Agile THz-range spectral multiplication of frequency combs using a multi-wavelength laser.

A breakthrough technology, on-chip frequency comb sources offer broadband combs while being compact, energy-efficient, and cost-effective solutions for various applications from lidar to telecommunications. Yet, these sources encounter a fundamental trade-off between controllability and bandwidth: broadband combs, generated in microresonators, lack free-spectral range or spectral envelope control, while combs generated with electro-optic modulators can be carefully tailored but are limited in bandwidth. Here, we overcome this trade-off through agile spectral multiplication of narrowband combs. Exploiting the nonlinear dynamics of a multi-wavelength laser under modulated optical injection, we achieve spectral multiplication at frequency offsets from 26 GHz to 1.3 THz. Moreover, on-chip control allows for nano-second switching of the frequency offset. Compatible with generic platforms, our approach can be scaled up to cover several THz. When combined with THz photomixers, our system could enable low-cost, compact, and power-efficient THz comb sources, paving the way towards a new generation of THz applications.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Mode-coupling effects in an optically-injected dual-wavelength laser.

Lasers designed to emit at multiple and controllable modes, or multi-wavelength lasers, have the potential to become key building blocks for future microwave photonic technologies. While many interesting schemes relying on optical injection have been proposed, the nonlinear mode coupling between different modes of a multi-wavelength laser and their dynamical behavior under optical injection remains vastly unexplored. Here, we experimentally and numerically study the effect of optical injection around the suppressed mode of a dual-wavelength laser and the resulting interactions with the dominant mode. We highlight a wavelength shift of the dominant mode triggered by injection locking of the suppressed mode and report a strong impact of the mode suppression ratio on the locking range. Finally, we show numerically that the cross-coupling parameter between the two modes might have a key role in this effect.

Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease: A Series of N-of-1 Diet Trials.

INTRODUCTION: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD). METHODS: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets. RESULTS: Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was <1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not. DISCUSSION: SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness.

Kaposi Sarcoma of the Gastrointestinal Tract in an Adolescent With AIDS.

Kaposi sarcoma (KS) of the gastrointestinal (GI) tract in a patient with acquired immunodeficiency syndrome (AIDS) has not been reported in an adolescent outside of Africa. We present a 16-year homosexual old male with AIDS, cutaneous KS, pulmonary KS, and gastrointestinal KS (GI-KS) lesions. Eighty percent of patients with GI-KS are asymptomatic, but our patient presented with a month-long history of dysphagia, abdominal pain, and hematochezia. Endoscopy with biopsies revealed multiple KS lesions within the stomach and lower GI tract. This novel case demonstrates the importance of considering early endoscopic screening in immunocompromised adolescents with cutaneous KS to improve morbidity and mortality.

Juvenile Retention Polyp in a Teenager.

The proper management of a prolapsed rectal mass in a child or teenager is challenging. Given that the underlying etiology of a prolapsed rectal mass in this population is not always immediately clear, interdisciplinary assessment is often required. Juvenile polyps, more commonly presenting with bleeding than a prolapsed mass, can mimic the appearance of both hemorrhoids and the rectum itself - making a purely clinical diagnosis difficult. Presented here is a case of a prolapsed colorectal polyp in a teenage boy, who underwent manual reduction of the mass, followed by colonoscopy and endoscopic ligation. Further histological evaluation revealed it to be a juvenile retention polyp. Despite the rarity of polyp prolapse as a presenting symptom, this case underscores the importance of considering colonic polyps as the etiology of a prolapsed anorectal mass in a teenager.

Hybrid external-cavity lasers (ECL) using photonic wire bonds as coupling elements.

Combining semiconductor optical amplifiers (SOA) on direct-bandgap III-V substrates with low-loss silicon or silicon-nitride photonic integrated circuits (PIC) has been key to chip-scale external-cavity lasers (ECL) that offer wideband tunability along with small optical linewidths. However, fabrication of such devices still relies on technologically demanding monolithic integration of heterogeneous material systems or requires costly high-precision package-level assembly, often based on active alignment, to achieve low-loss coupling between the SOA and the external feedback circuits. In this paper, we demonstrate a novel class of hybrid ECL that overcome these limitations by exploiting 3D-printed photonic wire bonds as intra-cavity coupling elements. Photonic wire bonds can be written in-situ in a fully automated process with shapes adapted to the mode-field sizes and the positions of the chips at both ends, thereby providing low-loss coupling even in presence of limited placement accuracy. In a proof-of-concept experiment, we use an InP-based reflective SOA (RSOA) along with a silicon photonic external feedback circuit and demonstrate a single-mode tuning range from 1515 to 1565 nm along with side mode suppression ratios above 40 dB and intrinsic linewidths down to 105 kHz. Our approach combines the scalability advantages of monolithic integration with the performance and flexibility of hybrid multi-chip assemblies and may thus open a path towards integrated ECL on a wide variety of integration platforms.

32QAM WDM transmission at 12 Tbit/s using a quantum-dash mode-locked laser diode (QD-MLLD) with external-cavity feedback.

Chip-scale frequency comb generators lend themselves as multi-wavelength light sources in highly scalable wavelength-division multiplexing (WDM) transmitters and coherent receivers. Among different options, quantum-dash (QD) mode-locked laser diodes (MLLD) stand out due to their compactness and simple operation along with the ability to provide a flat and broadband comb spectrum with dozens of equally spaced optical tones. However, the devices suffer from strong phase noise, which impairs transmission performance of coherent links, in particular when higher-order modulation formats are to be used. Here we exploit coherent feedback from an external cavity to drastically reduce the phase noise of QD-MLLD tones, thereby greatly improving the transmission performance. In our experiments, we demonstrate 32QAM WDM transmission on 60 carriers derived from a single QD-MLLD, leading to an aggregate line rate (net data rate) of 12 Tbit/s (11.215 Tbit/s) at a net spectral efficiency (SE) of 7.5 bit/s/Hz. To the best of our knowledge, this is the first time that a QD-MLLD optical frequency comb has been used to transmit an optical 32QAM signal. Based on our experimental findings, we perform simulations that show that feedback-stabilized QD-MLLD should also support 64QAM transmission with a performance close to the theoretical optimum across a wide range of technically relevant symbol rates.

Fundamental limitations of spectrally-sliced optically enabled data converters arising from MLL timing jitter.

The effect of phase noise introduced by optical sources in spectrally-sliced optically enabled DACs and ADCs is modeled and analyzed in detail. In both data converter architectures, a mode-locked laser is assumed to provide an optical comb whose lines are used to either synthesize or analyze individual spectral slices. While the optical phase noise of the central MLL line as well as of other optical carriers used in the analyzed system architectures have a minor impact on the system performance, the RF phase noise of the MLL fundamentally limits it. In particular, the corresponding jitter of the MLL pulse train is transferred almost one-to-one to the system-level timing jitter of the data converters. While MLL phase noise can in principle be tracked and removed by electronic signal processing, this results in electric oscillator phase noise replacing the MLL jitter and is not conducive in systems leveraging the ultra-low jitter of low-noise mode-locked lasers. Precise analytical models are derived and validated by detailed numerical simulations.

Performance of chip-scale optical frequency comb generators in coherent WDM communications.

Optical frequency combs have the potential to become key building blocks of wavelength-division multiplexing (WDM) communication systems. The strictly equidistant narrow-band spectral lines of a frequency comb can serve either as carriers for parallel WDM transmission or as local-oscillator (LO) tones for parallel coherent reception. When it comes to highly scalable WDM transceivers with compact form factor, chip-sale comb sources are of particular interest, and recent experiments have demonstrated the viability of such devices for high-speed communications with line rates of tens of Tbit/s. However, the output power of chip-scale comb sources is generally lower than that of their conventional discrete-element counterparts, thus requiring additional amplifiers and impairing the optical signal-to-noise ratio (OSNR). In this paper, we investigate the influence of the power and optical carrier-to-noise ratio (OCNR) of the comb lines on the performance of the WDM link. We identify two distinctively different regimes, where the transmission performance is either limited by the comb source or by the link and the associated in-line amplifiers. We further investigate the impact of line-to-line power variations on the achievable OSNR and link capacity using a soliton Kerr frequency comb as a particularly interesting example. We believe that our findings will help to compare different comb generator types and to benchmark them with respect to the achievable transmission performance.

Hybrid multi-chip assembly of optical communication engines by in situ 3D nano-lithography.

Three-dimensional (3D) nano-printing of freeform optical waveguides, also referred to as photonic wire bonding, allows for efficient coupling between photonic chips and can greatly simplify optical system assembly. As a key advantage, the shape and the trajectory of photonic wire bonds can be adapted to the mode-field profiles and the positions of the chips, thereby offering an attractive alternative to conventional optical assembly techniques that rely on technically complex and costly high-precision alignment. However, while the fundamental advantages of the photonic wire bonding concept have been shown in proof-of-concept experiments, it has so far been unclear whether the technique can also be leveraged for practically relevant use cases with stringent reproducibility and reliability requirements. In this paper, we demonstrate optical communication engines that rely on photonic wire bonding for connecting arrays of silicon photonic modulators to InP lasers and single-mode fibres. In a first experiment, we show an eight-channel transmitter offering an aggregate line rate of 448 Gbit/s by low-complexity intensity modulation. A second experiment is dedicated to a four-channel coherent transmitter, operating at a net data rate of 732.7 Gbit/s - a record for coherent silicon photonic transmitters with co-packaged lasers. Using dedicated test chips, we further demonstrate automated mass production of photonic wire bonds with insertion losses of (0.7 ± 0.15) dB, and we show their resilience in environmental-stability tests and at high optical power. These results might form the basis for simplified assembly of advanced photonic multi-chip systems that combine the distinct advantages of different integration platforms.

Comb-based WDM transmission at 10 Tbit/s using a DC-driven quantum-dash mode-locked laser diode.

Chip-scale frequency comb generators have the potential to become key building blocks of compact wavelength-division multiplexing (WDM) transceivers in future metropolitan or campus-area networks. Among the various comb generator concepts, quantum-dash (QD) mode-locked laser diodes (MLLD) stand out as a particularly promising option, combining small footprint with simple operation by a DC current and offering flat broadband comb spectra. However, the data transmission performance achieved with QD-MLLD was so far limited by strong phase noise of the individual comb tones, restricting experiments to rather simple modulation formats such as quadrature phase shift keying (QPSK) or requiring hardware-based compensation schemes. Here we demonstrate that these limitations can be overcome by digital symbol-wise blind phase search (BPS) techniques, avoiding any hardware-based phase-noise compensation. We demonstrate 16QAM dual-polarization WDM transmission on 38 channels at an aggregate net data rate of 10.68 Tbit/s over 75 km of standard single-mode fiber. To the best of our knowledge, this corresponds to the highest data rate achieved through a DC-driven chip-scale comb generator without any hardware-based phase-noise reduction schemes.

Coherent WDM transmission using quantum-dash mode-locked laser diodes as multi-wavelength source and local oscillator.

Quantum-dash (QD) mode-locked laser diodes (MLLD) lend themselves as chip-scale frequency comb generators for highly scalable wavelength-division multiplexing (WDM) links in future data-center, campus-area, or metropolitan networks. Driven by a simple DC current, the devices generate flat broadband frequency combs, containing tens of equidistant optical tones with line spacings of tens of GHz. Here we show that QD-MLLDs can not only be used as multi-wavelength light sources at a WDM transmitter, but also as multi-wavelength local oscillators (LO) for parallel coherent reception. In our experiments, we demonstrate transmission of an aggregate net data rate of 3.9 Tbit/s (23 × 45 GBd PDM-QPSK, 7% FEC overhead) over 75 km standard single-mode fiber (SSMF). To the best of our knowledge, this represents the first demonstration of a coherent WDM link that relies on QD-MLLD both at the transmitter and the receiver.

Novel Implementation of Genotype-Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial.

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype-guided pediatric dosing of PPI medications. Children aged 5-17 years old with gastric-acid-related conditions were randomized to receive either conventional dosing of a PPI or genotype-guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype-guided dosing arm (P < 0.001), but not in the conventional dosing arm. Prescribers waited for the genotype result before prescribing the PPI medication for 90% of the participants in the genotype-guided dosing arm. The number of participants who reported an infection was marginally lower in genotype-guided dosing vs. conventional dosing (20% vs. 44%; P = 0.07). Sinonasal symptoms were higher in the conventional dosing arm as compared with genotype-guided dosing arm: (2.6 (2.0, 3.4) vs. 1.8 (1.0, 2.3), P = 0.031). CYP2C19 genotype-guided PPI therapy is feasible in a clinical pediatric setting, well accepted by providers, resulted in differential PPI dosing, and may reduce PPI-associated infections. A future large scale randomized clinical trial of CYP2C19 genotype-guided pediatric dosing of PPI medications in children is warranted.

Microresonator-based solitons for massively parallel coherent optical communications.

Solitons are waveforms that preserve their shape while propagating, as a result of a balance of dispersion and nonlinearity. Soliton-based data transmission schemes were investigated in the 1980s and showed promise as a way of overcoming the limitations imposed by dispersion of optical fibres. However, these approaches were later abandoned in favour of wavelength-division multiplexing schemes, which are easier to implement and offer improved scalability to higher data rates. Here we show that solitons could make a comeback in optical communications, not as a competitor but as a key element of massively parallel wavelength-division multiplexing. Instead of encoding data on the soliton pulse train itself, we use continuous-wave tones of the associated frequency comb as carriers for communication. Dissipative Kerr solitons (DKSs) (solitons that rely on a double balance of parametric gain and cavity loss, as well as dispersion and nonlinearity) are generated as continuously circulating pulses in an integrated silicon nitride microresonator via four-photon interactions mediated by the Kerr nonlinearity, leading to low-noise, spectrally smooth, broadband optical frequency combs. We use two interleaved DKS frequency combs to transmit a data stream of more than 50 terabits per second on 179 individual optical carriers that span the entire telecommunication C and L bands (centred around infrared telecommunication wavelengths of 1.55 micrometres). We also demonstrate coherent detection of a wavelength-division multiplexing data stream by using a pair of DKS frequency combs-one as a multi-wavelength light source at the transmitter and the other as the corresponding local oscillator at the receiver. This approach exploits the scalability of microresonator-based DKS frequency comb sources for massively parallel optical communications at both the transmitter and the receiver. Our results demonstrate the potential of these sources to replace the arrays of continuous-wave lasers that are currently used in high-speed communications. In combination with advanced spatial multiplexing schemes and highly integrated silicon photonic circuits, DKS frequency combs could bring chip-scale petabit-per-second transceivers into reach.

Multi-wavelength coherent transmission using an optical frequency comb as a local oscillator.

Steadily increasing data rates of optical interfaces require spectrally efficient coherent transmission using higher-order modulation formats in combination with scalable wavelength-division multiplexing (WDM) schemes. At the transmitter, optical frequency combs (OFC) lend themselves to particularly precise multi-wavelength sources for WDM transmission. In this work we demonstrate that these advantages can also be leveraged at the receiver by using an OFC as a highly scalable multi-wavelength local oscillator (LO) for coherent detection. In our experiments, we use a pair of OFC that rely on gain switching of injection-locked semiconductor lasers both for WDM transmission and intradyne reception. We synchronize the center frequency and the free spectral range of the receiver comb to the transmitter, keeping the intradyne frequencies for all data channels below 15 MHz. Using 13 WDM channels, we transmit an aggregate line rate (net data rate) of 1.104 Tbit/s (1.032 Tbit/s) over a 10 km long standard single mode fiber at a spectral efficiency of 5.16 bit/s/Hz. To the best of our knowledge, this is the first demonstration of coherent WDM transmission using synchronized frequency combs as light source at the transmitter and as multi-wavelength LO at the receiver.

Index of suspicion.

Case 1: Facial and upper extremity weakness in a 16-year-old boy. Case 2: Hematochezia in a neonate. Case 3: bad body odor in a 13-year-old girl.