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Background Invasive disease caused by airway pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Moraxella catarrhalis, has high morbidity and mortality worldwide, with immunodeficiency being a known association with recurrent disease. The study aimed to describe the frequency of known immunodeficiency and predisposing factors in adult patients presenting with invasive infections and determine the frequency of screening for and detection of immunodeficiency. Methods A retrospective analysis was conducted at a large tertiary Australian health service, comprising multiple centers. Patients aged 18 years or older, in whom the above pathogens were isolated from sterile sites, were included as identified through a microbiology database, between 2015 and 2020. Using electronic medical records, patient demographics, medical history, outcomes of admission, and pathology results were captured and reviewed to address the aims. Results In 252 patients, S pneumoniae was the most common culprit, isolated in 73% (185/252), compared to 14.3% (36/252) and 11.5% (29/252) of infections caused by H influenzae and N meningitidis, respectively. Known diagnoses of secondary immunodeficiency were common (31% of patients). Of those presenting with invasive pneumococcal disease, 78% had at least 1 predisposing condition, though only 9 patients (6%) had previously received pneumococcal vaccination. Despite poor screening for immunodeficiency, 12 new diagnoses were made. While the commonest immunodeficiency was secondary, due to hematological and solid organ malignancies, 3 new primary immunodeficiency diagnoses were made. Conclusions Immunodeficiency is common in this patient population. Screening should be undertaken to ensure timely diagnosis and treatment of the underlying condition to avoid future morbidity and mortality.

Highlights • Systematic review and meta-analysis of 18 studies and more than 6000 participants. • Adults over the age of 60 had a pooled prevalence of pneumococcal carriage of 9%. • Risk factors: contact with children, smoking and residing in a nursing home., Summary Background Colonisation with Streptococcus pneumoniae can lead to invasive pneumococcal disease and pneumonia. Pneumococcal acquisition and prevalence of colonisation are high in children. In older adults, a population susceptible to pneumococcal disease, colonisation prevalence is reported to be lower, but studies are heterogeneous. Methods This is a systematic review and meta-analysis of prevalence of, and risk factors for, pneumococcal colonisation in adults ≥ 60 years of age (PROSPERO #42016036891). We identified peer-reviewed studies reporting the prevalence of S. pneumoniae colonisation using MEDLINE and EMBASE (until April 2016), excluding studies of acute disease. Participant-level data on risk factors were sought from each study. Findings Of 2202 studies screened, 29 were analysable: 18 provided participant-level data (representing 6290 participants). Prevalence of detected pneumococcal colonisation was 0–39% by conventional culture methods and 3–23% by molecular methods. In a multivariate analysis, colonisation was higher in persons from nursing facilities compared with the community (odds ratio (OR) 2•30, 95% CI 1•26–4•21 and OR 7•72, 95% CI 1•15–51•85, respectively), in those who were currently smoking (OR 1•69, 95% CI 1•12–2•53) or those who had regular contact with children (OR 1•93, 95%CI 1•27–2•93). Persons living in urban areas had significantly lower carriage prevalence (OR 0•43, 95%CI 0•27–0•70). Interpretation Overall prevalence of pneumococcal colonisation in older adults was higher than expected but varied by risk factors. Future studies should further explore risk factors for colonisation, to highlight targets for focussed intervention such as pneumococcal vaccination of high-risk groups. Funding No funding was required.

The transcription factor NF-ĸB is a master regulator of the innate immune response and plays a central role in inflammatory diseases by mediating the expression of pro-inflammatory cytokines. Ubiquitination-triggered proteasomal degradation of DNA-bound NF-ĸB strongly limits the expression of its target genes. Conversely, the deubiquitinase ubiquitin-specific peptidase 7 (USP7) opposes the activities of E3 ligases, stabilizes DNA-bound NF-ĸB, and thereby promotes NF-ĸB–mediated transcription. Using gene expression and synthetic peptide arrays on membrane support (SPOT) synthesis of peptides and overlay analyses, we found here that inhibiting USP7 increases NF-ĸB ubiquitination and degradation, prevents Toll-like receptor–induced pro-inflammatory cytokine expression, and represents an effective strategy for controlling inflammation. However, the broad regulatory roles of USP7 in cell death pathways, chromatin, and DNA damage responses limits the use of catalytic inhibitors of USP7 as anti-inflammatory agents. To this end, we identified an NF-ĸB–binding site in USP7, ubiquitin-like domain 2, that selectively mediates interactions of USP7 with NF-ĸB subunits, but is dispensable for interactions with other proteins. Moreover, we found that the amino acids 757LDEL760 in USP7 critically contribute to the interaction with the p65 subunit of NF-ĸB. Our findings support the notion that USP7 activity could be potentially targeted in a substrate-selective manner through the development of non-catalytic inhibitors of this deubiquitinase to abrogate NF-ĸB activity.

The aims of this study were to assess cognitions relating to hypoglycaemia in adults with type 1 diabetes and impaired awareness of hypoglycaemia before and after the multimodal HypoCOMPaSS intervention, and to determine cognitive predictors of incomplete response (one or more severe hypoglycaemic episodes over 24 months).This analysis included 91 adults with type 1 diabetes and impaired awareness of hypoglycaemia who completed the Attitudes to Awareness of Hypoglycaemia (A2A) questionnaire before, 24 weeks and 24 months after the intervention, which comprised a short psycho-educational programme with optimisation of insulin therapy and glucose monitoring.The age and diabetes duration of the participants were 48±12 and 29±12 years, respectively (mean±SD). At baseline, 91% reported one or more severe hypoglycaemic episodes over the preceding 12 months; this decreased to20% at 24 weeks and after 24 months (p=0.001). The attitudinal barrier 'hyperglycaemia avoidance prioritised' (ηParticipation in the HypoCOMPaSS RCT was associated with improvements in hypoglycaemia-associated cognitions, with 'hyperglycaemia avoidance prioritised' most prevalent. Incomplete prevention of subsequent severe hypoglycaemia episodes was associated with persistence of the cognition 'asymptomatic hypoglycaemia normalised'. Understanding and addressing cognitive barriers to hypoglycaemia avoidance is important in individuals prone to severe hypoglycaemia episodes.www.isrctn.org : ISRCTN52164803 and https://eudract.ema.europa.eu : EudraCT2009-015396-27.

A case of rifampin-induced acute tubular necrosis requiring hemodialysis in a patient receiving thrice-weekly rifampin with daily dapsone for retreatment of relapsed Hansen’s disease is reported. The patient had positive rifampin-dependent antiplatelet antibodies. Case reports of acute renal failure associated with the use of rifampin are summarized.

This technical note series under the Autonomous Transport Innovation research program is intended to be a primer on autonomous vehicles (AVs), their testing, and associated infrastructure. A review of the regulatory environment for autonomous vehicles is necessary to define rules imposed on technology or operations of autonomous vehicles in various capacities. Acknowledging such regulation will aid in productive closed-course site development by structuring the course based on what autonomous vehicle developers and manufacturers must program their vehicles to adhere to in a given setting.

Aims/hypothesis The molecular basis for the pathological impact of specific HLA molecules on autoimmune diseases such as type 1 diabetes remains unclear. Recent natural history studies in children have indicated a link between specific HLA genotypes and the first antigenic target against which immune responses develop. We set out to examine this link in vivo by exploring the diabetogenicity of islet antigens on the background of a common diabetes-associated HLA haplotype. Methods We generated a novel HLA-transgenic mouse model that expresses high-risk genes for type 1 diabetes (DRB1*03:01-DQA1*05:01-DQB1*02:01) as well as human CD80 under the rat insulin promoter and human CD4, on a C57BL/6 background. Adjuvanted antigen priming was used to reveal the diabetogenicity of candidate antigens and peptides. Results HLA-DR3-DQ2+huCD4+IA/IE−/−RIP.B7.1+ mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4+, CD8+ B220+, CD11b+ and CD11c+ immune cells). Disease was markedly accelerated and had deeper penetrance after adjuvanted antigen priming with proinsulin (mean onset 11 weeks and incidence 100% by 20 weeks post challenge). Moreover, the diabetogenic effect of proinsulin located to the 15-residue B29-C11 region. Conclusions/interpretation Our study identifies a proinsulin-derived peptide region that is highly diabetogenic on the HLA-DR3-DQ2 background using an in vivo model. This approach and the peptide region identified may have wider implications for future studies of human type 1 diabetes.

Phosphorylation of the NF-κB transcription factor is an important regulatory mechanism for the control of transcription. Here we identify serine 80 (S80) as a phosphorylation site on the p50 subunit of NF-κB, and IKKβ as a p50 kinase. Transcriptomic analysis of cells expressing a p50 S80A mutant reveals a critical role for S80 in selectively regulating the TNFα inducible expression of a subset of NF-κB target genes including pro-inflammatory cytokines and chemokines. S80 phosphorylation regulates the binding of p50 to NF-κB binding (κB) sites in a sequence specific manner. Specifically, phosphorylation of S80 reduces the binding of p50 at κB sites with an adenine at the −1 position. Our analyses demonstrate that p50 S80 phosphorylation predominantly regulates transcription through the p50:p65 heterodimer, where S80 phosphorylation acts in trans to limit the NF-κB mediated transcription of pro-inflammatory genes. The regulation of a functional class of pro-inflammatory genes by the interaction of S80 phosphorylated p50 with a specific κB sequence describes a novel mechanism for the control of cytokine-induced transcriptional responses.

Members of the Delphinidae family are widely distributed across the world's oceans. We used a viral metagenomic approach to identify viruses in orca (Orcinus orca) and short-finned pilot whale (Globicephala macrorhynchus) muscle, kidney, and liver samples from deceased animals. From orca tissue samples (muscle, kidney, and liver), we identified a novel polyomavirus (Polyomaviridae), three cressdnaviruses, and two genomoviruses (Genomoviridae). In the short-finned pilot whale we were able to identify one genomovirus in a kidney sample. The presence of unclassified cressdnavirus within two samples (muscle and kidney) of the same animal supports the possibility these viruses might be widespread within the animal. The orca polyomavirus identified here is the first of its species and is not closely related to the only other dolphin polyomavirus previously discovered. The identification and verification of these viruses expands the current knowledge of viruses that are associated with the Delphinidae family.

RationalePneumococcal colonisation is key to the pathogenesis of invasive disease, but is also immunogenic in young adults, protecting against re-colonisation. Colonisation is rarely detected in older adults, despite high rates of pneumococcal disease.ObjectivesTo establish experimental human pneumococcal colonisation in healthy adults aged 50—84 years, to measure the immune response to pneumococcal challenge, and to assess the protective effect of prior colonisation against autologous strain rechallenge.MethodsSixty-four participants were inoculated with Streptococcus pneumoniae (serotype 6B, 80,000CFU in each nostril). Colonisation was determined by bacterial culture of nasal wash, serum anti-6B capsular IgG responses by ELISA, and anti-protein immune responses by multiplex electrochemiluminescence.Measurements and Main ResultsExperimental colonisation was established in 39% of participants (25/64) with no adverse events. Colonisation occurred in 47% (9/19) of participants aged 50—59 compared with 21% (3/14) in those aged ≥70 years. Previous pneumococcal polysaccharide vaccination did not protect against colonisation. Colonisation did not confer serotype-specific immune boosting: GMT (95% CI) 2.7μg/mL (1.9—3.8) pre-challenge versus 3.0 (1.9—4.7) four weeks post-colonisation (p = 0.53). Furthermore, pneumococcal challenge without colonisation led to a drop in specific antibody levels from 2.8μg/mL (2.0—3.9) to 2.2μg/mL (1.6—3.0) post-challenge (p = 0.006). Anti-protein antibody levels increased following successful colonisation. Rechallenge with the same strain after a median of 8.5 months (IQR 6.7—10.1) led to recolonisation in 5/16 (31%).ConclusionsIn older adults, experimental pneumococcal colonisation is feasible and safe, but demonstrates different immunological outcomes compared with younger adults in previous studies.

Background Sepsis protocols in sub-Saharan Africa are typically extrapolated from high-income settings, yet sepsis in sub-Saharan Africa is likely caused by distinct pathogens and may require novel treatment strategies. Data to guide such strategies are lacking. We aimed to define causes and modifiable factors associated with sepsis outcomes in Blantyre, Malawi, in order to inform the design of treatment strategies tailored to sub-Saharan Africa. Methods We recruited 225 adults who met a sepsis case definition defined by fever and organ dysfunction in an observational cohort study at a single tertiary center. Etiology was defined using culture, antigen detection, serology, and polymerase chain reaction. The effect of treatment on 28-day outcomes was assessed using Bayesian logistic regression. Results There were 143 of 213 (67%) participants living with human immunodeficiency virus (HIV). We identified a diagnosis in 145 of 225 (64%) participants, most commonly tuberculosis (TB; 34%) followed by invasive bacterial infections (17%), arboviral infections (13%), and malaria (9%). TB was associated with HIV infection, whereas malaria and arboviruses with the absence of HIV infection. Antituberculous chemotherapy was associated with survival (adjusted odds ratio for 28-day death, 0.17; 95% credible interval, 0.05–0.49 for receipt of antituberculous therapy). Of those with confirmed etiology, 83% received the broad-spectrum antibacterial ceftriaxone, but it would be expected to be active in only 24%. Conclusions Sepsis in Blantyre, Malawi, is caused by a range of pathogens; the majority are not susceptible to the broad-spectrum antibacterials that most patients receive. HIV status is a key determinant of etiology. Novel antimicrobial strategies for sepsis tailored to sub-Saharan Africa, including consideration of empiric antituberculous therapy in individuals living with HIV, should be developed and trialed.

BackgroundCOVID-19 has especially affected care home residents.AimTo evaluate a nurse-led Enhanced Care Home Team (ECHT) enhanced SARS-CoV-2 testing strategy.Design and settingService evaluation in care homes in Norfolk UK.MethodResidents and staff received nose and throat swab tests (7 April to 29 June 2020). Resident test results were linked with symptoms on days 0-14 after test and mortality to 13 July 2020.ResultsResidents (n=518) in 44 homes and staff (n=340) in 10 care homes were tested. SARS-CoV-2 positivity was identified in 103 residents in 14 homes and 49 staff in seven homes. Of 103 SARS-CoV-2+ residents, just 38 had typical symptom(s) at time of test (new cough and/or fever). Amongst 54 residents who were completely asymptomatic when tested, 12 (22%) developed symptoms within 14 days. Compared to SARS-CoV-2 negative residents, SARS-CoV-2+ residents were more likely to exhibit typical symptoms (new cough (n=26, p=0.001); fever (n=24, p=ConclusionTesting identified asymptomatic and pre-symptomatic SARS-CoV-2+ residents and staff. Being ‘generally unwell’ was common amongst symptomatic residents and may indicate SARS-CoV-2 infection in older people in the absence of more ‘typical’ symptoms. Where a resident appears generally unwell SARS-CoV-2-infection should be suspected. Protocols for testing involved integrated health and social care teams.

Electrodeposited conducting polymer films derived from aromatic monomers are known to possess properties that depend significantly on the deposition protocol, particularly the electrochemical control function employed. This study explores the underlying reasons for this common observation for the specific case of polypyrrole films deposited from aqueous media onto gold electrodes under potentiostatic, potentiodynamic and galvanostatic control. Although the control functions impose different conditions, the control parameters (potential, potential range and scan rate, and current) were selected so as generate films at comparable rates; this avoids inappropriate attribution of structural and compositional variations to different thickness regimes, irrespective of how they were generated. In each case, film deposition was periodically interrupted and the film characterised by specular neutron reflectivity measurements. By using d4-pyrrole monomer in H2O solvent, the isotopic selectivity of neutron reflectivity was used to extract polymer and solvent concentration profiles as a function of distance from the electrode/film interface. Spatial integration of these profiles was used to quantify total film solvent populations; these are expressed as solvent volume fractions. Films grown under the three different control regimes have measurably distinct solvent volume fraction profiles and there is evolution of these profiles with increasing thickness. Ultimately, for the conditions employed, the order of increasing porosity (i.e. solvent content) by control function was potentiostatic

Two male travelers with histories of gout and hazardous alcohol consumption, presented with a triad of severe culture-positive disseminated gonococcal infection, crystal-positive polyarticular gout, and gonococcal soft tissue collections, following unprotected sexual contact in The Philippines. Both men initially attributed symptoms to gout, since their usual joints were affected, but clinical deterioration occurred with self-administration of anti-inflammatory agents alone. The clinical courses were severe and protracted, requiring aggressive management of infection with prolonged intravenous antimicrobials and repeated surgery, and prolonged anti-inflammatory agents for gout. Joint symptom onset in each case occurred within a week of sexual exposure in conjunction with hazardous alcohol ingestion. We speculate that acute dissemination of infection to previously damaged joints triggered polyarticular gout, with progressive infection, exacerbated by unopposed anti-inflammatory agents and delayed antibiotics. Disseminated gonococcal infection can occur with polyarticular gout and delays in recognition and treatment, including while traveling, can lead to severe disease from both.

Colonization of the upper respiratory tract by pneumococcus is important both as a determinant of disease and for transmission into the population. The immunological mechanisms that contain pneumococcus during colonization are well studied in mice but remain unclear in humans. Loss of this control of pneumococcus following infection with influenza virus is associated with secondary bacterial pneumonia. We used a human challenge model with type 6B pneumococcus to show that acquisition of pneumococcus induced early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function was associated with the clearance of pneumococcus. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate immune function and altered genome-wide nasal gene responses to the carriage of pneumococcus. Levels of the cytokine CXCL10, promoted by viral infection, at the time pneumococcus was encountered were positively associated with bacterial load.

Antigen-specific immunotherapy of autoimmune disease currently remains the only potentially curative approach. However, translation of promising pre-clinical results into successful clinical application has proven challenging. In part, this is because pre-clinical findings in mouse models have to be redesigned for human application due to differences in MHC II. To reduce the gap between pre-clinical and clinical studies, we have created a novel mouse model that expresses human HLA-DR4, but no endogenous MHC on antigen-presenting cells. Moreover, human B7.1 (CD80) is expressed in the pancreatic islets under the control of the rat insulin promoter. Although this model does not develop diabetes spontaneously, it is susceptible to the induction of type 1 diabetes by challenging mice with overlapping peptides derived from murine proinsulin-2 in adjuvant. Unlike the NOD model of spontaneous type 1 diabetes, but akin to the human condition, this model does not have a gender bias. Furthermore, similar to the human condition, the disease is characterised by a diverse leucocyte infiltration of the pancreatic islets and the formation of anti-proinsulin auto-antibodies. The model that we report here offers detailed insights into type-1 diabetes and is expected to prove instrumental when studying the mechanism of action in translational, antigen-specific immunotherapy.

Here, we describe new developments in the study of electrodeposition processes with time-resolved dynamic neutron reflectivity (NR) methods to achieve insights into the differences between growth of metal films using a range of electrochemical control functions. We show that the temporal resolution has increased from 1 to 2 h per data set (in our previous studies) to approximately 8 min. We have studied the electrochemical deposition of copper and silver as thin-film metals onto a gold electrode substrate from a deep eutectic solvent using potentiodynamic (PD), potentiostatic (PS) and galvanostatic (GS) electrochemical control functions. In particular, we have utilised novel developments in neutron reflectivity methods to acquire real-time data for the growing metal films. Event mode capture of neutron scattering events, as a function of momentum transfer vector, Q, during electrochemical growth has enabled time-resolved measurement of the neutron reflectivity, R(Q), profiles of the growing metal films. Subsequent fitting and iterative optimisation of the R(Q,t) data reveals the thickness, roughness and relative density (spatially resolved solvent content) of the metal film during growth. These data show that the different electrochemical growth methodologies exhibit different trends in thickness, roughness and solvation. Silver films show an increasing roughness trend with time but these trends are largely independent of growth method. In contrast, the roughness of copper films, grown under similar conditions, shows a strong dependency on growth method with PS methods producing smoothest films. These conclusions are confirmed by ex-situ AFM measurements. The fitted NR data show that the Cu and Ag films contain between 5 and 10% volume fraction solvent. Furthermore, we have explored different NR data fitting methodologies in order to process the large numbers of data sets produced. Gratifyingly, the different methodologies and starting conditions yield a very consistent picture of metal film growth.

A series of TTF and EDT-TTF derived donors bearing thiophene, bithiophene and terthiophene side chains is described, from which a group of six radical cation salts with polyiodide ions were formed and structurally characterised. Typically, they contain complex networks of pentaiodide or triiodide anions or both, in some cases including further iodine, with networks of eight, ten, twelve or sixteen iodine atoms. Donor monocations form face-to-face pairs, but tetrakis-substituted donors are slipped along their main axis so the donor side chains can wrap around each other.

Objective There is increasing evidence to suggest that, among those with chronic hepatitis B virus infection, the natural history and rate of progression to cirrhosis and hepatocellular carcinoma is influenced by hepatitis B virus genotype. The unique hepatitis B virus genotype C4 circulates among Indigenous Australians. The aim of this work is to describe the process of establishing this cohort and review the first 6 years of available data in an effort to understand the real-world clinical care and natural history of this subgenotype. Method We followed a longitudinal cohort of Indigenous Australians from the Northern Territory of Australia with established subgenotype C4 infections. We assigned phases of disease according to Gastroenterological Society of Australia and Asian Pacific Association for the Study of the Liver criteria using clinical and laboratory information that had been collected for clinical management. Results Of 193 patients followed over a median of 38 months, 58 (30%) individuals transitioned from 1 disease phase to another, 10 (5%) cleared hepatitis B e antigen, and 6 cleared hepatitis B surface antigen (3%). In this relatively young cohort (median age 40.3 years), 26 (13%) had cirrhosis by the end of the follow up period, with the majority of these being in the immune control phase of disease. Conclusions In this cohort of hepatitis B subgenotype C4 patients, we report an aggressive and dynamic clinical phenotype. High rates of cirrhosis at a young age appear to occur in the early phases of disease., Hepatitis B subgenotype C4 has been found exclusively in Indigenous Australians. This subgenotype appears to be associated with older age of e antigen seroconversion and relatively high rates of cirrhosis.

Over the last two decades, large molecule biologics such as MONOCLONAL ANTIBODIES (mAbs) have emerged as alternatives to small molecule chemical drugs for treating a wide range of human diseases, including AUTOIMMUNITY and cancer. There are currently over 50 mAbs and 4 Fc-fusion proteins (consisting of an endogenous RECEPTOR molecule linked to the Fc fragment of human IgG) currently approved for human use. Thirty one of these target immunological diseases such as RHEUMATOID ARTHRITIS (RA), MULTIPLE SCLEROSIS (MS), SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), inflammatory bowel disease (IBD), ASTHMA and organ transplant rejection [1]. The success of mAb-based therapeutics is due to their exquisite specificity, which, in combination with their multifunctional properties, high potency, long HALF-LIFE (permitting intermittent dosing and prolonged pharmacological effects) and general lack of off-target toxicity, makes them ideal therapeutics. Over time, knowledge has been acquired to understand what may limit the EFFICACY of mAbs such as immunogenicity and the challenges of certain routes of administration and to have a better understanding of the mechanism of action. This chapter aims to give a general introduction to the immune diseases and inflammatory pathways being targeted by mAbs, focusing on those that are approved or in late-stage clinical development.

Exquisite control of the electrodeposition of metal films and coatings is critical to a number of high technology and manufacturing industries, delivering functionality as\ud diverse as anti-corrosion and anti-wear coatings, electronic device interconnects and energy storage. The frequent involvement of more than one metal motivates the\ud capability to control, maintain and monitor spatial disposition of the component metals, whether as multilayers, alloys or composites. Here we investigate the deposition, evolution and dissolution of single and two-component metal layers involving Ag, Cu, and Sn on Au substrates immersed in the deep eutectic solvent (DES) Ethaline. During galvanostatically controlled stripping of the metals from two-component systems the potential signature in simultaneous thickness electrochemical potential (STEP) measurements provides identification of the dissolving metal; coulometric assay of deposition efficiency is an additional outcome. When combined with quartz crystal microbalance (QCM) frequency responses, the mass change : charge ratio provides oxidation state data; this is significant for Cu in the high chloride environment provided by Ethaline. The spatial distribution (solvent penetration and external roughness) of multiple components in bilayer systems is provided by specular neutron reflectivity (NR). Significantly, the use of the recently established event mode capability shortens the\ud observational timescale of the NR measurements by an order of magnitude, permitting dynamic in situ observations on practically useful timescales. Ag,Cu bilayers of both\ud spatial configurations give identical STEP signatures indicating that, despite theextremely low layer porosity, thermodynamic constraints (rather than spatial accessibility) dictate reactivity; thus, surprisingly, Cu dissolves first in both instances. Sn penetrates the Au electrode on the timescale of deposition; this can be prevented by interposing a layer of either Ag or Cu.

Background: Peptide immunotherapy (PIT) aims to modulate immune responses to specific antigens in order to restore immune tolerance. Recently, we reported outcomes of a phase 1b study of PIT at type 1 diabetes onset, showing safety, tolerability and changes in immune regulation pathways, following up to 12 doses of 10μg of a single proinsulin peptide that is naturally processed and presented by HLA-DR4 (DRB1*0401). Preclinical PIT studies show that multiple peptides in combination enhance tolerance induction. Aims: To evaluate the safety and clinical effects of PIT using a mix of multiple islet autoantigen peptides in adults with recent-onset type 1 diabetes. Methods: The MultiPepT1De study was a single centre, double-blind placebo-controlled, ascending dose, randomized trial recruiting adults aged 18-45 years within 4 years of diagnosis with HLA-DRB1*0401 genotype, positive islet autoantibodies and stimulated C-peptide >0.2pmol/mL. Study drug comprised of 6 naturally processed and presented, islet-derived peptides (MultiPepT1De). Participants were enrolled into 3 cohorts for monthly intradermal injections for 6 months. In each cohort, subjects were randomized to receive placebo (n=2) or MultiPepT1De (n=6) at 10µg (Cohort 1), 100µg (Cohort 2) or 500µg (Cohort 3) doses. Results: Twenty-seven participants were randomized; 3 participants withdrew for non-clinical reasons and were replaced. There were no episodes of systemic hypersensitivity, anaphylaxis or serious adverse reactions linked to MultiPepT1De administration. Analysis of changes in stimulated C-peptide, HbA1c and insulin dose per kg showed no evidence of disease acceleration following dosing compared with placebo. Mild transient injection site erythema was observed in all cohorts, with no increase on repeated dosing. Conclusions: Intradermal administration of multiple islet-derived peptides up to a cumulative dose of 3000µg, is well tolerated with no safety concerns. Disclosure Y. Liu: Other Relationship; Self; Novo Nordisk Limited. Research Support; Self; Bristol-Myers Squibb Company. J.K. Powrie: None. S. Arif: None. N. Fountoulakis: None. M. Joshi: None. E.L. Smith: Employee; Self; UCB, Inc. F. Strimenopoulou: Employee; Self; UCB, Inc. M. Thomson: Employee; Self; UCB, Inc. M. Peakman: Research Support; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Bristol-Myers Squibb Company. Consultant; Self; UCB, Inc.. Research Support; Self; UCB, Inc.. Advisory Panel; Self; T1D Exchange.

Secondary bacterial pneumonia following influenza infection is a significant cause of mortality worldwide. Upper respiratory tract pneumococcal carriage is important as both determinants of disease and population transmission. The immunological mechanisms that contain pneumococcal carriage are well-studied in mice but remain unclear in humans. Loss of this control of carriage following influenza infection is associated with secondary bacterial pneumonia during seasonal and pandemic outbreaks. We used a human type 6B pneumococcal challenge model to show that carriage acquisition induces early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function associated with clearance of pneumococcal carriage. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate function and altered genome-wide nasal gene responses to pneumococcal carriage. Levels of the cytokine IP-10 promoted by viral infection at the time of pneumococcal encounter was positively associated with bacterial density. These findings provide novel insights in nasal immunity to pneumococcus and viral-bacterial interactions during co-infection.

The widely used nasally-administered Live Attenuated Influenza Vaccine (LAIV) alters the dynamics of naturally occurring nasopharyngeal carriage ofStreptococcus pneumoniaein animal models. Using a human experimental model (serotype 6B) we tested two hypotheses: 1) LAIV increased the density ofS. pneumoniaein those already colonised; 2) LAIV administration promoted colonisation. Randomised, blinded administration of LAIV or nasal placebo either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density ofS. pneumoniaewas determined from nasal washes by bacterial culture and PCR. Overall acquisition for bacterial carriage were not altered by prior LAIV administration vs. controls (25/55 [45.5%] vs 24/62 [38.7%] respectively, p=0.46). Transient increase in acquisition was detected in LAIV recipients at day 2 (33/55 [60.0%] vs 25/62 [40.3%] in controls, p=0.03). Bacterial carriage densities were increased approximately 10-fold by day 9 in the LAIV recipients (2.82 vs 1.81 log10titers, p=0.03). When immunisation followed bacterial acquisition (n=163), LAIV did not change area under the bacterial density-time curve (AUC) at day 14 by conventional microbiology (primary endpoint), but significantly reduced AUC to day 27 by PCR (p=0.03). These studies suggest that LAIV may transiently increase nasopharyngeal density ofS. pneumoniae.Transmission effects should therefore be considered in the timing design of vaccine schedules.Trial registrationThe study was registered on EudraCT (2014-004634-26)FundingThe study was funded by the Bill and Melinda Gates Foundation and the UK Medical Research Council.

Objective: Observational studies using routinely collected data indicate that pain management programmes (PMPs) based on cognitive-behavioural principles are associated with clinically meaningful improvements for individuals with chronic pain. This study evaluated change across functional measures in a sample of chronic pain patients attending a 4-week residential PMP between 2006 and 2010. The findings were directly compared with published outcomes from an earlier period (1989–1998) at the same service. Methods: Participants included 760 consecutive completers of a multidisciplinary PMP. Data were collected at pre-PMP, post-PMP (1-month post-discharge) and at a 9-month follow-up session. Group-based treatment effects and the reliability and clinical significance of change across functional measures were calculated and compared across cohorts. Results: Effect sizes for the recent cohort ranged from small to medium (.43–.67) for pain and physical functioning outcomes to large (.90–1.12) for psychological outcomes at post-treatment ( n = 654), and from small (.30–.51) to medium (.58–.71) at 9-month follow-up ( n = 493). Clinically significant gains on pain and psychological measures were achieved by 19–55% of patients at post-treatment and 17–44% at follow-up. Comparisons with the earlier cohort showed significantly stronger post-treatment outcomes but differences at follow-up were less marked. Discussion: These results add to the evidence base supporting the effectiveness of cognitive-behavioural therapy (CBT)-based pain management interventions. There were significantly larger gains in patient functioning in the recent dataset, suggesting improved programme delivery. But effects were less marked in the longer term, indicating a need for improvements in therapeutic models and related methods to promote meaningful and lasting changes.

There is a growing socio-economic need for effective strategies to repair damaged bone resulting from disease, trauma and surgical intervention. Bone tissue engineering has received substantial investment over the last few decades as a result. A multitude of studies have sought to examine the efficacy of multiple growth factors, delivery systems and biomaterials within in vivo animal models for the repair of critical-sized bone defects. Defect repair requires recapitulation of in vivo signalling cascades, including osteogenesis, chondrogenesis and angiogenesis, in an orchestrated spatiotemporal manner. Strategies to drive parallel, synergistic and consecutive signalling of factors including BMP-2, BMP-7/OP-1, FGF, PDGF, PTH, PTHrP, TGF-β3, VEGF and Wnts have demonstrated improved bone healing within animal models. Enhanced bone repair has also been demonstrated in the clinic following European Medicines Agency and Food and Drug Administration approval of BMP-2, BMP-7/OP-1, PDGF, PTH and PTHrP. The current review assesses the in vivo and clinical data surrounding the application of growth factors for bone regeneration. This review has examined data published between 1965 and 2013. All bone tissue engineering studies investigating in vivo response of the growth factors listed above, or combinations thereof, utilising animal models or human trials were included. All studies were compiled from PubMed-NCBI using search terms including 'growth factor name', 'in vivo', 'model/animal', 'human', and 'bone tissue engineering'. Focus is drawn to the in vivo success of osteoinductive growth factors incorporated within material implants both in animals and humans, and identifies the unmet challenges within the skeletal regenerative area.

There is an unmet need for improved, effective tissue engineering strategies to replace or repair bone damaged through disease or injury. Recent research has focused on developing biomaterial scaffolds capable of spatially and temporally releasing combinations of bioactive growth factors, rather than individual molecules, to recapitulate repair pathways present in vivo. We have developed an ex vivo embryonic chick femur critical size defect model and applied the model in the study of novel extracellular matrix (ECM) hydrogel scaffolds containing spatio-temporal combinatorial growth factor-releasing microparticles and skeletal stem cells for bone regeneration. Alginate/bovine bone ECM (bECM) hydrogels combined with poly(d,l-lactic-co-glycolic acid) (PDLLGA)/triblock copolymer (10-30% PDLLGA-PEG-PLDLGA) microparticles releasing dual combinations of vascular endothelial growth factor (VEGF), chondrogenic transforming growth factor beta 3 (TGF-β3) and the bone morphogenetic protein BMP2, with human adult Stro-1+bone marrow stromal cells (HBMSCs), were placed into 2mm central segmental defects in embryonic day 11 chick femurs and organotypically cultured. Hydrogels loaded with VEGF combinations induced host cell migration and type I collagen deposition. Combinations of TGF-β3/BMP2, particularly with Stro-1+HBMSCs, induced significant formation of structured bone matrix, evidenced by increased Sirius red-stained matrix together with collagen expression demonstrating birefringent alignment within hydrogels. This study demonstrates the successful use of the chick femur organotypic culture system as a high-throughput test model for scaffold/cell/growth factor therapies in regenerative medicine. Temporal release of dual growth factors, combined with enriched Stro-1+HBMSCs, improved the formation of a highly structured bone matrix compared to single release modalities. These studies highlight the potential of a unique alginate/bECM hydrogel dual growth factor release platform for bone repair.

Current clinical treatments for skeletal conditions resulting in large-scale bone loss include autograft or allograft, both of which have limited effectiveness. In seeking to address bone regeneration, several tissue engineering strategies have come to the fore, including the development of growth factor releasing technologies and appropriate animal models to evaluate repair. Ex vivo models represent a promising alternative to simple in vitro systems or complex, ethically challenging in vivo models. We have developed an ex vivo culture system of whole embryonic chick femora, adapted in this study as a critical size defect model to investigate the effects of novel bone extracellular matrix (bECM) hydrogel scaffolds containing spatio-temporal growth factor-releasing microparticles and skeletal stem cells on bone regeneration, to develop a viable alternative treatment for skeletal degeneration. Alginate/bECM hydrogels combined with poly (D,L-lactic-co-glycolic acid) (PDLLGA)/triblock copolymer (10-30% PDLLGA-PEG-PDLLGA) microparticles releasing VEGF, TGF-β3 or BMP-2 were placed, with human adult Stro-1+ bone marrow stromal cells, into 2 mm central segmental defects in embryonic chick femurs. Alginate/bECM hydrogels loaded with HSA/VEGF or HSA/TGF-β3 demonstrated a cartilage-like phenotype, with minimal collagen I deposition, comparable to HSA-only control hydrogels. The addition of BMP-2 releasing microparticles resulted in enhanced structured bone matrix formation, evidenced by increased Sirius red-stained matrix and collagen expression within hydrogels. This study demonstrates delivery of bioactive growth factors from a novel alginate/bECM hydrogel to augment skeletal tissue formation and the use of an organotypic chick femur defect culture system as a high-throughput test model for scaffold/cell/growth factor therapies for regenerative medicine.

Background Lymphatic filariasis (LF) is a disfiguring parasitic disease and one of the leading causes of disability in the world. This study aimed to assess the severity of lymphoedema, the physical restrictions and socio-economic impact on affected individuals living in an endemic community in Malawi. Methods In a single health centre catchment area, a follow-up survey was conducted to assess 69 lymphoedema cases, and the impact of their condition in eight different areas of their lives. Differences were examined by sex, age and severity of disease. The overall level of disability was quantified and the impact of acute dermatolymphangioadenitis (ADLA) attacks was examined. Results Lymphoedema cases were most affected by pain/discomfort and anxiety/depression, which also had an economic impact. Male and older (>60 years) individuals reported more problems. Higher disability levels based on a quantified score were significantly associated with decreased walking distance and working hours. ADLA significantly increased pain/discomfort and reduced cognition, and also affected the individuals' self-care, social participation and ability to work. Conclusions Filarial lymphoedema causes significant hardship, particularly in relation to ADLAs, and the scale of the problem needs to be better defined with new specific tools so that the best support and care can be provided to those in greatest need.

Mindfulness-based cognitive therapy (MBCT) has been evidenced as a relapse prevention strategy for depression. Depression often influences and is influenced by intimate partnerships; thus, it makes sense to include both individuals in interventions. This study aimed to develop a theory of the process of engaging in MBCT as a partnership. As there was no theory or research that could be directly applied to understand the process of engaging in MBCT for depression, as a partnership, an exploratory grounded theory study seemed appropriate to generate rich data and a theory. Twelve participants who had attended an MBCT course as a partnership were interviewed. Analysis and interviews ran simultaneously, so that initial findings influenced subsequent data collection. Constant comparison of data and higher-level concepts facilitated the generation of a theory grounded in the data. The proposed theory captured the ‘process of learning new mindfulness skills together’. The partnership’s rationale for pursuing MBCT together seemed to influence engagement with the course. Participants’ accounts suggested that learning mindfulness skills together led to shifts in the relationship and how they managed depression. While partnerships learned similar mindfulness skills as in individual MBCT courses, learning as a partnership seemed to facilitate home practice, attendance and a sense of mutual support, which led to unique outcomes for the partnership and their sense of responsibility for each others’ well-being. It may be helpful for course facilitators to consider inviting intimate partners to attend where both partners are suffering or there is a willing partnership.

Scientific research and progress, particularly in the drug discovery and regenerative medicine fields, is typically dependent on suitable animal models to develop new and improved clinical therapies for injuries and diseases. In vivo model systems are frequently utilised, but these models are expensive, highly complex and pose a number of ethical considerations leading to the development and use of a number of alternative ex vivo model systems. The ex vivo embryonic chick long bone and limb bud models have been utilised in the scientific research field as a model to understand skeletal development for over eighty years. The rapid development of avian skeletal tissues, coupled with the ease of experimental manipulation, availability of genome sequence and the presence of multiple cell and tissue types has seen such model systems gain significant research interest in the last few years in the tissue engineering field. The models have been explored both as systems for understanding the developmental bone niche and as potential testing tools for tissue engineering strategies for bone repair and regeneration. This review details the evolution of the chick limb organ culture system and presents recent innovative developments and emerging techniques and technologies applied to these models that are aiding our understanding of skeletal developmental and regenerative medicine research and application.

The main focal area of the research into deep eutectic solvents (DESs) is currently the incorporation of metal ions into solution for metal deposition, metal dissolution, or metal processing. Although difficult to compete economically with existing electroplating systems for common metal applications, DESs can provide suitable media for the many technological goals of the industry.

Objective: This study examines the gender of home-based caregivers for people affected by lymphatic filariasis (LF) lymphoedema. Methods: In total, 69 LF lymphoedema cases in Malawi were questioned about the assistance they received with a focus on the gender of the caregiver and the type of support provided. Results: Of the 35 cases who required daily assistance, 27 indicated the gender of the caregiver, of which 20 were female (74.1%), and most commonly daughters, sisters or school-aged girls. This care was usually only provided during episodes of painful disabling acute-dermatolymphangioadenitis (ADLA) attacks. The males who provided care were most commonly husbands. Conclusion: The role of female caregivers is ‘unseen’ and this has considerable domestic, educational and economic implications. This gender imbalance also poses barriers to Goal 5 of the Sustainable Development Goals, specifically Target 5.4 that aims to recognize and value unpaid care and domestic work.

Sport participation is one way in which immigrants interact with established and long-term community residents. This involvement has the potential for facilitating immigrants' sense of inclusion an...

(2010). Metal finishing with ionic liquids: scale-up and pilot plants from IONMET consortium. Transactions of the IMF: Vol. 88, No. 6, pp. 285-293.

PurposeThe purpose of this paper is to present the optimisation of protocols for the immersion coating of silver onto copper‐track printed circuit board (PCB) assemblies, using a novel class of ionic liquid and to show the implementation of the scale up process.Design/methodology/approachVarious conditions (temperatures and silver concentrations) are studied individually under laboratory conditions and then optimised for a pilot scale demonstrator line that is used to process British Standard test coupons.FindingsThe use of these novel liquids for the immersion coating of silver produces silver dip coatings that are bright and even and which give solderability that is as good as the commercial aqueous, nitric acid based, electroless process without any solder‐mask interface etching.Research limitations/implicationsThe combined technology has been optimised for an immersion silver coating line. Further development work should be undertaken to tailor the technology for gold immersion coating of PCB assemblies.Originality/valueThe paper details a process in which no solder‐mask interface etching is observed; that does not require the use of strong inorganic acids or expensive catalysts to sustain deposition and which does not appear to be light sensitive in contrast to other processes.

Crown ether functionalised conducting polymer films were used to complex barium ions from acetonitrile solution. It was found that fully-functionalised N-derivatized polypyrrole films do not possess adequate mechanical stability, but dilution with unfunctionalised bithiophene co-monomer leads to a series of copolymer films with excellent stability. Film reactivity, composition and structure were investigated using electrochemical, nanogravimetric, FTIR, XPS and neutron reflectivity techniques. The first three of these provided spatially integrated barium populations and neutron reflectivity provided spatially resolved compositional profiles. Measurements at various stages of film fabrication yielded spatial distributions of co-monomer, crown ether, solvent and barium (as perchlorate) components. Critically, the amount of free volume to accommodate crown motifs and barium within the film was limited by the film's internal microstructure and solvent content; the low solvent volume fraction creates a different local environment to solution.

Here we describe the electrolytic deposition of a range of metallic coatings, alloys and composites from room temperature ionic liquids that have low environmental impact/toxicity, are inexpensive and easy to handle. We show that some of these systems can be considered as "drop-in" replacement technologies for existing aqueous processes that currently utilize strong inorganic acids and highly toxic reagents.

Time-resolved specular neutron reflectivity measurements are presented and interpreted for electroactive polyvinylferrocene (PVF) films subject to potentiodynamic electrochemical control. New data acquisition methodology allows an effective measurement time scale on the order of seconds, which is an improvement over conventional methodology by 2 to 3 orders of magnitude. Reflectivity profiles were obtained for PVF films exposed to aqueous 0.1 M NaClO4 in which PVF films are thermodynamically permselective, with contrast variation via H2O and D2O. Irrespective of any model, the raw profiles show chemically reversible film "breathing" due to redox-driven solvent entry and exit during polymer oxidation and reduction, respectively. Modeling reveals three compositionally distinct regions within the polymer film: interfacial regions at the electrode and solution interfaces and a "bulk" interior. The new methodology, supported by simultaneous in situ visible transmission spectroscopy, reveals an unprecedented level of insight into the temporal and spatial mechanistic details of film solvation changes, including a two-stage (de)solvation mechanism for redox switching, differences in interior (in)homogeneity for reduced and oxidized films, and permselectivity failure under dynamic electrochemical conditions for the reduced (but not oxidized) state, in contrast to static conditions that allow permselectivity for both states.

Little is known about the lived experiences of immigrants as coaches within the amateur sport ranks or about how amateur sport organizations are accommodating the needs of newcomers. The purpose of this study was to qualitatively explore these issues with the assistance of members of the newcomer and minority ethnic communities, and those who work as sport coaches, and administrators in a city in Atlantic Canada. Seventeen individuals participated in one-on-one semi-structured interviews and/or a follow-up focus group interview. Three major themes emerged: Differences in perceived versus expected levels of involvement and the influence of privilege on newcomers' involvement in sport; how to include newcomers in sport and, more specifically, barriers to and responsibility for inclusion in sport and coaching; and how sport organizations can best communicate information to newcomers about coaching opportunities. Barriers to participation in coaching by newcomers appear to be both personal and systemic in nature.