Familywise error for multiple time-to-event endpoints in a group sequential design.

We investigate the familywise error rate (FWER) for time-to-event endpoints evaluated using a group sequential design with a hierarchical testing procedure for secondary endpoints. We show that, in this setup, the correlation between the log-rank test statistics at interim and at end of study is not congruent with the canonical correlation derived for normal-distributed endpoints. We show, both theoretically and by simulation, that the correlation also depends on the level of censoring, the hazard rates of the endpoints, and the hazard ratio. To optimize operating characteristics in this complex scenario, we propose a simulation-based method to assess the FWER which, better than the alpha-spending approach, can inform the choice of critical values for testing secondary endpoints.

An adult-based genetic risk score for liver fat associates with liver and plasma lipid traits in children and adolescents.

BACKGROUND & AIMS: Genome-wide association studies have identified steatogenic variants that also showed pleiotropic effects on cardiometabolic traits in adults. We investigated the effect of eight previously reported genome-wide significant steatogenic variants, individually and combined in a weighted genetic risk score (GRS), on liver and cardiometabolic traits, and the predictive ability of the GRS for hepatic steatosis in children and adolescents. APPROACH & RESULTS: Children and adolescents with overweight (including obesity) from an obesity clinic group (n = 1768) and a population-based group (n = 1890) were included. Cardiometabolic risk outcomes and genotypes were obtained. Liver fat was quantified using 1 H-MRS in a subset of 727 participants. Variants in PNPLA3, TM6SF2, GPAM and TRIB1 were associated with higher liver fat (p < .05) and with distinct patterns of plasma lipids. The GRS was associated with higher liver fat content, plasma concentrations of alanine transaminase (ALT), aspartate aminotransferase (AST) and favourable plasma lipid levels. The GRS was associated with higher prevalence of hepatic steatosis (defined as liver fat ≥5.0%) (odds ratio per 1-SD unit: 2.17, p = 9.7E-10). A prediction model for hepatic steatosis including GRS alone yielded an area under the curve (AUC) of 0.78 (95% CI 0.76-0.81). Combining the GRS with clinical measures (waist-to-height ratio [WHtR] SDS, ALT, and HOMA-IR) increased the AUC up to 0.86 (95% CI 0.84-0.88). CONCLUSIONS: The genetic predisposition for liver fat accumulation conferred risk of hepatic steatosis in children and adolescents. The liver fat GRS has potential clinical utility for risk stratification.

The Laparoscopic Implantation of Neuroprosthesis Procedure Increases Leg Lean Mass in Individuals With Paraplegia Due To Traumatic Spinal Cord Injury.

OBJECTIVES: We hypothesized that the laparoscopic implantation of neuroprosthesis (LION) procedure would significantly alter the body composition of patients with chronic traumatic spinal cord injury (SCI). The objectives were to determine the effect of the LION procedure on lean mass (LM), fatty mass (FM), and bone mineral content (BMC) in patients with SCI. MATERIALS AND METHODS: Five consecutive patients underwent dual-energy x-ray absorptiometry scans before the LION procedure and at the one-year postoperative follow-up to determine changes in LM, FM, and BMC. Student paired t-test was used to determine significance. RESULTS: The patients gained 2506 ± 565 g of LM in the legs (p < 0.001), which was an 18% total increase in leg LM. Total body LM was significantly increased by 3523 ± 1048 g (p < 0.003). FM was unaffected, whereas total BMC showed a small but significant increase of 99 ± 42 g (p = 0.009). CONCLUSIONS: The LION procedure and subsequent neurostimulation procedures resulted in substantial increases in leg LM in patients with chronic traumatic SCI and paraplegia. A possible incremental effect on total BMC also was observed. Further studies are needed to confirm and expand these promising results.

Towards a Precise NMR Quantification of Acute Phase Inflammation Proteins from Human Serum.

Nuclear Magnetic Resonance (NMR) spectra of human serum and plasma show, besides metabolites and lipoproteins, two characteristic signals termed GlycA and B arising from the acetyl groups of glycoprotein glycans from acute phase proteins, which constitute good markers for inflammatory processes. Here, we report a comprehensive assignment of glycoprotein glycan NMR signals observed in human serum, showing that GlycA and GlycB signals originate from Neu5Ac and GlcNAc moieties from N-glycans, respectively. Diffusion-edited NMR experiments demonstrate that signal components can be associated with specific acute phase proteins. Conventionally determined concentrations of acute phase glycoproteins correlate well with distinct features in NMR spectra (R2 up to 0.9422, p-value <0.001), allowing the simultaneous quantification of several acute phase inflammation proteins. Overall, a proteo-metabolomics NMR signature of significant diagnostic potential is obtained within 10-20 min acquisition time. This is exemplified in serum samples from COVID-19 and cardiogenic shock patients showing significant changes in several acute phase proteins compared to healthy controls.

Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes. METHODS: This open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), BMI >25 kg/m2, eGFR >30 ml min-1 [1.73 m]-2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev). RESULTS: Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] -1.9 [-3.5, -0.3] mmol/mol [-0.18 (-0.32, -0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] -0.8 [-1.2, -0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] -4.1 [-5.9, -2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] -18 [-29, -6]%, p < 0.01) and liver fat content (by mean [95% CI] -26 [-45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets. CONCLUSIONS/INTERPRETATION: Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814694. FUNDING: The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.

Intravenous contrast medium extravasation: systematic review and updated ESUR Contrast Media Safety Committee Guidelines.

NEED FOR A REVIEW: Guidelines for management and prevention of contrast media extravasation have not been updated recently. In view of emerging research and changing working practices, this review aims to inform update on the current guidelines. AREAS COVERED: In this paper, we review the literature pertaining to the pathophysiology, diagnosis, risk factors and treatments of contrast media extravasation. A suggested protocol and guidelines are recommended based upon the available literature. KEY POINTS: • Risk of extravasation is dependent on scanning technique and patient risk factors. • Diagnosis is mostly clinical, and outcomes are mostly favourable. • Referral to surgery should be based on clinical severity rather than extravasated volume.

Was There Something Rotten in Denmark: Nephrogenic System Fibrosis Cases Occurring in Copenhagen.

More than half of all serious adverse drug reactions are identified seven years after FDA approval. One recent and unusual example involves a syndrome initially termed nephrogenic dermatopathic fibrosis, and then called nephrogenic systemic fibrosis (NSF).

Peritoneal dialysis resulting in discontinuance of recurring attacks of acute intermittent porphyria: A case report.

Acute intermittent porphyria is one of eight disorders arising from disturbances in heme biosynthesis where the precursors, 5-aminolevulinate and porphobilinogen, are elevated in plasma and urine. Attacks are characterized by severe abdominal pain, vomiting and/or obstipation, neurological manifestations, and psychological disturbances. The mainstay of treatment is hemin infusion to induce the negative feedback of heme synthesis. Hemodialysis is casuistically suggested as an alternative treatment. We present a case report of a 78-year-old male with acute intermittent porphyria and renal failure treated with peritoneal dialysis resulting in complete discontinuance of longstanding painful and disabling porphyria attacks.

Evaluation of the point-of-care devices KetoSureTM and StatStrip Express® blood ketone tests using ß-hydroxybutyrate spiked samples.

Measurement of ß-hydroxybutyrate (BHB) in blood is used clinically as a measure of ketosis when diabetic ketoacidosis is expected. With the introduction of point-of-care testing (POCT) for blood-BHB, nonproductive time is reduced to a minimum in a potential critical situation; however, studies have observed inferior quality of POCT-BHB. Recently, the POCT device KetoSure (Roche) has been introduced to the clinic. In this study, we evaluated the imprecision and linearity of KetoSure and compared this to the established StatStrip Express (Nova Biomedical) based on spiked full blood samples. We found comparable imprecision for KetoSure and StatStrip Express. However, linearity was only observed in the lower part of the measuring range for both devices. In a method comparison, higher values of BHB were measured by KetoSure than by an enzymatic endpoint spectrophotometric reference method (mean bias: 21% (95% confidence interval (CI): 4%-37%)). Conversely, StatStrip Express returned lower values of BHB (mean bias: -16% (95% CI: -38%-7%), while the widely applied POCT device FreeStyle Precision Neo (Abbott) returned values equivalent with the reference method (mean bias: 5% (95% CI: -14%-24%). In samples with concentrations of BHB above the measuring range, the POCT devices could be provoked to return falsely low results. In conclusion, the quality of KetoSure is in line with other established POCT devices; however, the KetoSure measures higher concentrations than other POCT devices. As, linearity only was observed in the lower part of the measuring range and as falsely low measures could be provoked, we advise users to interpret results with precaution.

The physics of knocking over LEGO minifigures with time reversal focused vibrations for use in a museum exhibit.

Time reversal (TR) is a method of focusing wave energy at a point in space. The optimization of a TR demonstration is described, which knocks over one selected LEGO minifigure among other minifigures by focusing the vibrations within an aluminum plate at the target minifigure. The aim is to achieve a high repeatability of the demonstration along with reduced costs to create a museum exhibit. By comparing the minifigure's motion to the plate's motion directly beneath its feet, it is determined that a major factor inhibiting the repeatability is that the smaller vibrations before the focal event cause the minifigure to bounce repeatedly and it ends up being in the air during the main vibrational focal event, which was intended to launch the minifigure. The deconvolution TR technique is determined to be optimal in providing the demonstration repeatability. The amplitude, frequency, and plate thickness are optimized in a laboratory setting. An eddy current sensor is then used to reduce the costs, and the impact on the repeatability is determined. A description is given of the implementation of the demonstration for a museum exhibit. This demonstration illustrates the power of the focusing acoustic waves, and the principles learned by optimizing this demonstration can be applied to other real-world applications.

Predictors of joint damage progression and stringent remission in patients with established rheumatoid arthritis in clinical remission.

OBJECTIVES: To study if clinical, radiographic and MRI markers can predict MRI and radiographic damage progression and achievement of stringent remission in patients with established RA in clinical remission followed by a targeted treatment strategy. METHODS: RA patients (DAS28-CRP <3.2, no swollen joints) receiving conventional synthetic DMARDs were randomized to conventional or MRI-targeted treat-to-target strategies with predefined algorithmic treatment escalations. Potentially predictive baseline variables were tested in multivariate logistic regression analyses. RESULTS: In the 171 patients included, baseline MRI osteitis independently predicted progression in MRI erosion [odds ratio (OR) 1.13 (95% CI 1.06, 1.22)], joint space narrowing [OR 1.15 (95% CI 1.07, 1.24)] and combined damage [OR 1.23 (95% CI 1.13, 1.37)], while tenosynovitis independently predicted MRI erosion progression [OR 1.13 (95% CI 1.03, 1.25)]. A predictor of radiographic erosion progression was age, while gender predicted progression in joint space narrowing. Following an MRI treat-to-target strategy predicted stringent remission across all remission definitions: Clinical Disease Activity Index remission OR 2.94 (95% CI 1.25, 7.52), Simplified Disease Activity Index remission OR 2.50 (95% CI 1.01, 6.66), ACR/EULAR Boolean remission OR 5.47 (95% CI 2.33, 14.13). Similarly, low tender joint count and low patient visual analogue scale pain and global independently predicted achievement of more stringent remission. CONCLUSION: Baseline MRI osteitis and tenosynovitis were independent predictors of 2 year MRI damage progression in RA patients in clinical remission, while independent predictors of radiographic damage progression were age and gender. Following an MRI treat-to-target strategy, low scores of patient-reported outcomes and low tender joint count predicted achievement of stringent remission. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01656278.

Acute ketosis inhibits appetite and decreases plasma concentrations of acyl ghrelin in healthy young men.

AIM: To investigate the acute effect of ketone ester (KE) ingestion on appetite and plasma concentrations of acyl ghrelin (AG), unacylated ghrelin (UAG) and glucagon-like peptide-1 (GLP-1) secretion, and to compare responses with those elicited by isocaloric glucose (GLU) administration. METHODS: We examined 10 healthy young men on three separate occasions using a placebo (PBO)-controlled crossover design. A KE versus taste-matched isovolumetric and isocaloric 50% GLU and taste-matched isovolumetric PBO vehicle was orally administered. Our main outcome measures were plasma concentrations of AG, UAG, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 along with appetite sensation scores assessed by visual analogue scale. RESULTS: KE ingestion resulted in an average peak beta-hydroxybutyrate concentration of 5.5 mM. AG and UAG were lowered by approximately 25% following both KE and GLU intake compared with PBO. In the case of AG, the differences were -52.1 (-79.4, -24.8) for KE and -48.4 (-75.4, -21.5) pg/mL for GLU intake (P < .01). Concentrations of AG remained lower with KE but returned to baseline and were comparable with PBO levels after GLU intake. GLP-1, GIP, gastrin and cholecystokinin were not affected by KE ingestion. CONCLUSION: Our results suggest that the suppressive effects on appetite sensation scores associated with hyperketonaemia are more probable to be mediated through reduced ghrelin concentrations than by increased activity of cholecystokinin, gastrin, GIP or GLP-1.

Body weight and metabolic risk factors in patients with type 2 diabetes on a self-selected high-protein low-carbohydrate diet.

PURPOSE: We previously reported beneficial glucoregulatory effects of a fully provided carbohydrate-reduced, high-protein (CRHP) diet in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, in which patients maintained their body weight. Here, we investigated physiological changes during an additional 6-month period on a self-selected and self-prepared CRHP diet. METHODS: Twenty-eight patients with T2DM were instructed to consume a CRHP diet (30% of energy from carbohydrate and 30% from protein) for 24 weeks, after an initial 2 × 6-week trial when all food was prepared and provided to them. Patients received dietary advice every 2 weeks. At weeks 0, 6, 12 and 36, they underwent a 3-h intravenous glucose tolerance test, a 4-h mixed meal test, and a 48-h continuous glucose monitoring. Liver, muscle, pancreas, and visceral fat contents were measured by magnetic resonance imaging. RESULTS: During the 24-week self-selected diet period (weeks 12-36), body weight, visceral fat, liver fat, and glycated haemoglobin were maintained at the same levels achieved at the end of the fully provided diet period, and were still lower than at baseline (P < 0.05). Postprandial insulinaemia and insulin secretion were significantly greater (P < 0.05). At week 36, fasting insulin and C-peptide levels increased (P < 0.01) and daily glycaemia decreased further (P < 0.05) when compared with the end of the fully provided diet period. CONCLUSION: Substituting dietary carbohydrate for protein and fat has metabolic benefits in patients with T2DM. These beneficial effects are maintained or augmented over the next 6 months when patients self-select and self-prepare this diet in a dietitian-supported setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02764021.

Change and consistency in Acta Radiologica over 100 years.

Acta Radiologica celebrates its 100th anniversary in 2021. In this article, the foundation of the journal and its editors are described. During 100 years, the manuscript structure changed from single-author verbose monographs to multi-author collaborations on statistically analyzed research subjects. The authorship changed from purely Nordic authors to a truly international cadre of authors, and the size of the journal increased considerably, in issues per year, printed pages, and published articles per year. The Foundation of Acta Radiologica has been able to give out two prizes, the Xenia Forsselliana and the Acta Radiologica International Scientific Prize for the best manuscripts each year. The increasing submissions of manuscripts is an indication that Acta Radiologica will continue to publish important scientific results for many years to come.

Trends in contrast media research the last 100 years.

This review focuses on the trends in contrast media (CM) research published in Acta Radiologica during the last 100 years, since the first edition in 1921. The main topics covered are the developments of iodine- and gadolinium-based CM. Other topics include manganese-based CM for magnetic resonance imaging (MRI) and barium for the investigation of the alimentary tract. From a historic point of view, special CM for use in cholegraphy and myelography are addressed in the review. Today, these imaging procedures are obsolete due to the development of computed tomography, MRI, and ultrasound. The historical use of radioactive thorium-based CM for angiography is also addressed. Furthermore, publications on adverse reactions to CM are reviewed.

Adherence to guidelines aimed at preventing post-contrast acute kidney injury (PC-AKI) in radiology practices: a survey study.

BACKGROUND: New insights into post-contrast acute kidney injury (PC-AKI) have recently led to the guidelines on the prevention of PC-AKI being updated. However, little is known about the barriers and facilitators involved in guideline adherence by radiology practices. PURPOSE: To evaluate barriers and facilitators to the adherence of PC-AKI guidelines. MATERIAL AND METHODS: Radiologists visiting the European Society of Urogenital Radiology (ESUR) 2018 meeting, as well as ESUR members were contacted to fill in an electronic questionnaire on the implementation of PC-AKI guidelines applying to their local radiology practices. RESULTS: Of the 145 responding radiologists representing radiology practices, 127 (88%) confirmed having a PC-AKI protocol in place in their radiology practice, of which 61 (48%) used a protocol as specified in a (inter)national guideline. The majority of radiology practices of the respondents used the ESUR guideline (40%). Barriers for not using PC-AKI prevention guidelines were related to a lack of outcome expectancy. Barriers for not using the protocol as specified were related to a lack of agreement with specific recommendations, lack of motivation, guideline-specific factors, and environmental factors. Self-reported facilitators consisted of guideline-specific factors. CONCLUSION: Guidelines for the prevention of PC-AKI seem to be widely implemented among radiology practices, and regularly locally modified because of barriers involved in agreement and behavior. Knowledge of the barriers and facilitators of guideline adherence will aid future efforts aimed at bridging the gap between awareness and implementation of evidence-based guidelines in radiology practices.

Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (<5% or ≥5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86; p < 0.001), which compared with a ROCAUC of 0.82 (95% CI 0.81, 0.83; p < 0.001) for a model including 9 clinically accessible variables. The IMI DIRECT prediction models outperformed existing noninvasive NAFLD prediction tools. One limitation is that these analyses were performed in adults of European ancestry residing in northern Europe, and it is unknown how well these findings will translate to people of other ancestries and exposed to environmental risk factors that differ from those of the present cohort. Another key limitation of this study is that the prediction was done on a binary outcome of liver fat quantity (<5% or ≥5%) rather than a continuous one. CONCLUSIONS: In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see: https://www.predictliverfat.org/) and made it available to the community. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814915.

Identifying multiply scattered wavepaths in strongly scattering and dispersive media.

The ability to extract information from scattered waves is usually limited to singly scattered energy even if multiple scattering might occur in the medium. As a result, the information in arrival times of higher-order scattered events is underexplored. This information is extracted using fingerprinting theory. This theory has never previously been applied successfully to real measurements, particularly when the medium is dispersive. The theory is used to estimate the arrival times and scattering paths of multiply scattered waves in a thin sheet using an automated scheme in a dispersive medium by applying an additional dispersion compensation method. Estimated times and paths are compared with predictions based on a sequence of straight ray paths for each scattering event given the known scatterer locations. Additionally, numerical modelling is performed to verify the interpretations of the compensated data. Since the source also acts as a scatterer in these experiments, initially, the predictions and the numerical results did not conform to the experimental observations. By reformulating the theory and the processing scheme and adding a source scatterer in the modelling, it is shown that predictions of all observed scattering events are possible with both prediction methods, verifying that the methods are both effective and practically achievable.

A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Dietary recommendations for treating type 2 diabetes are unclear but a trend towards recommending a diet reduced in carbohydrate content is acknowledged. We compared a carbohydrate-reduced high-protein (CRHP) diet with an iso-energetic conventional diabetes (CD) diet to elucidate the effects on glycaemic control and selected cardiovascular risk markers during 6 weeks of full food provision of each diet. METHODS: The primary outcome of the study was change in HbA1c. Secondary outcomes reported in the present paper include glycaemic variables, ectopic fat content and 24 h blood pressure. Eligibility criteria were: men and women with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), age >18 years, haemoglobin >6/>7 mmol/l (women/men) and eGFR >30 ml min-1 (1.73 m)-2. Participants were randomised by drawing blinded ballots to 6 + 6 weeks of an iso-energetic CRHP vs CD diet in an open label, crossover design aiming at body weight stability. The CRHP/CD diets contained carbohydrate 30/50 energy per cent (E%), protein 30/17E% and fat 40/33E%, respectively. Participants underwent a meal test at the end of each diet period and glycaemic variables, lipid profiles, 24 h blood pressure and ectopic fat including liver and pancreatic fat content were assessed at baseline and at the end of each diet period. Data were collected at Copenhagen University Hospital, Bispebjerg and Copenhagen University Hospital, Herlev. RESULTS: Twenty-eight participants completed the study. Fourteen participants carried out 6 weeks of the CRHP intervention followed by 6 weeks of the CD intervention, and 14 participants received the dietary interventions in the reverse order. Compared with a CD diet, a CRHP diet reduced the primary outcome of HbA1c (mean ± SEM: -6.2 ± 0.8 mmol/mol (-0.6 ± 0.1%) vs -0.75 ± 1.0 mmol/mol (-0.1 ± 0.1%); p < 0.001). Nine (out of 37) pre-specified secondary outcomes are reported in the present paper, of which five were significantly different between the diets, (p < 0.05); compared with a CD diet, a CRHP diet reduced the secondary outcomes (mean ± SEM or medians [interquartile range]) of fasting plasma glucose (-0.71 ± 0.20 mmol/l vs 0.03 ± 0.23 mmol/l; p < 0.05), postprandial plasma glucose AUC (9.58 ± 0.29 mmol/l × 240 min vs 11.89 ± 0.43 mmol/l × 240 min; p < 0.001) and net AUC (1.25 ± 0.20 mmol/l × 240 min vs 3.10 ± 0.25 mmol/l × 240 min; p < 0.001), hepatic fat content (-2.4% [-7.8% to -1.0%] vs 0.2% [-2.3% to 0.9%]; p < 0.01) and pancreatic fat content (-1.7% [-3.5% to 0.6%] vs 0.5% [-1.0% to 2.0%]; p < 0.05). Changes in other secondary outcomes, i.e. 24 h blood pressure and muscle-, visceral- or subcutaneous adipose tissue, did not differ between diets. CONCLUSIONS/INTERPRETATION: A moderate macronutrient shift by substituting carbohydrates with protein and fat for 6 weeks reduced HbA1c and hepatic fat content in weight stable individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02764021. FUNDING: The study was funded by grants from Arla Food for Health; the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; the Department of Clinical Medicine, Aarhus University; the Department of Nutrition, Exercise and Sports, University of Copenhagen; and Copenhagen University Hospital, Bispebjerg.

68Ga-PSMA-PET/CT in comparison with 18F-fluoride-PET/CT and whole-body MRI for the detection of bone metastases in patients with prostate cancer: a prospective diagnostic accuracy study.

OBJECTIVES: To determine the diagnostic accuracy of 68gallium prostate-specific membrane antigen (PSMA)-based positron emission tomography/computed tomography (PET/CT) in comparison with 18F-fluoride-based PET/CT (NaF-PET/CT) and whole-body magnetic resonance imaging (WB-MRI) for the detection of bone metastases in patients with prostate cancer. METHODS: Sixty patients with prostate cancer were included in the period May 2016 to June 2017. The participants underwent three scans (index tests) within 30 days: a NaF-PET/CT, a WB-MRI and a PSMA-PET/CT. Experienced specialists assessed the scans. In the absence of a histological reference standard, the final diagnosis was determined as a panel diagnosis. Measures of the diagnostic performances of the index tests were calculated from patient-based dichotomous outcomes (0 or ≥ 1 bone metastasis) and pairwise compared (McNemar test). For each index test, the agreement with the final diagnosis with regard to the number of bone metastases detected (0, 1-5, > 5) and the inter-reader agreement was calculated (kappa coefficients). RESULTS: Fifty-five patients constituted the final study population; 20 patients (36%) were classified as having bone metastatic disease as their final diagnosis. The patient-based diagnostic performances were (sensitivity, specificity, overall accuracy) PSMA-PET/CT (100%, 100%, 100%), NaF-PET/CT (95%, 97%, 96%) and WB-MRI (80%, 83%, 82%). The overall accuracy of PSMA-PET/CT was significantly more favourable compared to WB-MRI (p = 0.004), but not to NaF-PET/CT (p = 0.48). PSMA-PET/CT classified the number of bone metastases reliably compared to the final diagnosis (kappa coefficient 0.97) and with an "almost perfect" inter-reader agreement (kappa coefficient 0.93). CONCLUSIONS: The overall accuracy of PSMA-PET/CT was significantly more advantageous compared to WB-MRI, but not to NaF-PET/CT. KEY POINTS: • PSMA-PET/CT assessed the presence of bone metastases correctly in all 55 patients • PSMA-PET/CT was more advantageous compared to WB-MRI • No difference was found between PSMA-PET/CT and NaF-PET/CT.