Exome sequencing as first-tier test for fetuses with severe central nervous system structural anomalies.

OBJECTIVE: Prenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly. METHODS: This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed using ES to assess its ability to detect copy-number variants (CNVs). RESULTS: CMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty-six CMA-negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non-significantly higher compared with non-recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non-causative CNVs. CONCLUSIONS: In our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Detection of copy number variations in epilepsy using exome data.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

Homozygous deletion of RAG1, RAG2 and 5' region TRAF6 causes severe immune suppression and atypical osteopetrosis.

Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5' region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.

Numerical investigation of all-optical add-drop multiplexing for spectrally overlapping OFDM signals.

We propose a novel architecture for all-optical add-drop multiplexing of OFDM signals. Sub-channel extraction is achieved by means of waveform replication and coherent subtraction from the OFDM super-channel. Numerical simulations have been carried out to benchmark the performance of the architecture against critical design parameters.

Wavelength-selective switch with direct few mode fiber integration.

The first realization of a wavelength-selective switch (WSS) with direct integration of few mode fibers (FMF) is fully described. The free-space optics FMF-WSS dynamically steers spectral information-bearing beams containing three spatial modes from an input port to one of nine output ports using a phase spatial light modulator. Sources of mode dependent losses (MDL) are identified, analytically analyzed and experimentally confirmed on account of different modal sensitivities to fiber coupling in imperfect imaging and at spectral channel edges due to mode clipping. These performance impacting effects can be reduced by adhering to provided design guidelines, which scale in support of higher spatial mode counts. The effect on data transmission of cascaded passband filtering and MDL build-up is experimentally investigated in detail.

Compact all-optical bypass-exchange switch.

An electronically or optically addressed compact optical bypass-exchange switch is investigated and experimentally demonstrated.The switch is polarization based and consists of a controllable λ/2 platesandwiched between two polarizing beam displacers. The input and the output signals propagate normal to the switching array, which makes the switch extremely attractive for cascading switching arrays, as found in multistage interconnect networks. A complete, all-optical interconnection network is suggested.

Analysis of spatial-temporal converters for all-optical communication links.

We analyze parallel-to-serial transmitters and serial-to-parallel receivers that use ultrashort optical pulses to increase the bandwidth of a fiber-optic communication link. This method relies on real-time holographic material for conversion of information between spatial and temporal frequencies. The analysis reveals that the temporal output of the pulses will consist of chirped pulses, which has been verified experimentally. When the signal pulses are transmitted along with a reference pulse, the distortions of the received signal, caused by dispersion and other factors in the fiber, are canceled because of the phase-conjugation property of the receiver. This self-referencing scheme simplifies the receiver structure and ensures perfect timing for the serial-to-parallel conversion.

All-optical stage of an omega network.

All-optical multistage interconnection networks are desirable for overcoming the limitations of optical signal regeneration in switching systems. We present a new implementation of the perfect-shuffle interconnection pattern that is coupled with an all-optical switching element, forming a complete stage of a multistage network. Switching is performed with birefringent calcite crystals and a ferroelectric liquid-crystal device, while interconnection is achieved with a space-semivariant imaging configuration. Cascading the layout allows this system to be used to construct an all-optical multistage interconnection network. An experimental demonstration of the stage is presented.

Time reversal of ultrafast waveforms by wave mixing of spectrally decomposed waves.

Two different realizations of time-reversal experiments of ultrafast waveforms are carried out in real time by use of four-wave mixing arrangements of spectrally decomposed waves. The first, conventional, method is based on phase conjugation of the waveform's spectrum and achieves time reversal of real amplitude waveforms. The second arrangement of the spectrally decomposed waves spatially inverts the waveform's spectrum with respect to the optical axis of the processor and achieves true time reversal for complex-amplitude ultrafast waveforms. We compare and contrast these two real-time techniques.

Reply to "Comment on 'Time reversal of ultrafast waveforms by wave mixing spectrally decomposed waves'".

In response to a comment on our Letter [Opt. Lett. 25, 132 (2000)], we reiterate the distinction between the spectral inversion and the spectral phase conjugation processing techniques. The former achieves time reversal of the complex amplitude waveform, whereas the latter performs time reversal of the real electric field.

Hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis.

A 2-year-old child presented with fever and hepatosplenomegaly. Laboratory findings showed pancytopenia, hypertriglyceridemia, hyperferritinemia, and high levels of soluble-IL2 receptors. Initial bone marrow aspiration and biopsy revealed mild hemophagocytosis. A diagnosis of hemophagocytic lymphohistiocytosis was made and appropriate treatment was begun. Repeated marrow aspiration performed because of lack of clinical response revealed Leishmania amastigotes in macrophages in addition to active hemophagocytosis. Treatment with liposomal amphotericin resulted with rapid recovery. Visceral leishmaniasis should be considered in the differential diagnosis of hemophagocytic syndrome.

Linear and nonlinear operation of a time-to-space processor.

The operational characteristics of a time-to-space processor based on three-wave mixing for instantaneous imaging of ultrafast waveforms are investigated. We assess the effects of various system parameters on the processor's important attributes: time window of operation and signal conversion efficiency. Both linear and nonlinear operation regimes are considered, with use of a Gaussian pulse profile and a Gaussian spatial mode model. This model enables us to define a resolution measure for the processor, which is found to be an important characteristic. When the processor is operated in the linear interaction regime, we find that the conversion efficiency of a temporal signal to a spatial image is inversely proportional to the resolution measure. In the nonlinear interaction regime, nonuniform signal conversion due to fundamental wave depletion gives rise to a phenomenon that can be used to enhanced the imaging operation. We experimentally verify this nonlinear operation.

Intravenous leiomyomatosis with cardiac involvement in a pregnant woman.

Intravenous leiomyomatosis is a rare benign neoplasm that commonly grows into the pelvic veins and the inferior vena cava and, rarely, the right side of the heart. We report the first case of intravenous leiomyomatosis with cardiac involvement in a pregnant woman. The treatment of choice is surgical resection in two steps.

Significance of sporadic deceleration during antepartum testing in term pregnancies.

We have investigated the significance of single sporadic deceleration during reactive nonstress testing in normal pregnancies at term. A prospective study was performed during a 1-year period including 4742 nonstress tests performed between the 38th and 42nd weeks of pregnancy in patients referred to our department for antepartum testing and without any complication or pathology. Nonstress test (NST) was carried out with the patient lying on her left side, and was defined as reactive if at least two accelerations of 15 beats/min (bpm) or more lasting 15 sec were observed in a 20-min period. Sporadic deceleration was defined as a decrease in the fetal heart rate to less than 90 bpm or a decrease of 40 bpm below the baseline, lasting at least 2 min. The sporadic deceleration was considered as single when only one appeared in the first 20 min of monitoring and repeated when observed again once in at least one subsequent monitoring. Thirty-four cases of single sporadic deceleration were observed among women with reactive NST. In 14 cases there were repeated sporadic decelerations. The patients were divided into two groups according to the presence or absence of repeated decelerations. Outcomes of patients with repeated sporadic decelerations were compared with a group of 34 patients where sporadic decelerations were not observed during the antepartum testing. A significantly higher percentage of pathological fetal heart rate traces during labor were observed in the group of repeated decelerations. In conclusion the presence of repeated sporadic decelerations during a reactive NST suggests that the cause of cord compromise is persistent and recurrent cord compression is possible. Therefore, in these cases an increased fetal risk could be expected.

Clinical and laboratory impact of coagulase-negative staphylococci bacteremia in preterm infants.

UNLABELLED: A retrospective evaluation of the clinical and laboratory impact of coagulase-negative staphylococci (CONS) bacteremia in preterm infants was carried out. The study population included all preterm infants (n = 31) in whom two or more blood cultures were positive for CONS within a period of 4 d, with negative blood cultures 1 wk before and 1 wk after the CONS bacteremia. Clinical manifestations and the results of laboratory tests 7 d before and after the positive blood cultures, and on the first day of sepsis, were recorded and compared. During CONS bacteremia, the infants demonstrated apnoea and bradycardia (88%) and a need for oxygen (59%) and ventilatory support (69%). Significant laboratory findings were leukopenia below 5,000 cells/mm3 (12%), leukocytosis above 30,000 cells/mm3 (39%), and thrombocytopenia below 150,000/mm3 (25%). These clinical and laboratory manifestations differed significantly during the bacteremia infection compared with the week before and after. CONCLUSION: CONS bacteremia is a clinically significant infection in preterm infants, causing episodes of apnoea and bradycardia, and a need for ventilatory support.

Nitric oxide levels in preterm and term infants and in premature infants with bacteremia.

OBJECTIVE: To determine the serum nitric oxide levels in healthy neonates and in infants with bacteremia. METHODS: We performed a prospective study in a tertiary neonatal intensive care unit. The serum nitric oxide levels were measured in all infants at birth (basal) and in the infected neonates also on the first 2 days of bacteremia. RESULTS: Thirty-three neonates (10 term, 23 preterm) were included. Eleven preterm infants (mean gestational age 27 weeks) had bacteremia. The main blood culture isolates included coagulase-negative staphylococci (n=4), Klebsiella pneumoniae (n=3), and Escherichia coli (n=3). The serum nitric oxide levels increased during infection in 10 infants (p <0.008). The mean nitric oxide level before infection was 44 microM and during infection 96 microM (p=0.008). In the healthy babies, the mean nitric oxide level was 26 microM in those with a gestational age <27 weeks, 44 microM in those born between 28 and 36 weeks of gestation, and 63 microM in term infants. CONCLUSIONS: Bacteremic preterm infants produce significantly higher amounts of nitric oxide. The basal nitric oxide levels at birth may be correlated with gestational age.

Spatial temporal wave mixing for space time conversion.

A nonlinear optical processor that is capable of true real-time conversion of spatial-domain images to ultrafast time-domain optical waveforms is presented. The method is based on four-wave mixing between the optical waves of spectrally decomposed ultrashort pulses and spatially Fourier-transformed quasi-monochromatic images. To achieve efficient wave mixing at a femtosecond rate we utilize a cascaded second-order nonlinearity arrangement in a beta-barium borate crystal with type II phase matching. We use this ultrafast technique to experimentally generate several complex-amplitude temporal waveforms, with efficiency as high as 10%, by virtue of the cascaded nonlinearity arrangement.

Folded free-space polarization-controlled multistage interconnection network.

We present a folded free-space polarization-controlled optical multistage interconnection network (MIN) based on a dilated bypass-exchange switch (DBS) design that uses compact polarization-selective diffractive optical elements (PDOE's). The folded MIN design has several advantages over that of the traditional transparent MIN, including compactness, spatial filtering of unwanted higher-order diffraction terms leading to an improved signal-to-noise ratio (SNR), and ease of alignment. We experimentally characterize a folded 2 x 2 switch, as well as a 4 x 4 and an 8 x 8 folded MIN that we have designed and fabricated. We fabricated an array of off-axis Fresnel lenslet PDOE's with a 30:1 SNR and used it to construct a 2 x 2 DBS with a measured SNR of 60:1. Using this PDOE array in a 4 x 4 MIN resulted in an increased SNR of 120:1, highlighting the filtering effect of the folded design.