Characterization of 40-Gbit/s pulses generated using a lithium niobate modulator at 1550 nm using frequency resolved optical gating

The characteristics of 40-Gbit/s pulses generated by exploiting the nonlinear characteristics of a Mach-Zender Lithium Niobate modulator are presented. A high spectral resolution frequency resolved optical gating apparatus has been developed to allow for the complete characterization of the intensity and phase of these pulses. The use of these measurements to simplify the design and optimization of an 80-Gbit/s pulse source, based on this 40-Gbit/s source followed by a nonlinear fiber compressor and multiplexer, is also demonstrated

Optimization of optical data transmitters for 40-Gb/s lightwave systems using frequency resolved optical gating

The measurement technique of frequency resolved optical gating has been used to optimize the phase of a 40-GHz train of optical pulses generated using a continuous-wave laser gated with an external modulator. This technique will be vital for optimization of optical transmitters to be used in systems operating at 40 Gb/s and beyond, as standard measurement techniques will not suffice to optimize such high-speed systems

Optimization of 40 Gbit/s transmission systems using frequency resolved optical gating characterization techniques

To achieve multiterabit/s capacities in long-haul transport networks, it is anticipated that wavelength division multiplexed (WDM) systems will be upgraded to operate at line rates of 40 Gbit/s. We have shown that by employing the FROG measurement technique to optimize the generation of optical pulses for use in a 40 Gbit/s soliton transmission link, we ensure that the performance of the overall system using the generated optical pulses is optimum

Flexible terabit/s Nyquist-WDM super-channels using a gain-switched comb source

Terabit/s super-channels are likely to become the standard for next-generation optical networks and optical interconnects. A particularly promising approach exploits optical frequency combs for super-channel generation. We show that injection locking of a gain-switched laser diode can be used to generate frequency combs that are particularly well suited for terabit/s super-channel transmission. This approach stands out due to its extraordinary stability and flexibility in tuning both center wavelength and line spacing. We perform a series of transmission experiments using different comb line spacings and modulation formats. Using 9 comb lines and 16QAM signaling, an aggregate line rate (net data rate) of 1.296 Tbit/s (1.109 Tbit/s) is achieved for transmission over 150 km of standard single mode fiber (SSMF) using a spectral bandwidth of 166.5 GHz, which corresponds to a (net) spectral efficiency of 7.8 bit/s/Hz (6.7 bit/s/Hz). The line rate (net data rate) can be boosted to 2.112 Tbit/s (1.867 Tbit/s) for transmission over 300 km of SSMF by using a bandwidth of 300 GHz and QPSK modulation on the weaker carriers. For the reported net data rates and spectral efficiencies, we assume a variable overhead of either 7\% or 20\% for forward- error correction depending on the individual sub-channel quality after fiber transmission

Spectral amplitude and phase measurement of a 40 GHz free-running quantum-dash modelocked laser diode

We present a linear self-referenced measurement of the spectral amplitude and phase of a free-running quantum-dash modelocked laser diode. The technique is suitable for measuring optical signals with repetition rates up to 100 GHz. In contrast to many other linear techniques it requires no external electronic clock synchronized to the signal under test. Using this method we are able to compensate for the intracavity dispersion of the diode to demonstrate 500 fs pulses at a repetition rate of 39.8 GHz. We also use the technique to characterize the dependence of the diode’s intracavity dispersion on the applied current

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12- q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Valuing Health Gain from Composite Response Endpoints for Multisystem Diseases

Objectives: This study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. Methods: Data from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. Results: Within the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. Conclusions: Bespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy

Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.Peer reviewe