Pediatric autoimmune encephalitis in Denmark during 2011–17:A nationwide multicenter population-based cohort study

Background: The incidence of pediatric autoimmune encephalitis (AIE) is unknown. Our aim was to assess the incidence of pediatric AIE in Denmark 2011–17. Methods: In a nationwide population-based setting, we retrieved data on all children tested for AIE before age 18 years. We reviewed medical records in a) children with AIE antibodies (n = 18) to assess whether children fulfilled the AIE consensus criteria, b) children tested negative for AIE antibodies who were registered with an AIE diagnostic code to estimate the incidence of “antibody negative but probable AIE”, and c) a reference cohort (n = 596) to determine the positive predictive value of International Classification of Diseases (ICD) codes used for anti-NMDAR encephalitis. Results: 375 children were tested for AIE 2011–17 (median age 11.1 years; 54% girls); 18 children (5%) had AIE antibodies (percentage tested positive): CSF GAD 65 -IgG (3.1%), plasma NMDAR-IgG (2.8%), CSF NMDAR-IgG (1.8%), plasma GAD 65 -IgG (1.0%), and plasma CASPR2-IgG (0.4%). Five children fulfilled the criteria for probably/definite anti-NMDAR encephalitis (incidence: 0.07/100,000 person-years; 95% CI = 0.03–0.17), and 4 children with anti-GAD 65 associated AIE (incidence = 0.055/100,000 person-years, 95% CI = 0.021–0.15). The incidence of “antibody negative but probable AIE” was 0.055/100,000 person-years (95% CI = 0.021–0.15). The positive predictive value of ICD diagnostic codes used for anti-NMDAR encephalitis was 8%. Conclusions: We diagnosed only children with anti-NMDAR, anti-GAD 65 , and “antibody negative but probable AIE”. Before examining AIE antibodies, clinical presentation, paraclinical studies (CSF, EEG, and MRI), and incidence of pediatric AIEs should be considered. Updating the ICD to include AIE codes is warranted. </p

CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis:A National Cohort Study

Background and Objectives: The two most common autoimmune encephalitides (AE), N-methyl-D-Aspartate receptor (NMDAR) and Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis, have been known for more than a decade. Nevertheless, no well-established biomarkers to guide treatment or estimate prognosis exist. Neurofilament light chain (NfL) has become an unspecific screening marker of axonal damage in CNS diseases, and has proven useful as a diagnostic and disease activity marker in neuroinflammatory diseases. Only limited reports on NfL in AE exist. We investigated NfL levels at diagnosis and follow-up in NMDAR and LGI1-AE patients, and evaluated the utility of CSF-NfL as a biomarker in AE. Methods: Patients were included from the National Danish AE cohort (2009-present) and diagnosed based upon autoantibody positivity and diagnostic consensus criteria. CSF-NfL was analyzed by single molecule array technology. Clinical and diagnostic information was retrospectively evaluated and related to NfL levels at baseline and follow-up. NMDAR-AE patients were subdivided into: idiopathic/teratoma associated or secondary NMDAR-AE (post-viral or concomitant with malignancies/demyelinating disease). Results: A total of 74 CSF samples from 53 AE patients (37 NMDAR and 16 LGI1 positive) were included in the study. Longitudinal CSF-NfL levels was measured in 21 patients. Median follow-up time was 23.8 and 43.9 months for NMDAR and LGI1-AE respectively. Major findings of this study are: i) CSF-NfL levels were higher in LGI1-AE than in idiopathic/teratoma associated NMDAR-AE at diagnosis; ii) CSF-NfL levels in NMDAR-AE patients distinguished idiopathic/teratoma cases from cases with other underlying etiologies (post-viral or malignancies/demyelinating diseases) and iii) Elevated CSF-NfL at diagnosis seems to be associated with worse long-term disease outcomes in both NMDAR and LGI1-AE. Discussion: CSF-NfL measurement may be beneficial as a prognostic biomarker in NMDAR and LGI1-AE, and high CSF-NfL could foster search for underlying etiologies in NMDAR-AE. Further studies on larger cohorts, using standardized methods, are warranted.</p

Extra-cellular matrix proteins induce matrix metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma

Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms

Extraintestinal pathogenic <i>Escherichia coli</i> are associated with intestinal inflammation in patients with ulcerative colitis

E. coli of the phylogenetic group B2 harbouring Extra intestinal Pathogenic Escherichia coli (ExPEC) genes are frequently seen as colonizers of the intestine in patients with active ulcerative colitis (UC). In this study, we describe the influence of E. coli Nissle (EcN) B2 as add-on treatment to conventional therapies in patients with active UC. For this study one hundred active UC patients were randomized to ciprofloxacin or placebo for 1 week followed by EcN or placebo for 7 weeks. Stool samples were collected at weeks 0, 1, 8, 12, where E. coli were characterized and fecal calprotectin was measured. We showed that in the active UC patient group receiving Placebo/EcN, fewer patients reached remission, in comparison to the patient group receiving Placebo/placebo (p < 0.05). Active UC patients initially colonized with E. coli B2 had increased fecal calprotectin values and Colitis Activity Index scores in comparison to patients colonized with E. coli A and D (p < 0.05*). In conclusion, treatment of UC patients with E. coli Nissle (B2) does not promote clinical remission and active UC patients colonized with E. coli B2 have an increased intestinal inflammation

Benefits and harms of implementing [18F]FDG-PET/CT for diagnosing recurrent breast cancer:a prospective clinical study

BACKGROUND: [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) has been implemented sporadically in hospital settings as the standard of care examination for recurrent breast cancer. We aimed to explore the clinical impact of implementing [18F]FDG-PET/CT for patients with clinically suspected recurrent breast cancer and validate the diagnostic accuracy.METHODS: Women with suspected distant recurrent breast cancer were prospectively enrolled in the study between September 2017 and August 2019. [18F]FDG-PET/CT was performed, and the appearance of incidental benign and malignant findings was registered. Additional examinations, complications, and the final diagnosis were registered to reflect the clinical consequence of such findings. The diagnostic accuracy of [18F]FDG-PET/CT as a stand-alone examination was analyzed. Biopsy and follow-up were used as a reference standard.RESULTS: [18F]FDG-PET/CT reported breast cancer metastases in 72 of 225 women (32.0%), and metastases were verified by biopsy in 52 (52/225, 23.1%). Prior probability and posterior probability of a positive test for suspected metastatic cancer and incidental malignancies were 27%/85% and 4%/20%, respectively. Suspected malignant incidental findings were reported in 46 patients (46/225, 20.4%), leading to further examinations and final detection of nine synchronous cancers (9/225, 4.0%). These cancers originated from the lung, thyroid, skin, pancreas, peritoneum, breast, kidney, one was malignant melanoma, and one was hematological cancer. False-positive incidental malignant findings were examined in 37/225 patients (16.4%), mainly in the colon (n = 12) and thyroid gland (n = 12). Ten incidental findings suspicious for benign disease were suggested by [18F]FDG-PET/CT, and further examinations resulted in the detection of three benign conditions requiring treatment. Sensitivity, specificity, and AUC-ROC for diagnosing distant metastases were 1.00 (0.93-1.0), 0.88 (0.82-0.92), and 0.98 (95% CI 0.97-0.99), respectively.CONCLUSION: [18F]FDG-PET/CT provided a high posterior probability of positive test, and a negative test was able to rule out distant metastases in women with clinically suspected recurrent breast cancer. One-fifth of patients examined for incidental findings detected on [18F]FDG-PET/CT were diagnosed with clinically relevant conditions. Further examinations of false-positive incidental findings in one of six women should be weighed against the high accuracy for diagnosing metastatic breast cancer. Trial registration Clinical.Trials.gov. NCT03358589. Registered 30 November 2017-Retrospectively registered, http://www.ClinicalTrials.gov.</p

FDG-PET/CT in high-risk primary breast cancer:a prospective study of stage migration and clinical impact

Purpose: To investigate the clinical impact of FDG-PET/CT for staging and treatment planning in high-risk primary breast cancer. Methods: Women with high-risk primary breast cancer were enrolled between September 2017 and August 2019 at Odense University Hospital, Denmark. Conventional mammography with/without MRI was performed before staging by FDG-PET/CT. We studied the accuracy of FDG-PET/CT for the detection of distant metastases, the effect on the change of treatment, and the prevalence of incidental findings. Biopsy and follow-up were used as a reference standard for the accuracy analysis. Results: Of 103 women, 24 (23%) were diagnosed with distant metastases by FDG-PET/CT. Among these, breast surgery was omitted in 18 and could have been spared in six. Another sixteen (16%) patients were upstaged to more advanced loco-regional disease, leading to more extensive radiotherapy. Sensitivity and specificity for diagnosing distant metastases were 1.00 (95% confidence interval: 0.86–1.00) and 0.95 (0.88–0.99), respectively. Twenty-nine incidental findings were detected in 24 women (23%), leading to further examinations in 22 and diagnosis of eight (8/22, 36%) synchronous diseases: cancer (n = 4), thyroiditis (n = 2), aorta aneurysm (n = 1), and meningioma (n = 1). Conclusions: FDG-PET/CT had a substantial impact on staging and change of treatment in women with high-risk primary breast cancer, and further examination of incidental findings was considered clinically relevant. Our findings suggest that FDG-PET/CT should be considered for primary staging in high-risk primary breast cancer to improve treatment planning.</p

Evolutionary history of Serpulaceae (Basidiomycota): molecular phylogeny, historical biogeography and evidence for a single transition of nutritional mode

<p>Abstract</p> <p>Background</p> <p>The fungal genus <it>Serpula </it>(Serpulaceae, Boletales) comprises several saprotrophic (brown rot) taxa, including the aggressive house-infecting dry rot fungus <it>Serpula lacrymans</it>. Recent phylogenetic analyses have indicated that the ectomycorrhiza forming genera <it>Austropaxillus </it>and <it>Gymnopaxillus </it>cluster within <it>Serpula</it>. In this study we use DNA sequence data to investigate phylogenetic relationships, historical biogeography of, and nutritional mode transitions in Serpulaceae.</p> <p>Results</p> <p>Our results corroborate that the two ectomycorrhiza-forming genera, <it>Austropaxillus </it>and <it>Gymnopaxillus</it>, form a monophyletic group nested within the saprotrophic genus <it>Serpula</it>, and that the <it>Serpula </it>species <it>S. lacrymans </it>and <it>S. himantioides </it>constitute the sister group to the <it>Austropaxillus</it>-<it>Gymnopaxillus </it>clade. We found that both vicariance (Beringian) and long distance dispersal events are needed to explain the phylogeny and current distributions of taxa within Serpulaceae. Our results also show that the transition from brown rot to mycorrhiza has happened only once in a monophyletic Serpulaceae, probably between 50 and 22 million years before present.</p> <p>Conclusions</p> <p>This study supports the growing understanding that the same geographical barriers that limit plant- and animal dispersal also limit the spread of fungi, as a combination of vicariance and long distance dispersal events are needed to explain the present patterns of distribution in Serpulaceae. Our results verify the transition from brown rot to ECM within Serpulaceae between 50 and 22 MyBP.</p

Modelling silicon supply during the Last Interglacial (MIS 5e) at Lake Baikal

Limnological reconstructions of primary productivity have demonstrated its response over Quaternary timescales to drivers such as climate change, landscape evolution and lake ontogeny. In particular, sediments from Lake Baikal, Siberia, provide a valuable uninterrupted and continuous sequence of biogenic silica (BSi) records, which document orbital and sub-orbital frequencies of regional climate change. We here extend these records via the application of stable isotope analysis of silica in diatom opal (δ30Sidiatom) from sediments covering the Last Interglacial cycle (Marine Isotope Stage [MIS] 5e; c. 130 to 115 ka BP) as a means to test the hypothesis that it was more productive than the Holocene. δ30Sidiatom data for the Last Interglacial range between +1.29 to +1.78‰, with highest values between c. 127 to 124 ka BP (+1.57 to +1.78‰). Results show that diatom dissolved silicon (DSi) utilisation, was significantly higher (p=0.001) during MIS 5e than the current interglacial, which reflects increased diatom productivity over this time (concomitant with high diatom biovolume accumulation rates [BVAR] and warmer pollen-inferred vegetation reconstructions). Diatom BVAR are used, in tandem with δ30Sidiatom data, to model DSi supply to Lake Baikal surface waters, which shows that highest delivery was between c. 123 to 120 ka BP (reaching peak supply at c. 120 ka BP). When constrained by sedimentary mineralogical archives of catchment weathering indices (e.g. the Hydrolysis Index), data highlight the small degree of weathering intensity and therefore representation that catchment-weathering DSi sources had, over the duration of MIS 5e. Changes to DSi supply are therefore attributed to variations in within-lake conditions (e.g. turbulent mixing) over the period, where periods of both high productivity and modelled-DSi supply (e.g. strong convective mixing) account for the decreasing trend in δ30Sidiatom compositions (after c. 124 ka BP)

A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults

\ua9 2018, The Author(s). Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres