Alternative complement pathway inhibition does not abrogate meningococcal killing by serum of vaccinated individuals

Dysregulation of complement activation causes a number of diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. These conditions can be treated with monoclonal antibodies (mAbs) that bind to the complement component C5 and prevent formation of the membrane attack complex (MAC). While MAC is involved in uncontrolled lysis of erythrocytes in these patients, it is also required for serum bactericidal activity (SBA), i.e. clearance of encapsulated bacteria. Therefore, terminal complement blockage in these patients increases the risk of invasive disease by Neisseria meningitidis more than 1000-fold compared to the general population, despite obligatory vaccination. It is assumed that alternative instead of terminal pathway inhibition reduces the risk of meningococcal disease in vaccinated individuals. To address this, we investigated the SBA with alternative pathway inhibitors. Serum was collected from adults before and after vaccination with a meningococcal serogroup A, C, W, Y capsule conjugate vaccine and tested for meningococcal killing in the presence of factor B and D, C3, C5 and MASP-2 inhibitors. B meningococci were not included in this study since the immune response against protein-based vaccines is more complex. Unsurprisingly, inhibition of C5 abrogated killing of meningococci by all sera. In contrast, both factor B and D inhibitors affected meningococcal killing in sera from individuals with low, but not with high bactericidal anti-capsular titers. While the anti-MASP-2 mAb did not impair SBA, inhibition of C3 impeded meningococcal killing in most, but not in all sera. These data provide evidence that vaccination can provide protection against invasive meningococcal disease in patients treated with alternative pathway inhibitors

Inhibition of the different complement pathways has varying impacts on the serum bactericidal activity and opsonophagocytosis against Haemophilus influenzae type b

Defense against Haemophilus influenzae type b (Hib) is dependent on antibodies and complement, which mediate both serum bactericidal activity (SBA) and opsonophagocytosis. Here we evaluated the influence of capsule-specific antibodies and complement inhibitors targeting the central component C3, the alternative pathway (AP; fB, fD), the lectin pathway (LP; MASP-2) and the terminal pathway (C5) on both effector functions. Findings may be relevant for the treatment of certain diseases caused by dysregulation of the complement system, where inhibitors of complement factors C3 or C5 are used. Inhibitors against other complement components are being evaluated as potential alternative treatment options that may carry a reduced risk of infection by encapsulated bacteria. Serum and reconstituted blood of healthy adults were tested for bactericidal activity before and after vaccination with the Hib capsule-conjugate vaccine ActHIB. Most sera had bactericidal activity prior to vaccination, but vaccination significantly enhanced SBA titers. Independently of the vaccination status, both C3 and C5 inhibition abrogated SBA, whereas inhibition of the LP had no effect. AP inhibition had a major inhibitory effect on SBA of pre- vaccination serum, but vaccination mitigated this inhibition for all disease isolates tested. Despite this, SBA-mediated killing of some Hib isolates remained retarded. Even for the most serum-resistant isolate, SBA was the dominating defense mechanism in reconstituted whole blood, as addition of blood cells to the serum did not enhance bacterial killing. Limited Fc receptor-mediated opsonophagocytosis was unmasked when bacterial killing by the membrane attack complex was blocked. In the presence of C3 or C5 inhibitors, addition of post-vaccination, but not of pre-vaccination serum to the blood cells triggered opsonophagocytosis, leading to suppression of bacterial multiplication. Taken together, our data indicate that for host defense against Hib, killing by SBA is more efficient than by blood cell opsonophagocytosis. However, additional defense mechanisms, such as bacterial clearance by spleen and liver, may play an important role in preventing Hib-mediated sepsis, in particular for Hib isolates with increased serum-resistance. Results indicate potentially improved safety profile of AP inhibitors over C3 and C5 inhibitors as alternative therapeutic agents in patients with increased susceptibility to Hib infection

In vaccinated individuals serum bactericidal activity against B meningococci is abrogated by C5 inhibition but not by inhibition of the alternative complement pathway

INTRODUCTION: Several diseases caused by the dysregulation of complement activation can be treated with inhibitors of the complement components C5 and/or C3. However, complement is required for serum bactericidal activity (SBA) against encapsulated Gram-negative bacteria. Therefore, C3 and C5 inhibition increases the risk of invasive disease, in particular by Neisseria meningitidis. As inhibitors against complement components other than C3 and C5 may carry a reduced risk of infection, we compared the effect of inhibitors targeting the terminal pathway (C5), the central complement component C3, the alternative pathway (FB and FD), and the lectin pathway (MASP-2) on SBA against serogroup B meningococci. METHODS: Serum from adults was collected before and after vaccination with the meningococcal serogroup B vaccine 4CMenB and tested for meningococcal killing. Since the B capsular polysaccharide is structurally similar to certain human polysaccharides, 4CMenB was designed to elicit antibodies against meningococcal outer membrane proteins. RESULTS: While only a few pre-vaccination sera showed SBA against the tested B meningococcal isolates, 4CMenB vaccination induced potent complement-activating IgG titers against isolates expressing a matching allele of the bacterial cell surface-exposed factor H-binding protein (fHbp). SBA triggered by these cell surface protein-specific antibodies was blocked by C5 and reduced by C3 inhibition, whereas alternative (factor B and D) and lectin (MASP-2) pathway inhibitors had no effect on the SBA of post-4CMenB vaccination sera. DISCUSSION: Compared to the SBA triggered by A,C,W,Y capsule polysaccharide conjugate vaccination, SBA against B meningococci expressing a matching fHbp allele was remarkably resilient against the alternative pathway inhibition

The Los Alamos Trapped Ion Quantum Computer Experiment

The development and theory of an experiment to investigate quantum computation with trapped calcium ions is described. The ion trap, laser and ion requirements are determined, and the parameters required for quantum logic operations as well as simple quantum factoring are described.Comment: 41 pages, 16 figures, submitted to Fortschritte der Physi

Abundances of metal-weak thick-disc candidates

High resolution spectra of 5 candidate metal-weak thick-disc stars suggested by Beers & Sommer-Larsen (1995) are analyzed to determine their chemical abundances. The low abundance of all the objects has been confirmed with metallicity reaching [Fe/H]=-2.9. However, for three objects, the astrometric data from the Hipparcos catalogue suggests they are true halo members. The remaining two, for which proper-motion data are not available, may have disc-like kinematics. It is therefore clear that it is useful to address properties of putative metal-weak thick-disc stars only if they possess full kinematic data. For CS 22894-19 the abundance pattern similar to those of typical halo stars is found, suggesting that chemical composition is not a useful discriminant between thick-disc and halo stars. CS 29529-12 is found to be C enhanced with [C/Fe]=+1.0; other chemical peculiarities involve the s process elements: [Sr/Fe]=-0.65 and [Ba/Fe]=+0.62, leading to a high [Ba/Sr] considerably larger than what is found in more metal-rich carbon-rich stars, but similar to LP 706-7 and LP 625-44 discussed by Norris et al (1997a). Hipparcos data have been used to calculate the space velocities of 25 candidate metal-weak thick-disc stars, thus allowing us to identify 3 bona fide members, which support the existence of a metal-poor tail of the thick-disc, at variance with a claim to the contrary by Ryan & Lambert (1995).Comment: to be published in MNRA

Patient Priorities in Autoimmune Hepatitis: The Need for Better Treatments, More Education and Challenging Stigma

BACKGROUND: Data show that patients with autoimmune hepatitis have significantly reduced quality-of-life and that corticosteroids carry marked side effects. AIMS: This study explored patients’ experiences of autoimmune hepatitis and its treatments; key aspects for developing safe and effective new approaches to therapy. METHODS: An anonymised, internet-based survey collected data including patient demographics, treatments, side-effects, impact on day-to-day life, sources of support and attitudes towards autoimmune hepatitis between December 2019–January 2020. Semi-structured interviews were conducted with 13 patients to further explore their support networks, treatment experiences and health priorities. Descriptive and quantitative analyses were undertaken using R and free text responses were subject to thematic analysis. RESULTS: In total, 270 survey responses were received (median age 55 years and 94% female). Perceived medication side-effects were reported by 66% (169/257) and 73% responded negatively about their experience of corticosteroids. The majority (62·3% [(109/175]) would ‘definitely’ or ‘probably’ consider clinical trial participation to improve their care. Only 18·7% (31/166) reported access to a specialist liver nurse and nearly half were involved in support groups. Interview and survey data suggested that major issues were stigma, loss of control and fatigue. CONCLUSIONS: This study provides insights into the realities of living with autoimmune hepatitis with clear issues around lack of support networks, need for patient empowerment and stigma surrounding liver disease. Patient priorities are better therapies to slow disease progression, avoiding corticosteroids and minimising side-effects. Patient willingness to participate in trials suggests that they are achievable provided they have the right design and clinical endpoints

Comparison of the ICare® rebound tonometer with the Goldmann tonometer in a normal population

The aim of this study was to evaluate the accuracy of measurement of intraocular pressure (IOP) using a new induction/impact rebound tonometer (ICare) in comparison with the Goldmann applanation tonometer (AT). The left eyes of 46 university students were assessed with the two tonometers, with induction tonometry being performed first. The ICare was handled by an optometrist and the Goldmann tonometer by an ophthalmologist. In this study, statistically significant differences were found when comparing the ICare rebound tonometer with applanation tonometry (AT) (p < 0.05). The mean difference between the two tonometers was 1.34 +/- 2.03 mmHg (mean +/- S.D.) and the 95% limits of agreement were +/-3.98 mmHg. A frequency distribution of the differences demonstrated that in more than 80% of cases the IOP readings differed by <3 mmHg between the ICare and the AT. In the present population the ICare overestimates the IOP value by 1.34 mmHg on average when compared with Goldmann tonometer. Nevertheless, the ICare tonometer may be helpful as a screening tool when Goldmann applanation tonometry is not applicable or not recommended, as it is able to estimate IOP within a range of +/-3.00 mmHg in more than 80% of the populatio

Effect of Finite Mass on Primordial Nucleosynthesis

We have calculated the small effect of finite nucleon mass on the weak-interaction rates that interconvert protons and neutrons in the early Universe. We have modified the standard code for primordial nucleosynthesis to include these corrections and find a small, systematic increase in the 4He yield, $\delta Y / Y \simeq (0.47 - 0.50)$, depending slightly on the baryon-to-photon ratio. The fractional changes in the abundances of the other light elements are a few percent or less for interesting values of the baryon-to-photon ratio.Comment: 15 pages, 8 figures, uses psfig.st

Evidence of egg laying grounds for critically endangered flapper skate (Dipturus intermedius) off Orkney, UK

Funding information: Surveys were supported by a grant from WWF Netherlands. The writing of this paper was funded via the SeaMonitor project; supported by the European Union’s INTERREG VA Programme (Environment Theme) and managed by the Special EU Programmes Body (SEUPB) (Grant IVA5060).Essential fish habitats (EFHs) are critical for fish life-history events, including spawning, breeding, feeding or growth. Here we provide evidence of EFH for the Critically Endangered flapper skate (Dipturus intermedius) in the waters around the Orkney Isles, Scotland based on citizen-science observation data. The habitats of potential egg laying sites were parametrised as >20m depth, with boulders or exposed bedrock, in moderate current flow (0.3 - 2.8 knots) with low sedimentation. This information provides a significant contribution to our understanding of EFH for flapper skate. Publisher PDFPeer reviewe

National survey of feasibility of NIV trials for management of children with bronchiolitis.

Background: Bronchiolitis is a major cause of admission to hospital in children. Non-invasive ventilation (NIV) support with continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) oxygen is routinely used for infants in the UK with bronchiolitis. Objective: To establish UK paediatric practice regarding management of bronchiolitis, and to explore issues pertinent to the design of a potential future randomised controlled trial of NIV. Design: Screening logs were completed in hospitals in England capturing information on paediatric bronchiolitis admissions. An online national survey of clinical practice was disseminated to healthcare professionals (HCPs) across the UK to ascertain current management strategies. Results: Screening logs captured data on 393 infants from 8 hospitals. Reasons for admission were most commonly respiratory distress and/or poor fluid intake. Oxygen was administered for 54% of admissions. Respiratory (CPAP and HFNC) and non-respiratory support administered varied considerably. The national survey was completed by 111 HCPs from 76 hospitals. Data were obtained on criteria used to commence and wean NIV, responsibilities for altering NIV settings, minimum training requirements for staff managing a child on NIV, and numbers of trained staff. Most centres were interested in and capable of running a trial of NIV, even out of normal office hours. Conclusions: Respiratory and non-respiratory management of bronchiolitis in UK centres varies widely. A trial of HFNC oxygen therapy in this group of patients is feasible and HCPs would be willing to randomise patients into such a trial. Future work should focus on defining trial eligibility criteria