Switzerland has one of the highest annual Legionnaires’ disease (LD) notification rates in Europe (7.8 cases/100,000 population in 2021). The main sources of infection and the cause for this high ...rate remain largely unknown. This hampers the implementation of targeted
Legionella
spp. control efforts. The
SwissLEGIO
national case–control and molecular source attribution study investigates risk factors and infection sources for community-acquired LD in Switzerland. Over the duration of one year, the study is recruiting 205 newly diagnosed LD patients through a network of 20 university and cantonal hospitals. Healthy controls matched for age, sex, and residence at district level are recruited from the general population. Risk factors for LD are assessed in questionnaire-based interviews. Clinical and environmental
Legionella
spp. isolates are compared using whole genome sequencing (WGS). Direct comparison of sero- and sequence types (ST), core genome multilocus sequencing types (cgMLST), and single nucleotide polymorphisms (SNPs) between clinical and environmental isolates are used to investigate the infection sources and the prevalence and virulence of different
Legionella
spp. strains detected across Switzerland. The
SwissLEGIO
study innovates in combining case–control and molecular typing approaches for source attribution on a national level outside an outbreak setting. The study provides a unique platform for national Legionellosis and
Legionella
research and is conducted in an inter- and transdisciplinary, co-production approach involving various national governmental and national research stakeholders.
Abstract Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show ...signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac’s syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac’s Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.
RNF4 (RING finger protein 4) is a STUbL SUMO (small ubiquitin-related modifier)-targeted ubiquitin ligase controlling PML (promyelocytic leukaemia) nuclear bodies, DNA double strand break repair and ...other nuclear functions. In the present paper, we describe that the sequence and spacing of the SIMs (SUMO-interaction motifs) in RNF4 regulate the avidity-driven recognition of substrate proteins carrying SUMO chains of variable length.
Myocardial inflammation often complicates leptospirosis, a re-emerging global zoonosis. Leptospirosis associated myocardial dysfunction is equivocal and the pattern of cardiac involvement may not ...differ from that of sepsis associated myocarditis.
We prospectively compared cardiac involvement in 113 intensive care unit patients with severe leptospirosis to 31 patients with sepsis syndrome using a comprehensive assessment comprising of clinical presentation, electrocardiography, two-dimensional echocardiography (with global longitudinal strain calculation), and cardiac biomarker evaluation. Binomial logistic regression was performed to identify independent predictors of left ventricular systolic dysfunction in leptospirosis.
Compared to sepsis syndrome, leptospirosis patients were younger, had higher body mass index measurements and were more likely to be smokers. Electrocardiography abnormalities were common and similar in both groups. Myocardial systolic dysfunction was common in both groups (leptospirosis: 55.86% vs sepsis syndrome: 51.61%,
=0.675) with subclinical left ventricular systolic dysfunction (characterized by abnormal global longitudinal strain and normal left ventricular ejection fraction) being most frequent followed by isolated right ventricular systolic dysfunction, isolated left ventricular systolic dysfunction, and bi-ventricular systolic dysfunction (leptospirosis: 31.43%, 18.42%, 13.16%, 10.53%, respectively; sepsis syndrome: 22.22%, 12.00%, 12.00%, 8.00%, respectively (
>0.05 for each comparator)). Leptospirosis patients had a trend towards greater troponin-T elevation (61.0% vs 40.0%,
=0.057). ST-segment elevation and elevated troponin were independent predictors of reduced left ventricular ejection fraction in leptospirosis.
Cardiac involvement in leptospirosis appears to be similar to that of sepsis syndrome, with myocardial systolic dysfunction being common. As such, clinical vigilance pertaining to cardiac status is paramount in these high-risk patients.
Summary
We take advantage of the new large AlpArray Seismic Network (AASN) as part of the AlpArray research initiative (www.alparray.ethz.ch), to establish a consistent seismicity-catalogue for the ...greater Alpine region (GAR) for the time period 2016 January 1–2019 December 31. We use data from 1103 stations including the AASN backbone composed of 352 permanent and 276 (including 30 OBS) temporary broad-band stations (network code Z3). Although characterized by a moderate seismic hazard, the European Alps and surrounding regions have a higher seismic risk due to the higher concentration of values and people. For these reasons, the GAR seismicity is monitored and routinely reported in catalogues by a 11 national and 2 regional seismic observatories. The heterogeneity of these data set limits the possibility of extracting consistent information by simply merging to investigate the GAR's seismicity as a whole. The uniformly spaced and dense AASN provides, for the first time, a unique opportunity to calculate high-precision hypocentre locations and consistent magnitude estimation with uniformity and equal uncertainty across the GAR. We present a new, multistep, semi-automatic method to process ∼50 TB of seismic signals, combining three different software. We used the SeisComP3 for the initial earthquake detection, a newly developed Python library ADAPT for high-quality re-picking, and the well-established VELEST algorithm both for filtering and final location purposes. Moreover, we computed new local magnitudes based on the final high-precision hypocentre locations and re-evaluation of the amplitude observations. The final catalogue contains 3293 seismic events and is complete down to local magnitude 2.4 and regionally consistent with the magnitude 3+ of national catalogues for the same time period. Despite covering only 4 yr of seismicity, our catalogue evidences the main fault systems and orogens’ front in the region, that are documented as seismically active by the EPOS-EMSC manually revised regional bulletin for the same time period. Additionally, we jointly inverted for a new regional minimum 1-D P-wave velocity model for the GAR and station delays for both permanent station networks and temporary arrays. These results provide the base for a future re-evaluation of the past decades of seismicity, and for the future seismicity, eventually improving seismic-hazard studies in the region. Moreover, we provide a unique, consistent seismic data set fundamental to further investigate this complex and seismically active area. The catalogue, the minimum 1-D P-wave velocity model, and station delays associated are openly shared and distributed with a permanent DOI listed in the data availability section.
Cytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed ...in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis. We showed that PlexinD1 is cleaved by metalloproteases in SMA and that this cleavage switches its function from an attractant to repellent. Moreover, we found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling.
The ca. 1.8
Ga Duck Creek Formation, Western Australia, preserves 1000
m of carbonates and minor iron formation that accumulated along a late Paleoproterozoic ocean margin. Two upward-deepening ...stratigraphic packages are preserved, each characterized by peritidal precipitates at the base and iron formation and carbonate turbidites in its upper part. Consistent with recent studies of Neoarchean basins, carbon isotope ratios of Duck Creek carbonates show no evidence for a strong isotopic depth gradient, but carbonate minerals in iron formations can be markedly depleted in
13C. In contrast, oxygen isotopes covary strongly with depth; δ
18O values as positive as 2‰ VPDB in peritidal facies systematically decline to values of −6 to −16‰ in basinal rocks, reflecting, we posit, the timing of diagenetic closure. The Duck Creek Formation contains microfossils similar to those of the Gunflint Formation, Canada; they are restricted to early diagenetic cherts developed in basinal facies, strengthening the hypothesis that such fossils capture communities driven by iron metabolism. Indeed, X-ray diffraction data indicate that the Duck Creek basin was ferruginous throughout its history. The persistence of ferruginous waters and iron formation deposition in Western Australia for at least several tens of millions of years after the transition to sulfidic conditions in Laurentia suggests that the late Paleoproterozoic expansion of sulfidic subsurface waters was globally asynchronous.
A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. ...The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab.
This open-label, multicentre, randomised phase 3b trial included adults with active, moderate-to-severe Crohn's disease (Crohn's Disease Activity Index CDAI 220-450 and Simple Endoscopic Score in Crohn's Disease SES-CD ≥3) for whom conventional therapy or one biologic therapy, or both, had failed. Patients received intravenous ustekinumab approximating 6 mg/kg at baseline and subcutaneous ustekinumab 90 mg at week 8. At week 16, patients with a CDAI improvement of 70 or more points from baseline were randomly assigned (1:1) to receive standard-of-care or treat-to-target maintenance treatment through week 48. Randomisation was balanced by using randomly permuted blocks and was stratified by biologic history status and baseline SES-CD score. All patients who signed informed consent, who were not screening failures, and who received at least one dose of study treatment were included in week 16 analyses. All patients included in week 16 analyses and randomly assigned to one of the maintenance treatment regimens were included in the week 48 efficacy and safety analyses (ie, on an intention-to-treat basis). Patients assigned to the treat-to-target arm received ustekinumab every 12 weeks or every 8 weeks based on SES-CD improvement from baseline and could escalate to every 4 weeks through week 48 if prespecified targets were missed. Patients assigned to the standard-of-care arm received ustekinumab every 12 weeks or every 8 weeks; those receiving treatment every 12 weeks could escalate per European labelling. The primary efficacy endpoint was endoscopic response at week 48 (SES-CD score ≥50% decrease from baseline), analysed by non-responder imputation. This trial is registered at ClinicalTrials.gov, NCT03107793, and is active but not recruiting.
498 patients received standard induction treatment, of whom 440 were randomly assigned to the treat-to-target group (n=219) or the standard-of-care group (n=221). At week 48, there was no significant difference in endoscopic response (83 38% of 219 patients vs 66 30% of 221 patients; p=0·087), endoscopic remission (25 11% vs 32 15%; p=0·334), mucosal healing (31 14% vs 37 17%; p=0·449), and clinical remission (135 62% vs 154 70%; p=0·072) between the two groups; clinical response was significantly lower in the treat-to-target group than in the standard-of-care group (149 68% vs 172 78%; p=0·020). Other endoscopic, clinical, and biomarker outcomes were generally not significantly different between groups. The most commonly reported treatment-emergent adverse events were nasopharyngitis (29 13% of 219 patients in the treat-to-target group vs 29 13% of 221 patients in the standard-of-care group), abdominal pain (23 11% vs 19 9%), arthralgia (24 11% vs 19 9%), and headache (24 11% vs 21 10%).
Timely escalation of ustekinumab therapy for patients with Crohn's disease, based on early endoscopic response, clinical symptoms, and biomarkers, did not result in significantly better endoscopic outcomes at week 48 than symptom-driven decisions alone. Future studies need to confirm if some subgroups of patient might benefit from a treat-to-target strategy with ustekinumab.
Janssen-Cilag.
► Electrorotation offers a non-invasive tool for dielectric analysis of fish embryos. ► The three-shell dielectric model matches the rotation spectra of medaka eggs. ► The capacitance value suggests ...a double-membrane structure of yolk envelope.
The Japanese medaka fish, Oryzias latipes, has become a powerful vertebrate model organism in developmental biology and genetics. The present study explores the dielectric properties of medaka embryos during pre-hatching development by means of the electrorotation (ROT) technique. Due to their layered structure, medaka eggs exhibited up to three ROT peaks in the kHz–MHz frequency range. During development from blastula to early somite stage, ROT spectra varied only slightly. But as the embryo progressed to the late-somite stage, the ROT peaks underwent significant changes in frequency and amplitude. Using morphological data obtained by light and electron microscopy, we analyzed the ROT spectra with a three-shell dielectric model that accounted for the major embryonic compartments. The analysis yielded a very high value for the ionic conductivity of the egg shell (chorion), which was confirmed by independent osmotic experiments. A relatively low capacitance of the yolk envelope was consistent with its double-membrane structure revealed by transmission electron microscopy. Yolk-free dead eggs exhibited only one co-field ROT peak, shifted markedly to lower frequencies with respect to the corresponding peak of live embryos. The dielectric data may be useful for monitoring the development and changes in fish embryos’ viability/conditions in basic research and industrial aquaculture.
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