On-chip gain switched frequency comb generation using a two sectioned single cavity laser without additional optical injection.

A tunable comb source is demonstrated on a monolithically integrated photonic integrated circuit (PIC). The PIC is a two section device designed to produce a single mode tunable spectrum, and the comb is generated by gain switching one section of the two sectioned laser. The laser produces a single mode spectra with a tunable range of 1543 - 1565 nm, and combs were generated with a frequency range of 1 - 10 GHz without requiring additional optical injection to maintain the phase coherence.

Tunable, coherent optical comb source via on-chip bidirectional coupling.

A tunable comb source is demonstrated through gain switching on a three-sectioned photonic integrated circuit (PIC). The PIC consists of two mutually coupled lasers connected by a passive waveguide. One of these is a tunable, two-section, single mode laser. The second laser is a simple Fabry-Perot cavity laser which can be phase-locked with the single mode laser via bidirectional coupling. Frequency combs are produced by gain switching the Fabry-Perot laser by applying a high-power radio frequency signal. Combs are generated with line spacings ranging from 3.5 to 8 GHz. The on-chip bidirectional coupling causes the comb to also be generated in the two-section device. Despite the lack of on-chip optical isolation between the lasers, the resulting combs are stable. Numerical simulations using a delay-differential model reproduce the results and reveal the important role played by the short delay times inherent to on-chip integration in this stability.

Population pharmacokinetics and probability of target attainment in patients with sepsis under renal replacement therapy receiving continuous infusion of meropenem: Sustained low-efficiency dialysis and continuous veno-venous haemodialysis.

AIMS: To describe the population pharmacokinetics (PK) and probability of target attainment (PTA) of continuous infusion (CI) of meropenem in septic patients receiving renal replacement therapy (RRT). METHODS: Fifteen patients without RRT, 13 patients receiving sustained low-efficiency dialysis and 12 patients receiving continuous veno-venous haemodialysis were included. Population PK analysis with Monte Carlo simulations for different dosing regimens was performed. For minimum inhibitory concentration 2 mg/L was chosen. The target was set as 50% time ≥4× minimum inhibitory concentration. RESULTS: The PK of meropenem was best described by a 1-compartment model with linear elimination. Serum creatinine, residual diuresis and time on RRT, with no difference between sustained low-efficiency dialysis and continuous veno-venous haemodialysis, were found to be significant covariates affecting clearance, explaining >20% of the clearance between subject variability. PTA analysis showed that in patients with RRT, 2 g/24 h, meropenem CI achieved a PTA of 95%. In patients without RRT, the target was achieved with 3 g/24 h CI or prolonged infusion of 1 g meropenem over 8 hours but not with bolus application of 1 g meropenem for 8 hours. Only 2 patients (both without RRT) had meropenem concentrations below the target level. However, approximately half of the patients with RRT receiving CI 3 g/24 h meropenem had toxic concentrations. CONCLUSION: We found relevant PK variability for meropenem CI in septic patients with or without RRT, leading to a substantial risk for overdosing in patients with RRT. This finding highlights the strong demand for personalized dosing in critically ill patients.

Study on the proximity of QWI in InP-based AlGaInAs MQWs using the IFVD method and its application in single frequency teardrop laser diodes.

This paper presents our research on quantum well intermixing (QWI) of InP-based AlGaInAs/AlGaInAs multi-quantum wells using impurity-free vacancy-disordering (IFVD) and the QWI mask proximity effect and its application in the design and fabrication of a teardrop laser. Using a Si3N4 film deposited by plasma-enhanced chemical vapor deposition (PECVD) as a QWI promoter mask and annealing under 700°C for 2 minutes, a 70 nm wavelength blue shift of a FP laser is achieved using InP-based AlGaInAs quantum well laser material. It is found that a 5 µm separation is needed between the QWI mask edges and the non-QWI area during the QWI process. Based on the QWI technique and proximity effect, the designed and fabricated teardrop laser demonstrated continuous wave (CW) lasing above 40 mA and single frequency operation with a side mode suppression ratio of 32.6 dB at 77.3 mA.

Integrated dual optical frequency comb source.

A monolithically integrated dual-channel optical frequency comb source is demonstrated in this paper. Three lasers are integrated on a single chip using a regrowth-free fabrication process in a master-slave-slave configuration. The master laser's power is split equally using a 1x2 multimode interference coupler and injection locks the two slave lasers. The slave lasers are gain-switched to produce dual optical frequency combs at 4.1 GHz and 5 GHz. To the best of our knowledge, this is the first demonstration of a dual optical frequency comb source with all light sources monolithically integrated in a photonic integrated circuit (PIC).

Dynamics of on-chip asymmetrically coupled semiconductor lasers.

We investigate the dynamics of asymmetrically coupled semiconductor lasers on photonic integrated circuits in experiment and theory. The experimental observations are explained using a rate-equation model for coupled lasers incorporating a saturable coupling waveguide. We perform a bifurcation analysis of the coupled laser dynamics, focusing on the effects of the coupling phase and the dynamical difference between passive and saturable coupling waveguides. For a passive waveguide, we find a bifurcation scenario closely resembling the well-known optical injection setup, which is largely insensitive to the coupling phase. When the coupling waveguide is saturable, the dynamics become increasingly complex and unpredictable, with a strong phase-dependence. Our results show the possibility of a simple layout for reproducible laser dynamics on a chip.

Harmonic frequency locking and tuning of comb frequency spacing through optical injection.

We show, both experimentally and theoretically, that a slave laser injected with an optical frequency comb can undergo two distinct locking mechanisms, both of which decrease the output optical comb's frequency spacing. We report that, for certain detuning and relative injection strengths, slave laser relaxation oscillations can become undamped and lock to rational frequencies of the optical comb spacing, creating extra comb tones by nonlinear dynamics of the injected laser. We also study the frequency locking of the slave laser at detunings in between the injected comb lines, which add the slave laser's frequency to the comb. Our results demonstrate the effect of the α parameter and stability of the locked states and indicate how the frequency of the relaxation oscillations affect both of these locking mechanisms. These optical locking mechanisms can be applied to regenerate or multiply optical combs.

Comparative study on the metabolism of the ergot alkaloids ergocristine, ergocryptine, ergotamine, and ergovaline in equine and human S9 fractions and equine liver preparations.

1. Ergopeptine alkaloids like ergovaline and ergotamine are suspected to be associated with fescue toxicosis and ergotism in horses. Information on the metabolism of ergot alkaloids is scarce, especially in horses, but needed for toxicological analysis of these drugs in urine/feces of affected horses. The aim of this study was to investigate the metabolism of ergovaline, ergotamine, ergocristine, and ergocryptine in horses and comparison to humans. 2. Supernatants of alkaloid incubations with equine and human liver S9 fractions were analyzed by reversed-phase liquid-chromatography coupled to high-resolution tandem mass spectrometry with full scan and MS2 acquisition. Metabolite structures were postulated based on their MS2 spectra in comparison to those of the parent alkaloids. All compounds were extensively metabolized yielding nor-, N-oxide, hydroxy and dihydro-diole metabolites with largely overlapping patterns in equine and human liver S9 fractions. However, some metabolic steps e.g. the formation of 8'-hydroxy metabolites were unique for human metabolism, while formation of the 13/14-hydroxy and 13,14-dihydro-diol metabolites were unique for equine metabolism. Incubations with equine whole liver preparations yielded less metabolites than the S9 fractions. 3. The acquired data can be used to develop metabolite-based screenings for these alkaloids, which will likely extend their detection windows in urine/feces from affected horses.

Off-Axis Cavity-Enhanced Absorption Spectroscopy of 14NH3 in Air Using a Gain-Switched Frequency Comb at 1.514 µm.

A custom-designed gain-switched frequency comb (GSFC) source was passively coupled to a medium finesse (F ≈ 522) cavity in off-axis configuration for the detection of ammonia (14NH3) in static dry air. The absorption of ammonia was detected in the near infrared spectral region between 6604 and 6607 cm-1 using a Fourier transform detection scheme. More than 30 lines of the GSFC output (free spectral range 2.5 GHz) overlapped with the strongest ro-vibrational ammonia absorption features in that spectral region. With the cavity in off-axis configuration, an NH3 detection limit of ∼3.7 ppmv in 20 s was accomplished in a laboratory environment. The experimental performance of the prototype spectrometer was characterized; advantages, drawbacks and the potential for future applications are discussed.

Data transmission at 1300 nm using optical interposer comprising hybrid integrated silicon waveguide and dilute nitride electroabsorption modulator.

High speed back-to-back transmission of NRZ data at 12.5 Gbit/s was achieved over a repeaterless optical network without the use of forward error correction or optical clock recovery using a hybrid integrated silicon photonics optical interconnect. The interconnect comprises an electroabsorption modulator based on dilute nitride multiple quantum well material on GaAs substrate optically coupled to large core silicon waveguide using passive alignment and flip-chip bonding.

CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer.

BACKGROUND: Although radical surgery remains the cornerstone of cure in resectable gastric cancer, survival remains poor. Current evidence-based (neo)adjuvant strategies have shown to improve outcome, including perioperative chemotherapy, postoperative chemoradiotherapy and postoperative chemotherapy. However, these regimens suffer from poor patient compliance, particularly in the postoperative phase of treatment. The CRITICS-II trial aims to optimize preoperative treatment by comparing three treatment regimens: (1) chemotherapy, (2) chemotherapy followed by chemoradiotherapy and (3) chemoradiotherapy. METHODS: In this multicentre phase II non-comparative study, patients with clinical stage IB-IIIC (TNM 8th edition) resectable gastric adenocarcinoma are randomised between: (1) 4 cycles of docetaxel+oxaliplatin+capecitabine (DOC), (2) 2 cycles of DOC followed by chemoradiotherapy (45Gy in combination with weekly paclitaxel and carboplatin) or (3) chemoradiotherapy. Primary endpoint is event-free survival, 1 year after randomisation (events are local and/or regional recurrence or progression, distant recurrence, or death from any cause). Secondary endpoints include: toxicity, surgical outcomes, percentage radical (R0) resections, pathological tumour response, disease recurrence, overall survival, and health related quality of life. Exploratory endpoints include translational studies on predictive and prognostic biomarkers. DISCUSSION: The aim of this study is to select the most promising among three preoperative treatment arms in patients with resectable gastric adenocarcinoma. This treatment regimen will subsequently be compared with the standard therapy in a phase III trial. TRIAL REGISTRATION: clinicaltrials.gov NCT02931890 ; registered 13 October 2016. Date of first enrolment: 21 December 2017.

Intravenous Iron for Treatment of Anemia in the 3 Perisurgical Phases: A Review and Analysis of the Current Literature.

Anemia is a common comorbidity throughout the entire hospital stay. Treatment options include intravenous (IV) iron, oral iron, erythropoietin, and red blood cell (RBC) transfusions. IV iron has gained in popularity with the implementation of patient blood management programs. A variety of studies have been performed to investigate the use of IV iron in preoperative, perioperative, and postoperative settings. An objective review on these studies has yet to be performed. The current narrative review provides an overview of trials investigating IV iron use in the preoperative, perioperative, and postoperative settings. We performed a literature research of English articles published between 1964 and March 2017 in Pubmed including Medline and The Cochrane Library. Only studies with a control group were included. The final review includes 20 randomized controlled trials (RCTs), 7 observational trials, and 5 retrospective studies. Measured outcomes included hemoglobin (Hb) levels, reticulocyte counts, and/or RBC concentrates. Meta-analyses of RCTs using IV iron administration before surgery led to an increase in Hb levels, a reduction of RBC use, and an improvement in patient outcome. Only a few studies investigated the use of IV iron in the perioperative setting. These studies recommended the use of perioperative IV iron in cases of severe anemia in orthopedic surgery but not in all types of surgery. Published RCTs in the postoperative setting have shown positive effects of IV iron on Hb levels, length of hospital stay, and transfusion requirements. Some studies demonstrated an increase of Hb of 0.5-1 g/dL over 4 weeks postoperatively, but the clinical relevance and effect of this increase on an improvement of patient's long-term outcomes are uncertain. To summarize, the evidence to use IV iron is strongest in the preoperative setting, while it remains an individual treatment decision to administer IV iron perioperatively or postoperatively.

Dynamics of two identical mutually delay-coupled semiconductor lasers in photonic integrated circuits.

We theoretically investigate a system of two mutually delay-coupled semiconductor lasers, in a face to face configuration for integration in a photonic integrated circuit. This system is described by single-mode rate equations, which are a system of delay differential equations with one fixed delay. Several bifurcation scenarios involving multistabilities are presented, followed by a comprehensive frequency analysis of the symmetric and symmetry-broken, one-color and two-color states.

Modeling mutually coupled non-identical semiconductor lasers on photonic integrated circuits.

We model the situation of two lasers in a face-to-face arrangement, optically coupled through an attenuating element, where the distance between the lasers is on a scale typical in photonic integration (hundreds of micrometers to millimeters). We account for the existence of a frequency difference between the two single-mode lasers. Modified versions of the Lang-Kobayashi equations were employed to describe the interaction. By solving this delay differential equation system, we characterized different dynamical regimes including one- and two-color states and self-pulsations. We focus on the effect varying coupling strength and detuning between the lasers has on the frequencies of the lasers. Using the results of this frequency study, we identify the bifurcations causing changes between the different frequency regimes.

Post-Operative Iron Carboxymaltose May Have an Effect on Haemoglobin Levels in Cardiothoracic Surgical Patients on the ICU - an Observational Pilot Study about Anaemia Treatment with Intravenous Iron.

BACKGROUND: Post-operative anaemia is associated with increased morbidity and mortality. Positive effects of post-operative intravenous iron (IVI) after elective orthopaedic, abdominal and genitourinary surgery have been reported. The current observational trial investigated the prevalence of post-operative anaemia, the effect of IVI on haemoglobin levels, the use of blood transfusions and diagnoses related to infections. METHODS: 1,265 patients on five ICUs of Münster University Hospital were screened for post-operative anaemia. On one ICU, patients were screened for iron deficiency and, if indicated, supplemented with 500 mg of ferric carboxymaltose. Primary outcome measures were haemoglobin levels, C-reactive protein, white blood cell count, transfusion requirements, documented infection and antibiotic treatment. RESULTS: Anaemia was prevalent in 86.2% of patients upon ICU admission. 429 patients were screened for iron deficiency anaemia. 95 patients were eligible, 35 were treated with IVI. An increase of +0.4 g/dl in Hb levels 7 days after IVI compared to -0.1 g/dl in non-treated anaemic patients was observed. The number of RBC transfusions, ICD codes related to infections and infectious parameters were similar between groups. Conclusions: IVI treatment was safe and resulted in higher median Hb levels. Randomized controlled trials are required to support the hypotheses of this study.

Regrowth-free integration of injection locked slotted laser with an electroabsorption modulator.

Optical injection locking was used to red shift an integrated semiconductor laser up to 30 nm away from the main free running lasing mode. This injection locking of the laser beyond its band edge enabled its integration with an electroabsorption modulator to produce a 2.5 Gb/s eye diagram. The electroabsorption modulator was shown to have a 3 dB bandwidth of 5.5 GHz, which was limited by the contact capacitance. This paper demonstrates that such devices could be applied in a regrowth free, monolithic coherent wavelength division multiplexing transmitter.

Neutrophil Recovery in Breast Cancer Patients Receiving Docetaxel-Containing Chemotherapy with and without Granulocyte Colony-Stimulating Factor Prophylaxis.

OBJECTIVE: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts. METHODS: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only. RESULTS: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle. CONCLUSION: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles.

Cost Efficacy of Metal Stents for Palliation of Extrahepatic Bile Duct Obstruction in a Randomized Controlled Trial.

BACKGROUND & AIMS: Endoscopic stents are placed for palliation of extrahepatic bile duct obstruction. Although self-expandable metal stents (SEMS) remain patent longer than plastic stents, they are more expensive. We aimed to evaluate which type of stent (plastic, uncovered SEMS [uSEMS], or partially covered SEMS [pcSEMS]) is the most effective and we assessed costs. METHODS: We performed a multicenter randomized trial in 219 patients at 18 hospitals in The Netherlands from February 2008 through February 2013. Patients were assigned randomly for placement of a plastic stent (n = 73), uSEMS (n = 75), or pcSEMS (n = 71) during endoscopic retrograde cholangiopancreatography. Patients were followed up for up to 1 year. Researchers were not blinded to groups. The main study end points included functional stent time and costs. RESULTS: The mean functional stent times were 172 days for plastic stents, 288 days for uSEMS, and 299 days for pcSEMS (P < .005 for uSEMS and pcSEMS vs plastic). The initial placement of plastic stents (€1042 or $1106) cost significantly less than placement of SEMS (€1973 or $2094) (P = .001). However, the total cost per patient at the end of the follow-up period did not differ significantly between plastic stents (€7320 or $7770) and SEMS (€6932 or $7356) (P = .61). Furthermore, in patients with short survival times (≤3 mo) or metastatic disease, the total cost per patient did not differ between plastic stents and SEMS. No differences in costs were found between pcSEMS and uSEMS. CONCLUSIONS: Although placement of SEMS (uncovered or partially covered) for palliation of extrahepatic bile duct obstruction initially is more expensive than placement of plastic stents, SEMS have longer functional time. The total costs after 1 year do not differ significantly with stent type. Dutch Clinical Trial Registration no: NTR1361.

Analysis of multimode interferometers.

A general analytical formula describing the transfer function between the input and output of an arbitrary rectangular multimode interference (MMI) coupler has been derived using the elliptic theta function ϑ(x', z'). This formula provides the positions, amplitudes and relative phases of all the self-images of a given source. It is shown how the transfer function can be used as a propagation matrix for any rectangular NxM MMI. Specific simplified solutions for NxN, symmetric and paired MMIs are also derived from the general formula.

Three-coherent-output narrow-linewidth and tunable single frequency 1x2 multi-mode-interferometer laser diode.

A 1x2 multi-mode-interferometer (MMI) laser diode was successfully designed and fabricated, which demonstrated three coherent outputs of tunable single frequency emission with more than 30dB side mode suppression ratio (SMSR), a tuning range of 25nm in C and L band, as well as 750 kHz linewidth. This 1x2 MMI laser could be expanded to more advanced configurations such as 1xN or MxN (M≥1, N>2) MMI lasers to achieve a multiple coherent output source. In addition, these lasers do not require material regrowth and high resolution gratings which can significantly increase the yield and reduce the cost.