| 1. |
- Alfvén, Tobias, et al.
(author)
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Dödligheten minskar, men fortfarande dör 7 miljoner barn varje år
- 2013
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In: Läkartidningen. - 0023-7205 .- 1652-7518. ; 110:1-2, s. 28-30
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Journal article (other academic/artistic)abstract
- Millenniemål 4 lyder: »Barnadödligheten under de fem första levnadsåren ska minska med två tredjedelar till 2015 jämfört med år 1990«.Barnadödligheten minskar i stora delar av världen, men inte i tillräckligt snabb takt för att uppnå målet. Den skiljer sig också kraftigt mellan länder och mellan olika grupper inom länderna.Sex dödsorsaker står för mer än 90 procent av alla dödsfall före 5 års ålder: neonatal mortalitet, lunginflammation, diarré, malaria, mässling och HIV/aids. Undernäring beräknas vara delorsak till cirka en tredjedel av dessa dödsfall.Vi har kunskap och metoder att med kostnadseffektiva lösningar reducera barnadödligheten med två tredjedelar. Fortsatt internationellt samarbete, utökade resurser samt lokal, nationell politisk vilja krävs för att lyckas.
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| 2. |
- Anh, Nhi, et al.
(author)
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High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing
- 2018
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
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Journal article (peer-reviewed)abstract
- The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.
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| 3. |
- Appelqvist, Emma, et al.
(author)
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Exploring nurses' experiences of a tailored intervention to increase MMR vaccine acceptance in a Somali community in Stockholm, Sweden : a qualitative interview study
- 2023
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In: BMJ Open. - : BMJ. - 2044-6055. ; 13:2, s. 067169-067169
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To explore nurses' experiences of a tailored intervention that supported them with knowledge and tools to use during encounters and dialogue with parents with low vaccine acceptance. DESIGN: A qualitative study with in-depth interviews conducted in 2017. Data were analysed using thematic analysis. SETTING: This study was part of a multicomponent intervention targeting Somali parents and the nurses at child health centres in the Rinkeby and Tensta neighbourhoods of Stockholm. An area with documented low measles, mumps and rubella (MMR) vaccination coverage. Previous research has revealed that Somali parents in the community delayed MMR vaccination due to fear of autism despite lack of scientific evidence. The interventions were implemented in 2015-2017. PARTICIPANTS: Eleven nurses employed at the child health centres involved in the intervention participated in interviews. The tailored intervention targeting nurses included a series of seminars, a narrative film and an information card with key messages for distribution to parents. RESULTS: The qualitative analysis revealed an overarching theme: perception of improved communication with parents. Two underlying themes were identified: (1) feeling more confident to address parents' MMR vaccine concerns and (2) diverse tools as useful support to dispel myth and reduce language barriers. CONCLUSION: From the nurses' perspective, the tailored intervention was useful to improve communication with parents having vaccine concerns. Nurses have a crucial role in vaccine uptake and acceptance. Interventions aiming to strengthen their communication with parents are therefore essential, especially in areas with lower vaccine acceptance.
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| 4. |
- Appelqvist, Emma, et al.
(author)
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Parental views and the key role of nurses for high vaccine acceptance in Sweden – a focus group study
- 2023
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In: BMC Public Health. - 1471-2458. ; 23:1
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Journal article (peer-reviewed)abstract
- Background: In Sweden, vaccine uptake is exceptionally high due to an efficient child immunization program. More than 97% of Swedish children were vaccinated at child health care centers (CHCs) according to the schedule at 2 years of age in 2021. From the age of 6 years, vaccinations are given within the school health care. Maintaining high vaccination coverage over time is one of the central motives to explore and understand drivers for vaccine acceptance. The current study aimed to assess parental vaccine acceptance concerning the national immunization program and explore factors contributing to the high vaccine acceptance in Sweden. Methods: Parents of children aged 1–2 years and 8–12 years were recruited through purposive sampling and asked to participate in focus groups held in three cities in Sweden, in February and March 2019. In total, 47 parents participated in two focus groups per city, one session for parents of younger (1–2 years) and older (8–12 years) children respectively. The focus group discussions were analyzed using qualitative content analysis. Results: Parents of children aged 1–2 years expressed the themes; strong compliance to and protection of the value of vaccinations; parents feel safe with an attentive relationship with their nurse; the spectrum of communication needs is essential to meet. For parents to children aged 8–12 years, the themes expressed were; vaccinate to do good for the individual and society; a foundation of trust is built at CHCs for decisions later on; decisions for vaccination become more complex as children get older; communication changes as children get older and need to be explicit and tailored to the situation. Conclusion: Both individual and societal perspectives were shown to influence the vaccination decision for childhood immunizations, as manifested in parental reflections and experiences. As nurses have a key role, it is important to provide them with continued support and tools to facilitate their support for parents in making informed decisions. Continuous work for supporting driving factors for vaccination over time is needed to maintain high vaccine acceptance in Sweden.
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| 5. |
- Batkovskyte, D., et al.
(author)
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Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders
- 2023
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In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 38:5, s. 692-706
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Journal article (peer-reviewed)abstract
- Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located.
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| 6. |
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| 7. |
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| 8. |
- Byström, Emma, et al.
(author)
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Confidence in the National Immunization Program among parents in Sweden 2016 – A cross-sectional survey
- 2020
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In: Vaccine. - : Elsevier BV. - 0264-410X. ; 38:22, s. 3909-3917
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Journal article (peer-reviewed)abstract
- Background: Vaccination coverage for infant vaccinations in the Swedish National Immunization Program (NIP) has been high for more than a decade, with approximately 97% of 2-year-old children fully immunized. Vaccination coverage against Human Papilloma Virus (HPV) has been around 80% since introduction for girls in 2012. This indicates high parental confidence in the NIP, but as seen in other European countries rapid shifts in confidence may occur. This study examined vaccine confidence and attitudes towards vaccinations among parents in the Swedish population. Methods: A web-based survey was sent to 1046 parents with children aged 0–15 years, in a panel administrated by The Public Health Agency of Sweden. The survey included questions on vaccination awareness, safety and information channels. The response rate was 87%. Data were weighted to adjust for non-responders and for representativeness of the Swedish population. Results: Parents were categorized as acceptors (79%), questioning acceptors (19%) or selective refusers (2%). When excluding responses for HPV vaccination, the proportion of acceptors increased to 91%. The main reasons for questioning or refusing a vaccine were worry over adverse events, negative or lack of information. Along a spectrum of beliefs, acceptors and questioning acceptors were more similar compared to selective refusers. Nurses at child health clinics constituted the most used vaccination information source for acceptors, whereas selective refusers to a greater extent searched information online and in social media. Conclusions: The study demonstrates that parents in Sweden have confidence in and are positive towards vaccinations given within the NIP. One in five parents question vaccines, particularly regarding the HPV vaccine, but still concur to the NIP. Information on vaccines online and at vaccination appointments, including vaccine safety, is important for maintaining confidence in vaccination. Conducting recurring studies is valuable for monitoring vaccine confidence and changes in attitudes towards vaccination.
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| 9. |
- Byström, Emma, et al.
(author)
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Parental attitudes and decision-making regarding MMR vaccination in an anthroposophic community in Sweden – A qualitative study
- 2014
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In: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 32:50, s. 6752-6757
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Journal article (peer-reviewed)abstract
- Measles outbreaks occur regularly throughout Europe, up to 31500 cases in the previous year, particularly where there are pockets of populations with lower vaccination coverage than the recommended ≥95%. Anthroposophic communities in Europe are one of several groups with relatively low vaccination coverage. In Sweden, outbreaks of measles and rubella were reported from an anthroposophic community. Thus the aim of this qualitative study was to explore facilitators and barriers to MMR vaccination among parents living in anthroposophic communities in Sweden. Twenty parents living in an anthroposophic community were interviewed, focusing on their views and decisions on MMR vaccination. The interviews were analyzed using qualitative content analysis. Two overarching views of health emerged, differentiating broadly parents who vaccinate vs. parents who do not vaccinate. Four themes describing parental attitudes toward measles vaccination were developed and three of these, the conformers, the pragmatists and the attentive delayers describe different approaches toward vaccinations among those who actually vaccinate. The last theme, promoters of natural immunity, represents those postponing or refusing vaccination beyond childhood. This study suggests that there is a spectrum of parental beliefs regarding MMR vaccination in this anthroposophic community. Interventions specifically targeted to the anthroposophic community and strengthening health workers capacity for a constructive dialog on vaccine's benefit and risks may contribute to higher vaccination coverage. This is believed to minimize the risk of future epidemics and contribute to the WHO European Region's goal of eliminating measles.
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| 10. |
- Chrapkowska, Cecilia, et al.
(author)
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Validation of the new Swedish vaccination register – Accuracy and completeness of register data
- 2020
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In: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 38:25, s. 4104-4110
-
Journal article (peer-reviewed)abstract
- Objective: The aims of this study are to validate infant vaccination data in the Swedish Vaccination Register (SVR) to the Swedish administrative coverage reports, and to assess differences in register-based vaccination coverage estimates between providers using different data reporting methods. Methods: The study population included all infants born in Sweden with a Swedish Personal Identity Number during 2014 and 2015 (n = 230,220). Data on all National Immunisation Programme vaccinations administered before 24 months of age were collected from the SVR and from administrative coverage reports. Information regarding data registration methods in the SVR were collected from national and regional authorities. Coverage from health care providers using single registration methods, where vaccination data were transferred automatically from the electronic health care record to the SVR, was compared to that from providers using double registration methods where data had to be added into the SVR in a separate process. Results: For 98,4% of the study population at least one vaccination was recorded in the SVR. The coverage of 3-dose DTP-containing (87,1%) and 1 dose MMR (91,1%) in the register did not reach administrative data coverage (97,4% for 3-dose DTP-containing and 97,0% for MMR). Single registration procedures yielded significantly higher coverage than double registration procedures (92,24% vs 87,10%, p < 0,0001). A regional switch from double to single registration increased coverage from 80,0 to 95,2%. Conclusions: The SVR is a valuable data source for vaccination coverage monitoring. For research purposes, the SVR provides valuable data, since every health care provider is obliged to register all vaccine doses given within the national immunisation program. The SVR shows a high completeness validated by comparison to a very well-functioning administrative data system. Single-registration procedures give more complete data and should be supported by health systems while creating health care registers.
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| 11. |
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| 12. |
- Engdahl, Ingrid, 1952-
(author)
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Toddlers as social actors in the Swedish preschool
- 2011
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Doctoral thesis (other academic/artistic)abstract
- This thesis focuses on interaction among young toddlers during their second year of life in a Swedish preschool. The overall aim of this thesis was to explore interaction, communication and the creation of friendship between the young children during self initiated play activities. In addition, this thesis presents the background of Early Childhood Education in Sweden, which may serve as an extended context for the study. An ethnographic study was carried out in a toddler unit with 15 children. Six one year old girls and boys were in focus during the observations for nine months. Participatory methods, photos, fieldnotes and videorecordings, were used for the data collection. The theoretical framework for the study is built on phenomenology, the view of the child as a social person and a child oriented perspective. The overall findings support a theoretical perspective where the young toddlers are seen as social actors, with social competencies. Their play invitation strategies, as well as their play enactment and play-closing moves, were mostly found to be based on nonverbal communication such as movements, gestures, voice quality and facial expressions. The competencies of attunement, taking others’ perspectives and turn-taking were found in play among the young toddlers, and they also showed negotiating skills while playing. The findings also show how young toddlers make friends. During their second year of life, they monitor and pay attention to individual peers, displaying intentionality and agency by spontaneously greeting their peers, by offering play invitations, and by helping peers. Mutual awareness, joint attention, shared smiles, coordinated movements, as well as other types of synchronized actions are seen as parts of nonverbal elements in emerging friendship. The findings in this thesis support an understanding of young toddlers as social persons in the preschool, engaged in consistent interest and attention towards each other while playing.
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| 13. |
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| 14. |
- Frisk, Sofia, et al.
(author)
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Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth
- 2019
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In: Clinical Genetics. - : WILEY. - 0009-9163 .- 1399-0004. ; 96:2, s. 118-125
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Journal article (peer-reviewed)abstract
- PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.
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| 15. |
- Jama, Asha, et al.
(author)
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Design and implementation of tailored intervention to increase vaccine acceptance in a Somali community in Stockholm, Sweden - based on the Tailoring Immunization Programmes approach
- 2022
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In: Public Health in Practice. - : Elsevier BV. - 2666-5352. ; 4
-
Journal article (peer-reviewed)abstract
- Objectives: Sweden has had a high and stable vaccination coverage for measles-mumps-rubella (MMR) vaccine (>96%) through the national immunization program (NIP), but coverage rates highlight local pockets of lower vaccination coverage. This project addressed low MMR vaccine acceptance among parents in a Somali community, in Stockholm. The objective of the intervention was to increase vaccine confidence and MMR-vaccine uptake and also to inform practices addressing vaccine acceptance. Study design: This paper describes the design and implementation of a multi-component intervention based on the Tailoring Immunization Programmes (TIP) approach, developed by the WHO European Regional Office. Methods: The theoretical underpinning of TIP is the Capability, Opportunity, and Motivation Model (COM-B model) and Behaviour Change Wheel framework (BCW), adapted for vaccination. The COM-model was used to identify barriers and drivers to vaccination and intervention types. The TIP-phases described in this paper are: pre-TIP (planning), three succeeding TIP phases (situational analysis, formative research, intervention design) and the post-TIP phase (implementation). Results: The situation analysis and formative research revealed that parents feared the MMR vaccine due to autism or that their child would stop talking following vaccination, despite lack of scientific evidence for an association between autism and MMR vaccines. Barriers were linked to their associated COM-B factors and mapped to appropriate intervention types for two target groups: Somali parents and nurses at the Child Health Centres (CHC). Selected intervention types targeting parents were education, persuasion and modelling whereas education and training were selected for CHC nurses. The intervention activities included community engagement for parents, while the activities for nurses focused on improving encounters and dialogue with parents having low vaccine acceptance. Following the intervention design the activities were developed, pilot tested and implemented. Conclusion: This study confirm that the TIP approach is valuable for guiding a stepwise working process for a thorough understanding of barriers and drivers for MMR vaccination among parents in this Somali community. It facilitated the design of a theory and evidence-informed intervention targeting parents and nurses.
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| 16. |
- Kalyango, Joan N., et al.
(author)
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Increased Use of Community Medicine Distributors and Rational Use of Drugs in Children Less than Five Years of Age in Uganda Caused by Integrated Community Case Management of Fever
- 2012
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In: American Journal of Tropical Medicine and Hygiene. - : American Society of Tropical Medicine and Hygiene. - 0002-9637 .- 1476-1645. ; 87:suppl 5, s. 36-45
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Journal article (peer-reviewed)abstract
- We compared use of community medicine distributors (CMDs) and drug use under integrated community case management and home-based management strategies in children 6–59 months of age in eastern Uganda. A cross-sectional study with 1,095 children was nested in a cluster randomized trial with integrated community case management (CMDs treating malaria and pneumonia) as the intervention and home-based management (CMDs treating only malaria) as the control. Care-seeking from CMDs was higher in intervention areas (31%) than in control areas (22%; P = 0.01). Prompt and appropriate treatment of malaria was higher in intervention areas (18%) than in control areas (12%; P = 0.03) and among CMD users (37%) than other health providers (9%). The mean number of drugs among CMD users compared with other health providers was 1.6 versus 2.4 in intervention areas and 1.4 versus 2.3 in control areas. Use of CMDs was low. However, integrated community case management of childhood illnesses increased use of CMDs and rational drug use.Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the views of Swedish International Development Cooperation Agency or the United Nations Children's Fund/ United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases.
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| 17. |
- Kapferer-Seebacher, Ines, et al.
(author)
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Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement
- 2016
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In: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 99:5, s. 1005-1014
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Journal article (peer-reviewed)abstract
- 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.
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| 18. |
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| 19. |
- Kvarnung, Malin, et al.
(author)
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Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186
- 2019
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In: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 10
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Journal article (peer-reviewed)abstract
- The etiology of hereditary ataxia syndromes is heterogeneous, and the mechanisms underlying these disorders are often unknown. Here, we utilized exome sequencing in two siblings with progressive ataxia and muscular weakness and identified a novel homozygous splice mutation (c.3020-1G > A) in neurofascin (NFASC). In RNA extracted from fibroblasts, we showed that the mutation resulted in inframe skipping of exon 26, with a deprived expression of the full-length transcript that corresponds to NFASC isoform NF186. To further investigate the disease mechanisms, we reprogrammed fibroblasts from one affected sibling to induced pluripotent stem cells, directed them to neuroepithelial stem cells and finally differentiated to neurons. In early neurogenesis, differentiating cells with selective depletion of the NF186 isoform showed significantly reduced neurite outgrowth as well as fewer emerging neurites. Furthermore, whole-cell patch-clamp recordings of patient-derived neuronal cells revealed a lower threshold for openings, indicating altered Na+ channel kinetics, suggesting a lower threshold for openings as compared to neuronal cells without the NFASC mutation. Taken together, our results suggest that loss of the full-length NFASC isoform NF186 causes perturbed neurogenesis and impaired neuronal biophysical properties resulting in a novel early-onset autosomal recessive ataxia syndrome.
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| 20. |
- Laurell, Tobias, et al.
(author)
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Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease.
- 2014
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In: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 2:5, s. 402-411
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Journal article (peer-reviewed)abstract
- Nonsense mutations in FGF16 have recently been linked to X-linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit (MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X-linked recessive MF4 in three unrelated families. We performed whole-exome sequencing, and identified three novel mutations in FGF16. The functional impact of FGF16 loss was further studied using morpholino-based suppression of fgf16 in zebrafish. In addition, clinical investigations revealed reduced penetrance and variable expressivity of the MF4 phenotype. Cardiac disorders, including myocardial infarction and atrial fibrillation followed the X-linked FGF16 mutated trait in one large family. Our findings establish that a mutation in exon 1, 2 or 3 of FGF16 results in X-linked recessive MF4 and expand the phenotypic spectrum of FGF16 mutations to include a possible correlation with heart disease.
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| 21. |
- Lindstrand, Anna, et al.
(author)
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From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
- 2019
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In: Genome Medicine. - : BMC. - 1756-994X. ; 11:1
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Journal article (peer-reviewed)abstract
- BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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| 22. |
- Lindstrand, Anna, et al.
(author)
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Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability
- 2022
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In: Genetics in Medicine. - : ELSEVIER SCIENCE INC. - 1098-3600 .- 1530-0366. ; 24:11, s. 2296-2307
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Journal article (peer-reviewed)abstract
- Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 23. |
- Lindstrand, Ann
(author)
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Impact of pneumococcal conjugate vaccine on pneumococcal disease, carriage and serotype distribution : comparative studies in Sweden and Uganda
- 2016
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 24. |
- Lindstrand, Anna, et al.
(author)
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Molecular and clinical characterization of patients with overlapping 10p deletions
- 2010
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In: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 152A:5, s. 1233-1243
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Journal article (peer-reviewed)abstract
- Chromosome 10p terminal deletions have been associated with DiGeorge phenotype, and within the same genomic region haploinsufficiency of GATA3 causes the HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia). We have performed detailed molecular analysis of four patients with partial overlapping 10p deletions by using FISH-mapping, array-CGH, and custom-designed high-resolution oligonucleotide array. All four patients had mental retardation and speech impairment and three of them showed variable signs of HDR syndrome. In addition, two patients had autistic behaviors and had similar dysmorphic features giving them a striking physical resemblance. A review of the literature identified 10 previously published cases with similar 10p deletions and reliable molecular or molecular cytogenetic mapping data. The combined information of present and previous cases suggests that partial deletions of 10p14-p15 represent a syndrome with a distinct and more severe phenotype than previously assumed. The main characteristics include severe mental retardation, language impairment, autistic behavior, and characteristic clinical features. A critical region involved in mental retardation and speech impairment is defined within 1.6 Mb in 10p15.3. In addition, deletion of 4.3 Mb within 10p14 is associated with autism and characteristic clinical findings.
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| 25. |
- Lindstrand, Ann, et al.
(author)
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Pneumococcal Carriage in Children under Five Years in Uganda-Will Present Pneumococcal Conjugate Vaccines Be Appropriate?
- 2016
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:11
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Journal article (peer-reviewed)abstract
- BACKGROUND: Pneumonia is the major cause of death in children globally, with more than 900,000 deaths annually in children under five years of age. Streptococcus pneumoniae causes most deaths, most often in the form of community acquired pneumonia. Pneumococcal conjugate vaccines (PCVs) are currently being implemented in many low-income countries. PCVs decrease vaccine-type pneumococcal carriage, a prerequisite for invasive pneumococcal disease, and thereby affects pneumococcal disease and transmission. In Uganda, PCV was launched in 2014, but baseline data is lacking for pneumococcal serotypes in carriage.OBJECTIVES: To study pneumococcal nasopharyngeal carriage and serotype distribution in children under 5 years of age prior to PCV introduction in Uganda.METHODS: Three cross-sectional pneumococcal carriage surveys were conducted in 2008, 2009 and 2011, comprising respectively 150, 587 and 1024 randomly selected children aged less than five years from the Iganga/Mayuge Health and Demographic Surveillance Site. The caretakers were interviewed about illness history of the child and 1723 nasopharyngeal specimens were collected. From these, 927 isolates of S. pneumoniae were serotyped.RESULTS: Overall, the carriage rate of S. pneumoniae was 56% (957/1723). Pneumococcal carriage was associated with illness on the day of the interview (OR = 1.50, p = 0.04). The most common pneumococcal serotypes were in descending order 19F (16%), 23F (9%), 6A (8%), 29 (7%) and 6B (7%). One percent of the strains were non-typeable. The potential serotype coverage rate for PCV10 was 42% and 54% for PCV13.CONCLUSION: About half of circulating pneumococcal serotypes in carriage in the Ugandan under-five population studied was covered by available PCVs.
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| 26. |
- Lindstrand, V, et al.
(author)
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Fouling of electrodialysis membranes by organic substances
- 2000
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In: Desalination. - 1873-4464. ; 128:1, s. 91-102
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Journal article (peer-reviewed)abstract
- 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.
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| 27. |
- Lindstrand, V, et al.
(author)
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Organic fouling of electrodialysis membranes with and without applied voltage
- 2000
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In: Desalination. - 1873-4464. ; 130:1, s. 73-84
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Journal article (peer-reviewed)abstract
- 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.
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| 28. |
- Nazaryan-Petersen, Lusine, et al.
(author)
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Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization
- 2018
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In: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 14:11
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Journal article (peer-reviewed)abstract
- Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.
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| 29. |
- Nordgren, Ann, 1964, et al.
(author)
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Precision medicine and rare diseases in pediatric urology
- 2023
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In: Journal of Pediatric Urology. - : Elsevier BV. - 1477-5131 .- 1873-4898. ; 19:3, s. 335-338
-
Journal article (peer-reviewed)abstract
- Precision Medicine holds promise for helping us manage specific phenotypes of common diseases. For rare diseases such as hypospadias, DSD, and pediatric solid tumors, it can also reveal underlying risk factors and pathogenesis. Professors Ann Nordgren and Anna Lindstrand share their experi-ences in the development and ongoing initiatives of the Swedish national project on Precision Medicine and how it could change the care of pediatric urol-ogy patients.
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| 30. |
- Pena-Perez, Lucia, et al.
(author)
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Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma
- 2022
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In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:17, s. 5009-5023
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Journal article (peer-reviewed)abstract
- Multiple myeloma (MM) is an incurable and aggressive plasma cell malignancy characterized by a complex karyotype with multiple structural variants (SVs) and copy-number variations (CNVs). Linked-read whole-genome sequencing (lrWGS) allows for refined detection and reconstruction of SVs by providing long-range genetic information from standard short-read sequencing. This makes lrWGS an attractive solution for capturing the full genomic complexity of MM. Here we show that high-quality lrWGS data can be generated from low numbers of cells subjected to fluorescence-activated cell sorting (FACS) without DNA purification. Using this protocol, we analyzed MM cells after FACS from 37 patients with MM using lrWGS. We found high concordance between lrWGS and fluorescence in situ hybridization (FISH) for the detection of recurrent translocations and CNVs. Outside of the regions investigated by FISH, we identified > 150 additional SVs and CNVs across the cohort. Analysis of the lrWGS data allowed for resolution of the structure of diverse SVs affecting the MYC and t(11;14) loci, causing the duplication of genes and gene regulatory elements. In addition, we identified private SVs causing the dysregulation of genes recurrently involved in translocations with the IGH locus and show that these can alter the molecular classification of MM. Overall, we conclude that lrWGS allows for the detection of aberrations critical for MM prognostics and provides a feasible route for providing comprehensive genetics. Implementing lrWGS could provide more accurate clinical prognostics, facilitate genomic medicine initiatives, and greatly improve the stratification of patients included in clinical trials.
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| 31. |
- Pettersson, Maria, et al.
(author)
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Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity
- 2017
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In: American Journal of Medical Genetics. Part A. - : John Wiley & Sons. - 1552-4825 .- 1552-4833. ; 173:5, s. 1396-1399
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Journal article (peer-reviewed)abstract
- Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.
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| 32. |
- Pramling, Ingrid, et al.
(author)
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27 forskare i upprop mot skärmfri förskola
- 2024
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In: Förskolan. - Stockholm : Sveriges Lärare.
-
Journal article (pop. science, debate, etc.)abstract
- VI LÄRARE DEBATT: Regeringens uppdrag till Skolverket – att göra utbildningen i förskolan skärmfri – riskerar att ge negativa och allvarliga konsekvenser, särskilt för barn som är i störst behov av att möta en digitaliserad värld med stöd av utbildade förskollärare och barnskötare. Det skriver 27 barn- och förskoleforskare i ett gemensamt upprop.
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| 33. |
- Pramling Samuelsson, Ingrid, et al.
(author)
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27 forskare i upprop mot skärmfri förskola
- 2024
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In: Förskolan. - Stockholm : Sveriges Lärare.
-
Journal article (pop. science, debate, etc.)abstract
- VI LÄRARE DEBATT: Regeringens uppdrag till Skolverket – att göra utbildningen i förskolan skärmfri – riskerar att ge negativa och allvarliga konsekvenser, särskilt för barn som är i störst behov av att möta en digitaliserad värld med stöd av utbildade förskollärare och barnskötare. Det skriver 27 barn- och förskoleforskare i ett gemensamt upprop.
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| 34. |
- Runheim, Hannes, et al.
(author)
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The cost-effectiveness of whole genome sequencing in neurodevelopmental disorders
- 2023
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In: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 13:1
-
Journal article (peer-reviewed)abstract
- Whole genome sequencing (WGS) has the potential to be a comprehensive genetic test, especially relevant for individuals with neurodevelopmental disorders, syndromes and congenital malformations. However, the cost consequences of using whole genome sequencing as a first-line genetic test for these individuals are not well understood. The study objective was to compare the healthcare costs and diagnostic yield when WGS is performed as the first-line test instead of chromosomal microarray analysis (CMA). Two cohorts were analyzed retrospectively using register data, cohort CMA (418 patients referred for CMA at the department of Clinical Genetics, Karolinska University Hospital, during 2015) and cohort WGS (89 patients included in a WGS-first prospective study in 2017). The analysis compared healthcare consumption over a 2-year period after referral for genetic testing, the diagnostic yield over a 2- and 3-year period after referral was also compiled. The mean healthcare cost per patient in cohort WGS was $2,339 lower compared to cohort CMA ($ - 2339, 95% CI - 12,238-7561; P = 0.64) including higher costs for genetic investigations ($1065, 95% CI 834-1295; P < 0.001) and lower costs for outpatient care ($ - 2330, 95% CI - 3992 to (- 669); P = 0.006). The diagnostic yield was 23% higher for cohort WGS (cohort CMA 20.1%, cohort WGS 24.7%) (0.046, 95% CI - 0.053-0.145; P = 0.36). WGS as a first-line diagnostic test for individuals with neurodevelopmental disorders is associated with statistically non-significant lower costs and higher diagnostic yield compared with CMA. This indicates that prioritizing WGS over CMA in health care decision making will yield positive expected outcomes as well as showing a need for further research.
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| 35. |
- Schollin Ask, Lina, et al.
(author)
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Receiving early information and trusting Swedish child health centre nurses increased parents' willingness to vaccinate against rotavirus infections
- 2017
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In: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 106:8, s. 1309-1316
-
Journal article (peer-reviewed)abstract
- Aim: Rotavirus vaccines are effective against severe infections, but have a modest impact on mortality in high-income countries. Parental knowledge and attitudes towards vaccines are crucial for high vaccination coverage. This study aimed to identify why parents refused to let their infant have the vaccination or were unsure. Methods: This cross-sectional study was based on 1,063 questionnaires completed by the parents of newborn children in 2014. Stepwise logistic regression was used to identify the main predictors. Results: Most (81%) parents intended to vaccinate their child against the rotavirus, while 19% were unwilling or uncertain. Parents with less education and children up to five weeks of age were more likely to be unwilling or uncertain about vaccinating their child. Factors associated with a refusal or uncertainty about vaccinating were not having enough information about the vaccine, no intention of accepting other vaccines, paying little heed to the child health nurses' recommendations, thinking that the rotavirus was not a serious illness and not believing that the vaccine provided protection against serious forms of gastroenteritis. Conclusion: Early information, extra information for parents with less education and close positive relationships between parents and child health nurses were important factors in high rotavirus vaccination rates.
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| 36. |
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| 37. |
- Tesi, Bianca, et al.
(author)
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Precision medicine in rare diseases : What is next?
- 2023
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 294:4, s. 397-412
-
Research review (peer-reviewed)abstract
- Molecular diagnostics is a cornerstone of modern precision medicine, broadly understood as tailoring an individual's treatment, follow-up, and care based on molecular data. In rare diseases (RDs), molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies. Due to decreasing DNA sequencing costs, genome sequencing (GS) is emerging as the primary method for precision diagnostics in RDs. Several ongoing European initiatives for precision medicine have chosen GS as their method of choice. Recent research supports the role for GS as first-line genetic investigation in individuals with suspected RD, due to its improved diagnostic yield compared to other methods. Moreover, GS can detect a broad range of genetic aberrations including those in noncoding regions, producing comprehensive data that can be periodically reanalyzed for years to come when further evidence emerges. Indeed, targeted drug development and repurposing of medicines can be accelerated as more individuals with RDs receive a molecular diagnosis. Multidisciplinary teams in which clinical specialists collaborate with geneticists, genomics education of professionals and the public, and dialogue with patient advocacy groups are essential elements for the integration of precision medicine into clinical practice worldwide. It is also paramount that large research projects share genetic data and leverage novel technologies to fully diagnose individuals with RDs. In conclusion, GS increases diagnostic yields and is a crucial step toward precision medicine for RDs. Its clinical implementation will enable better patient management, unlock targeted therapies, and guide the development of innovative treatments.
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| 38. |
- Tham, Emma, et al.
(author)
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A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9.
- 2015
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In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813.
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Journal article (peer-reviewed)abstract
- A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. We studied two unrelated families including three affected fetuses with Gillessen-Kaesbach-Nishimura syndrome using whole-exome and Sanger sequencing, comparative genome hybridization and homozygosity mapping. All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T>A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation. RNA analysis demonstrated skipping of exon 10, leading to shorter RNA. Mass spectrometric analysis showed an increase in monoglycosylated transferrin as compared with control tissues, confirming that this is a congenital disorder of glycosylation (CDG). Only three liveborn children with ALG9-CDG have been previously reported, all with missense variants. All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia. Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype. The skeletal features overlap with that previously reported for ALG3- and ALG12-CDG, suggesting that this subset of glycosylation disorders constitutes a new diagnostic group of skeletal dysplasias.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.91.
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| 39. |
- Vesikari, Timo, et al.
(author)
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Immunogenicity and Safety of a Trivalent Inactivated Influenza Vaccine in Children 6 Months to 17 Years of Age, Previously Vaccinated with an AS03-Adjuvanted A(H1N1)Pdm09 Vaccine Two Open-label, Randomized Trials
- 2015
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In: The Pediatric Infectious Disease Journal. - 0891-3668 .- 1532-0987. ; 34:7, s. 774-782
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Journal article (peer-reviewed)abstract
- Background: During the influenza pandemic 2009-2010, an AS03-adjuvanted A(H1N1) pdm09 vaccine was used extensively in children 6 months of age and older, and during the 2010-2011 influenza season, the A(H1N1) pdm09 strain was included in the seasonal trivalent inactivated influenza vaccine (TIV) without adjuvant. We evaluated the immunogenicity and safety of TIV in children previously vaccinated with the AS03-adjuvanted A(H1N1) pdm09 vaccine. Methods: Healthy children were randomized (1:1) to receive TIV or a control vaccine. Children were aged 6 months to 9 years (n = 154) and adolescents 10-17 years (n = 77) when they received AS03-adjuvanted A(H1N1) pdm09 vaccine at least 6 months before study enrolment. Hemagglutination inhibition (HI) and neutralizing antibody responses against the A(H1N1) pdm09 strain were evaluated before (day 0) and at day 28 and month 6 after study vaccination. Reactogenicity was assessed during the 7 day postvaccination period, and safety was assessed for 6 months. Results: At day 0, >93.9% of all children had HI titers >= 1:40 for the A(H1N1) pdm09 strain, which increased to 100% at both day 28 and month 6 in the TIV group. Between days 0 and 28, HI antibody geometric mean titers against A(H1N1) pdm09 increased by 9-fold and 4-fold in children 6 months to 9 years of age and 10-17 years of age, respectively. Conclusion: AS03-adjuvanted A(H1N1) pdm09 vaccine-induced robust immune responses in children that persisted into the next season, yet were still boosted by TIV containing A(H1N1) pdm09. The reactogenicity and safety profile of TIV did not appear compromised by prior receipt of AS03adjuvanted A(H1N1) pdm09 vaccine.
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