Estimation of country-specific tuberculosis resistance antibiograms using pathogen genomics and machine learning.

BACKGROUND: Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance Mycobacterium tuberculosis (Mtb) whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction. METHODS: We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling. Validation leveraged a national DR survey conducted in South Africa. RESULTS: Mtb isolates from 29 countries (n=19 149) met sequence quality criteria. Global marginal genotypic resistance among mono-resistant TB estimates overlapped with the South African DR survey, except for isoniazid, ethionamide and second-line injectables, which were underestimated (n=3134). Among multidrug resistant (MDR) TB (n=268), estimates overlapped for the fluoroquinolones but overestimated other drugs. Globally pooled mono-resistance to isoniazid was 10.9% (95% CI: 10.2-11.7%, n=14 012). Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% (0.1-11%), n=111 and India 2.8% (0.08-9.4%), n=114). Given the recent interest in drugs enhancing ethionamide activity and their expected activity against isolates with resistance discordance between isoniazid and ethionamide, we measured this rate and found it to be high at 74.4% (IQR: 64.5-79.7%) of isoniazid-resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3964). CONCLUSIONS: This is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics, but public WGS data demonstrates oversampling of isolates with higher resistance levels than MDR. Nevertheless, our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug-susceptible TB in South Asia and indicate underutilisation of ethionamide in MDR treatment.

First malaria in pregnancy followed in Philippine real-world setting: proof-of-concept of probabilistic record linkage between disease surveillance and hospital administrative data.

BACKGROUND: Although the Philippines targets malaria elimination by 2030, it remains to be a disease that causes considerable morbidity in provinces that report malaria. Pregnant women residing in endemic areas are a vulnerable population, because in addition to the risk of developing severe malaria, their pregnancy is not followed through, and the outcome of their pregnancy is unknown. This study determined the utility of real-world data integrated with disease surveillance data set as real-world evidence of pregnancy and delivery outcomes in areas endemic for malaria in the Philippines. METHODS: For the period of 2015 to 2019, electronic data sets of malaria surveillance data and Ospital ng Palawan hospital admission log of pregnant women residing in the four selected barangays of Rizal, Palawan were merged using probabilistic linkage. The source data for record linkage were first and last names, birth date, and address as the mutual variable. The data used for characteristics of the pregnant women from the hospital data set were admission date, discharge date, admitting and final diagnosis and body weight on admission. From the malaria surveillance data these were date of consultation, and malaria parasite species. The Levenshtein distance formula was used for a fuzzy string-matching algorithm. Chi-square test, and Mann-Whitney U test were used to compare the means of the two data sets. RESULTS: The prevalence of pregnant women admitted to the tertiary referral hospital, Ospital ng Palawan, was estimated to be 8.34/100 overall, and 11.64/100 from the four study barangays; that of malaria during pregnancy patients was 3.45/100 and 2.64/100, respectively. There was only one true-positive matched case from 238 women from the hospital and 54 women from the surveillance data sets. The overall Levenshstein score was 97.7; for non-matched cases, the mean overall score was 36.6 (35.6-37.7). The matched case was a minor who was hospitalized for severe malaria. The outcome of her pregnancy was detected from neither data set but from village-based records. CONCLUSIONS: This proof-of-concept study demonstrated that probabilistic record linkage could match real-world data in the Philippines with further validation required. The study underscored the need for more integrated and comprehensive database to monitor disease intervention impact on pregnancy and its outcome in the Philippines.

Molecular characterization of drug-resistant Mycobacterium tuberculosis among Filipino patients derived from the national tuberculosis prevalence survey Philippines 2016.

Tuberculosis, caused by Mycobacterium tuberculosis, remains a high burden disease and leading cause of mortality in the Philippines. Understanding the genetic diversity of M. tuberculosis strains in the population, including those that are multi-drug resistant (MDR), will aid in formulating strategies for effective TB control and prevention. By whole genome sequencing of M. tuberculosis isolates (n = 100) from patients of the Philippine 2016 National Tuberculosis Prevalence Survey, we sought to provide a baseline assessment of the genotypic and phylogenetic characteristics of the isolates. The majority (96/100) of the isolates were EAI2-Manila strain-type (lineage 1), with one Lineage 2 (Beijing), one Lineage 3 (CAS1), and two Lineage 4 (LAM9) strains. The EAI2-Manila clade was not significantly associated with patient's phenotypic and in silico drug resistance profile. Five (5/6) MDR-TB isolates predicted by in silico profiling were concordant with phenotypic drug resistance profile. Twenty-one mutations were identified in nine drug resistance-related genes, all of which have been reported in previous studies. Overall, the results from this study contribute to the growing data on the molecular characteristics of Philippine M. tuberculosis isolates, which can help in developing tools for rapid diagnosis of TB in the country, and thereby reducing the high burden of disease.

Factors Associated with Loss to Follow-up during Treatment for Multidrug-Resistant Tuberculosis, the Philippines, 2012-2014.

To identify factors associated with loss to follow-up during treatment for multidrug-resistant (MDR) tuberculosis (TB) in the Philippines, we conducted a case-control study of adult patients who began receiving treatment for rifampin-resistant TB during July 1-December 31, 2012. Among 91 case-patients (those lost to follow-up) and 182 control-patients (those who adhered to treatment), independent factors associated with loss to follow-up included patients' higher self-rating of the severity of vomiting as an adverse drug reaction and alcohol abuse. Protective factors included receiving any type of assistance from the TB program, better TB knowledge, and higher levels of trust in and support from physicians and nurses. These results provide insights for designing interventions aimed at reducing patient loss to follow-up during treatment for MDR TB.

Theoretical analysis and modeling of a photonic integrated circuit for frequency 8-tupled and 24-tupled millimeter wave signal generation: erratum.

A novel photonic circuit design for implementing frequency 8-tupling and 24-tupling was presented [Opt. Lett.39, 6950 (2014)10.1364/OL.39.006950OPLEDP0146-9592], and although its key message remains unaltered, there were typographical errors in the equations that are corrected in this erratum.

Dual-function photonic integrated circuit for frequency octo-tupling or single-side-band modulation.

A dual-function photonic integrated circuit for microwave photonic applications is proposed. The circuit consists of four linear electro-optic phase modulators connected optically in parallel within a generalized Mach-Zehnder interferometer architecture. The photonic circuit is arranged to have two separate output ports. A first port provides frequency up-conversion of a microwave signal from the electrical to the optical domain; equivalently single-side-band modulation. A second port provides tunable millimeter wave carriers by frequency octo-tupling of an appropriate amplitude RF carrier. The circuit exploits the intrinsic relative phases between the ports of multi-mode interference couplers to provide substantially all the static optical phases needed. The operation of the proposed dual-function photonic integrated circuit is verified by computer simulations. The performance of the frequency octo-tupling and up-conversion functions is analyzed in terms of the electrical signal to harmonic distortion ratio and the optical single side band to unwanted harmonics ratio, respectively.

Theoretical analysis and modeling of a photonic integrated circuit for frequency 8-tupled and 24-tupled millimeter wave signal generation.

A photonic circuit design for implementing frequency 8-tupling and 24-tupling is proposed. The front- and back-end of the circuit comprises 4×4 MMI couplers enclosing an array of four pairs of phase modulators and 2×2 MMI couplers. The proposed design for frequency multiplication requires no optical or electrical filters, the operation is not limited to carefully adjusted modulation indexes, and the drift originated from static DC bias is mitigated by making use of the intrinsic phase relations of multi-mode interference couplers. A transfer matrix approach is used to represent the main building blocks of the design and hence to describe the operation of the frequency 8-tupling and 24-tupling. The concept is theoretically developed and demonstrated by simulations. Ideal and imperfect power imbalances in the multi-mode interference couplers, as well as ideal and imperfect phases of the electric drives to the phase modulators, are analyzed.

320 Gb/s all-optical clock recovery and time de-multiplexing after transmission enabled by single quantum dash mode-locked laser.

We report, to the best of our knowledge, the first demonstration of 320 Gb/s all-optical clock recovery and all-optical time de-multiplexing after 51 km transmission by exploiting single-quantum dash mode-locked laser diode (QD-MLLD). Based on injection locking of the QD-MLLD, the 40 GHz synchronized optical clock pulses were recovered from the 320 Gb/s with a pulse width of 1.9 ps and timing jitter of 135 fs, which allowed directly time de-multiplexing of 320-40 Gb/s without additional complex optoelectronic circuitry. The 320-40 Gb/s all-optical de-multiplexing was achieved with averaging a power penalty of 4.5 dB at BER of 1E-6.

Low polarization-sensitive asymmetric multi-quantum well semiconductor amplifier for next-generation optical access networks.

A broadband and low-polarization-sensitive multi-quantum well semiconductor optical amplifier with an asymmetric structure is reported for operation in the E-band wavelength range. A gain peak of 20 dB for a bandwidth of more than 50 nm is measured for both TE and TM polarizations. A maximum polarization sensitivity of 3 dB is measured for a broad wavelength range from 1340 to 1440 nm.

Method to improve the noise figure and saturation power in multi-contact semiconductor optical amplifiers: simulation and experiment.

The consequences of tailoring the longitudinal carrier density along the active layer of a multi-contact bulk semiconductor optical amplifier (SOA) are investigated using a rate equation model. It is shown that both the noise figure and output power saturation can be optimized for a fixed total injected bias current. The simulation results are validated by comparison with experiment using a multi-contact SOA. The inter-contact resistance is increased using a focused ion beam in order to optimize the carrier density control. A chip noise figure of 3.8 dB and a saturation output power of 9 dBm are measured experimentally for a total bias current of 150 mA.

40 GHz mode-beating with 8 Hz linewidth and 64 fs timing jitter from a synchronized mode-locked quantum-dash laser diode.

Linewidth narrowing of the radio frequency beat-tones and the optical-modes is experimentally investigated in a ∼40 GHz quantum-dash mode-locked laser diode subject to optical injection of 10 GHz pulses. In comparison to the 75 kHz linewidth exhibited by the beat-tones in passive mode-locking conditions, a remarkable reduction to less than 8 Hz is achieved when the laser is under optical injection. From this beat-tone signal, an integrated root-mean-square timing jitter of 64 fs is calculated. In addition, a quadratic profile of the optical linewidth with the wavelength is observed in active locking, reaching a minimum of 1.7 MHz for the longitudinal modes around 1530 nm and progressively increasing to 37.4 MHz for modes at 1525 nm.

Impact of bias current distribution on the noise figure and power saturation of a multicontact semiconductor optical amplifier.

We present an experimental investigation of a multicontact semiconductor optical amplifier. This first-generation device allows for direct control of the carrier density profile along the length of the waveguide. This is used to control the device noise figure, with a minimum value of 5 dB observed at a gain of 15 dB for an optimum carrier density profile. The opposite carrier density profile results in an increase of the power saturation by 3 dB.

Experimental investigation of harmonic and subharmonic synchronization of 40 GHz mode-locked quantum-dash laser diodes.

Synchronization of a 40 GHz quantum-dash mode-locked (ML) Fabry-Perot laser diode with optically injected pulse streams is experimentally studied. Injected signals consist of nonmodulated and modulated trains of 1.6 ps pulses at various repetition rates, ranging from 10 to 160 GHz and 10 to 160 Gbps, respectively. Subharmonic, fundamental, and harmonic synchronization of the ML laser allows retrieval of stable 40 GHz clock pulses featuring a width of 1.8 ps. Frequency components at 10 and 20 GHz do not create any amplitude modulation on the recovered 40 GHz clock pulses when injecting signals at 10 and 20 GHz/Gbps. In addition, external synchronization of the laser with pulse streams at 80 and 160 GHz/Gbps is sustained despite the absence of significant components at or below 40 GHz.

Timing-jitter, optical, and mode-beating linewidths analysis on subpicosecond optical pulses generated by a quantum-dash passively mode-locked semiconductor laser.

Timing-jitter measurements in optically generated subpicosecond pulses by a quantum-dash passively mode-locked semiconductor laser as a function of the bias current are reported. All the measurements are retrieved from a second-harmonic-generation frequency-resolved optical gating system. A decreasing trend in the pulse width and the associated timing jitter is found with the bias current. Additionally, the optical and mode-beating linewidths are analyzed in terms of both the mode wavelength and the bias current. From our results, we can conclude that once the optical modes are phase locked, the optical linewidth associated to every individual longitudinal mode of the device under test does not have a significant impact on the mode-beating signal on neither the pulse width nor its respective timing jitter.

Sub-picosecond pulse generation by 40-GHz passively mode-locked quantum-dash 1-mm-long Fabry-Pérot laser diode.

Optical pulses at a repetition rate of 39.8 GHz have been observed in a dc-biased passively mode-locked quantum-dash Fabry-Pérot laser diode. The pulses generated by this diode are studied in the temporal and spectral domains using a second harmonic generation frequency-resolved optical gating system. By using a tunable band-pass filter, it is observed that the pulse width decreases as the number of lasing modes selected by the filter increases. Furthermore, by controlling the phase difference of the modes using a 450 m-long single mode fibre, a passive compression of the pulses is obtained. A minimum pulse width of 720 fs has been measured with this type of mode-locked Fabry-Pérot laser.

Polarization dependence of non-linear gain compression factor in semiconductor optical amplifier.

We investigate the power and the polarization dependence of the intraband dynamics in a bulk semiconductor optical amplifier using both a 2.5-ps pump-probe experimental set-up in contra-propagation and a theoretical model. Our model is based on the rate equations and takes into account the polarization dependence of the gain. By comparing experimental and computational results we are able to highlight the dependences of the intraband dynamics and to extract the non-linear gain compression factor as a function of both pulse energy and polarization of the injected pulses.