| 1. |
- Clark, Andrew G., et al.
(author)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Journal article (peer-reviewed)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 2. |
- Haghighi, Mona, et al.
(author)
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A Comparison of Rule-based Analysis with Regression Methods in Understanding the Risk Factors for Study Withdrawal in a Pediatric Study
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper demonstrates the value of using rule-based analysis methods that can identify subgroups with heterogeneous risk profiles in a population without imposing assumptions on the subgroups or method. The rules define the risk pattern of subsets of individuals by not only considering the interactions between the risk factors but also their ranges. We compared the rule-based analysis results with the results from a logistic regression model in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Both methods detected a similar suite of risk factors, but the rule-based analysis was superior at detecting multiple interactions between the risk factors that characterize the subgroups. A further investigation of the particular characteristics of each subgroup may detect the special health needs of the subgroup and lead to tailored interventions.
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| 3. |
- Lundgren, Markus, et al.
(author)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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In: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 4. |
- Nene, Vishvanath, et al.
(author)
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Genome sequence of Aedes aegypti, a major arbovirus vector.
- 2007
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In: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5832, s. 1718-23
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Journal article (peer-reviewed)abstract
- We present a draft sequence of the genome of Aedes aegypti, the primary vector for yellow fever and dengue fever, which at approximately 1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae. Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of approximately 4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster. Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of approximately 2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.
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| 5. |
- Battaglia, Manuela, et al.
(author)
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Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes
- 2020
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:1, s. 5-12
-
Journal article (peer-reviewed)abstract
- The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
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| 6. |
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| 7. |
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| 8. |
- De Jong, Wim H., et al.
(author)
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Round robin study to evaluate the reconstructed human epidermis (RhE) model as an in vitro skin irritation test for detection of irritant activity in medical device extracts
- 2018
-
In: Toxicology in Vitro. - : Elsevier BV. - 0887-2333 .- 1879-3177. ; 50, s. 439-449
-
Journal article (peer-reviewed)abstract
- Assessment of skin irritation is an essential component of the safety evaluation of medical devices. OECD Test Guideline 439 describes the use of reconstructed human epidermis (RhE) as an in vitro test system for classification of skin irritation by neat chemicals. An international round robin study was conducted to evaluate the RhE method for determination of skin irritant potential of medical device extracts. Four irritant polymers and three non-irritant controls were obtained or developed that had demonstrated their suitability to act as positive or negative test samples. The RhE tissues (EpiDerm™ and SkinEthic™ RHE) were dosed with 100 μL aliquots of either saline or sesame oil extract. Incubation times were 18 h (EpiDerm™) and 24 h (SkinEthic™ RHE). Cell viability reduction > 50% was indicative of skin irritation. Both the EpiDerm™ and SkinEthic™ RHE tissues were able to correctly identify virtually all of the irritant polymer samples either in the saline, sesame oil or both solvent extracts. Our results indicate that RhE tissue models can detect the presence of strong skin irritants at low levels in dilute medical device polymer extracts. Therefore, these models may be suitable replacements for the rabbit skin irritation test to support the biological evaluation of medical devices.
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| 9. |
- Jonsdottir, Berglind, et al.
(author)
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Early appearance of thyroid autoimmunity in children followed from birth for type 1 diabetes risk
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In: The Journal of clinical endocrinology and metabolism. - 1945-7197.
-
Journal article (peer-reviewed)abstract
- PURPOSE: Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define pre-clinical autoimmune thyroid disease (AITD) which can progress to either clinical hypo- or hyperthyroidism. We determined the age at seroconversion in children genetically at risk for type 1 diabetes.METHODS: TPOAb and TgAb seropositivity were determined in 5066 healthy children with HLA DR3 or DR4 containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Children seropositive on the cross-sectional initial screen at 8-13 years of age had longitudinally collected samples (from 3.5 months of age) screened retrospectively and prospectively for thyroid autoantibodies to identify the age at seroconversion. First-appearing autoantibody was related to sex, HLA genotype, family history of AITD, and subsequent thyroid dysfunction and disease.RESULTS: The youngest appearance of TPOAb and TgAb was 10 and 15 months of age, respectively. Girls had higher incidence rates of both autoantibodies. Family history of AITD was associated with a higher risk of TPOAb hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.17, 3.08; and TgAb HR 2.55, 95% CI 1.91, 3.41. The risk of progressing to hypo- or hyperthyroidism was not different between TgAb and TPOAb, but children with both autoantibodies appearing at the same visit had a higher risk compared to TPOAb appearing first (HR 6.34, 95% CI 2.72, 14.76).MAIN CONCLUSION: Thyroid autoantibodies may appear during the first years of life, especially in girls, and in children with a family history of AITD. Simultaneous appearance of both autoantibodies increases the risk for hypo- or hyperthyroidism.
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| 10. |
- Lehmann-Werman, Roni, et al.
(author)
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Identification of tissue-specific cell death using methylation patterns of circulating DNA
- 2016
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:13, s. E1826-E1834
-
Journal article (peer-reviewed)abstract
- Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic beta-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.
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| 11. |
- Matsui, Yasuhiro, et al.
(author)
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Widely tuneable modulated grating Y-branch Chirp Managed Laser
- 2009
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In: 35th European Conference on Optical Communication, 2009. ECOC ’09.
-
Conference paper (peer-reviewed)abstract
- We developed a 45 nm tuneable 18 GHz 3-dB bandwidth Modulated-Grating Y-branch laser and demonstrated a error-free 200- km transmission at 10 Gb/s with a drive voltage of 1.5 Vpp using Chirp Managed Laser technology.
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| 12. |
- Ostrovskis, Armands, et al.
(author)
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170 Gbaud On-Off-Keying SiP Ring Resonator Modulator-based Link for Short-Reach Applications
- 2024
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In: 2024 IEEE Silicon Photonics Conference, SiPhotonics 2024 - Proceedings. - : Institute of Electrical and Electronics Engineers (IEEE).
-
Conference paper (peer-reviewed)abstract
- We demonstrate a record 170 Gbaud on-off keying C-band silicon photonics ring resonator modulator-based transmitter with performance below the 6.7% overhead HD-FEC threshold after optical back-to-back and transmission over 100 meters of single mode fiber.
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| 13. |
- Ozolins, Oskars, et al.
(author)
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High-Baudrate Silicon Photonics Ring Resonator and Mach-Zehnder Modulators for Short-Reach Applications
- 2023
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In: 2023 23rd International Conference on Transparent Optical Networks, ICTON 2023. - : Institute of Electrical and Electronics Engineers (IEEE).
-
Conference paper (peer-reviewed)abstract
- Silicon photonics (SiP) is a key enabling technology for high-baudrate communication. It is a key technology for future 800 Gbps and 1.6 Tbps solutions to meet the ever-increasing demands. The 800G pluggable multi-source agreement (MSA) suggests that intensity-modulated direct-detection (IM/DD) is the most sustainable way forward [1]. The high operational bandwidth of each transceiver component is essential. An ultra-compact SiP slow light modulator with record-high bandwidth of 110 GHz shows the potential [2]. Therefore, both multilevel pulse amplitude modulation (PAM) and on-off keying (OOK) should be considered. SiP offers excellent production yield and has a substantial role in optical interconnects. SiP ring resonator modulators (RRM) have unique advantages like a small footprint, simple driver configuration, low power consumption, and suitability for multichannel applications. On the other hand, the SiP Mach-Zehnder modulator (MZM) offers differential drive benefits.
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| 14. |
- Ozolins, Oskars, et al.
(author)
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High-Baudrate Silicon Photonics Ring Resonator Modulators for Short-Reach Applications
- 2023
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In: 2023 Asia Communications and Photonics Conference/2023 International Photonics and Optoelectronics Meetings, ACP/POEM 2023. - : Institute of Electrical and Electronics Engineers (IEEE).
-
Conference paper (peer-reviewed)abstract
- We demonstrate up to 160 Gbaud on-off keying with first ring resonator modulator and up to 128 Gbaud on-off keying with second ring resonator modulator. Both modulators achieve performance below 6.25% OH HD-FEC threshold.
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| 15. |
- Ozolins, Oskars, et al.
(author)
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High-Baudrate SiP and InP Modulators for Data Center Interconnects
- 2023
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In: 2023 31st International Conference on Software, Telecommunications and Computer Networks, SoftCOM 2023. - : Institute of Electrical and Electronics Engineers (IEEE).
-
Conference paper (peer-reviewed)abstract
- The booming internet traffic sets highly challenging requirements for high-speed computing where low latency is required. This leads to a choice of intensity modulation and direct detection system with the highest baudrate possible. Furthermore, record baudrate supporting modulators will be the key technology for future optical interconnect applications. Therefore, we demonstrated silicon photonics and indium phosphide modulators at highest possible sysmbolrate.
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| 16. |
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| 17. |
- Ozolins, Oskars, et al.
(author)
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Optical spectral reshaping for directly modulated 4-pulse amplitude modulation signals
- 2017
-
In: Transparent Optical Networks (ICTON), 2017 19th International Conference on. - : Institute of Electrical and Electronics Engineers (IEEE). - 9781538608609 ; , s. 1-1
-
Conference paper (peer-reviewed)abstract
- The tremendous traffic growth in intra/inter-datacenters requires low-cost high-speed integrated solutions [1]. To enable a significantly reduced footprint directly modulated lasers (DMLs) have been proposed instead of large external modulators. However, it is challenging to use DMLs due to their low dispersion tolerance and limited achievable extinction ratio (ER). A promising solution to this problem is optical spectral reshaping (OSR) since it is possible to increase the dispersion tolerance as well as to enhance the achievable ER for both on-of-keying [2] and 4-pulse amplitude modulation (PAM) [3] signals. However, moving to 4-PAM,many of the impressive demonstrations reported so far rely heavily on off-line digital signal processing (DSP), which increases latency, power consumption and cost. In this talk, we report on (i) a detailed numerical analysis on the complex transfer function of the optical filter for optical spectral reshaping in case of pulse amplitude modulation and(ii) an experimental demonstration of real-time dispersion-uncompensated transmission of 10-GBd and 14-GBd 4-PAM signals up to 10- and 26-km SSMF. This is achieved by combining a commercial 10-Gb/s DML with optical spectral shaping, thus removing the need for any complex off-line DSP and improving dispersion tolerance. These achievements are enabled by OSR based on a passive microring resonator fabricated on the SOI platform [4]. Significant improvement in receiver sensitivities was observed for both a 10-GBd signal after 10-km SSMF transmission and 14-GBd with no penalty after 26-km SSMF transmission.
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| 18. |
- Phillip, Moshe, et al.
(author)
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Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes
-
In: Diabetes Care. - 1935-5548.
-
Journal article (peer-reviewed)abstract
- Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings. To inform this monitoring, JDRF, in conjunction with international experts and societies, developed consensus guidance. Broad advice from this guidance includes the following: 1) partnerships should be fostered between endocrinologists and primary care providers to care for people who are IAb+; 2) when people who are IAb+ are initially identified, there is a need for confirmation using a second sample; 3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; 4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; 5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and 6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasizes significant unmet needs for further research on early-stage type 1 diabetes to increase the rigor of future recommendations and inform clinical care.
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| 19. |
- Phillip, Moshe, et al.
(author)
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Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes
-
In: Diabetologia. - 1432-0428.
-
Journal article (peer-reviewed)abstract
- Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.
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| 20. |
- Schatz, Patrik, et al.
(author)
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A tapetal-like fundus reflex in a healthy male: evidence against a role in the pathophysiology of retinal degeneration?
- 2012
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In: Molecular Vision. - 1090-0535. ; 18:119-20, s. 1147-1155
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Journal article (peer-reviewed)abstract
- Purpose: To report on the retinal function and structure in a 37-year-old male who presented with a tapetal-like reflex (TLR) indistinguishable from that seen in female carriers of X-linked retinitis pigmentosa (XLRP). Methods: Clinical examination included dark adaptometry, full-field electroretinography (ERG), multifocal ERG, optical coherence tomography, and fundus autofluorescence photography. Molecular genetic testing included screening for known mutations in autosomal dominant, autosomal recessive, and X linked retinitis pigmentosa (RP) genes with a commercially available chip, and sequencing analysis of retinitis pigmentosa GTPase regulator (RPGR)-open reading frame 15 (ORF15). Results: Fundus examination revealed a bilateral TLR, which is typical of female carriers of XLRP. Imaging studies and electrophysiological testing was unremarkable, except for a significant increase in full-field ERG amplitudes after prolonged dark adaptation as compared to after standard dark adaptation. Mutation screening was negative. Conclusions: TLR was found for the first time, to the best of our knowledge, in a male subject. There were no definitive signs of retinal degeneration, suggesting that this reflex in itself is not necessarily a precursor of the retinal degeneration that can be seen in female carriers of XLRP.
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| 21. |
- Schatz, Patrik, et al.
(author)
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Evaluation of Macular Structure and Function by OCT and Electrophysiology in Patients with Vitelliform Macular Dystrophy Due to Mutations in BEST1
- 2010
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In: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783 .- 0146-0404. ; 51:9, s. 4754-4765
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Journal article (peer-reviewed)abstract
- PURPOSE. To analyze retinal structure and function in vitelliform macular dystrophy (VMD) due to mutations in BEST1. METHODS. Patients from five Swedish and four Danish families were examined with electrooculography (EOG), full-field electroretinography (ffERG), multifocal ERG (mfERG), optical coherence tomography (OCT), and fundus autofluorescence photography (FAF). Genetic analysis of the BEST1 gene was performed by direct sequencing. RESULTS. Mutations in BEST1 have been reported previously in the Swedish families. In the Danish families, four disease-causing missense mutations were found, one of which is novel: c.936C>A (p.Asp312Glu). The mutation was homozygous in a 9-year-old boy and heterozygous in his father in a consanguineous family. ffERG rod response was reduced in the homozygous boy, but normal in the heterozygous father. EOG was reduced in all but two patients and did not correlate with the ffERG results. OCT ranged from normal to cystoid edema and thickening of the outer retina-choroid complex. Decreased mfERG amplitudes, increased mfERG latencies, and loss of integrity of the foveal photoreceptor inner/outer segment junction, correlated with decreased vision. FAF demonstrated hyperautofluorescence beyond the ophthalmoscopic changes in several patients. CONCLUSIONS. The finding of a homozygous dominant mutation in a patient with VMD and evidence of widespread retinal degeneration may imply that the pathogenesis of the generalized retinal degeneration differs from that of the macular degeneration. A relative agreement between hyperautofluorescence by FAF, reduced retinal function, and VMD implies that the hyperautofluorescence emanates from lipofuscin and A2E. A potential therapy for VMD, involving the inhibition of the retinoid cycle, is suggested. (Invest Ophthalmol Vis Sci. 2010;51:4754 - 4765) DOI:10.1167/iovs.10-5152
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| 22. |
- Schatz, Patrik, et al.
(author)
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Fundus Albipunctatus Associated with Compound Heterozygous Mutations in RPE65.
- 2011
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In: Ophthalmology. - : Elsevier BV. - 1549-4713 .- 0161-6420. ; 118, s. 888-894
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Journal article (peer-reviewed)abstract
- PURPOSE:: To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations. DESIGN:: Observational study. PARTICIPANTS:: Four family members. METHODS:: Clinical examinations included full-field electroretinogram (ffERG) after standard (30-minute) and prolonged (17-hour) dark adaptation, multifocal electroretinogram (mfERG), optical coherence tomography (OCT), and fundus autofluorescence (FAF). Molecular genetic testing included sequencing of RDH5 and RLBP1 and screening for known autosomal-recessive retinitis pigmentosa mutations by a commercially available microarray technique. RPE65 sequencing was performed after the identification of a known heterozygous splice-site mutation by array screening. MAIN OUTCOME MEASURES:: We recorded ffERG and mfERG amplitudes, OCT characteristics, the FAF intensity index, and the outcomes of DNA sequencing regarding RPE65 mutations. RESULTS:: Uniform, yellow-white dots typical of fundus albipunctatus were demonstrated in the proband. These dots corresponded with discrete, hyperreflective formations extending from the Bruch's membrane and retinal pigment epithelium (RPE) into the level of the external limiting membrane, thus spanning along the entire RPE and photoreceptor outer and inner segments. A reduced thickness of the central retina and the RPE-outer segment complex was demonstrated. The intensity of the FAF was severely reduced in the entire fundus. At age 18, ffERG-including prolonged dark adaptation-demonstrated a barely recordable rod response after standard dark adaptation and normalization (increase by more than 700%) of the response after prolonged dark adaptation. The cone 30-Hz flicker response was reduced after standard dark adaptation and increased by >50% after prolonged dark adaptation. In addition, mfERG demonstrated reduced central and peripheral responses. Molecular genetic analysis demonstrated compound heterozygous mutations (IVS1+5G>A and c.344T>C) in RPE65. No mutations were found in RDH5 or RLBP1. No significant abnormalities of retinal structure or function were detected in the parents and sister carrying single heterozygous mutations in RPE65. CONCLUSIONS:: This is the first reported association between compound heterozygous RPE65 mutations and fundus albipunctatus, indicative of a mutation-specific phenotypic effect in this gene. This finding, together with the reduced FAF, supports that disruption of retinoid recycling in the RPE is essential for the development of fundus albipunctatus. FINANCIAL DISCLOSURE(S):: The authors have no proprietary or commercial interest in any of the materials discussed in this article.
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| 23. |
- Schatz, Patrik, et al.
(author)
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LACK OF AUTOFLUORESCENCE IN FUNDUS ALBIPUNCTATUS ASSOCIATED WITH MUTATIONS IN RDH5.
- 2010
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In: Retina. - 1539-2864. ; Okt, s. 1704-1713
-
Journal article (peer-reviewed)abstract
- PURPOSE:: The purpose of this study was to characterize the phenotype of fundus albipunctatus associated with RDH5 mutations. METHODS:: Four unrelated patients (patients 1-4) aged 35, 32, 19, and 8 years were examined with full-field electroretinography, multifocal electroretinography, optical coherence tomography, and fundus autofluorescence photography. Molecular genetic investigations included sequencing of RDH5 and RLBP1. RESULTS:: Patients 1 to 3 harbored homozygous mutations (c.881G>C, c.625C>T, and c.382G>A, respectively) and patient 4 harbored the compound heterozygous mutations (c.95delT and c.712G>T) in RDH5. A large variability in retinal dysfunction caused by RDH5 mutations was found but not fully explained by a simple prediction of reduced enzymatic function. All patients showed lack of autofluorescence of the fundus, indicating a reduced supply of 11-cis retinal to the photoreceptors. The lesions corresponding to the white dots did not autofluoresce and were seen on optical coherence tomography as discrete hyperreflective elements in the outer retina extending from the external limiting membrane to Bruch membrane. CONCLUSION:: Mutations in RDH5 associated with fundus albipunctatus seem to prevent normal lipofuscin accumulation. A relatively good functional status of 2 of 3 adult patients indicates that interference with 11-cis retinol dehydrogenase function may be a promising strategy for therapeutic intervention in retinal disorders featuring excessive lipofuscin accumulation.
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| 24. |
- Schatz, Patrik, et al.
(author)
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Retinal structure in young patients aged 10 years or less with Best vitelliform macular dystrophy.
- 2015
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In: Graefe's Archive for Clinical and Experimental Ophthalmology. - : Springer Science and Business Media LLC. - 1435-702X .- 0721-832X.
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Journal article (peer-reviewed)abstract
- Our aim was to analyze retinal structure in young patients with Best disease with reference to future gene therapy. This was a retrospective observational spectral domain optical coherence tomography study of four patients aged 10 years or less with Best disease. Findings ranged from subtle thickening at the level of the retinal pigment epithelium-photoreceptor interdigitation line, to subretinal fluid and precipitate-like changes at the level of the photoreceptor outer segments, and further to choroidal neovascularization. The photoreceptor inner segment ellipsoid layer could be visualized seemingly undisturbed above the vitelliform lesions, except in the case of choroidal neovascularization. Clinical variability is evident even among young patients aged 10 years or less with Best disease. The earliest structural alterations seem to occur at the level of the retinal pigment epithelium-photoreceptor interdigitation line. The photoreceptor inner segment seems to be unaffected unless choroidal neovascularization develops, which seems promising regarding future gene therapy.
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| 25. |
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| 26. |
- Sharon, Dror, et al.
(author)
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Ocular phenotype analysis of a family with biallelic mutations in the BEST1 gene.
- 2014
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In: American Journal of Ophthalmology. - : Elsevier BV. - 1879-1891 .- 0002-9394. ; 157:3, s. 697-709
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Journal article (peer-reviewed)abstract
- To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy. To investigate whether Bestrophin may be expressed in normal human retina.
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| 27. |
- Tavakoli, Samira, et al.
(author)
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Perceptual quality of HTTP adaptive streaming strategies : Cross-experimental analysis of multi-laboratory and crowdsourced subjective studies
- 2016
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In: IEEE Journal on Selected Areas in Communications. - : Institute of Electrical and Electronics Engineers (IEEE). - 0733-8716 .- 1558-0008. ; 34:8, s. 2141-2153
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Journal article (peer-reviewed)abstract
- Today's packet-switched networks are subject to bandwidth fluctuations that cause degradation of the user experience of multimedia services. In order to cope with this problem, HTTP adaptive streaming (HAS) has been proposed in recent years as a video delivery solution for the future Internet and being adopted by an increasing number of streaming services, such as Netflix and Youtube. HAS enables service providers to improve users' quality of experience (QoE) and network resource utilization by adapting the quality of the video stream to the current network conditions. However, the resulting time-varying video quality caused by adaptation introduces a new type of impairment and thus novel QoE research challenges. Despite various recent attempts to investigate these challenges, many fundamental questions regarding HAS perceptual performance are still open. In this paper, the QoE impact of different technical adaptation parameters, including chunk length, switching amplitude, switching frequency, and temporal recency, are investigated. In addition, the influence of content on perceptual quality of these parameters is analyzed. To this end, a large number of adaptation scenarios have been subjectively evaluated in four laboratory experiments and one crowdsourcing study. A statistical analysis of the combined data set reveals results that partly contradict widely held assumptions and provide novel insights in perceptual quality of adapted video sequences, e.g., interaction effects between quality switching direction (up/down) and switching strategy (smooth/abrupt). The large variety of experimental configurations across different studies ensures the consistency and external validity of the presented results that can be utilized for enhancing the perceptual performance of adaptive streaming services.
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| 28. |
- Vehik, Kendra, et al.
(author)
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Rising Hemoglobin A1c in the Nondiabetic Range Predicts Progression of Type 1 Diabetes As Well As Oral Glucose Tolerance Tests
- 2022
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 45:10, s. 2342-2349
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies.RESEARCH DESIGN AND METHODS: Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190).RESULTS: A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7-18.6, P < 0.0001) and TrialNet (HR 5.09, 95% CI 3.3-7.9, P < 0.0001). Furthermore, the composite model using HbA1c ≥10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC 0.82).CONCLUSIONS: An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies.
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| 29. |
- Wang, Gang, et al.
(author)
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Photovoltaic Blend Microstructure for High Efficiency Post-Fullerene Solar Cells. To Tilt or Not To Tilt?
- 2019
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 141:34, s. 13410-13420
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Journal article (peer-reviewed)abstract
- Achieving efficient polymer solar cells (PSCs) requires a structurally optimal donor-acceptor heterojunction morphology. Here we report the combined experimental and theoretical characterization of a benzodithiophene-benzo-thiadiazole donor polymer series (PBTZF4-R; R = alkyl substituent) blended with the non-fullerene acceptor ITIC-Th and analyze the effects of substituent dimensions on blend morphology, charge transport, carrier dynamics, and PSC metrics. Varying substituent dimensions has a pronounced effect on the blend morphology with a direct link between domain purity, to some extent domain dimensions, and charge generation and collection. The polymer with the smallest alkyl substituent yields the highest PSC power conversion efficiency (PCE, 11%), reflecting relatively small, high-purity domains and possibly benefiting from "matched" donor polymer-small molecule acceptor orientations. The distinctive morphologies arising from the substituents are investigated using molecular dynamics (MD) simulations which reveal that substituent dimensions dictate a well-defined set of polymer conformations, in turn driving chain aggregation and, ultimately, the various film morphologies and mixing with acceptor small molecules. A straightforward energetic parameter explains the experimental polymer domain morphological trends, hence PCE, and suggests strategies for substituent selection to optimize PSC materials morphologies.
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| 30. |
- Warncke, Katharina, et al.
(author)
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The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study
- 2024
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In: Journal of the Endocrine Society. - 2472-1972. ; 8:7
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Journal article (peer-reviewed)abstract
- CONTEXT: The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty.OBJECTIVE: We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes.METHODS: The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios.RESULTS: Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P = .019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P < .001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. CONCLUSION: Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms.
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