Impact of pneumococcal conjugate vaccine on pneumococcal disease, carriage and serotype distribution : comparative studies in Sweden and Uganda

Background: Streptococcus pneumoniae is a leading infectious cause of child deaths worldwide. Pneumococcal conjugate vaccine (PCV) was first introduced in the US in the year 2000, and included the major seven pneumococcal serotypes (PCV7) causing invasive pneumococcal disease (IPD) there. Current PCVs include 10 or 13 of the more than 97 known pneumococcal serotypes. In Stockholm County, Sweden, PCV7 was introduced for infants born from July 2007, at 3, 5, and 12 months of age and in 2010 it was changed to PCV13. Uganda started national PCV10 implementation in 2014. Aims: To study the effects of the introduction of PCV in the childhood vaccination program in Stockholm on incidence, serotypes and antibiotic resistance patterns of IPD, hospitalization due to severe sinusitis and pneumonia in children, and pneumococcal carriage. Also, to study pneumococcal carriage and serotype distribution in healthy children <5 years prior to PCV introduction in Uganda, and estimate the potential effectiveness of PCV. Methods: All cases of IPD in Stockholm registered in the national mandatory reporting system from 2005 to 2014 were included (n=2519). The pneumococcal isolates were characterized with serotyping (n=2336), including some with molecular typing and antibiotic resistance pattern. All hospitalizations from 2003 to 2012 in Stockholm, ICD-10 coded as sinusitis or pneumonia (N=678, 5051, respectively) in children, were collected from hospital registries. Nasopharyngeal pneumococcal isolates from children <5 years in Stockholm were collected at regular visits to Child Health Centers from 4 to 8 years after PCV introduction from 2011 to 2015 (N=916). Pneumococcal carriage was compared to carriage data in children attending day-care centers in 2004 (N=246), which was before vaccine introduction. OR for invasive disease potential of the pneumococcal isolates in carriage was calculated using data on IPD in all ages from 2011 to 2015. Nasopharyngeal carriage of pneumococci in children <5 in Uganda was assessed through collecting isolates at the Health and Demographic Surveillance Site in Iganga/Maygue districts (N=1761). Results: We show that PCV introduction in Stockholm has been successful in decreasing the incidence of IPD, from 28.4 to 10.3 cases /100,000 children <2 years (RR 0.36, 95% CI 0.2-0.6) when comparing the time periods 2005-2007 to 2009-2014, Serotypes included in the PCV7 decreased from 22.7 to 0 cases/ 100,000 in this age group (RR 0.0, 95% CI 0.0-0.1). The IPD incidence also decreased in older children and adults, excluding the elderly. However, PCV7 serotypes have decreased in all age groups. There was a decrease in hospitalizations due to severe sinusitis (RR 0.34, 95% CI 0.2-0.5) and pneumonia (RR 0.81, 95% CI 0.7-0.9) in children <2 years. A near elimination of most vaccine serotypes with a high invasiveness potential was seen in carriage. Emerging both in carriage among children and as cause of IPD (all ages) were instead non-vaccine types of lower invasive potential. Carriage data before PCV introduction in Uganda shows that vaccine serotypes were much less prevalent in children <5 years old (PCV10 for 42% and PCV13 for 54%) than what was observed in children <5 years old in Sweden before the PCV implementation (PCV10 63%, PCV13 82%), which may reduce potential vaccine effectiveness in Uganda. Conclusions: PCV introduction in Stockholm has had a positive overall impact on pneumococcal morbidity in young children, and serotypes included in the vaccine are decreasing in IPD and carriage. PCVs have the potential to save many children’s lives in the coming years, both in Sweden and Uganda. The extent of the impact is still not known, as PCV effectiveness depends on factors such as pneumococcal serotype distribution in carriage before and after PCV implementation, the extent of serotype replacement in carriage as well as in IPD in different age groups following PCV, vaccination coverage, and the serotype content of future pneumococcal vaccines, which may cover more or all pathogenic serotypes

Immunization programs to support primary health care and achieve universal health coverage

Gains in immunization coverage and delivery of primary health care service have stagnated in recent years. Remaining gaps in service coverage reflect multiple underlying reasons that may be amenable to improved health system design. Immunization systems and other primary health care services can be mutually supportive, for improved service delivery and for strengthening of Universal Health Coverage. Improvements require that dynamic and multi-faceted barriers and risks be addressed. These include workforce availability, quality data systems and use, leadership and management that is innovative, flexible, data driven and responsive to local needs. Concurrently, improvements in procurement, supply chain, logistics and delivery systems, and integrated monitoring of vaccine coverage and epidemiological disease surveillance with laboratory systems, and vaccine safety will be needed to support community engagement and drive prioritized actions and communication. Finally, political will and sustained resource commitment with transparent accountability mechanisms are required. The experience of the impact of COVID-19 pandemic on essential PHC services and the challenges of vaccine roll-out affords an opportunity to apply lessons learned in order to enhance vaccine services integrated with strong primary health care services and universal health coverage across the life course

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network

Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1—c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)—both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis

Immunisation of migrants in EU/EEA countries: Policies and practices

In recent years various EU/EEA countries have experienced an influx of migrants from low and middle-income countries. In 2018, the “Vaccine European New Integrated Collaboration Effort (VENICE)” survey group conducted a survey among 30 EU/EEA countries to investigate immunisation policies and practices targeting irregular migrants, refugees and asylum seekers (later called “migrants” in this report). Twenty-nine countries participated in the survey. Twenty-eight countries reported having national policies targeting children/adolescent and adult migrants, however vaccinations offered to adult migrants are limited to specific conditions in seven countries. All the vaccinations included in the National Immunisation Programme (NIP) are offered to children/adolescents in 27/28 countries and to adults in 13/28 countries. In the 15 countries offering only certain vaccinations to adults, priority is given to diphtheria-tetanus, measles-mumps-rubella and polio vaccinations. Information about the vaccines given to child/adolescent migrants is recorded in 22 countries and to adult migrants in 19 countries with a large variation in recording methods found across countries. Individual and aggregated data are reportedly not shared with other centres/institutions in 13 and 15 countries, respectively. Twenty countries reported not collecting data on vaccination uptake among migrants; only three countries have these data at the national level. Procedures to guarantee migrants’ access to vaccinations at the community level are available in 13 countries. In conclusion, although diversified, strategies for migrant vaccination are in place in all countries except for one, and the strategies are generally in line with international recommendations. Efforts are needed to strengthen partnerships and implement initiatives across countries of origin, transit and destination to develop and better share documentation in order to guarantee a completion of vaccination series and to avoid unnecessary re-vaccination. Development of migrant-friendly strategies to facilitate migrants' access to vaccination and collection of vaccination uptake data among migrants is needed to meet existing gaps

A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Funder: The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257Abstract: The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Fouling of electrodialysis membranes by organic substances

In this investigation, the influence of various kinds of organic solutes on the fouling of an anion and a cation selective ED membrane was studied. Fouling by adsorption of organic matter onto the membrane was measured as an increase in the membrane resistance with time. Experiments were performed with a fatty acid (octanoic acid), two anionic surfactants (sodium octanoate and sodium dodecylbenzene sulphonate) and an alkaline bleach plant filtrate from a sulphate pulp mill. A marked difference was observed between the increase in the membrane resistance of the anion selective membrane and that of the cation selective membrane. The cation selective membrane was slightly fouled by the bleach plant filtrate, but was only marginally affected by the other organic solutes. The anion selective membrane, on the other hand, was markedly fouled by all solutes

Organic fouling of electrodialysis membranes with and without applied voltage

In this investigation organic fouling of ED membranes was studied with and without applied voltage. Fouling without the application of voltage, i.e., adsorption, was observed as an increase in the membrane resistance, and fouling with the application of voltage, i.e., conventional ED, was observed as an increase in the voltage drop across the membrane. Experiments were performed with three different carboxylic acids (propanoic, octanoic and decanoic acid) and an alkaline bleach plant filtrate from a sulphate pulp mill. An anion-selective (Selemion AMV) and a cation-selective (Selemion CMV) membrane were used in the investigation. A significant difference was observed between the fouling of the two membranes. The membrane resistance and voltage drop across the cation-selective membrane did not increase in any of the experiments, i.e., the cation-selective membrane was not fouled. The anion-selective membrane, on the other hand, was fouled by all solutes except sodium propanoate