Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis

The evaluation of vaccines for human use requires reliable models of infection, that are predictive of protective efficacy. Traditionally whole cell pertussis vaccines (Pw) have been controlled using the Kendrick test, which measures protection following intracerebral challenge with Bordetella pertussis. However, this test is unsuitable for assessing the potency o f the new acellular pertussis vaccines (Pa). In this study, it was demonstrated that protection in a murine respiratory challenge model correlates with the protective efficacy of Pa and Pw in children, but vaccine potency could not be predicted on the basis of antibody responses against individual antigens. Furthermore, the murine model was shown to be a reliable method for the determination of consistency between different batches o f Pa and Pw. This study highlights the possible applications of the murine model in the regulatory control and future development of pertussis vaccines. The murine model of infection has been used in the elucidation of the protective mechanisms induced following immunization with Pw or Pa, revealing roles for both antibody and T-cells in protection against B. p ertu ssis. It has been demonstrated that children still appear to be protected against infection, despite a rapid decline in antibody levels after vaccination. In the murine model, antibody levels quickly decline after immunization, but significant levels of protection were observed following aerosol challenge. Recall T-cell responses detectable for prolonged periods after immunization, together with an anamnestic antibody response post-challenge suggest that immunological memory is more significant in protection, than the induction of immediate antibody responses in vaccine-induced protection against B. pertussis. It has been demonstrated that Thl responses and particularly the cytokine IFN-y, play a critical role in immunity to B. pertussis. In the present study, the role of IL-12 and IL-18 in the induction of a protective Thl response to B. p ertu ssis was examined. Lack of IL-12 during primary and secondary infection effected protection only at the early stages of infection, suggesting that IL-12 plays an important role at the induction stage of the immune response to B. pertussis, but also suggests that other cytokines may be involved. IL-18 is rapidly produced in the lungs of B. p ertu ssis infected IL-1 2~'~ and wild-type mice, which may compensate for the lack of IL-12 at the later stages of infection. The importance of Thl responses and IFN-y were fiirther highlighted in this study, through the investigation of the effect of helminth infection on the outcome o f B. p ertu ssis infection, or immunization with Pw. Infection with the parasite Fasciolahepatica , was shown to suppress B. pertussis-specific Thl responses, and delay bacterial clearance from the lungs, and was also shown to inhibit this Thl response after it had become established. Furthermore, it was demonstrated that infection with F. hepatic a was capable of downregulating the Thl response induced by systemic immunization with Pw, and reducing its protective efficacy. In addition, a role for IL-4 was demonstrated in the parasite-induced immunoregulation

Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis

The evaluation of vaccines for human use requires reliable models of infection, that are predictive of protective efficacy. Traditionally whole cell pertussis vaccines (Pw) have been controlled using the Kendrick test, which measures protection following intracerebral challenge with Bordetella pertussis. However, this test is unsuitable for assessing the potency o f the new acellular pertussis vaccines (Pa). In this study, it was demonstrated that protection in a murine respiratory challenge model correlates with the protective efficacy of Pa and Pw in children, but vaccine potency could not be predicted on the basis of antibody responses against individual antigens. Furthermore, the murine model was shown to be a reliable method for the determination of consistency between different batches o f Pa and Pw. This study highlights the possible applications of the murine model in the regulatory control and future development of pertussis vaccines. The murine model of infection has been used in the elucidation of the protective mechanisms induced following immunization with Pw or Pa, revealing roles for both antibody and T-cells in protection against B. p ertu ssis. It has been demonstrated that children still appear to be protected against infection, despite a rapid decline in antibody levels after vaccination. In the murine model, antibody levels quickly decline after immunization, but significant levels of protection were observed following aerosol challenge. Recall T-cell responses detectable for prolonged periods after immunization, together with an anamnestic antibody response post-challenge suggest that immunological memory is more significant in protection, than the induction of immediate antibody responses in vaccine-induced protection against B. pertussis. It has been demonstrated that Thl responses and particularly the cytokine IFN-y, play a critical role in immunity to B. pertussis. In the present study, the role of IL-12 and IL-18 in the induction of a protective Thl response to B. p ertu ssis was examined. Lack of IL-12 during primary and secondary infection effected protection only at the early stages of infection, suggesting that IL-12 plays an important role at the induction stage of the immune response to B. pertussis, but also suggests that other cytokines may be involved. IL-18 is rapidly produced in the lungs of B. p ertu ssis infected IL-1 2~'~ and wild-type mice, which may compensate for the lack of IL-12 at the later stages of infection. The importance of Thl responses and IFN-y were fiirther highlighted in this study, through the investigation of the effect of helminth infection on the outcome o f B. p ertu ssis infection, or immunization with Pw. Infection with the parasite Fasciolahepatica , was shown to suppress B. pertussis-specific Thl responses, and delay bacterial clearance from the lungs, and was also shown to inhibit this Thl response after it had become established. Furthermore, it was demonstrated that infection with F. hepatic a was capable of downregulating the Thl response induced by systemic immunization with Pw, and reducing its protective efficacy. In addition, a role for IL-4 was demonstrated in the parasite-induced immunoregulation

Multimodal Sparse Coding for Event Detection

Unsupervised feature learning methods have proven effective for classification tasks based on a single modality. We present multimodal sparse coding for learning feature representations shared across multiple modalities. The shared representations are applied to multimedia event detection (MED) and evaluated in comparison to unimodal counterparts, as well as other feature learning methods such as GMM supervectors and sparse RBM. We report the cross-validated classification accuracy and mean average precision of the MED system trained on features learned from our unimodal and multimodal settings for a subset of the TRECVID MED 2014 dataset.Comment: Multimodal Machine Learning Workshop at NIPS 201

Protection against Bordetella pertussis in mice in the absence of detectable circulating antibody: implications for long-term immunity in children

Most vaccines used for humans work through humoral immunity, yet many appear to be protective even after specific circulating antibody levels have waned to undetectable levels. Furthermore, it has been difficult to define a serologic correlate of protection against a number of infectious diseases, including those caused by Bordetella pertussis. B. pertussis clearance in immunized mice has been shown to correlate with pertussis vaccine efficacy in children. This murine respiratory challenge model was used to demonstrate persistent vaccine-induced protection against B. pertussis in the absence of circulating antibody at the time of challenge. Whole-cell and acellular pertussis vaccines induced persistent memory T and B cells and anamnestic antibody responses after challenge. The findings suggest that immunologic memory is more significant in protection than is the induction of immediate antibody responses and imply that vaccinated children still may be protected against disease following the disappearance of specific serum IgG

The implementation of a nurse led SACT clinic to reduce waiting times for patients with soft tissue sarcoma attending for systemic anti-cancer treatment (SACT). A service improvement project

Introduction: The principal aim of the project was to reduce the amount of time spent in hospital when attending for Day Case SACT treatment for soft tissue sarcoma. Additional aims included measuring patient satisfaction and assessing efficiency of the new service. Methods: The project was run following the Lean Six Sigma DMAIC framework; defining and measuring the problem of patients spending longer than necessary in hospital during day case appointments, with patient diaries and mapping current clinic flow. Points in the pathway were identified for improvement and optimum time was calculated. A new process map was then developed, and patient satisfaction questionnaires completed. One year review looked at reduction of time in clinic, efficiency of the nurse led service and patient satisfaction. Results Total time in hospital was reduced from 8 hours 31 minutes on average, to 3 hours 57 minutes. This is a reduction of 4 hours 34 minutes (53.6%). If treatment was authorized the day beforehand, time in hospital was reduced further, to 3 hours 18 minutes, reducing pre project time in hospital by 61.3% Patient questionnaires were completed by 12 patients and showed high rates of satisfaction. The majority of answers were scored (out of 5) 5 excellent, or 4 very good. Conclusion: The implementation of a nurse led SACT clinic led to a significant reduction in the amount of time patients spent in hospital on the day of their treatment. The nurse led service was successful in delivering SACT more efficiently and patients were highly satisfied

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized

Bathing Adaptations in the Homes of Older Adults (BATH-OUT-2) : study protocol for a randomised controlled trial, economic evaluation and process evaluation

Background The onset of disability in bathing is particularly important for older adults as it can be rapidly followed by disability in other daily activities; this may represent a judicious time point for intervention in order to improve health, well-being and associated quality of life. An important environmental and preventative intervention is housing adaptation, but there are often lengthy waiting times for statutory provision. In this randomised controlled trial (RCT), we aim to evaluate the effectiveness and cost-effectiveness of bathing adaptations compared to no adaptations and to explore the factors associated with routine and expedited implementation of bathing adaptations. Methods BATH-OUT-2 is a multicentre, two-arm, parallel-group RCT. Adults aged 60 and over who are referred to their local authority for an accessible level access shower will be randomised, using pairwise randomisation, 1:1, to receive either an expedited provision of an accessible shower via the local authority or a usual care control waiting list. Participants will be followed up for a maximum of 12 months and will receive up to four follow-ups in this duration. The primary outcome will be the participant’s physical well-being, assessed by the Physical Component Summary score of the Short Form-36 (SF-36), 4 weeks after the intervention group receives the accessible shower. The secondary outcomes include the Mental Component Summary score of the SF-36, self-reported falls, health and social care resource use, health-related quality of life (EQ-5D-5L), social care-related quality of life (Adult Social Care Outcomes Toolkit (ASCOT)), fear of falling (Short Falls Efficacy Scale), independence in bathing (Barthel Index bathing question), independence in daily activities (Barthel Index) and perceived difficulty in bathing (0–100 scale). A mixed-methods process evaluation will comprise interviews with stakeholders and a survey of local authorities with social care responsibilities in England. Discussion The BATH-OUT-2 trial is designed so that the findings will inform future decisions regarding the provision of bathing adaptations for older adults. This trial has the potential to highlight, and then reduce, health inequalities associated with waiting times for bathing adaptations and to influence policies for older adults. Trial registration ISRCTN Registry ISRCTN48563324. Prospectively registered on 09/04/2021

A randomized trial to assess the impact of opinion leader endorsed evidence summaries on the use of secondary prevention strategies in patients with coronary artery disease: the ESP-CAD trial protocol [NCT00175240]

BACKGROUND: Although numerous therapies have been shown to be beneficial in the prevention of myocardial infarction and/or death in patients with coronary disease, these therapies are under-used and this gap contributes to sub-optimal patient outcomes. To increase the uptake of proven efficacious therapies in patients with coronary disease, we designed a multifaceted quality improvement intervention employing patient-specific reminders delivered at the point-of-care, with one-page treatment guidelines endorsed by local opinion leaders ("Local Opinion Leader Statement"). This trial is designed to evaluate the impact of these Local Opinion Leader Statements on the practices of primary care physicians caring for patients with coronary disease. In order to isolate the effects of the messenger (the local opinion leader) from the message, we will also test an identical quality improvement intervention that is not signed by a local opinion leader ("Unsigned Evidence Statement") in this trial. METHODS: Randomized trial testing three different interventions in patients with coronary disease: (1) usual care versus (2) Local Opinion Leader Statement versus (3) Unsigned Evidence Statement. Patients diagnosed with coronary artery disease after cardiac catheterization (but without acute coronary syndromes) will be randomly allocated to one of the three interventions by cluster randomization (at the level of their primary care physician), if they are not on optimal statin therapy at baseline. The primary outcome is the proportion of patients demonstrating improvement in their statin management in the first six months post-catheterization. Secondary outcomes include examinations of the use of ACE inhibitors, anti-platelet agents, beta-blockers, non-statin lipid lowering drugs, and provision of smoking cessation advice in the first six months post-catheterization in the three treatment arms. Although randomization will be clustered at the level of the primary care physician, the design effect is anticipated to be negligible and the unit of analysis will be the patient. DISCUSSION: If either the Local Opinion Leader Statement or the Unsigned Evidence Statement improves secondary prevention in patients with coronary disease, they can be easily modified and applied in other communities and for other target conditions