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Aim: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18FDG-PET/CT) in patients where standard investigations were non-diagnostic. Methods: We reviewed medical records of previously healthy children who had 18FDG-PET/CT performed at Copenhagen University Hospital in 2015–2020 due to unexplained fever. Results: Thirty-five of 819 paediatric 18FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18FDG-uptake, but 18FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). Conclusion: 18FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

AIM This study explored hypoglycaemia and metabolic crises, including hyperketosis, in patients with spinal muscular atrophy (SMA). METHODS The study comprised four adolescents aged 15-17 and six adults aged 19-37 with SMA type II and eight adult controls aged 21-41, who were recruited by the Rigshospitalet, Denmark, from May 1st to October 30th 2017. We used stable isotope technique and indirect calorimetry to investigate fat and glucose metabolism during a 24-h fast or until hypoglycaemia occurred. RESULTS All patients with SMA II developed moderate to severe hyperketosis and 60% had symptoms of hypoglycaemia or blood glucose levels below 3 mmol/L. None of the controls developed hyperketosis or hypoglycaemia. Plasma bicarbonate decreased, in line with increased ketone bodies, indicating the start of metabolic acidosis in patients with SMA II. Increased fat production and utilisation were seen in healthy controls during the fasting period, but were absent in patients with SMA II, indicating blunted fat oxidation. CONCLUSION Low skeletal muscle mass was the best explanation for why patients with SMA II had an increased risk of hypoglycaemia, hyperketosis, metabolic acidosis and disturbed fat and glucose metabolism during fasting. These risks have implications for children facing surgery and those with severe illnesses.

Introduction Bethlem myopathy is caused by dysfunctional collagen VI assembly, leading to varying degrees of hyperlaxity, contractures and muscle weakness. Previous studies demonstrate that cardiovascular training is safe and beneficial in patients with myopathies. However, exercise exacerbates the dystrophic phenotype in collagen VI-knockout mice. Methods Six men with Bethlem myopathy were included (4 training; 2 controls). After training, 2 patients detrained. Patients performed 10 weeks of home-based, moderate-intensity exercise monitored by a pulse-watch. The primary outcome was change in peak oxygen uptake (VO2peak ). Secondary outcomes were performances in functional tests. Results VO2peak improved in the training group (16%, P = 0.017). Detraining led to regression of VO2peak toward baseline values (-8%; P = 0.03). No change was seen in the control group (-7%; P = 0.47). Performance in functional tests did not change significantly. Creatine kinase values were stable during the study. Conclusions Moderate-intensity exercise seems to safely improve oxidative function in patients with Bethlem myopathy. Muscle Nerve 60: 183-188, 2019.

There is an unmet need to identify biomarkers sensitive to change in rare, slowly progressive neuromuscular diseases. Quantitative magnetic resonance imaging (MRI) of muscle may offer this opportunity, as it is noninvasive and can be carried out almost independent of patient cooperation and disease severity. Muscle fat content correlates with muscle function in neuromuscular diseases, and changes in fat content precede changes in function, which suggests that muscle MRI is a strong biomarker candidate to predict prognosis and treatment efficacy. In this paper, we review the evidence suggesting that muscle MRI may be an important biomarker for diagnosis and to monitor change in disease severity. ANN NEUROL 2020;88:669-681.

This case series describes the role of oral drug challenge in the diagnosis of fixed drug eruption in the setting of polypharmacy. Practical testing guidelines are provided. The literature describing the histopathology of acute fixed drug reaction is also reviewed and compared with the findings in this series.

Fourteen cases of α-methylacyl-CoA racemase (AMACR) deficiency have been published (10 adults, 4 children) (1-13). AMACR deficiency typically has an adult onset with variable severity and a range of predominant symptoms (figure 1a). More rarely, AMACR deficiency presents in childhood with coagulopathy and hepatic disease. AMACR is involved in perioxsomal metabolism by racemizing 2R-pristanic acid, thus preparing the substrate for β-oxidation, which is stereoisomer specific (14). We describe a case with AMACR deficiency in whom relapsing episodes of hyperCKemia was one of the dominating symptoms.

Glycogen storage disease type V (GSDV) is a rare inborn error of carbohydrate metabolism. Patients present with exercise intolerance due to blocked glycogen breakdown in skeletal muscle. Introducing alternative fuel substrates, such as ketone bodies (KBs), could potentially alleviate muscle symptoms. This pilot study investigates which of three different modified ketogenic diet regimes is optimal for GSDV-patients to follow in a future large-scale study. Participants were randomised to follow one of three diet regimes for 3 weeks (#1: 65%/15%/20%; #2: 75%/15%/10%, or #3: 80%/15%/5%, fat/protein/carbohydrate). The primary outcome was exercise tolerance assessed by heart rate (HR) changes during constant load cycling. Secondary outcomes included levels of ketosis, and changes in perceived exertion and indirect calorimetry measures during exercise. Ten GSDV-patients were included. Eight completed the study. The other two were excluded. Diet #3 showed the highest average KB level (1.1 mmol/L) vs #2 (0.5 mmol/L) and #1 (0.3 mmol/L). Five patients reported subjective symptom relief, all of whom were on diets #2 and #3. All diet regimes seemed to improve fatty acid oxidation rates and exercise capacity as indicated by a small decrease in HR and perceived exertion. The results of this open-label pilot study show that diets #2 and #3 induce ketosis and improve symptoms and exercise capacity in GSDV-patients. Diet #2 had the highest acceptability score and was superior or equal to diet #3 in all other parameters, except level of ketosis. Based on this, we suggest testing diet #2 in a large-scale, placebo-controlled study in GSDV.

OBJECTIVE: The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene.METHODS: We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current.RESULTS: We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands' muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1.INTERPRETATION: Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832-843.

We document that since 1994, the equity premium is earned entirely in weeks 0, 2, 4, and 6 in Federal Open Market Committee (FOMC) cycle time, that is, even weeks starting from the last FOMC meeting. We causally tie this fact to the Fed by studying intermeeting target changes, Fed funds futures, and internal Board of Governors meetings. The Fed has affected the stock market via unexpectedly accommodating policy, leading to large reductions in the equity premium. Evidence suggests systematic informal communication of Fed officials with the media and financial sector as a channel through which news about monetary policy has reached the market.

OBJECTIVE Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive disease with weakness of bulbar and extremity muscles. There is no curative treatment for the disease, but several clinical trials have been conducted over the past years. The results from these trials have uncovered a great need to develop quantitative, reliable outcome measures. In this study, we prospectively investigated disease progression over 18 months in 29 patients with genetically confirmed SBMA, using quantitative outcome measures, including Dixon magnetic resonance imaging (MRI). METHODS We used MRI to assess changes in muscle fat content and stationary dynamometry to assess changes in muscle strength. Disease progression was also investigated with the SBMA functional rating scale, bulbar rating scale, 6-minute walk test, and blood samples, among others. RESULTS Mean muscle fat content, muscle strength in knee extensors, handgrip strength, walking distance, and creatinine levels changed significantly. Mean muscle fat content increased by 2 ± 1.25%, and knee extension strength decreased from 83 ± 60 to 76 ± 56Nm, handgrip strength from 31 ± 13 to 29 ± 13kg, walking distance from 362 ± 216 to 336 ± 219m, and creatinine level from 58 ± 21 to 54 ± 20 μmol/l. Functional rating scores did not change. INTERPRETATION The present study demonstrates a slow and steady disease progression in SBMA. Dixon MRI detected increases in muscle fat content in all investigated muscles and is therefore a suitable candidate for an outcome measure in natural history or treatment studies in SBMA. The 6-minute walk test and handgrip strength also seem to be reliable outcome measures for SBMA. Ann Neurol 2018;84:762-773.

Background Laser and intense pulsed light (IPL) are standard symptomatic treatments for superficial telangiectasias, but postoperative erythema, oedema, and pain may prolong downtime. Objectives To investigate whether topical brimonidine reduces IPL-induced inflammation in patients with moderate to severe facial telangiectasias. Methods A randomized, two-centre, single-blinded, split-face trial on adjuvant brimonidine and air-cooling versus air-cooling alone (control) in 19 patients treated in Denmark (n = 10 patients) and Belgium (n = 9). Brimonidine was applied to the allocated side after each of three facial IPL-treatments, given at 3-week intervals. Patients were assessed up to 1 month after the final treatment. Outcome measures included blinded clinical on-site evaluation of erythema and oedema (5-point-scales), objective erythema-scores (red-filter analysis), patient-evaluated pain (Visual Analogue Scale), IPL-efficacy (blinded photo-evaluation of telangiectasia clearance), and patient preference. Results In total, 19 patients were enrolled and completed the study. IPL induced moderate to severe erythema after each treatment. Application of brimonidine, reduced erythema to baseline values compared to air-cooling alone and sustained efficacy 24 hours after treatment (median difference reduction: score 1 at each assessment, P ≤ 0.022). Objective erythema-scores supported clinical findings, demonstrating a median erythema reduction of 50-95% after application of brimonidine and air-cooling compared to 9-28% reduction after air-cooling alone (P ≥ 0.002). No difference in reduction of IPL-induced oedema was observed between facial sides (P ≥ 0.227). Brimonidine and air-cooling slightly and consistently reduced postoperative pain compared to air-cooling alone (VAS 1.0 after brimonidine versus VAS 1.5-2.0 after air-cooling alone at treatment 1-3, P ≤ 0.032). At 1-month follow-up, patients experienced excellent clearance of telangiectasias (75-100% clearance) on both facial sides (P = 1.000). Patient preference supported clinical data and 79% of patients preferred brimonidine to control (P = 0.019). Conclusion Compared to air-cooling alone, adjuvant brimonidine reduces IPL-induced erythema and associated pain while maintaining a high IPL-efficacy. Lasers Surg. Med. 50:1002-1009, 2018. © 2018 Wiley Periodicals, Inc.

Carriers of the mitochondrial mutation m.3243A>G presents highly variable phenotypes including mitochondrial encephalomyopathy, lactoacidosis and stroke-like episodes (MELAS). We conducted a follow-up study to evaluate changes in leucocyte heteroplasmy and the clinical phenotypes in m.3243A>G carriers. Leucocyte heteroplasmy was determined by next generation sequencing covered by 100 000X reads in 32 individuals with a median follow-up of 10.2 years. Ten-year clinical follow-up is reported in 46 individuals. The annual leucocyte mutation level declined by −0.7 (±0.4) percentage points/year (P G carriers died and clinical symptoms progressed. This longitudinal study shows the decline in leucocyte m.3243A>G heteroplasmy associates with the level of the initial sample. Further, there was a high mortality among carriers.