Pneumococcal Vaccine Breakthrough and Failure in Infants and Children: A Narrative Review.

Globally, Streptococcus pneumoniae is a leading cause of vaccine-preventable morbidity and mortality in infants and children. In recent decades, large-scale pediatric immunization programs have substantially reduced the incidence of invasive pneumococcal disease. Despite this, residual vaccine-type pneumococcal disease remains in the form of vaccine breakthrough and vaccine failure. This targeted literature review aims to discuss aspects of vaccine breakthrough and failure in infants and children, including disease epidemiology, clinical presentation, risk factors, vaccination schedules, vaccine serotypes, correlates of protection, comorbidities, disease surveillance, and potential implications for future vaccine development.

Economic Evaluation of the Protecting Teeth @ 3 Randomized Controlled Trial.

INTRODUCTION: An economic evaluation (EE) was conducted alongside a randomized controlled trial (the Protecting Teeth @ 3 Study [PT@3]), exploring the additional preventive value of fluoride varnish (FV) application at 6-monthly intervals in nursery schools compared to treatment as usual (TAU) in the same nurseries. TAU represented a multicomponent national child oral health improvement intervention, the Childsmile program, apart from nursery FV. METHODS: The EE was a within-trial cost-utility analysis (CUA) comparing the FV and TAU groups. The CUA was conducted from a National Health Service perspective and followed relevant methods guidance. Within-trial costs included intervention costs and health care resource use costs. Health outcomes were expressed in quality-adjusted life years (QALYs) accrued over the 2-y follow-up period. The Child Health Utility 9 Dimensions questionnaire was used to obtain utility scores. National reference costs were used, a discount rate of 1.5% for public health interventions was adopted, multiple imputation methods for missing data were employed, sensitivity analyses were conducted, and incremental cost-utility ratios were calculated. RESULTS: Data from 534 participants from the 2014-2015 PT@3 intake were used in the EE analyses, n = 265 (50%) in the FV arm and n = 269 (50%) in the TAU arm. Mean incremental cost per child in the FV arm was £68.37 (P = 0.382; 95% confidence interval [CI], -£18.04 to £143.82). Mean incremental QALY was -0.004 (P = 0.636; 95% CI, -0.016 to 0.007). The probability that the FV intervention was cost-effective at the UK £20,000 threshold was 11.3%. CONCLUSION: The results indicate that applying FV in nurseries in addition to TAU (all other components of Childsmile, apart from nursery FV) would not be deemed cost-effective given current UK thresholds. In view of previously proven clinical effectiveness and economic worthiness of the universal nursery toothbrushing component of Childsmile, continuation of the additional, targeted nursery FV component in its pre-COVID-19 form should be reviewed given its low probability of cost-effectiveness. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by child oral health policy makers and dental public health professionals. They can form part of the evidence to inform the Scottish, UK, and international guidance on community-based child oral health promotion programs.

Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Using consensus methods to develop a Social Prescribing Learning Needs Framework for practitioners in Wales.

AIMS: Social prescribing is being widely implemented in Wales, but there is no consensus on the necessary learning, training and education needs for people delivering social prescribing. The purpose of the study was to develop an education and training needs conceptual framework for social prescribers in Wales, which could be used by commissioners and providers for the development of social prescribing curricula. METHODS: This study used two consensus methods. First, Group Concept Mapping using Concept Systems Global MaxTM software which identified the important and available learning needs of 18 (n = 18) geographically spread social prescribing practitioners. Second, a world café style workshop asked 85 (n = 85) social prescribers to identify when training and support would be most appropriate and valuable in developing their role and skills. RESULTS: A Social Prescribing Learning Needs Framework was developed identifying important learning needs and their availability across a timeline from induction onwards. This was conceptualised from a group concept mapping cluster map and go-zone report. The map comprises five clusters of statements (compassion, interpersonal relationships, socioeconomic disadvantage, networking and monitoring data) from the original 120 statements of learning needs identified by participants. The Go-Zone report displayed how each learning need was rated by participants on scales of importance and availability. A large number of training needs (45%) that were identified as important, are not currently available to social prescribers. All training needs were placed within the first year of the social prescriber working timeline, with 39% placed in an induction period. CONCLUSION: The use of two different consensus methods enabled social prescribers geographically spread across Wales to engage with the study. The Social Prescribing Learning Needs Framework will be used to inform the commissioning and decommissioning of training for people delivering social prescribing in Wales.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Ensemble of Convolutional Neural Networks Improves Automated Segmentation of Acute Ischemic Lesions Using Multiparametric Diffusion-Weighted MRI.

BACKGROUND AND PURPOSE: Accurate automated infarct segmentation is needed for acute ischemic stroke studies relying on infarct volumes as an imaging phenotype or biomarker that require large numbers of subjects. This study investigated whether an ensemble of convolutional neural networks trained on multiparametric DWI maps outperforms single networks trained on solo DWI parametric maps. MATERIALS AND METHODS: Convolutional neural networks were trained on combinations of DWI, ADC, and low b-value-weighted images from 116 subjects. The performances of the networks (measured by the Dice score, sensitivity, and precision) were compared with one another and with ensembles of 5 networks. To assess the generalizability of the approach, we applied the best-performing model to an independent Evaluation Cohort of 151 subjects. Agreement between manual and automated segmentations for identifying patients with large lesion volumes was calculated across multiple thresholds (21, 31, 51, and 70 cm3). RESULTS: An ensemble of convolutional neural networks trained on DWI, ADC, and low b-value-weighted images produced the most accurate acute infarct segmentation over individual networks (P < .001). Automated volumes correlated with manually measured volumes (Spearman ρ = 0.91, P < .001) for the independent cohort. For the task of identifying patients with large lesion volumes, agreement between manual outlines and automated outlines was high (Cohen κ, 0.86-0.90; P < .001). CONCLUSIONS: Acute infarcts are more accurately segmented using ensembles of convolutional neural networks trained with multiparametric maps than by using a single model trained with a solo map. Automated lesion segmentation has high agreement with manual techniques for identifying patients with large lesion volumes.

Cost-impact study of rotavirus vaccination programme in Scotland.

Aim: In July 2013, the Scottish Government introduced a rotavirus vaccination programme into the childhood immunisation schedule. The aim of this research was to estimate the cost-impact of this programme. Methods: Data for rotavirus-related resource use were identified including laboratory reports, hospitalisations, attendances at accident and emergency departments (A&E), general practice consultations (GP), calls to the National Health Service telephone helpline (NHS24) and prescriptions for common rehydration treatments. We used an interrupted time series analysis approach to assess the impact on resource utilisation in all categories. Appropriate costs were added to the models and predicted pre-and post-vaccination mean annual costs were estimated. The cost of the vaccination programme was estimated using costs from the literature. Results: The vaccination programme was associated with a reduction in utilisation in all measured healthcare resource categories. These reductions were all statistically significant (at the 95% level) with p-values less than 0.001. Reductions ranged from 18% in calls to NHS24 to 73% in positive laboratory reports. The vaccination programme was associated with a reduction in annual healthcare resource costs of 38% (£595,000 per 100,000 infants < 5 years old) in our measured categories (including £495,000 from a reduction in hospital stays). The annual overall cost-impact of the rotavirus vaccination programme (the cost of delivering the programme minus the reduction in resource costs) was estimated at approximately £435,000 per 100,000 infants < 5 years old. Conclusion: The rotavirus vaccination programme was associated with a reduction in all measured categories of rotavirus-related resource use by infants < 5 years old.

Healthcare-associated infections: potential for prevention through vaccination.

The challenge of healthcare-associated infections is compounded by the higher incidence of resistant organisms and the decreasing utility of antimicrobial agents. Historic and current vaccines have already contributed to reductions in healthcare-associated infections, and future vaccines have the potential to reduce these infections further. Through examples of bacterial and viral vaccines, this review will attempt to chart the way forward.

Potential Cost-Effectiveness of RSV Vaccination of Infants and Pregnant Women in Turkey: An Illustration Based on Bursa Data.

BACKGROUND: Worldwide, respiratory syncytial virus (RSV) is considered to be the most important viral cause of respiratory morbidity and mortality among infants and young children. Although no active vaccine is available on the market yet, there are several active vaccine development programs in various stages. To assess whether one of these vaccines might be a future asset for national immunization programs, modeling the costs and benefits of various vaccination strategies is needed. OBJECTIVES: To evaluate the potential cost-effectiveness of RSV vaccination of infants and/or pregnant women in Turkey. METHODS: A multi-cohort static Markov model with cycles of one month was used to compare the cost-effectiveness of vaccinated cohorts versus non-vaccinated cohorts. The 2014 Turkish birth cohort was divided by twelve to construct twelve monthly birth cohorts of equal size (111,459 new-borns). Model input was based on clinical data from a multicenter prospective study from Bursa, Turkey, combined with figures from the (inter)national literature and publicly available data from the Turkish Statistical Institute (TÜÏK). Incremental cost-effectiveness ratios (ICERs) were expressed in Turkish Lira (TL) per quality-adjusted life year (QALY) gained. RESULTS: Vaccinating infants at 2 and 4 months of age would prevent 145,802 GP visits, 8,201 hospitalizations and 48 deaths during the first year of life, corresponding to a total gain of 1650 QALYs. The discounted ICER was estimated at 51,969 TL (26,220 US $ in 2013) per QALY gained. Vaccinating both pregnant women and infants would prevent more cases, but was less attractive from a pure economic point of view with a discounted ICER of 61,653 TL (31,106 US $ in 2013) per QALY. Vaccinating only during pregnancy would result in fewer cases prevented than infant vaccination and a less favorable ICER. CONCLUSION: RSV vaccination of infants and/or pregnant women has the potential to be cost-effective in Turkey. Although using relatively conservative assumptions, all evaluated strategies remained slightly below the threshold of 3 times the GDP per capita.

Serum bactericidal antibody assays - The role of complement in infection and immunity.

Complement is an essential component of the immune system and human pathogenic organisms have developed various mechanisms for evading complement mediated serum killing. The "gold standard" for measuring the ability of vaccine-induced antibody to kill Neisseria meningitidis is the serum bactericidal antibody (SBA) assay which measures complement mediated killing via antibody. This assay requires active complement, either intrinsic from the serum being tested or the addition of exogenous complement, either from a human or from another species such as rabbit. For serogroup C, an SBA titre of ≥4 was established as the correlate of protection when using human complement and ≥8 as the threshold when using rabbit complement, based on comparative assay results. Licensure of meningococcal vaccines, including polysaccharide protein conjugate vaccines and serogroup B vaccines has been based on the immune responses measured with the SBA assay, thus on a surrogate of vaccine efficacy. This review examines the use of complement and the SBA assay to assess immunity to meningococcal infection, and provides examples of vaccine trials in different age groups where various assays have been used.

Prevention of rare diseases: how revolutionary techniques can help vulnerable individuals-the example of serogroup B meningococcal infection.

In countries with established programmes for vaccination of infants, toddlers and adolescents with meningococcal conjugate vaccines, serogroup B invasive meningococcal disease remains the major cause of septicaemia and meningitis in the paediatric and adolescent age groups. Novartis has developed a serogroup B meningococcal vaccine, 4CMenB, to meet this need. We reviewed all 4CMenB studies. The studies found 4CMenB to be highly immunogenic when administered in all schedules, with protective antibody levels (serum bactericidal antibody titres ≥4 or ≥5 with human complement, hSBA) against serogroup B strains expressing vaccine antigens in >95% of vaccinated cohorts. When antibody levels waned, all tested groups demonstrated booster responses. Although possibly an underestimation, the Meningococcal Antigen Typing System (MATS) technique predicts that global coverage of 4CMenB against all serogroup B strains is in the range 66% (Canada) to 91% (USA). The vaccine was found to be generally well tolerated, although local and systemic reactions, notably fever in infants, typical of many vaccines, were increased following concomitant administration of 4CMenB with routine vaccines. When tested, prophylactic paracetamol significantly decreased the frequency and severity of reactions in infants, with no clinically significant impact on immunogenicity of 4CMenB or concomitant routine vaccines. The vaccine is approved for use in the following age groups in the European Union (2 months+), Canada (2 months through 17 years), Australia (2 months+) and Chile (2 months+), following clinical evaluation in 4843 infants and toddlers, and 1712 adolescents and adults, in schedules including a three-dose (2, 3, 4 or 2, 4, 6 months) and a two-dose (6-11 months) infant series with a booster in the second year of life, a two-dose series in toddlers (12-23 months) and children (2-10 years) given 2 months apart (with a booster at least in the EU), and a two-dose series in adolescents (11-17 years) given 1-6 months apart. 4CMenB presents a solution to the unmet medical need of offering protection against serogroup B invasive meningococcal disease in all age groups above 2 months.

Note: A simple model for thermal management in solenoids.

We describe a model of the dynamical temperature evolution in a solenoid winding. A simple finite element analysis is calibrated by accurately measuring the thermally induced resistance change of the solenoid, thus obviating the need for accurate knowledge of the mean thermal conductivity of the windings. The model predicts quasi thermal runaway for relatively modest current increases from the normal operating conditions. We demonstrate the application of this model to determine the maximum current that can be safely applied to solenoids used for helium spin-echo measurements.

Potential cost-effectiveness of pneumococcal conjugate vaccine (PCV) in Turkey.

BACKGROUND: Pneumococcal infection is an important and preventable cause of morbidity and mortality. The Turkish government introduced 7-valent pneumococcal conjugate vaccine (PCV) into the national immunization program in 2009. This suggests that replacing 7-valent PCV with a higher-valent version could at least maintain "standard of care" if not improve it, and that it could be affordable. OBJECTIVES AND METHODS: The aim of this analysis was to assess the potential direct cost-effectiveness of 13-valent PCV in Turkey, a country with a birth cohort of 1.4 million, against a "no vaccine" state, against the default 7-valent PCV state, and against a 10-valent PCV state, using a published cohort model with a 5-year horizon. RESULTS AND CONCLUSIONS: The cost per life-year gained is below the 1 × per-capita gross domestic product threshold across large changes in key input parameters, indicating that the model is stable and suggesting that any PCV would be very cost-effective in a Turkish national pediatric immunization schedule.

Measurement of the phason dispersion of misfit dislocations on the Au(111) surface.

We report measurements of the acoustic and optical phason dispersion curves associated with the lattice of partial dislocations on the reconstructed (111) surface of gold. Our measurements of these low energy (<0.5 meV) weakly dispersive modes have been enabled by the very high resolution of the novel helium spin-echo technique. The results presented here constitute the first measurement of the phason dispersion of misfit dislocations, and possibly of excitations associated with any type of crystalline dislocations.

Efflux: how bacteria use pumps to control their microenvironment.

Efflux pumps are a potent and clinically important cause of antibiotic resistance. The particular focus of this chapter is on the efflux pump as a target for antimicrobial therapy and the development of new antibacterials to address the efflux problem.Tigecycline is an example of how old antibiotics, in this case tetracyclines, which have become substrates for efflux pumps, can be extensively modified to restore antimicrobial activity and clinical efficacy.

Meningococcal vaccine development--from glycoconjugates against MenACWY to proteins against MenB--potential for broad protection against meningococcal disease.

Novartis Vaccines has a long-standing research and development interest in the prevention of invasive meningococcal disease. From the initial licensure of the monovalent meningococcal C glycoconjugate vaccine, Menjugate(®), in response to the emergence of a virulent serogroup C ST-11 strain in the United Kingdom to the more recent development and licensure of a quadrivalent meningococcal ACWY glycoconjugate vaccine, Menveo(®), Novartis has a continuing commitment to the development of more effective tools for the control of meningococcal disease. Menveo is now licensed for use in adolescents and adults in over 50 countries and results from phase III studies have shown the vaccine to be well-tolerated and highly immunogenic in infants with vaccination beginning from 2 months of age. The 'holy grail' of meningococcal disease control is a broadly protective vaccine against serogroup B (MenB), preferably a vaccine that protects all age groups including infants. As the serogroup B capsule is poorly immunogenic, efforts over the past 40 years have focused on identifying conserved proteins expressed on the bacterial surface that elicit bactericidal antibodies. Novartis has approached this problem utilizing genomic tools to identify proteins meeting these criteria in a process now known as 'reverse vaccinology'[1]. This process has resulted in a novel multicomponent MenB vaccine (4CMenB) that consists of four major immunogenic components (three subcapsular MenB protein antigens plus outer membrane vesicles (OMVs) which themselves provide multiple subcapsular antigens, the immunodominant one being PorA). These all induce bactericidal antibodies against the antigens that are important in determining the survival, function, and virulence of the meningococci. Phase II studies of 4CMenB have been completed and have demonstrated that the vaccine is highly immunogenic against reference meningococcal strains selected to support licensure. Post-vaccination sera from clinical studies have also been tested against a diverse panel of serogroup B strains to support the development of the Meningococcal Antigen Typing System (MATS), a tool used to predict vaccine strain coverage [2] This overview is intended to give a broad summary of the key clinical data derived from the Menveo and 4CMenB clinical development programs.