Synthesis and biodistribution of immunoconjugates of a human IgM and polymeric drug carriers

The synthesis and purification of radiolabelled immunoconjugates, composed of a human IgM monoclonal antibody directed against an intracellular tumour-associated antigen and either poly (alpha-L-glutamic acid) (PGA) or poly[N5-(2-hydroxyethyl)-L-glutamine] (PHEG) is described. Coupling of polymers to the antibody was performed through disulfide bond formation involving a single thiol group at the C-terminus of the polymer chain and 2-pyridyldisulfide groups introduced onto the antibody. The antibody was iodinated with 131I before conjugation. The polymers contained tyrosinamide in a low degree of substitution and were radiolabelled with 125I. 125I-labelled PGA and PHEG were found to be stable for at least 3 days in murine and human plasma. The biodistribution in mice of the doubly labelled immunoconjugates was studied and was compared with the pharmacokinetics of the individual components.\ud \ud PHEG showed a relatively slow blood clearance, the half-life being approximately 10 h with low uptake in liver, kidneys and spleen. PGA was rapidly cleared from the circulation and was significantly taken up in liver, kidneys and spleen. The biodistribution of both immunoconjugates was indistinguishable from that of the IgM proper, with plasma half-lives of approximately 6 h, indicating that the pharmacokinetic properties of the immunoconjugates are largely determined by the antibody part

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

Accessing HE for non-traditional students: 'Outside of my position'

Widening participation within higher education and increasing social mobility have been high on the agendas of former and current governments. This paper examines the admissions procedure of a Foundation degree in Early Years programme using Bourdieu's concept of capital as a vehicle for analysis. During the process of an admissions interview, the interviewer is required to make decisions regarding a student's suitability to fit into the existing field of the programme as they often feel it is outside of their position. The stories of three non-traditional students are explored to highlight existing capital and dispositions that they bring to the programme. Research findings showed that there are many variables that impact on a student's ability to gain entry and be successful on an HE programme, including accumulation of capital, emotional drivers and potential to acquire capital throughout the programme. © 2014 Further Education Research Association

Seroprevalence and infection fatality rate of the SARS-CoV-2 Omicron variant in Denmark:A nationwide serosurveillance study

BACKGROUND: Introduction of the Omicron variant caused a steep rise in SARS-CoV-2 infections despite high vaccination coverage in the Danish population. We used blood donor serosurveillance to estimate the percentage of recently infected residents in the similarly aged background population with no known comorbidity. METHODS: To detect SARS-CoV-2 antibodies induced due to recent infection, and not vaccination, we assessed anti-nucleocapsid (anti-N) immunoglobulin G (IgG) in blood donor samples. Individual level data on SARS-CoV-2 RT-PCR results and vaccination status were available. Anti-N IgG was measured fortnightly from January 18 to April 3, 2022. Samples from November 2021 were analysed to assess seroprevalence before introduction of the Omicron variant in Denmark. FINDINGS: A total of 43 088 donations from 35 309 Danish blood donors aged 17–72 years were screened. In November 2021, 1·2% (103/8 701) of donors had detectable anti-N IgG antibodies. Adjusting for test sensitivity (estimates ranging from 74%–81%) and November seroprevalence, we estimate that 66% (95% confidence intervals (CI): 63%–70%) of the healthy, similarly aged Danish population had been infected between November 1, 2021, and March 15, 2022. One third of infections were not captured by SARS-CoV-2 RT-PCR testing. The infection fatality rate (IFR) was 6·2 (CI: 5·1–7·5) per 100 000 infections. INTERPRETATION: Screening for anti-N IgG and linkage to national registers allowed us to detect recent infections and accurately assess assay sensitivity in vaccinated or previously infected individuals during the Omicron outbreak. The IFR was lower than during previous waves. FUNDING: The Danish Ministry of Health

Social and occupational factors associated with psychological distress and disorder among disaster responders: a systematic review

BACKGROUND: When disasters occur, there are many different occupational groups involved in rescue, recovery and support efforts. This study aimed to conduct a systematic literature review to identify social and occupational factors affecting the psychological impact of disasters on responders. METHODS: Four electronic literature databases (MEDLINE®, Embase, PsycINFO® and Web of Science) were searched and hand searches of reference lists were carried out. Papers were screened against specific inclusion criteria (e.g. published in peer-reviewed journal in English; included a quantitative measure of wellbeing; participants were disaster responders). Data was extracted from relevant papers and thematic analysis was used to develop a list of key factors affecting the wellbeing of disaster responders. RESULTS: Eighteen thousand five papers were found and 111 included in the review. The psychological impact of disasters on responders appeared associated with pre-disaster factors (occupational factors; specialised training and preparedness; life events and health), during-disaster factors (exposure; duration on site and arrival time; emotional involvement; peri-traumatic distress/dissociation; role-related stressors; perceptions of safety, threat and risk; harm to self or close others; social support; professional support) and post-disaster factors (professional support; impact on life; life events; media; coping strategies). CONCLUSIONS: There are steps that can be taken at all stages of a disaster (before, during and after) which may minimise risks to responders and enhance resilience. Preparedness (for the demands of the role and the potential psychological impact) and support (particularly from the organisation) are essential. The findings of this review could potentially be used to develop training workshops for professionals involved in disaster response. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40359-016-0120-9) contains supplementary material, which is available to authorized users

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Optisch-spektroskopische Bestimmung der Permeabilität von Ultrabarrierematerialien

Die Qualität und Haltbarkeit von Produkten (z.B. Lebensmittel, Pharmaerzeugnisse) werden im entscheidenden Maße von der Durchlässigkeit des Verpackungsmaterials gegenüber der umgebenden Atmosphäre bestimmt. Dabei spielt der Ausschluss von Feuchte und Sauerstoff aufgrund der Permeabilitätseigenschaften des Verpackungsmaterials die dominierende Rolle. Im Gegensatz zu den Permeationseigenschaften von herkömmlichen Verpackungsmaterialien stellen die transparenten und flexiblen Verkapselungen von organischen Halbleiterstrukturen, wie beispielsweise für LCD- und OLED- Displays, eine wesentlich größere Herausforderung dar. Für einen stabilen Langzeitbetrieb werden Wasserdampfdurchlässigkeiten von bis zu 10-6 g/(m2 d) gefordert, wobei für LCD-Systemen diese um mindestens zwei Größenordungen und bei OLEDs diese um mindestens 5 Größenordnungen unter denen von Standardverpackungen liegen. Zur Entwicklung, Optimierung und Qualitätskontrolle der entsprechenden Barriereschichtsysteme bzw. deren Herstellungsprozesse ist ein hochempfindliches Messsystem zur Bestimmung niedrigster Permeationsraten erforderlich, welches zudem eine möglichst einfache, schnelle und kostengünstige Messung der Permeationsrate ermöglicht. Ein auf Basis der Laserdiodenspektroskopie entwickeltes Permeationsmesssystem ermöglicht eine signifikante Verbesserung der Nachweisempfindlichkeit um bis zu zwei Größenordnungen im Vergleich zu derzeit kommerziell verfügbaren Messsystemen. Im Mittelpunkt der Entwicklungsarbeiten standen dabei Fragen zur Konditionierung des Messsystems, zum Erreichen stabiler Gleichgewichtszustände bei statischem und dynamischem Betrieb, bzw. zu den daraus abgeleiteten Messbedingungen und Auswertalgorithmen. Des Weiteren wird das Messsystem hinsichtlich Zuverlässigkeit der Messergebnisse und der Reproduzierbarkeit der für Ultrabarriereschichten kritischen Folieneinspannung diskutiert