Western Eurasia witnessed several large-scale human migrations during the Holocene
. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly ...from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death.
We linked data from two Danish type 2 diabetes cohorts, ...the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) and the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), to national health care registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios (IRRs) of CVD and all-cause mortality comparing MNSIq scores ≥4 with scores <4. Analyses were adjusted for a range of established CVD risk factors.
In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores <4, MNSIq scores ≥4 were associated with higher incidence rate of CVD, with IRRs of 1.79 (95% CI 1.38-2.31) in ADDITION-Denmark, 1.57 (CI 1.27-1.94) in the DD2, and a combined IRR of 1.65 (CI 1.41-1.95) in a fixed-effect meta-analysis. MNSIq scores ≥4 did not associate with mortality; combined mortality rate ratio was 1.11 (CI 0.83-1.48).
The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes with a high incidence rate of subsequent CVD. MNSIq scores ≥4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors.
Objective
Molecular monitoring of treatment response in patients with chronic myelogenous leukemia is performed using the Europe Against Cancer (EAC) qPCR assay using the International Scale (IS). ...The assay amplifies both e13a2 and e14a2 BCR‐ABL1 transcript variants. Observing distinct variant‐dependent amplification curves during qPCR, we aimed to determine if this affected quantitation of BCR‐ABL1.
Methods
We investigated the qPCR efficiency at three Danish diagnostic centers (Zealand University Hospital ZUH, Aarhus University Hospital AU, and Rigshospitalet RH) on cell lines expressing either the e13a2 or e14a2 BCR‐ABL1 transcript variants and compared %IS values from 219 chronic myeloid leukemia patients from the centers with either the e13a2 (n = 113) or e14a2 (n = 106) transcript variants obtained by qPCR with absolute quantitation by droplet digital PCR (ddPCR).
Results
Although no significant differences were found in amplification efficiencies of the transcript variants, Bland‐Altman analysis of qPCR vs ddPCR values for patient samples revealed a significant average difference in the bias between variants (e3a2/e14a2) of 4.6‐, 6.5‐, and 1.8‐fold for ZUH, AU, and RH, respectively. Furthermore, qPCR %IS values of diagnostic patient samples revealed a significant 4.7‐fold difference between the e13a2 and e14a2 variants.
Conclusion
Our findings suggest that the EAC qPCR assay may underestimate the e14a2 variant compared to the e13a2 variant.
This paper is considering the application of a novel pump controlled cylinder drive, the so-called Speed-variable Switched Differential Pump (SvSDP), for knuckle boom crane actuation. Especially the ...control system for the SvSDP drive is considered, and aiming on improving energy efficiency a refinement of the existing control structure is proposed. An energy efficient sizing algorithm for the SvSDP drive is developed, and fundamental differences between the achievable operating range for the SvSDP drive compared to a conventional valve-cylinder drive are discussed. A case study is conducted with knuckle boom crane actuation, and compared to a conventional valve actuation. Simulation results show that the motion tracking performance is on a similar level compared to the valve actuation approach, while the energy consumption is drastically decreased. For the given test trajectory the valve actuation system consumes 0.79 kWh of electrical energy, while the SvSDP drive consume 0.06 kWh, if ideal energy recovery and storage is assumed.
Outcome data of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) beyond the second line are scarce outside of clinical trials. Novel therapies in the R/R setting have ...been approved based on single-arm trials, but results need to be contextualized by real-world outcomes. Medical records from 3753 Danish adults diagnosed with DLBCL were reviewed. Patients previously treated with rituximab and anthracycline-based chemotherapy who received the third or later line (3 L+) of treatment after 1 January 2015, were included. Only 189 patients with a median age of 71 years were eligible. The median time since the last line of therapy was 6 months. Patients were treated with either best supportive care (22%), platinum-based salvage therapy (13%), low-intensity chemotherapy (22%), in clinical trial (14%) or various combination treatments (32%). The 2-year OS-/PFS estimates were 25% and 12% for all patients and 49% and 17% for those treated with platinum-based salvage therapy. Age ≥70, CNS involvement, elevated LDH and ECOG ≥2 predicted poor outcomes, and patients with 0-1 of these risk factors had a 2-year OS estimate of 65%. Only a very small fraction of DLBCL patients received third-line treatment and were eligible for inclusion. Outcomes were generally poor, but better in intensively treated, fit young patients with limited disease.
Background
Drivers of differences in disease presentation and symptom duration in Lyme neuroborreliosis (LNB) are currently unknown.
Objectives
We hypothesized that neurofilament light (NfL) in ...cerebrospinal fluid (CSF) would predict disease location and sequelae in a historic LNB cohort.
Design
Using a cross-sectional design and archived CSF samples from 185 patients diagnosed with LNB, we evaluated the content of NfL in the total cohort and in a subgroup of 84 patients with available clinical and paraclinical information.
Methods
Individuals were categorized according to disease location: a. Central nervous system (CNS) with stroke (N=3), b. CNS without stroke (N=11), c. Peripheral nervous system (PNS) with cranial nerve palsy (CNP) (N=40) d. PNS without CNP (N=30). Patients with hospital follow-up more than 6 months after completed antibiotic therapy were categorized as having LNB associated sequelae (N=15).
Results
At diagnosis concentration of NfL exceeded the upper reference level in 60% (105/185), especially among individuals above 30 years. Age-adjusted NfL was not found to be associated with symptom duration. Age-adjusted NfL was significantly higher among individuals with CNS involvement. Category a. (stroke) had significantly higher NfL concentrations in CSF compared to all other categories, category b. (CNS involvement without stroke) had significantly higher values compared to the categories of PNS involvement. We found no significant difference between the categories with PNS involvement (with or without CNP). Significantly higher NfL was found among patients with follow-up in hospital setting.
Conclusion
Comparison of NfL concentrations between the 4 groups of LNB disease manifestations based on clinical information revealed a hierarchy of neuron damage according to disease location and suggested evolving mechanisms with accelerated injury especially when disease is complicated by stroke. Higher values of NfL among patients with need of follow-up in hospital setting suggest NfL could be useful to identify rehabilitative needs.
Objective
Given a proposed role for PD‐L1+ and IL‐10‐producing B‐cell subsets in promoting certain cancers, we sought to characterize the frequency and phenotype of B cells in patients with chronic ...myeloproliferative neoplasms (MPNs) and the influence of ruxolitinib and interferon‐α2 therapy.
Methods
We analyzed B‐cell frequencies and phenotype in patients with MPNs (n = 107), before and during treatment with ruxolitinib (n = 29), interferon‐α2 (n = 21), or the two drugs in combination (COMBI; n = 42) and healthy donors (HDs; n = 52) using flow cytometry.
Results
Myelofibrosis patients had lower lymphocyte counts and proportions of B cells than patients with essential thrombocythemia or polycythemia vera and HDs. The B‐cell count correlated inversely with JAK2‐V617F allele burden and spleen size and increased after ruxolitinib or COMBI treatment. The proportions of PD‐L1+ B cells and PD‐1+ B cells were significantly higher in patients with myelofibrosis or polycythemia vera than in HDs and decreased during ruxolitinib and COMBI treatment. The proportions of TNF‐α+ and IL‐6+ B cells were elevated in myelofibrosis patients. The proportion of IL‐6+ B cells decreased, and the proportion of IL‐10+ B cells increased during ruxolitinib treatment.
Conclusion
B‐cell frequency and phenotype were altered in MPN patients. Ruxolitinib therapy had marked effects on both frequency and phenotype.
In early 2021, the SARS-CoV-2 lineage B.1.1.7 (Alpha variant) became dominant across large parts of the world. In Denmark, comprehensive and real-time test, contact-tracing, and sequencing efforts ...were applied to sustain epidemic control. Here, we use these data to investigate the transmissibility, introduction, and onward transmission of B.1.1.7 in Denmark.
We analyzed a comprehensive set of 60,178 SARS-CoV-2 genomes generated from high-throughput sequencing by the Danish COVID-19 Genome Consortium, representing 34% of all positive cases in the period 14 November 2020 to 7 February 2021. We calculated the transmissibility of B.1.1.7 relative to other lineages using Poisson regression. Including all 1976 high-quality B.1.1.7 genomes collected in the study period, we constructed a time-scaled phylogeny, which was coupled with detailed travel history and register data to outline the introduction and onward transmission of B.1.1.7 in Denmark.
In a period with unchanged restrictions, we estimated an increased B.1.1.7 transmissibility of 58% (95% CI: 56%, 60%) relative to other lineages. Epidemiological and phylogenetic analyses revealed that 37% of B.1.1.7 cases were related to the initial introduction in November 2020. The relative number of cases directly linked to introductions varied between 10 and 50% throughout the study period.
Our findings corroborate early estimates of increased transmissibility of B.1.1.7. Both substantial early expansion when B.1.1.7 was still unmonitored and continuous foreign introductions contributed considerably to case numbers. Finally, our study highlights the benefit of balanced travel restrictions and self-isolation procedures coupled with comprehensive surveillance efforts, to sustain epidemic control in the face of emerging variants.
Importation and transmission of measles via air travel is a public health concern to countries, which are close to or have achieved elimination, i.e., to the majority of countries in Europe. In 2018, ...two measles cases occurred in Berlin residents, who flew within Europe while being infectious. In addition to contact tracing through passenger manifests, we contacted national authorities in flight destination countries or embarking countries and inquired about epidemiologically linked measles cases to the two Berlin index cases. We identified eight epidemiologically linked cases (six males, median age: 32 years) from three countries associated with three air-travels. Consequently measles was imported to Germany (Bavaria), Denmark and possibly Sweden. Our investigations revealed impediments to an effective public health response indicating the need to revisit current guidelines and methods to better control transmission of measles related to air travel.
An active molecular plasmonics system is demonstrated where a supramolecular chromophore generated in a host−guest binding event couples with the localized surface plasmon resonance (LSPR) arising ...from gold nanodisc gratings. This coupling was achieved by wavelength-matching the chromophore and the LSPR with the laser excitation, thus giving rise to surface-enhanced resonance Raman scattering (SERRS). The chromophore is a broad charge-transfer (CT) band centered at 865 nm (ε = 3500 M−1 cm−1) generated by the complexation of cyclobis(paraquat-p-phenylene) (CBPQT4+) and the guest molecule tetrathiafulvalene (TTF). The substrates consist of sub-1-μm gold nanodisc arrays which display dimension-tunable plasmon wavelengths (600−1000 nm). The vibrational spectra of the complex arising from SERRS (λexc = 785 nm) were generated by irradiating an array (λLSPR = 765 nm) through the solution to give a chromophore-specific signature with the intensities surface enhanced by ∼105. Surface adsorption of the empty and complexed CBPQT4+ is also implicated in bringing the chromophore into the electric field arising from the surface-localized plasmon. In a titration experiment, the SERRS effect was then used to verify the role of resonance in turning on the spectrum and to accurately quantify the binding between surface-adsorbed CBPQT4+ and TTF. The use of a nonpatterned gold substrate as well as a color mismatched complex did not show the enhancement, thus validating that spectral overlap between the chromophore and plasmon resonance is key for resonance surface enhancement. Simulations of the electric fields of the arrays are consistent with interdisc plasmon coupling and the observed enhancement factors. The creation of a responsive plasmonic device upon the addition of the guest molecule and the subsequent coupling of the CT chromophore to the plasmon presents favorable opportunities for applications in molecular sensing and active molecular plasmonics.
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