. In the first and the last session, participants also underwent arterial spin labeling (ASL) and resting-state fMRI imaging. We assessed tinnitus severity using the TFI questionnaire before all sessions, directly after all sessions and six weeks after all sessions. We then compared neuroimaging results from neurofeedback using a general linear model (GLM) and region-of-interest analysis as well as behavior measures employing a repeated-measures ANOVA. In addition, we looked at the seed-based connectivity of the auditory cortex using resting-state data and the cerebral blood flow using ASL data.

GLM group analysis revealed that a considerable part of the target region within the auditory cortex was significantly deactivated during neurofeedback. When comparing continuous and intermittent feedback groups, the continuous group showed a stronger deactivation of parts of the target region, specifically the secondary auditory cortex. This result was confirmed in the region-of-interest analysis that showed a significant down-regulation effect for the continuous but not the intermittent group. Additionally, continuous feedback led to a slightly stronger effect over time while intermittent feedback showed best results in the first session. Behaviorally, there was no significant effect on the total TFI score, though on a descriptive level TFI scores tended to decrease after all sessions and in the six weeks follow up in the continuous group. Seed-based connectivity with a fixed-effects analysis revealed that functional connectivity increased over sessions in the posterior cingulate cortex, premotor area and part of the insula when looking at all patients while cerebral blood flow did not change significantly over time.

Overall, these results show that continuous feedback is suitable for long-term neurofeedback experiments while intermittent feedback presentation promises good results for single session experiments when using the auditory cortex as a target region. In particular, the down-regulation effect is more pronounced in the secondary auditory cortex, which might be more susceptible to voluntary modulation in comparison to a primary sensory region.

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first-(single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-ofinterest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

Introduction The fetal origin of the posterior cerebral artery (fPCA) is a frequent vascular variant in 11-29% of the population. For the fPCA, blood flow in the PCA originates from the anterior instead of the posterior circulation. We tested whether this blood supply variant impacts the cerebral blood flow assessed by arterial spin labeling (ASL), cerebrovascular reserve as well as resting-state static functional connectivity (sFC) in the sense of a systematic confound. Methods The study included 385 healthy, elderly subjects (mean age: 74.18 years [range: 68.9-90.4]; 243 female). Participants were classified into normal vascular supply (n = 296, 76.88%), right fetal origin (n = 23, 5.97%), left fetal origin (n = 16, 4.16%), bilateral fetal origin (n = 4, 1.04%), and intermediate (n = 46, 11.95%, excluded from further analysis) groups. ASL-derived relative cerebral blood flow (relCBF) maps and cerebrovascular reserve (CVR) maps derived from a CO2 challenge with blocks of 7% CO2 were compared. Additionally, sFC between 90 regions of interest (ROIs) was compared between the groups. Results CVR was significantly reduced in subjects with ipsilateral fPCA, most prominently in the temporal lobe. ASL yielded a non-significant trend towards reduced relCBF in bilateral posterior watershed areas. In contrast, conventional atlas-based sFC did not differ between groups. Conclusions In conclusion, fPCA presence may bias the assessment of cerebrovascular reserve by reducing the response to CO2. In contrast, its effect on ASL-assessed baseline perfusion was marginal. Moreover, fPCA presence did not systematically impact resting-state sFC. Taken together, this data implies that perfusion variables should take into account the vascularization patterns.

The mechanisms linking ovarian hormones to negative affect are poorly characterized, but important clues may come from the examination of the brain's intrinsic organization. Here, we studied the effects of both the menstrual cycle and oral contraceptives (OCs) on amygdala and salience network resting-state functional connectivity using a double-blind, randomized, and placebo-controlled design. Hormone levels, depressive symptoms, and resting-state functional connectivity were measured in 35 healthy women (24.9±4.2 years) who had previously experienced OC-related negative affect. All participants were examined in the follicular phase of a baseline cycle and in the third week of the subsequent cycle during treatment with either a combined OC (30 μg ethinyl estradiol/0.15 mg levonorgestrel) or placebo. The latter time point targeted the midluteal phase in placebo users and steady-state ethinyl estradiol and levonorgestrel concentrations in OC users. Amygdala and salience network connectivity generally increased with both higher endogenous and synthetic hormone levels, although amygdala-parietal cortical connectivity decreased in OC users. When in the luteal phase, the naturally cycling placebo users demonstrated higher connectivity in both networks compared with the women receiving OCs. Our results support a causal link between the exogenous administration of synthetic hormones and amygdala and salience network connectivity. Furthermore, they suggest a similar, potentially stronger, association between the natural hormonal variations across the menstrual cycle and intrinsic network connectivity.

BACKGROUND: The mechanisms leading to neurological deterioration and the devastating course of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) are still not well understood. Bedside xenon-enhanced computerized tomography (XeCT) enables measurements of regional cerebral blood flow (rCBF) during neurosurgical intensive care. In the present study, CBF characteristics in the early phase after severe SAH were explored and related to clinical characteristics and early clinical course outcome.

MATERIALS AND METHODS: Patients diagnosed with SAH and requiring mechanical ventilation were prospectively enrolled in the study. Bedside XeCT was performed within day 0 to 3.

RESULTS: Data from 64 patients were obtained. Median global CBF was 34.9 mL/100 g/min (interquartile range [IQR], 26.7 to 41.6). There was a difference in CBF related to age with higher global CBF in the younger patients (30 to 49 y). CBF was also related to the severity of SAH with lower CBF in Fisher grade 4 compared with grade 3. rCBF disturbances and hypoperfusion were common; in 43 of the 64 patients rCBF<20 mL/100 g/min was detected in more than 10% of the region-of-interest (ROI) area and in 17 patients such low-flow area exceeded 30%. rCBF was not related to the localization of the aneurysm; there was no difference in rCBF of ipsilateral compared with contralateral vascular territories. In patients who initially were in Hunt & Hess grade I to III, median global CBF day 0 to 3 was significantly lower for patients who were in poor neurological state at discharge compared with patients in good neurological state, 25.5 mL/100 g/min (IQR, 21.3 to 28.3) versus 37.8 mL/100 g/min (IQR, 30.5 to 47.6).

CONCLUSIONS: CBF disturbances are common in the early phase after SAH. In many patients, CBF was heterogenic and substantial areas with low rCBF were detected. Age and CT Fisher grade were factors influencing global cortical CBF. Bedside XeCT may be a tool to identify patients at risk of deteriorating so they can receive intensified management, but this needs further exploration.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Bakgrund: Inom nuklearmedicin är det essentiellt att följa goda strålhygiensrutiner med hjälp av skyddsåtgärder och att tillägna sig kunskaper om strålningsfysik.

Syfte: Studien riktas mot röntgensjuksköterskor på nuklearmedicinska avdelningar i Sverige, där syftet är att utforska vilka strålskydd som tillämpas, om de är tillräckliga och om det finns ett behov av kunskapsutveckling. Vidare utreds hur röntgensjuksköterskor upplever arbetsrutiner kring strålning och säkerhet.

Metod: Studien är kvantitativ där röntgensjuksköterskor på nuklearmedicinska avdelningar har tillfrågats att svara på en enkät. Urvalet är anpassat efter exklusions- och inklusionkriterier. Resultatet analyserades via statistikprogrammet SPSS. Svar erhölls från 48 röntgensjuksköterskor från sammanlagt 8 sjukhus.

Resultat: I resultatet framgår det att 38 deltagare huvudsakligen använder blyförkläde som strålskydd vid arbetet. Motsvarande 38 deltagare använder plasthandskar som skyddsmedel. Utfallet konstaterar att 22 röntgensjuksköterskor alltid använder någon form av strålskydd. Sammanlagt upplever 43 deltagare att befintliga strålskydd är tillräckliga. Av deltagarna anser 36 att kunskapsutveckling om strålning inom arbetet är behövligt. Vidare anser 30 deltagare att kunskapsutveckling inom strålskydd är behövligt. Bland deltagarna svarade 45 att vederbörandes arbetsplats erbjuder arbetsplatskurser. Totalt uttrycker sig 42 röntgensjuksköterskor positivt gentemot rådande arbetsrutiner.

Slutsats: Enligt resultatet används primärt blyförkläden som strålskydd men även plasthandskar som skyddande komplement. Resultatet fastslår att strålskydd används överlag av studiens röntgensjuksköterskor och att de upplevs som tillräckliga. Det konstateras även att röntgensjuksköterskor i allmänhet anser kunskapsutveckling som nödvändig inom strålning och strålskydd, samt att alla sjukhus i studien erbjuder arbetsplatskurser av olika slag. Slutligen framhåller studien att flertalet röntgensjuksköterskor är positivt inställda till gällande arbetsrutiner. 

Aims/hypothesis

Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investi-gate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet lowin energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the globaland tissue-specific level in individuals with obesity but not diabetes.

Methods

In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding,sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery(n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTTand hyperinsulinaemic–euglycaemic clamps during which concomitant simultaneous whole-body [ 18 F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change.

Results

One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight(mean ± SD: −7.7±1.4 kg and −7.4±2.2 kg, respectively), adipose tissue volume (7%) and liver fat content (2% units).HOMA-IR, a main endpoint, was significantly reduced following OS (−26.3% [95% CI −49.5, −3.0], p=0.009) and non-significantly following LCD (−20.9% [95% CI −58.2, 16.5). For both groups, there were similar reductions in triglyceridesand LDL-cholesterol. Fasting plasma glucose and insulin were also significantly reduced only following OS. There was anincrease in glucose AUC in response to an OGTT in the OS group (by 20%) but not in the LCD group. During hyperinsuli-naemia, only the OS group showed a significantly increased PET-derived glucose uptake rate in skeletal muscle but a reduceduptake in the heart and abdominal adipose tissue. Both liver and brain glucose uptake rates were unchanged after surgery orLCD. Whole-body glucose disposal and endogenous glucose production were not significantly affected.

Conclusions/interpretation

The short-term metabolic effects seen 4 weeks after OS are not explained by loss of body fat alone.Thus OS, but not LCD, led to reductions in fasting plasma glucose and insulin resistance as well as to distinct changes in insulin-stimulated glucose fluxes to different tissues. Such effects may contribute to the prevention or reversal of type 2 diabetes followingOS. Moreover, the full effects on whole-body insulin resistance and plasma glucose require a longer time than 4 weeks.

Trial registration

ClinicalTrials.gov NCT02988011

Funding

This work was supported by AstraZeneca R&D, the Swedish Diabetes Foundation, the European Union’s Horizon Europe Research project PAS GRAS, the European Commission via the Marie Sklodowska Curie Innovative Training Network TREATMENT, EXODIAB, the Family Ernfors Foundation, the P.O. Zetterling Foundation, Novo Nordisk Foundation, the Agnes and Mac Rudberg Foundation and the Uppsala University Hospital ALF grants

AIMS/HYPOTHESIS: Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investigate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet low in energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the global and tissue-specific level in individuals with obesity but not diabetes.

METHODS: In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding, sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery (n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTT and hyperinsulinaemic-euglycaemic clamps during which concomitant simultaneous whole-body [¹⁸F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change.

RESULTS: One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight (mean ± SD: -7.7±1.4 kg and -7.4±2.2 kg, respectively), adipose tissue volume (7%) and liver fat content (2% units). HOMA-IR, a main endpoint, was significantly reduced following OS (-26.3% [95% CI -49.5, -3.0], p=0.009) and non-significantly following LCD (-20.9% [95% CI -58.2, 16.5). For both groups, there were similar reductions in triglycerides and LDL-cholesterol. Fasting plasma glucose and insulin were also significantly reduced only following OS. There was an increase in glucose AUC in response to an OGTT in the OS group (by 20%) but not in the LCD group. During hyperinsulinaemia, only the OS group showed a significantly increased PET-derived glucose uptake rate in skeletal muscle but a reduced uptake in the heart and abdominal adipose tissue. Both liver and brain glucose uptake rates were unchanged after surgery or LCD. Whole-body glucose disposal and endogenous glucose production were not significantly affected.

CONCLUSIONS/INTERPRETATION: The short-term metabolic effects seen 4 weeks after OS are not explained by loss of body fat alone. Thus OS, but not LCD, led to reductions in fasting plasma glucose and insulin resistance as well as to distinct changes in insulin-stimulated glucose fluxes to different tissues. Such effects may contribute to the prevention or reversal of type 2 diabetes following OS. Moreover, the full effects on whole-body insulin resistance and plasma glucose require a longer time than 4 weeks.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02988011 FUNDING: This work was supported by AstraZeneca R&D, the Swedish Diabetes Foundation, the European Union's Horizon Europe Research project PAS GRAS, the European Commission via the Marie Sklodowska Curie Innovative Training Network TREATMENT, EXODIAB, the Family Ernfors Foundation, the P.O. Zetterling Foundation, Novo Nordisk Foundation, the Agnes and Mac Rudberg Foundation and the Uppsala University Hospital ALF grants.

Objective: To obtain direct quantifications of glucose turnover, volumes and fat content of several tissues in the development of type 2 diabetes (T2D) using a novel integrated approach for whole-body imaging.

Design and methods: Hyperinsulinemic-euglycemic clamps and simultaneous whole-body integrated [18F]FDG-PET/MRI with automated analyses were performed in control (n = 12), prediabetes (n = 16) and T2D (n = 13) subjects matched for age, sex and BMI.

Results: Whole-body glucose uptake (Rd) was reduced by approximately 25% in T2D vs control subjects, and partitioning to brain was increased from 3.8% of total Rd in controls to 7.1% in T2D. In liver, subcutaneous AT, thigh muscle, total tissue glucose metabolic rates (MRglu) and their % of total Rd were reduced in T2D compared to control subjects. The prediabetes group had intermediate findings. Total MRglu in heart, visceral AT, gluteus and calf muscle was similar across groups. Whole-body insulin sensitivity assessed as glucose infusion rate correlated with liver MRglu but inversely with brain MRglu. Liver fat content correlated with MRglu in brain but inversely with MRglu in other tissues. Calf muscle fat was inversely associated with MRglu only in the same muscle group.

Conclusions: This integrated imaging approach provides detailed quantification of tissue-specific glucose metabolism. During T2D development, insulin-stimulated glucose disposal is impaired and increasingly shifted away from muscle, liver and fat toward the brain. Altered glucose handling in the brain and liver fat accumulation may aggravate insulin resistance in several organs.

Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on T_h2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [¹¹C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [¹¹C]methyl iodide followed by hydrolysis to obtain [¹¹C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [¹¹C]MK-7246 in human males was estimated based on the biodistribution in rat.

Results: [¹¹C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [¹¹C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

Conclusions: Initial preclinical in vitro and in vivo evaluation of [¹¹C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

Study Objective To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD) and asymptomatic controls. Background Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women. Methods Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP), radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs): the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain". Results There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001). Menstrual phase changes in this asymmetry (premenstrual-follicular) correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (pre-menstrual-follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity in the dorsolateral prefrontal ROI (r(s) = -0.635; 0.027). The control group showed no such correlation. Conclusion Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral prefrontal cortices was found to strongly correlate to premenstrual irritability. A causal relationship here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger studies.

There currently exists no imaging methodology to monitor viable islet mass following clinical intraportal islet transplantation. We investigated the potential of the endocrine positron emission tomography (PET) marker [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP) for this purpose. In a preclinical proof of concept study, the ex vivo and in vivo [(11)C]5-HTP signal was compared to the number of islets transplanted in rats. In a clinical study, human subjects with an intraportal islet graft (n=8) performed two [(11)C]5-HTP PET and MRI examinations 8 months apart. The tracer concentration in the liver as a whole, or in defined hotspots was correlated to measurements of islet graft function. In rat, hepatic uptake of [(11)C]5-HTP correlated with number of transplanted islets. In human subjects, uptake in hepatic hotspots showed a correlation with metabolic assessments of islet function. Change in hotspot SUV predicted loss of graft function in one subject whereas hotspot SUV was unchanged in subjects with stable graft function. The endocrine marker [(11)C]5-HTP thus show correlation between hepatic uptake and transplanted islet function, and show promise as a tool for non-invasive detection of viable islets. The evaluation procedure described herein can be used as benchmark for novel agents targeting intraportally transplanted islets.

Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with Ga-68. The resulting PET tracer [Ga-68]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [Ga-68]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [Ga-68]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [Ga-68]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [Ga-68]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [Ga-68]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.

Background Computed tomography (CT) is superior to conventional radiography (CR) for assessing internal fixation of pelvic fractures, but with a higher radiation exposure. Low-dose CT (LDCT) could possibly have a sufficient diagnostic accuracy but with a lower radiation dose. Purpose To compare postoperative diagnostic accuracy of LDCT and CR after open reduction and internal fixation of pelvic fracture. Material and Methods Twenty-one patients were examined with LDCT and CR 0-9 days after surgery. The examinations were reviewed by two musculoskeletal radiologists. Hardware, degree of fracture reduction, image quality, and reviewing time were assessed, and effective radiation dose was calculated. Inter-reader agreement was calculated. Results LDCT was significantly better than CR in determining whether hardware positioning was assessable ( P < 0.001). Acetabular congruence was assessable in all fractured patients with LDCT. In 12 of the 32 assessments with CR of patients with an acetabular fracture, joint congruence was not assessable due to overlapping hardware ( P = 0.001). Image quality was significantly higher for LDCT. Median time to review was 240 s for LDCT compared to 180 s for CR. Effective dose was 0.79 mSv for LDCT compared to 0.32 mSv for CR ( P < 0.001). Conclusion LDCT is more reliable than CR in assessing hardware position and fracture reduction. Joint congruency is sometimes not possible to assess with CR, due to overlapping hardware. The image quality is higher, but also the effective dose, with LDCT than with CR.

BACKGROUND: Computed tomography (CT) has the potential to acquire the data needed for migration studies of orthopedic joint implants of patients who have had tantalum beads implanted at the time of joint replacement surgery. This can be accomplished with the same precision as radiostereometric analysis (RSA). Switching to CT would increase availability without the need for the specific facilities required for RSA. However, higher effective dose is a concern.

PURPOSE: To investigate if migration measurements can be done with CT with an accuracy and effective dose comparable to that of conventional RSA.

MATERIAL AND METHODS: Fourteen scanning protocols were tested in a hip phantom that incorporated tantalum beads and an uncemented femoral stem. The protocols were graded for clinical practice according to the three parameters of image quality, effective dose, and robustness of numerical data. After grading, the two protocols that graded best overall were applied to a pilot patient.

RESULTS: All protocols produced scans in which the numerical data were sufficient for a migration analysis at least as precise as would be expected using RSA. A protocol with an effective dose of 0.70 mSv was shown to be applicable in a pilot patient.

CONCLUSION: Low-dose CT scans with an effective dose comparable to a set of routine plain radiographs can be used for precise migration measurements.

The longitudinal alterations of the pancreatic β-cell and islet mass in the progression of type 1 diabetes (T1D) are still poorly understood. The objective of this study was to repeatedly assess the endocrine volume and the morphology of the pancreas for up to 24 months after T1D diagnosis (n = 16), by ¹¹C-5-hydroxytryptophan (¹¹C-5-HTP) positron emission tomography (PET) and MRI. Study participants were examined four times by PET/MRI: at recruitment and then after 6, 12, and 24 months. Clinical examinations and assessment of β-cell function by a mixed-meal tolerance test and fasting blood samples were performed in connection with the imaging examination. Pancreas volume has a tendency to decrease from 50.2 ± 10.3 mL at T1D debut to 42.2 ± 14.6 mL after 24 months (P < 0.098). Pancreas uptake of ¹¹C-5-HTP (e.g., the volume of the endocrine pancreas) did not decrease from T1D diagnosis (0.23 ± 0.10 % of injected dose) to 24-month follow-up, 0.21 ± 0.14% of injected dose, and exhibited low interindividual changes. Pancreas perfusion was unchanged from diagnosis to 24-month follow-up. The pancreas uptake of ¹¹C-5-HTP correlated with the long-term metabolic control as estimated by HbA_1c (P < 0.05). Our findings argue against a major destruction of β-cell or islet mass in the 2-year period after diagnosis of T1D.

AIMS: Perfusion of the pancreas and the islets of Langerhans is sensitive to physiological stimuli and is dysregulated in metabolic disease. Pancreatic perfusion can be assessed by both positron emission tomography (PET) and magnetic resonance imaging (MRI), but the methods have not been directly compared or benchmarked against the gold-standard microsphere technique.

METHODS: Pigs (n = 4) were examined by [¹⁵O]H₂O PET and intravoxel incoherent motion (IVIM) MRI technique simultaneously using a hybrid PET/MRI scanner. The pancreatic perfusion was measured both at basal conditions and after intravenous (IV) administration of up to 0.5 g/kg glucose.

RESULTS: Pancreatic perfusion increased by 35%, 157%, and 29% after IV 0.5 g/kg glucose compared to during basal conditions, as assessed by [¹⁵O]H₂O PET, IVIM MRI, and microspheres, respectively. There was a correlation between pancreatic perfusion as assessed by [¹⁵O]H₂O PET and IVIM MRI (r = 0.81, R² = 0.65, p < 0.01). The absolute quantification of pancreatic perfusion (ml/min/g) by [¹⁵O]H₂O PET was within a 15% error of margin of the microsphere technique.

CONCLUSION: Pancreatic perfusion by [¹⁵O]H₂O PET was in agreement with the microsphere technique assessment. The IVIM MRI method has the potential to replace [¹⁵O]H₂O PET if the pancreatic perfusion is sufficiently large, but not when absolute quantitation is required.

Introduction: Development of a selective and specific high affinity PET tracer, [C-11]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine V-T. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. Results: 3-5 GBq of [C-11]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65 GBq/mu mol. In vitro binding showed high selective binding towards SV2A. [C-11]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the V-T could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [C-11]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. Conclusions: We have developed the novel PET tracer, [C-11]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400 MBq of [C-11]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline V-T values. This will have to be further validated in human studies.