Amino acid based gallium-68 chelators capable of radiolabeling at neutral pH

Gallium-68 ( 68 Ga) has been the subject of increasing interest for its potential in the production of radiotracers for diagnosis of diseases. In this work we report the complexation of 68 Ga by the amino acid based tripodal chelate H 3 Dpaa, and two bifunctional derivatives, H 3 Dpaa.dab and H 4 Dpaa.ga, under a range of conditions with particular emphasis on the rapid complexation of 68 Ga at pH 7.4. 100 μM H 3 Dpaa achieved a radiochemical yield of 95% at pH 7.4 in 5 minutes at 37 °C. The bifunctional derivatives H 4 Dpaa.ga and H 3 Dpaa.dab achieved 94% and 84% radiochemical yields, respectively, under the same conditions. The resulting Ga(iii) complexes show thermodynamic stabilities of logK GaDpaa = 18.53, logK GaDpaa.dab = 22.08, logK GaDpaa.ga = 18.36. Unfortunately, the resulting radiolabelled species do not present sufficient serum stability for in vivo application. Herein we show a flexible synthesis for bifunctional chelators based on amino acids that rapidly complex 68 Ga under physiological conditions

Density, porosity, mineralogy, and internal structure of cosmic dust and alteration of its properties during high velocity atmospheric entry

X-ray microtomography (XMT), X-ray diffraction (XRD) and magnetic hysteresis measurements were used to determine micrometeorite internal structure, mineralogy, crystallography, and physical properties at ~μm resolution. The study samples include unmelted, partially melted (scoriaceous) and completely melted (cosmic spherules) micrometeorites. This variety not only allows comparison of the mineralogy and porosity of these three micrometeorite types, but also reveals changes in meteoroid properties during atmospheric entry at various velocities. At low entry velocities, meteoroids do not melt, and their physical properties do not change. The porosity of unmelted micrometeorites varies considerably (0-12%) with one friable example having porosity around 50%. At higher velocities, the range of meteoroid porosity narrows, but average porosity increases (to 16-27%) due to volatile evaporation and partial melting (scoriaceous phase). Metal distribution seems to be mostly unaffected at this stage. At even higher entry velocities, complete melting follows the scoriaceous phase. Complete melting is accompanied by metal oxidation and redistribution, loss of porosity (1 ± 1%), and narrowing of the bulk (3.2 ± 0.5 g/cm3) and grain (3.3 ± 0.5 g/cm3) density range. Melted cosmic spherules with a barred olivine structure show an oriented crystallographic structure, whereas other subtypes do not.Peer reviewe

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Two Reliable Methodical Approaches for Non-Invasive RHD Genotyping of a Fetus from Maternal Plasma

Noninvasive fetal RHD genotyping is an important tool for predicting RhD incompatibility between a pregnant woman and a fetus. This study aimed to assess a methodological approach other than the commonly used one for noninvasive fetal RHD genotyping on a representative set of RhD-negative pregnant women. The methodology must be accurate, reliable, and broadly available for implementation into routine clinical practice. A total of 337 RhD-negative pregnant women from the Czech Republic region were tested in this study. The fetal RHD genotype was assessed using two methods: real-time PCR and endpoint quantitative fluorescent (QF) PCR. We used exon-7-specific primers from the RHD gene, along with internal controls. Plasma samples were analyzed and measured in four/two parallel reactions to determine the accuracy of the RHD genotyping. The RHD genotype was verified using DNA analysis from a newborn buccal swab. Both methods showed an excellent ability to predict the RHD genotype. Real-time PCR achieved its greatest accuracy of 98.6% (97.1% sensitivity and 100% specificity (95% CI)) if all four PCRs were positive/negative. The QF PCR method also achieved its greatest accuracy of 99.4% (100% sensitivity and 98.6% specificity (95% CI)) if all the measurements were positive/negative. Both real-time PCR and QF PCR were reliable methods for precisely assessing the fetal RHD allele from the plasma of RhD-negative pregnant women

Vpliv informacij s spletnih družbenih omrežij na zaposlovanje v Češki republiki

Background: This paper is focused on the usage of social networking sites (SNS) for human resources departments in the process of hiring new employees. It also maps the development and influence of SNS on recruiter’s behavior and customs. The main aim is to find out, whether SNS could/will replace traditional online job boards in the Czech Republic. The motivation for the research is to determine whether SNS can be used for serious and practical business purposes. Methods: The paper presents authors’ empirical research with two interconnected instruments used for data col­lection: (1) Questionnaire with 15 questions devoted to usability, evaluation and comparison of SNS with job portals (N=286 HR specialists) and (2) Comparison of 3 online job advertising methods – job portals, SNS and business website. Results: HR specialists regularly use publicly available information on candidates’ Facebook profiles. Similar results have been observed using both instruments. SNS’s in the Czech Republic are not yet used by recruiters as the main tool for recruitment, however, are often used as a support tool for decision making in the final stage of recruitment. Use of SNS’s by recruiters is universal; we have not found any significant differences in terms of demographics (men, women, old, young HR professionals). The rate of utilization of SNS’s by recruiters in the Czech Republic is gradually increasing, but does not reach the US level. Conclusion: Our findings confirm the rising importance of social networking sites (SNS) usage as a new recruiting technology. However, as a major player in the field of recruitment, job boards (eg. Jobs.cz) are still important. However, the expectation is that in the near future, this will change and SNS‘s may replace the job boards.Ozadje: Članek obravnava proces zaposlovanja v kadrovskih oddelkih z uporabo spletnih družbenih omrežij. Ravno tako izpostavlja razvoj in vpliv spletnih družbenih omrežij na vedenje in navade kandidatov za zaposlitev. Glavni cilj je bil ugotoviti, ali spletna družbena omrežja lahko nadomestijo tradicionalne spletne portale na Češkem. Vodilo raziskave je bilo ugotoviti, ali spletna družbena omrežja lahko uporabljamo za resne in praktične poslovne namene. Metode: V članku je predstavljena empirična raziskava, kjer smo uporabili dva med seboj povezana instrumenta za zbiranje podatkov: (1) vprašalnik s 15 vprašanji v zvezi z uporabnostjo, koristnostjo in primerjavo družabnih omrežij s zaposlitvenimi portali (N = 286 kadrovskih strokovnjakov) in (2) primerjava treh spletnih metod oglaševanja: zaposlitvenih portalov, družab­nih omrežij in poslovnih spletnih strani. Rezultati: Kadrovski strokovnjaki redno uporabljajo javno dostopne informacije kandidatov, ki jih najdejo n.pr. na Facebook profilih. Podobne rezultate smo dobili z uporabo obeh instrumentov. Družbena omrežja na Češkem še niso glavno orodje pri izbiri kandidatov za zaposlitev, se pa pogosto uporabljajo kot pomoč pri odločitvah o zaposlitvi kandidatov, predvsem v končni fazi postopka zaposlovanja. Uporaba družbenih omrežij pri kadrovanju je splošna; nismo ugotovili pomembnih razlik v smislu demografije (moški, ženske, starejši, mladi strokovnjaki). Kadroviki v Češki republiki vse več uporabljajo družbena omrežja, vendar uporaba ne dosega ravni Združenih držav Amerike. Zaključek: Naše ugotovitve potrjujejo, da narašča pomen socialnih omrežij kot ene novih tehnologij pri zaposlovanju. Vendar glavni akterji na področju zaposlovanja, zaposlitveni portali (n.pr. Jobs.cz) še vedno ostajajo pomembni. Pričakovati pa je, da se v bodoče to lahko spremeni, da bodo družbena omrežja nadomestila zaposlitvene portale