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The global polio eradication campaign has had remarkable success in reducing wildtype poliovirus infection, largely built upon the live attenuated Sabin oral poliovirus vaccine. Whilst rare, vaccine poliovirus strainsmay cause infection and subsequently revert to a neurovirulent type, termed vaccine-derived poliovirus (VDPV). Persistent, vaccine derived infection may occur in an immunocompromised host (iVDPV), where it is a recognised complication following receipt of the Sabin vaccine. This has significant implications for the global polio eradication campaign and there is currently no agreed global strategy to manage such patients. Here we describe a case of a 50-year-old man with common variable immune deficiency, persistently infected with a neurovirulent vaccine-derived type 2 poliovirus following vaccination in childhood. iVDPV infection had proven resistant to multiple prior attempts at treatment with human breast milk, ribavirin and oral administration of a normal human pooled immunoglobulin product. His iVDPV infection subsequently resolved after 12 days treatment with remdesivir, an adenosine analogue prodrug that is an inhibitor of viral RNA-dependent RNA polymerase, administered as treatment for a prolonged, moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. iVDPV from the patient, isolated prior to treatment, was subsequently demonstrated to be sensitive to remdesivir in vitro. Based on the observationsmade in this case, and the mechanistic rationale for use with iVDPV, there is strong justification for further clinical studies of remdesivir treatment as a potentially curative intervention in patients with iVDPV infection. [ABSTRACT FROM AUTHOR]

Those with anaphylaxis to food or with spontaneous anaphylaxis reported a bigger impact on their anaphylaxis-specific QoL compared to those with medication or venom as a cause. Poorer anaphylaxis-specific QoL (as measured by the A-QoL-Adults) significantly related to greater anxiety ( I r i = .69), depression ( I r i = .54), stress ( I r i = .38) and poorer generic physical ( I r i = -.50), psychological ( I r i = -.45), social ( I r i = -.36) and environmental QoL ( I r i = -.48). Keywords: adults; anaphylaxis; mental health; quality of life; stress EN adults anaphylaxis mental health quality of life stress 121 125 5 01/27/23 20230101 NES 230101 Key messages Poorer anaphylaxis-specific QoL is significantly related to greater stress, depression, anxiety, demographic and clinical variables. Post hoc tests showed that those with anaphylaxis to medication reported significantly worse physical QoL than those reporting anaphylaxis to venom ( I p i < .01) (Table 2). [Extracted from the article]

Summary: Currently, there is no guideline to support the use of immunoglobulin replacement therapy (IgRT) in primary and secondary immunodeficiency disorders in UK. The UK Primary Immunodeficiency Network (UK-PIN) and the British Society of Immunology (BSI) joined forces to address this need. Given the paucity of evidence, a modified Delphi approach was used covering statements for the initiation, monitoring, discontinuation of IgRT as well as home therapy programme. A group of six consultant immunologists and three nurse specialists created the statements, reviewed responses and feedback and agreed on final recommendations. This guideline includes 22 statements for initiation, 22 statements for monitoring, 11 statement for home therapy, and 19 statements for discontinuation of IgRT. Further areas of research are proposed to improve future delivery of care. [ABSTRACT FROM AUTHOR]

Background: Individuals with primary and secondary immunodeficiency (PID/SID) were showntobeat riskofpooroutcomesduringtheearly stagesoftheSARS-CoV-2pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients. Objectives: To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed following the deployment of vaccination and therapeutics in the context of the emergence of novel viral variants of concern. Methods: The outcomes of two cohorts of patients with PID and SID were compared: the first, infected between March and July 2020, prior to vaccination and treatments, the second after these intervention became available between January 2021 and April 2022. Results: 22.7% of immunodeficient patients have been infected at least once with SARS-CoV-2 since the start of the pandemic, compared to over 70% of the general population. Immunodeficient patients were typically infected later in the pandemic when the B.1.1.529 (Omicron) variant was dominant. This delay was associated with receipt of more vaccine doses and higher pre-infection seroprevalence. Compared to March-July 2020, hospitalization rates (53.3% vs 17.9%, p<0.0001) and mortality (Infection fatality rate 20.0% vs 3.4%, p=0.0003) have significantly reduced for patients with PID but remain elevated compared to the general population. The presence of a serological response to vaccination was associated with a reduced duration of viral detection by PCR in the nasopharynx. Early outpatient treatment with antivirals or monoclonal antibodies reduced hospitalization during the Omicron wave. Conclusions: Most individuals with immunodeficiency in the United Kingdom remain SARS-CoV-2 infection naïve. Vaccination, widespread availability of outpatient treatments and, possibly, the emergence of the B.1.1.529 variant have led to significant improvements in morbidity and mortality followings SARS-CoV-2 infection since the start of the pandemic. However, individuals with PID and SID remain at significantly increased risk of poor outcomes compared to the general population; mitigation, vaccination and treatment strategies must be optimized to minimize the ongoing burden of the pandemic in these vulnerable cohorts. [ABSTRACT FROM AUTHOR]

Polydimethylsiloxane (PDMS) is a widely used material for microfluidic devices due to its low cost, superior optical properties and fast iterative design process. Its softness however creates challenges for the device design and operation because part of the applied pressures contributes to deform chips instead of controlling the flow. The resulting dynamic behaviour is often ignored in passive microfluidic that focuses on the static behaviour of the chip, however, can cause low accuracy to active microfluidic that actuates flow frequently. Therefore, understanding the dynamic behaviour of microfluidic devices due to material compliance is of fundamental and practical importance. In this study, the microfluidic chip compliance is carefully considered by separating it from the sample tubing compliance. The capacitance is retrieved by assuming a symmetric RC circuit based on the experimentally determined time constant and chip resistance. The experimental capacitance is compared to a theoretical formula for chip designs with different height-to-width ratios and height-to-length ratios and for various fluids. The accuracy is within one order of magnitude that is much closer than previous approximations. [ABSTRACT FROM AUTHOR]

Background: Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. Objectives: COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination. Methods: Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs. Results: A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine. Conclusion: SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection. [ABSTRACT FROM AUTHOR]

Background: Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity. Objectives: To determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency. Methods: Participants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, livevirus neutralisation and ELISPOT assays. Results: Following a two-dose schedule, 100% of healthy controls mounted a serological response to SARS-CoV-2 vaccination, however, 38.6% of individuals with antibody deficiency remained seronegative. A third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infectionnaive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell response following their third vaccine dose (61.5% vs 11.1%). Conclusion: These data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency. [ABSTRACT FROM AUTHOR]

Background: Berotralstat (BCX7353) is an oral, once‐daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long‐term safety study of berotralstat in patients with HAE. Methods: APeX‐S is an ongoing, phase 2, open‐label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE‐C1‐INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long‐term safety and the secondary objective was to evaluate effectiveness. Results: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150‐mg and 110‐mg groups, respectively. Treatment‐emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug‐related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug‐related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. Conclusions: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. Trial registration: The study is registered with ClinicalTrials.gov (NCT03472040). [ABSTRACT FROM AUTHOR]

Microfluidics typically uses either a syringe pump that regulates the flow rate in microchannels or a pressure pump that controls the inlet pressures to drive the flow. In the context of pressure-driven flow, a reservoir holder containing liquid samples is normally used to interface the pressure pump with the microfluidic chip via soft tubing. The tubing connecting the pump and holder transports the pressurized air while the tubing connecting the holder and chip transports the liquid samples. The pressure output from the pump is usually assumed to be stable and the same as that applied to the liquid in the chip; however, in practice this assumption is often incorrect and may negatively impact chip performance. This assumption is critically challenged when applied to microfluidic chips involving dynamic control of fluids since the pressures are constantly varied (at > 10 Hz). This study presents a method for investigating, quantifying and modelling the pump stability and the dynamics of the air tubing using two pressure sensors. The relationship between the pressure output from the pump and the reservoir holder pressure is generalized as a first-order linear system. This relationship allows the software that controls the pressure pump to output the required pressure to the reservoir holder and thus to the microfluidic chip. These results should significantly improve the performance of microfluidic chips using active fluid control, and may also benefit passive fluid control applications. [ABSTRACT FROM AUTHOR]

Gas extraction in the Groningen Province in the Netherlands has caused seismicity. A method was needed for probabilistic assessments of the seismic performance of the levees that protect low-lying polders against flooding. By combining the First Order Reliability Method with response surfaces it proved possible to strongly reduce the required number of simulations with advanced numerical models to obtain reliable failure probability estimates. To illustrate the workings of the method, an application to a levee cross-section along the Eemscanal with a sheet pile wall is presented. The probabilistic method can be used for probabilistic assessments and the probability-based calibration of partial factors, and it could serve as a starting point for quantitative risk analyses for levee systems in earthquake prone regions. [ABSTRACT FROM AUTHOR]

Background: An increasing number of adults are being diagnosed with anaphylaxis, but its impact on health‐related quality of life (HRQol) is not known. Objective: The aim of this study was to explore the impact of anaphylaxis on HRQoL of newly diagnosed adults. Methods: Interviews were conducted with 13 adults (aged 40‐71; five males) with anaphylaxis (meeting WAO diagnostic criteria) to drugs, food, venom or spontaneous anaphylaxis, recruited using purposive sampling from allergy clinics in Birmingham, UK. Data were transcribed verbatim and analysed using thematic analysis. Results: Four themes were generated from the analysis: the journey from fear to frustration; the need to maintain a healthy identity; control over uncertainty; and the supportive role of others. Participants described their first experiences of anaphylaxis as frightening. Managing the condition was associated with frustration and anxiety, in part due to uncertainty regarding when anaphylaxis might occur. Participants did not consider their allergy as an illness and wanted to retain an identity as a healthy person. They felt a strong need to have control over their anaphylaxis so that it did not take over their lives. The support from others was extremely important, but a lack of understanding of anaphylaxis sometimes hindered that support. Conclusions and Clinical Relevance: Anaphylaxis has an adverse impact on the HRQoL of adults irrespective of the cause. More information about anaphylaxis and its management from healthcare professionals may help patients gain a sense of control over their condition and reduce the worry and anxiety associated with it. [ABSTRACT FROM AUTHOR]

Summary: Common variable immunodeficiency (CVID) represents a heterogeneous group of rare disorders. There is considerable morbidity and mortality as a result of non‐infectious complications, and this presents clinicians with management challenges. Clinical guidelines to support the management of CVID are urgently required. The UK Primary Immunodeficiency Network and the British Society for Immunology funded a joint project to address this. A modified Delphi Survey was conducted for the assessment, diagnosis and treatment of the non‐infectious blood, respiratory, gut and liver complications of CVID. A steering group of 10 consultant immunologists and one nurse specialist developed and reviewed the survey statements and agreed the final recommendations. In total, 22 recommendations and three areas for research were developed. [ABSTRACT FROM AUTHOR]

Anaphylaxis is a type I hypersensitivity reaction that is potentially fatal if not promptly treated. It is a clinical diagnosis, although measurement of serial serum total mast cell tryptase (MCT) is gold standard and may help differentiate anaphylaxis from its mimics. The performance characteristics of MCT assays in anaphylaxis has been variable in previous studies, due to multiple factors including differences in the definition of anaphylaxis, methods of MCT interpretation, clinical setting of anaphylaxis, causative agents, and timing of blood sample. An international consensus equation for MCT to interpret mast cell activation has been proposed and recently validated in the context of peri-operative anaphylaxis during general anesthesia. There has been an interest in the detection of newer biomarkers in anaphylaxis including platelet activation factor (PAF), chymase, carboxypeptidase A3, dipeptidyl peptidase I (DPPI), basogranulin, and CCL-2. The key determinants of an ideal biomarker in anaphylaxis are half-life, sample handling and processing requirements, and cost. There may be a role for metabolomics and systems biology in the exploration of novel biomarkers in anaphylaxis. Future studies applying these approaches might provide greater insight into factors determining severity, clinical risk stratification, identification of mast cell disorders and improving our understanding of this relatively complex acute immunological condition. Post mortem MCT evaluation is used in Forensic Medicine during autopsy for cases involving sudden death or suspected anaphylaxis. Interpretation of post mortem MCT is challenging since there is limited published evidence and the test is confounded by multiple variables largely linked to putrefaction and site of sampling. Thus, there is no international consensus on a reference range. In this state of the art review, we will focus on the practical challenges in the laboratory diagnosis of anaphylaxis and critically appraise (a) performance characteristics of MCT in anaphylaxis in different clinical scenarios (b) the role for novel biomarkers and (c) post mortem MCT and its role in fatal anaphylaxis. [ABSTRACT FROM AUTHOR]

The most flexible means of transferring components between machines within a work cell is provided by robotic manipulation. This implicitly requires that a stable grasp of each component can be determined. The CAD representation of the part may be used for this purpose. A conventional search over the solid model representation of the part for the optimal grasp can be computationally expensive, especially when non-planar surfaces are present. In this paper, we present a logical evaluation of the solid feature model of the component, that finds an acceptable grasp with little computational effort. While the procedure does not guarantee that a grasp will be found, its efficiency and success for the majority of components more than justify its use before an exhaustive search is conducted. The technique is illustrated by means of an example. [ABSTRACT FROM AUTHOR]

Summary: Good's syndrome (thymoma and hypogammaglobulinaemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK‐Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy‐eight patients with a median age of 64 years, 59% of whom were female, were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and nine (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T cells were significantly lower in these patients with malignant thymoma. Seventy‐four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB‐type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, systemic lupus erythematosus, Sjögren's syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good's syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinaemia. Good's syndrome (thymoma and hypogammaglobulinemia is a rare secondary immunodeficiency. This is one of the largest series of patients with this condition collating information on the clinical features, laboratory parameters, complications and mortality of this disease. Prospective translational studies are required to better understand the pathogenesis of this disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1‐INH‐HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS‐2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. Methods: OPuS‐2 was a Phase 3, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator‐confirmed attacks. Results: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack‐free during the 84‐day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE‐QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. Conclusions: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1‐INH‐HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo. [ABSTRACT FROM AUTHOR]

Summary: This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well‐established registry. [ABSTRACT FROM AUTHOR]

Summary: Vaccine‐specific antibody responses are essential in the diagnosis of antibody deficiencies. Responses to Pneumovax II are used to assess the response to polysaccharide antigens, but interpretation may be complicated. Typhim Vi®, a polysaccharide vaccine for Salmonella typhoid fever, may be an additional option for assessing humoral responses in patients suspected of having an immunodeficiency. Here we report a UK multi‐centre study describing the analytical and clinical performance of a Typhi Vi immunoglobulin (Ig)G enzyme‐linked immunosorbent assay (ELISA) calibrated to an affinity‐purified Typhi Vi IgG preparation. Intra‐ and interassay imprecision was low and the assay was linear, between 7·4 and 574 U/ml (slope = 0·99–1·00; R2 > 0·99); 71% of blood donors had undetectable Typhi Vi IgG antibody concentrations. Of those with antibody concentrations  > 7·4 U/ml, the concentration range was 7·7–167 U/ml. In antibody‐deficient patients receiving antibody replacement therapy the median Typhi Vi IgG antibody concentrations were  < 25 U/ml. In vaccinated normal healthy volunteers, the median concentration post‐vaccination was 107 U/ml (range 31–542 U/ml). Eight of eight patients (100%) had post‐vaccination concentration increases of at least threefold and six of eight (75%) of at least 10‐fold. In an antibody‐deficient population (n = 23), only 30% had post‐vaccination concentration increases of at least threefold and 10% of at least 10‐fold. The antibody responses to Pneumovax II and Typhim Vi® correlated. We conclude that IgG responses to Typhim Vi® vaccination can be measured using the VaccZyme Salmonella typhi Vi IgG ELISA, and that measurement of these antibodies maybe a useful additional test to accompany Pneumovax II responses for the assessment of antibody deficiencies. [ABSTRACT FROM AUTHOR]

Background: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled.Methods: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers.Results: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 μg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months.Conclusions: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination. [ABSTRACT FROM AUTHOR]

There is no standardized method for assessing serum total mast cell tryptase ( MCT) in anaphylaxis. The consensus equation (peak MCT should be>1.2× baseline tryptase+2 mg/L) has been proposed to interpret acute MCT in mast cell activation syndrome ( MCAS). To validate consensus equation in a perioperative setting analyses of cases of suspected perioperative anaphylaxis during general anaesthesia ( GA) were performed. Anaphylaxis was defined as per World Allergy Organisation ( WAO) criteria. Timed serial MCT measurements were mapped against the consensus equation and receiver operating characteristic ( ROC) curves produced. A total of 82 patients (60 females, mean age 56.5 years± SD17.2) underwent investigation. Sixty (73%) patients fulfilled WAO criteria for anaphylaxis, and 22 patients did not. Aetiology included 59% IgE-mediated anaphylaxis, 2% non-IgE-mediated anaphylaxis, 12% anaphylaxis of unknown cause and 27% deemed non-anaphylaxis. IgE-mediated anaphylaxis included the following: NMBA (35%), antibiotics (46%), chlorhexidine (8%), patent blue dye (8%) and others (8%). An acute MCT with a comparable baseline was available in 71 of 82 (87%) patients (60 anaphylaxis and 11 controls). The median interquartile range ( IQR) time from reaction to peak MCT was 1.34 (0.82-2.51) hours. Analyses confirmed that a rise in acute MCT greater than that defined by the equation had a sensitivity, specificity, positive predictive value ( PPV) and negative (N) PV of 78%, 91%, 98% and 44%, respectively. The magnitude of increase in acute MCT above the threshold predicted by consensus equation was higher in the anaphylaxis group compared to controls ( P=.0001). This equation has a high specificity, PPV with a moderate NPV and sensitivity in perioperative anaphylaxis. [ABSTRACT FROM AUTHOR]

Approximately 90-99% of patients with a label of penicillin allergy (PenA) are not allergic when comprehensively investigated. An inaccurate label of PenA has major public health implications-longer hospital stay, more frequent hospital admissions, greater use of fluoroquinolones, glycopeptides, cephalosporins and other expensive antibiotics resulting in significantly higher costs to the health service and predisposing to Clostridium difficile, methicillin-resistant Staphylococcus aureus infections and vancomycin-resistant enterococcus. We describe lessons learnt from recent studies regarding possible reasons contributing to an inaccurate label of PenA as well as propose a concerted multidisciplinary approach to address this important public health problem. Given the unmet need for allergy services in the UK and several other countries and knowledge gaps regarding PenA amongst healthcare professionals, we describe the potential role for a computerized clinical decision support system to enable non-specialists rapidly identify and de-label 'low-risk' hospitalized patients with a label of PenA thereby obviating the need for allergy tests. This approach however needs rigorous evaluation for feasibility, safety, patient and physician acceptability, cost-effectiveness and its compatibility with information technology systems currently employed in the health service. [ABSTRACT FROM AUTHOR]

In this paper, we consider the adaptive attitude control of spacecraft with time-varying inertial properties. We use a coordinate independent approach for the purpose of designing the control and estimation laws in terms of the rotation matrices representing the spacecraft body frame and reference tracking signals. This method helps to overcome the difficulties regarding the attitude representation on SO(3) such as ambiguities associated with quaternion representation and inherent singularities inside Euler parameters. We model the time variations in inertial parameters in two different ways, and design adaptive control schemes for each case. As the first uncertain dynamic model, we consider a setting of spacecraft with multiple moving appendages, and based on this model, design an adaptive control scheme with three different versions, where Frobenious norm is used in measuring the deviation of the estimated inertia tensors from their actual values. The proposed adaptive control scheme is later extended for the more direct model where the inertia tensor of the spacecraft has a nonlinear relation with the norm of the input moment. Further, we derive the allowable sets of initial conditions to ensure the convergence of the tracking error. Simulation results are provided to illustrate the effectiveness of our proposed approach. [ABSTRACT FROM AUTHOR]

This review discusses how the T-cell compartment in common variable immunodeficiency is marked by the premature arrest in thymic output, leading to T-cell exhaustion and immune dysregulation. Although B cells have been the main focus of the disorder, ample experimental data suggest that T-cell abnormalities can be seen in a large proportion of Freiburg Group 1a patients and those suffering from inflammatory complications. The reductions in T-cell receptor excision circles, naïve T cells, invariant NKT cells and regulatory T cells suggest a diminished thymic output, while CD8 T cells are driven towards exhaustion either via an antigen-dependent or an antigen-independent manner. The theoretical risk of anti-T-cell therapies is discussed, highlighting the need for an international effort in generating longitudinal data in addition to better-defined underlying molecular characterisation. [ABSTRACT FROM AUTHOR]

This paper considers the fast and accurate estimation of motion variables of a rigid body object whose movement occurs from intermittent contacts with coordinating manipulators in nonprehensile manipulation tasks. The estimator operates under multiple sensory data including visual, joint torque, joint position and/or tactile measurements which are combined at the lower level to compensate for the latency and the slow sampling of the visual data. The estimator is real-time in the sense that it provides the motion data of the target object at the same fast sample rate of the servo controller without delay. The basic formulation is the multi-rate Kalman filter with the contact force vector as its process input, and the visual observation as its measurement output signal which is the down-sampled and delayed version of the configuration of the target object. Experimental tests are conducted for the case of planar object manipulation as well as the non-centroidal rotation under gravity using a robotic hand, and their results are presented to demonstrate the validity of the proposed estimation scheme. [ABSTRACT FROM AUTHOR]

Telemedicine refers to the application of telecommunication and information technology ( IT) in the delivery of health and clinical care at a distance or remotely and can be broadly considered in two modalities: store-and-forward and real-time interactive services. Preliminary studies have shown promising results in radiology, dermatology, intensive care, diabetes, rheumatology and primary care. However, the evidence is limited and hampered by small sample sizes, paucity of randomized control studies and lack of data relating to cost-effectiveness, health-related quality of life and patient and clinician satisfaction. This review appraises the evidence from studies that have employed telemedicine tools in other disciplines and makes suggestions for its potential applications in specific clinical scenarios in adult allergy services. Possible examples include: triaging patients to determine the need for allergy tests; pre-assessment for specialized treatments such as allergen immunotherapy, follow-up to assess treatment response and side effects; and education in self-management plan including training updates for self-injectable adrenaline and nasal spray use. This approach might improve access for those with limited mobility or living far away from regional centres, as well as bringing convenience and cost savings for the patient and service provider. These potential benefits need to be carefully weighed against evidence of service safety and quality. Keys to success include delineation of appropriate clinical scenarios, patient selection, training, IT support and robust information governance framework. Well-designed prospective studies are needed to evaluate its role. [ABSTRACT FROM AUTHOR]

Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype. This study used data from the national UK Primary Immune Deficiency (UKPID) registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. A total of 801 adults labelled with idiopathic hypogammaglobulinaemia and CVID aged 18-96 years from 10 UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leucocyte numbers and serum immunoglobulin concentrations) were collated and analysed using uni- and multivariate statistics. Low serum immunoglobulin (Ig)G pre-immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy [5 (range 1-13 years) versus 9 (range 2-24) years]. Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication [7 (range 2-22) years versus 5 (range 1-13) years]. Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinaemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both haematological and non-haematological, was associated with significantly lower absolute CD8+ T cell but not natural killer (NK) cell numbers, raising the question as to what extent immune senescence, particularly of CD8+ T cells, might contribute to the increased risk of cancers as individuals age. [ABSTRACT FROM AUTHOR]

Background: The incidence of anaphylaxis in South Asians (Indian, Pakistani and Bangladeshi ethnicity) is unknown. Birmingham is a British city with a disproportionately large population of South Asians (22.5%) compared with the rest of the UK (4.9%). The main aims of this study were to determine the incidence and severity of anaphylaxis in this population and to investigate the differences between the South Asian and White populations. Methods: A retrospective electronic search of emergency department attendances at three hospitals in Birmingham during 2012 was carried out. Wide search terms were used, medical notes were scrutinized, and the World Allergy Organization diagnostic criteria for anaphylaxis were applied. Patients' age, sex, ethnicity and home postal code were collected, reactions were graded by severity, and other relevant details including specialist assessment were extracted. Multivariate analysis was undertaken using 2011 UK census data. Results: Age-, sex- and ethnicity-standardized incidence rate of anaphylaxis was 34.5 per 100 000 person-years. Multivariate logistic regression which controlled for the confounders of age, sex and level of socioeconomic deprivation showed that incidence was higher in the South Asian population (OR 1.48, P = 0.005). Incidence rate in the South Asian population was 58.3 cases per 100 000 personyears compared to 31.5 in the White population. South Asian children were more likely to present with severe anaphylaxis (OR 5.31, P = 0.002). Conclusions: Incidence of anaphylaxis is significantly higher in British South Asians compared to the white population. British South Asian children are at a greater risk of severe anaphylaxis than White children. [ABSTRACT FROM AUTHOR]

Introduction: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management. Methods: Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software. Results: Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects ( p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects. Conclusion: The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients. [ABSTRACT FROM AUTHOR]

The combination of common population prevalence and the likelihood of vaccines precipitating symptoms in those with CSU/A presents an immediate risk to the SARS-CoV-2 global vaccine programme. A proportion of patients with CSU/A can be expected to experience worsened symptoms in association with recent SARS-CoV-2 vaccination, which may be easily misinterpreted as "vaccine allergy". Forewarned is forearmed: chronic spontaneous urticaria as a potential risk to effective SARS-CoV-2 vaccine uptake and global public health. [Extracted from the article]