Evaluation of ImpENSA technology-enabled behaviour change module delivered to healthcare professionals in South Africa to improve micronutrient nutrition during the first 1000 days.

Healthcare professionals (HCPs) have vital roles in providing evidence-based care to promote healthy micronutrient nutrition in early life. Providing such care requires scalable training to strengthen knowledge and confident application of effective behaviour change skills. Among 33 public and private HCPs (primarily dietitians) in South Africa, we evaluated the behaviour change aspects of a technology-enabled National Qualification Sub-Framework level 6 programme, Improving Early Nutrition and Health in South Africa ('ImpENSA'). This programme comprises two self-directed micronutrient and behaviour change knowledge-based eLearning and one facilitated online practical skills modules to improve maternal and infant micronutrient nutrition. Using assessments, questionnaires and interviews, we collected data at baseline, after module completion and at 3-month follow-up after programme completion. Questionnaire and interview data showed major improvements in understanding of and attitudes towards person-centred behaviour change support immediately following the eLearning module on behaviour change. The assessment pass rate increased from 38% at baseline to 88% postmodule, demonstrating significant knowledge gain in behaviour change support. Intention to change practice towards a person-centred approach was high and many had already started implementing changes. Three months postprogramme, support was centred around patients' needs. Open relationships with patients, improved patient outcomes and increased job satisfaction were among reported outcomes. Many reported becoming better change facilitators and reflective practitioners. Additional improvements in understanding and attitudes to behaviour change support were evident, reinforced by making changes and experiencing positive outcomes. The findings suggest that technology-enabled learning can equip HCPs with knowledge and skills to effectively support behaviour change for healthy micronutrient nutrition during pregnancy and infancy.

Role of overnight oximetry in assessing the severity of obstructive sleep apnoea in typically developing children: a multicentre study.

BACKGROUND AND OBJECTIVE: Cardiorespiratory polygraphy (CRP) is the predominant technology used to diagnose obstructive sleep apnoea (OSA) in tertiary centres in the UK. Nocturnal pulse oximetry (NPO) is, however, cheaper and more accessible. This study evaluated the ability of NPO indices to predict OSA in typically developing (TD) children. METHODS: Indices from simultaneous NPO and CRP recordings were compared in TD children (aged 1-16 years) referred to evaluate OSA in three tertiary centres. OSA was defined as an obstructive apnoea-hypopnoea index (OAHI) ≥1 event/hour. Receiver operating characteristic curves assessed the diagnostic accuracy of NPO indices including ODI3 (3% Oxygen Desaturation Index, ODI4 (4% Oxygen Desaturation Index), delta 12 s index and minimum oxygen saturation. Two-by-two tables were generated to determine the sensitivities and specificities of whole number cut-off values for predicting OAHIs ≥1, 5 and 10 events/hour. RESULTS: Recordings from 322 TD children, 197 male (61.2%), median age 4.9 years (range 1.1-15.6), were reviewed. OAHI was ≥1/hour in 144 (44.7%), ≥5/hour in 61 (18.9%) and ≥10/hour in 28 (8.7%) cases. ODI3 and ODI4 had the best diagnostic accuracy. ODI3 ≥7/hour and ODI4 ≥4/hour predicted OSA in TD children with sensitivities/specificities of 57.6%/85.4% and 46.2%/91.6%, respectively. ODI3 ≥8/hour was the best predictor of OAHI ≥5/hour (sensitivity 82.0%, specificity 84.3%). CONCLUSION: Raised ODI3 and ODI4 predict OSA in TD children with high specificity but variable sensitivity. NPO may be an alternative to diagnose moderate-severe OSA if access to CRP is limited. Low sensitivities to detect mild OSA mean that confirmatory CRP is needed if NPO is normal.

An Exploratory Study Provides Insights into MMP9 and Aß Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients.

Matrix metalloproteinase-9 (MMP9) and total amyloid-beta (Aß) are prospective biomarkers of ocular ageing and retinopathy. These were quantified by ELISA in the vitreous and blood from controls (n = 55) and in a subset of age-related macular degeneration (AMD) patients (n = 12) for insights and possible additional links between the ocular and systemic compartments. Vitreous MMP9 levels in control and AMD groups were 932.5 ± 240.9 pg/mL and 813.7 ± 157.6 pg/mL, whilst serum levels were 2228 ± 193 pg/mL and 2386.8 ± 449.4 pg/mL, respectively. Vitreous Aß in control and AMD groups were 1173.5 ± 117.1 pg/mL and 1275.6 ± 332.9 pg/mL, whilst plasma Aß were 574.3 ± 104.8 pg/mL and 542.2 ± 139.9 pg/mL, respectively. MMP9 and Aß showed variable levels across the lifecourse, indicating no correlation to each other or with age nor AMD status, though the smaller AMD cohort was a limiting factor. Aß and MMP9 levels in the vitreous and blood were unrelated to mean arterial pressure. Smoking, another modifiable risk, showed no association with vitreous Aß. However, smoking may be linked with vitreous (p = 0.004) and serum (p = 0.005) MMP9 levels in control and AMD groups, though this did not reach our elevated (p = 0.001) significance. A bioinformatics analysis revealed promising MMP9 and APP/Aß partners for further scrutiny, many of which are already linked with retinopathy.

Implementing effective eLearning for scaling up global capacity building: findings from the malnutrition elearning course evaluation in Ghana.

BACKGROUND: Global demand for capacity building has increased interest for eLearning. As eLearning resources become more common, effective implementation is required to scale up utilization in Low- and Middle-Income Countries (LMICs). OBJECTIVE: This paper describes the process of implementing a malnutrition eLearning course, effectiveness of course delivery models devised, factors affecting course completion, and cost comparison between the models and face-to-face training at healthcare and academic institutions in Ghana. METHODS: Four delivery models: Mobile Training Centre (MTC), Online Delivery (OD), Institutional Computer Workstation (ICW) and Mixed Delivery (MD) - a combination of OD and ICW - were determined. Participants were enabled to access the course using one of the four models where contextually appropriate. Pre and post-assessments and questionnaires were administered to compare participants' course completion status and knowledge gain between delivery models. The effect of access to computer and Internet at home and relevance of course to job and academic progression on course completion were further investigated. Comparison of delivery model costs against face-to-face training was also undertaken. RESULTS: Of 7 academic and 9 healthcare institutions involving 915 people, 9 used MTC (34.8%), 3 OD (18.8%), 3 ICW (34.2%) and 1 MD (12.2%). Course completion was higher among institutions where the course was relevant to job or implemented as part of required curriculum activities. Knowledge gain was significant among most participants, but higher among those who found the course relevant to job or academic progression. The implementation costs per participant for training with MTC were £51.0, OD £2.2, ICW £1.2 and MD £1.1, compared with a face-to-face training estimate of £105.0 (1 GHS = 0.14 GBP). CONCLUSION: The malnutrition eLearning course makes global capacity building in malnutrition management achievable. Adopting contextually appropriate delivery models and ensuring training is relevant to job/academic progression can enhance eLearning effectiveness in LMICs.

Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer's Disease.

Drainage of interstitial fluid from the brain occurs via the intramural periarterial drainage (IPAD) pathways along the basement membranes of cerebral capillaries and arteries against the direction of blood flow into the brain. The cerebrovascular smooth muscle cells (SMCs) provide the motive force for driving IPAD, and their decrease in function may explain the deposition of amyloid-beta as cerebral amyloid angiopathy (CAA), a key feature of Alzheimer's disease. The α-adrenoceptor subtype α1A is abundant in the brain, but its distribution in the cerebral vessels is unclear. We analysed cultured human cerebrovascular SMCs and young, old and CAA human brains for (a) the presence of α1A receptor and (b) the distribution of the α1A receptor within the cerebral vessels. The α1A receptor was present on the wall of cerebrovascular SMCs. No significant changes were observed in the vascular expression of the α1A-adrenergic receptor in young, old and CAA cases. The pattern of vascular staining appeared less punctate and more diffuse with ageing and CAA. Our results show that the α1A-adrenergic receptor is preserved in cerebral vessels with ageing and in CAA and is expressed on cerebrovascular smooth muscle cells, suggesting that vascular adrenergic receptors may hold potential for therapeutic targeting of IPAD.

Health-related quality of life, functional impairment and comorbidity in people with mild-to-moderate chronic kidney disease: a cross-sectional study.

OBJECTIVES: To determine the associations between comorbidities, health-related quality of life (HRQoL) and functional impairment in people with mild-to-moderate chronic kidney disease (CKD) in primary care. DESIGN: Cross-sectional analysis at 5-year follow-up in a prospective cohort study. SETTING: Thirty-two general practitioner surgeries in England. PARTICIPANTS: 1008 participants with CKD stage 3 (of 1741 people recruited at baseline in the Renal Risk in Derby study) who survived to 5 years and had complete follow-up data for HRQoL and functional status (FS). PRIMARY AND SECONDARY OUTCOME MEASURES: HRQoL assessed using the 5-level EQ-5D version (EQ-5D-5L, with domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression and index value using utility scores calculated from the English general population), and FS using the Karnofsky Performance Status scale (functional impairment defined as Karnofksy score ≤70). Comorbidity was defined by self-reported or doctor-diagnosed condition, disease-specific medication or blood result. RESULTS: Mean age was 75.8 years. The numbers reporting some problems in EQ-5D-5L domains were: 582 (57.7%) for mobility, 166 (16.5%) for self-care, 466 (46.2%) for usual activities, 712 (70.6%) for pain/discomfort and 319 (31.6%) for anxiety/depression. Only 191 (18.9%) reported no problems in any domain. HRQoL index values showed greater variation among those with lower FS (eg, for those with Karnofsky score of 60, the median (IQR) EQ-5D index value was 0.45 (0.24 to 0.68) compared with 0.94 (0.86 to 1) for those with Karnofsky score of 90). Overall, 234 (23.2%) had functional impairment.In multivariable logistic regression models, functional impairment was independently associated with experiencing problems for all EQ-5D-5L domains (mobility: OR 16.87 (95% CI 8.70 to 32.79, p<0.001, self-care: OR 13.08 (95% CI 8.46 to 20.22), p<0.001, usual activities: OR 8.27 (95% CI 5.43 to 12.58), p<0.001, pain/discomfort: OR 2.94 (95% CI 1.86 to 4.67), p<0.001, anxiety/depression: 3.08 (95% CI 2.23 to 4.27), p<0.001). Higher comorbidity count and obesity were independently associated with problems in mobility, self-care, usual activities and pain/discomfort: for three or more comorbidities versus none: (mobility: OR 2.10 (95% CI 1.08 to 4.10, p for trend 0.002), self-care: OR 2.64 (95% CI 0.72 to 9.67, p for trend 0.05), usual activities: OR 4.20 (95% CI 2.02 to 8.74, p for trend <0.001), pain/discomfort: OR 3.06 (95% CI 1.63 to 5.73, p for trend <0.001)), and for obese (body mass index (BMI) ≥30 kg/m2) versus BMI <25 kg/m2: (mobility: OR 2.44 (95% CI 1.61 to 3.69, p for trend <0.001), self-care: OR 1.98 (95% CI 1.06 to 3.71, p for trend 0.003), usual activities: OR 1.82 (95% CI 1.19 to 2.76, p for trend 0.019), pain/discomfort: OR 2.37 (95% CI 1.58 to 3.55, p for trend <0.001)). Female sex, lower FS and lower educational attainment were independently associated with anxiety/depression (ORs 1.60 (95% CI 1.18 to 2.16, p 0.002), 3.08 (95% CI 2.23 to 4.27, p<0.001) and 1.67 (95% CI 1.10 to 2.52, p 0.009), respectively). Older age, higher comorbidity count, albuminuria (≥30 mg/mmol vs <3 mg/mmol), lower educational attainment (no formal qualifications vs degree level) and obesity were independently associated with functional impairment (ORs 1.07 (95% CI 1.04 to 1.09, p<0.001), 2.18 (95% CI 0.80 to 5.96, p for trend <0.001), 1.74 (95% CI 0.82 to 3.68, p for trend 0.005), 2.08 (95% CI 1.26 to 3.41, p for trend <0.001) and 4.23 (95% CI 2.48 to 7.20), respectively). CONCLUSIONS: The majority of persons with mild-to-moderate CKD reported reductions in at least one HRQoL domain, which were independently associated with comorbidities, obesity and functional impairment. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632.

ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes.

The accumulation of amyloid-ß (Aß) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aß from the brain. Aß is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage-IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aß affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aß flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aß, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy.

In the absence of lymphatics, fluid and solutes such as amyloid-ß (Aß) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries-the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aß is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results: AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA (p = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA.

Quantitative proteomic profiling of white matter in cases of cerebral amyloid angiopathy reveals upregulation of extracellular matrix proteins and clusterin.

Aims: Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid beta (Aß) in the walls of cerebral arterioles, arteries and capillaries. Changes in the white matter in CAA are observed as hyperintensities and dilated perivascular spaces on MRI suggesting impairment of fluid drainage but the pathophysiology behind these changes is poorly understood. We tested the hypothesis that proteins associated with clearance of Aß peptides are upregulated in the white matter in cases of CAA. Methods: In this study, we compare the quantitative proteomic profile of white matter from post-mortem brains of patients with CAA and age-matched controls in order to gain insight into the cellular processes and key molecules involved in the pathophysiology of CAA. Results: Our proteomic analysis resulted in the profiling of 3,734 proteins (peptide FDR p<0.05). Of these, 189 were differentially expressed in CAA vs. control. Bioinformatics analysis of these proteins showed significant enrichment of proteins related to cell adhesion | cell-matrix interaction, mitochondrial dysfunction and hypoxia. Upregulated proteins in CAA included EMILIN2, COL4A2, TLN1, CLU, HSPG2. Downregulated proteins included DSP, IDE, HBG1. Conclusions: The present study reports an in-depth quantitative proteomic profiling of white matter from patients with CAA, highlighting extracellular matrix proteins and clusterin as key molecules in the pathophysiology of white matter changes in cases of CAA.

Improved care and survival in severe malnutrition through eLearning.

BACKGROUND: Scaling up improved management of severe acute malnutrition (SAM) has been identified as the nutrition intervention with the greatest potential to reduce child mortality but it requires improved operational capacity. OBJECTIVE: To investigate whether an eLearning course, which can be used at scale in resource-poor countries, leads to improved diagnosis, clinical management and survival of children with SAM. DESIGN: A 2-year preintervention and postintervention study between January 2015 and February 2017. SETTING: Eleven healthcare facilities: nine in Ghana, one in Guatemala, and one in El Salvador. INTERVENTION: Scenario-based eLearning course 'Caring for infants and young children with severe malnutrition'. MAIN OUTCOME MEASURES: Identification of children with SAM, quality of care, case-fatality rate. METHODS: Medical record reviews of children aged 0-60 months attending eleven hospitals between August 2014 and July 2016, observations in paediatric wards, and interviews with senior hospital personnel. RESULTS: Postintervention there was a significant improvement in the identification of SAM: more children had the requisite anthropometric data (34.9% (1300/3723) vs 15.9% (629/3953)) and more were correctly diagnosed (58.5% (460/786) vs 47.1% (209/444)). Improvements were observed in almost all aspects of the WHO 'Ten Steps' of case-management, and case-fatality fell from 5.8% (26/449) to 1.9% (14/745) (Post-pre difference=-3.9%, 95% CI -6.6 to -1.7, p<0.001). CONCLUSIONS: High quality, interactive eLearning can be an effective intervention in scaling up capacity building of health professionals to manage SAM effectively, leading to a reduction in mortality.

Protein kinase C inhibitors override ZEB1-induced chemoresistance in HCC.

Epithelial-mesenchymal transition (EMT) is a process by which tumour cells lose epithelial characteristics, become mesenchymal and highly motile. EMT pathways also induce stem cell features and resistance to apoptosis. Identifying and targeting this pool of tumour cells is a major challenge. Protein kinase C (PKC) inhibition has been shown to eliminate breast cancer stem cells but has never been assessed in hepatocellular cancer (HCC). We investigated ZEB family of EMT inducer expression as a biomarker for metastatic HCC and evaluated the efficacy of PKC inhibitors for HCC treatment. We showed that ZEB1 positivity predicted patient survival in multiple cohorts and also validated as an independent biomarker of HCC metastasis. ZEB1-expressing HCC cell lines became resistant to conventional chemotherapeutic agents and were enriched in CD44high/CD24low cell population. ZEB1- or TGFß-induced EMT increased PKCα abundance. Probing public databases ascertained a positive association of ZEB1 and PKCα expression in human HCC tumours. Inhibition of PKCα activity by small molecule inhibitors or by PKCA knockdown reduced viability of mesenchymal HCC cells in vitro and in vivo. Our results suggest that ZEB1 expression predicts survival and metastatic potential of HCC. Chemoresistant/mesenchymal HCC cells become addicted to PKC pathway and display sensitivity to PKC inhibitors such as UCN-01. Stratifying patients according to ZEB1 and combining UCN-01 with conventional chemotherapy may be an advantageous chemotherapeutic strategy.

Microbial epidemiology and carriage studies for the evaluation of vaccines.

Respiratory tract infections are responsible for over 2.8 million deaths per year worldwide. Colonization is the first step in the process of microbes occupying the respiratory tract, which may lead to subsequent infection. Carriage, in contrast, is defined as the occupation of microbial species in the respiratory tract. The duration of carriage may be affected by host immunity, the composition and interactions between members of the microbial community, and the characteristics of colonizing bacteria, including physiology associated with being present in a bacterial biofilm. Numerous vaccines have been implemented to control infections caused by bacteria that can colonize and be subsequently carried. Such vaccines are often species-specific and may target a limited number of strains thereby creating a vacant niche in the upper respiratory tract. Epidemiological changes of bacteria found in both carriage and disease have therefore been widely reported, since the vacant niche is filled by other strains or species. In this review, we discuss the use of carriage-prevalence studies in vaccine evaluation and argue that such studies are essential for (1) examining the epidemiology of carriage before and after the introduction of new vaccines, (2) understanding the dynamics of the respiratory tract flora and (3) identifying the disease potential of emerging strains. In an era of increasing antibiotic resistance, bacterial carriage-prevalence studies are essential for monitoring the impact of vaccination programmes.

Effectiveness of the Malnutrition eLearning Course for Global Capacity Building in the Management of Malnutrition: Cross-Country Interrupted Time-Series Study.

BACKGROUND: Scaling up improved management of severe acute malnutrition has been identified as the nutrition intervention with the largest potential to reduce child mortality, but lack of operational capacity at all levels of the health system constrains scale-up. We therefore developed an interactive malnutrition eLearning course that is accessible at scale to build capacity of the health sector workforce to manage severely malnourished children according to the guidelines of the World Health Organization. OBJECTIVE: The aim of this study was to test whether the malnutrition eLearning course improves knowledge and skills of in-service and preservice health professionals in managing children with severe acute malnutrition and enables them to apply the gained knowledge and skills in patient care. METHODS: This 2-year prospective, longitudinal, cross-country, interrupted time-series study took place in Ghana, Guatemala, El Salvador, and Colombia between January 2015 and February 2017. A subset of 354 in-service health personnel from 12 hospitals and 2 Ministries of Health, 703 preservice trainees from 9 academic institutions, and 204 online users participated. Knowledge gained after training and retention over time was measured through pre- and postassessments comprising questions pertaining to screening, diagnosis, pathophysiology and treatment, and prevention of malnutrition. Comprehension, application, and integration of knowledge were tested. Changes in perception, confidence, and clinical practice were assessed through questionnaires and interviews. RESULTS: Before the course, awareness of the World Health Organization guidelines was 36.73% (389/1059) overall, and 26.3% (94/358) among in-service professionals. The mean score gain in knowledge after access to the course in 606 participants who had pre- and postassessment data was 11.8 (95% CI 10.8-12.9; P<.001)-a relative increase of 41.5%. The proportion of participants who achieved a score above the pass mark posttraining was 58.7% (356/606), compared with 18.2% (110/606) in pretraining. Of the in-service professionals, 85.9% (128/149) reported applying their knowledge by changing their clinical practice in screening, assessment, diagnosis, and management. This group demonstrated significantly increased retained knowledge 6 months after training (mean difference [SD] from preassessment of 12.1 [11.8]), retaining 65.8% (12.1/18.4) of gained knowledge from the training. Changes in the management of malnutrition were reported by trained participants, and institutional, operational, and policy changes were also found. CONCLUSIONS: The malnutrition eLearning course improved knowledge, understanding, and skills of health professionals in the diagnosis and management of children with severe acute malnutrition, and changes in clinical practice and confidence were reported following the completion of the course.

Ecology and diversity in upper respiratory tract microbial population structures from a cross-sectional community swabbing study.

PURPOSE: Respiratory tract infections (RTIs) are responsible for over 2.8 million deaths per year worldwide with pathobiont carriage a required precursor to infection. We sought to determine carriage epidemiology for both bacterial and viral respiratory pathogens as part of a large population-based cross-sectional carriage study. METHODOLOGY: Nose self-swab samples were collected in two separate time-points, May to August 2012 (late spring/summer) and February to April 2013 (winter/early spring). The presence of six bacterial species: S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, P. aeruginosa and N. meningitidis in addition to respiratory syncytial virus, influenza viruses A and B, rhinovirus/enterovirus, coronavirus, parainfluenza viruses 1-3 and adenovirus was determined using culture and PCR methods.Results/Key findings. Carriage was shown to vary with age, recent RTI and the presence of other species. Spatial structures of microbial communities were more disordered in the 0-4 age group and those with recent RTI. Species frequency distributions were flatter than random expectation in young individuals (X2=20.42, P=0.002), indicating spatial clumping of species consistent with facilitative relationships. Deviations from a neutral model of ecological niches were observed in summer samples and from older individuals but not in the winter or younger individuals (0-4 years), suggesting the presence of seasonal and age-dependent niche processes in respiratory community assembly. CONCLUSION: The application of epidemiological methods and ecological theory to respiratory tract samples has yielded novel insights into the factors that drive microbial community composition.

Pneumococcal conjugate vaccine implementation in middle-income countries.

BACKGROUND: Since 2000, the widespread adoption of pneumococcal conjugate vaccines (PCVs) has had a major impact in the prevention of pneumonia. Limited access to international financial support means some middle-income countries (MICs) are trailing in the widespread use of PCVs. We review the status of PCV implementation, and discuss any needs and gaps related to low levels of PCV implementation in MICs, with analysis of possible solutions to strengthen the PCV implementation process in MICs. MAIN BODY: We searched PubMed, PubMed Central, Ovid MEDLINE, and SCOPUS databases using search terms related to pneumococcal immunization, governmental health policy or programmes, and MICs. Two authors independently reviewed the full text of the references, which were assessed for eligibility using pre-defined inclusion and exclusion criteria. The search terms identified 1,165 articles and the full texts of 21 were assessed for suitability, with eight articles included in the systematic review. MICs are implementing PCVs at a slower rate than donor-funded low-income countries and wealthier developed countries. A significant difference in the uptake of PCV in lower middle-income countries (LMICs) (71%) and upper middle-income countries (UMICs) (48%) is largely due to an unsuccessful process of "graduation" of MICs from GAVI assistance, an issue that arises as countries cross the income eligibility threshold and are no longer eligible to receive the same levels of financial assistance. A lack of country-specific data on disease burden, a lack of local expertise in economic evaluation, and the cost of PCV were identified as the leading causes of the slow uptake of PCVs in MICs. Potential solutions mentioned in the reviewed papers include the use of vaccine cost-effectiveness analysis and the provision of economic evidence to strengthen decision-making, the evaluation of the burden of disease, and post-introduction surveillance to monitor vaccine impact. CONCLUSION: The global community needs to recognise the impediments to vaccine introduction into MICs. Improving PCV access could help decrease the incidence of pneumonia and reduce the selection pressure for pneumococcal antimicrobial resistance.

Language Outcomes in Deaf or Hard of Hearing Teenagers Who Are Spoken Language Users: Effects of Universal Newborn Hearing Screening and Early Confirmation.

OBJECTIVES: This study aimed to examine whether (a) exposure to universal newborn hearing screening (UNHS) and b) early confirmation of hearing loss were associated with benefits to expressive and receptive language outcomes in the teenage years for a cohort of spoken language users. It also aimed to determine whether either of these two variables was associated with benefits to relative language gain from middle childhood to adolescence within this cohort. DESIGN: The participants were drawn from a prospective cohort study of a population sample of children with bilateral permanent childhood hearing loss, who varied in their exposure to UNHS and who had previously had their language skills assessed at 6-10 years. Sixty deaf or hard of hearing teenagers who were spoken language users and a comparison group of 38 teenagers with normal hearing completed standardized measures of their receptive and expressive language ability at 13-19 years. RESULTS: Teenagers exposed to UNHS did not show significantly better expressive (adjusted mean difference, 0.40; 95% confidence interval [CI], -0.26 to 1.05; d = 0.32) or receptive (adjusted mean difference, 0.68; 95% CI, -0.56 to 1.93; d = 0.28) language skills than those who were not. Those who had their hearing loss confirmed by 9 months of age did not show significantly better expressive (adjusted mean difference, 0.43; 95% CI, -0.20 to 1.05; d = 0.35) or receptive (adjusted mean difference, 0.95; 95% CI, -0.22 to 2.11; d = 0.42) language skills than those who had it confirmed later. In all cases, effect sizes were of small size and in favor of those exposed to UNHS or confirmed by 9 months. Subgroup analysis indicated larger beneficial effects of early confirmation for those deaf or hard of hearing teenagers without cochlear implants (N = 48; 80% of the sample), and these benefits were significant in the case of receptive language outcomes (adjusted mean difference, 1.55; 95% CI, 0.38 to 2.71; d = 0.78). Exposure to UNHS did not account for significant unique variance in any of the three language scores at 13-19 years beyond that accounted for by existing language scores at 6-10 years. Early confirmation accounted for significant unique variance in the expressive language information score at 13-19 years after adjusting for the corresponding score at 6-10 years (R change = 0.08, p = 0.03). CONCLUSIONS: This study found that while adolescent language scores were higher for deaf or hard of hearing teenagers exposed to UNHS and those who had their hearing loss confirmed by 9 months, these group differences were not significant within the whole sample. There was some evidence of a beneficial effect of early confirmation of hearing loss on relative expressive language gain from childhood to adolescence. Further examination of the effect of these variables on adolescent language outcomes in other cohorts would be valuable.

Deposition of amyloid ß in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy.

Deposition of amyloid ß (Aß) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aß from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aß accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aß and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aß initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aß. The pattern of development of CAA in the human brain suggests expansion of Aß from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aß in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

The impact of universal newborn hearing screening on long-term literacy outcomes: a prospective cohort study.

OBJECTIVE: To determine whether the benefits of universal newborn hearing screening (UNHS) seen at age 8 years persist through the second decade. DESIGN: Prospective cohort study of a population sample of children with permanent childhood hearing impairment (PCHI) followed up for 17 years since birth in periods with (or without) UNHS. SETTING: Birth cohort of 100 000 in southern England. PARTICIPANTS: 114 teenagers aged 13-19 years, 76 with PCHI and 38 with normal hearing. All had previously their reading assessed aged 6-10 years. INTERVENTIONS: Birth in periods with and without UNHS; confirmation of PCHI before and after age 9 months. MAIN OUTCOME MEASURE: Reading comprehension ability. Regression modelling took account of severity of hearing loss, non-verbal ability, maternal education and main language. RESULTS: Confirmation of PCHI by age 9 months was associated with significantly higher mean z-scores for reading comprehension (adjusted mean difference 1.17, 95% CI 0.36 to 1.97) although birth during periods with UNHS was not (adjusted mean difference 0.15, 95% CI -0.75 to 1.06). The gap between the reading comprehension z-scores of teenagers with early compared with late confirmed PCHI had widened at an adjusted mean rate of 0.06 per year (95% CI -0.02 to 0.13) during the 9.2-year mean interval since the previous assessment. CONCLUSIONS: The benefit to reading comprehension of confirmation of PCHI by age 9 months increases during the teenage years. This strengthens the case for UNHS programmes that lead to early confirmation of permanent hearing loss. TRIAL REGISTRATION NUMBER: ISRCTN03307358.