Molecular and Growth-Based Drug Susceptibility Testing of Mycobacterium tuberculosis Complex for Ethambutol Resistance in the United States.

Ethambutol (EMB) is used as a part of drug regimens for treatment of tuberculosis (TB). Susceptibility of Mycobacterium tuberculosis complex (MTBC) isolates to EMB can be discerned by DNA sequencing to detect mutations in the embB gene associated with resistance. US Public Health Laboratories (PHL) primarily use growth-based drug susceptibility test (DST) methods to determine EMB resistance. The Centers for Disease Control and Prevention (CDC) provides a service for molecular detection of drug resistance (MDDR) by DNA sequencing and concurrent growth-based DST using agar proportion. PHL and CDC test results were compared for 211 MTBC samples submitted to CDC from September 2009 through February 2011. Concordance between growth-based DST results from PHL and CDC was 88.2%. A growth-based comparison of 39 samples, where an embB mutation associated with EMB resistance was detected, revealed a higher percentage of EMB resistance by CDC (84.6%) than by PHL (59.0%) which was significant (P value = 0.002). Discordance between all growth-based test results from PHL and CDC was also significant (P value = 0.003). Most discordance was linked to false susceptibility using the BACTEC™ MGIT™ 960 (MGIT) growth-based system. Our analysis supports coalescing growth-based and molecular results for an informed interpretation of potential EMB resistance.

DNA sequencing for confirmation of rifampin resistance detected by Cepheid Xpert MTB/RIF assay.

DNA sequencing of rpoB and culture-based drug susceptibility results were evaluated for samples referred for confirmation of rifampin resistance detected by the Cepheid Xpert MTB/RIF assay. Silent mutations and mutations associated with low-level resistance were found in the study population. These data support CDC recommendations to confirm Xpert rifampin resistance results.

Si⁺-implanted Si-wire waveguide photodetectors for the mid-infrared.

CMOS-compatible Si⁺-implanted Si-waveguide p-i-n photodetectors operating at room temperature and at mid-infrared wavelengths from 2.2 to 2.3 µm are demonstrated. Responsivities of 9.9 ± 2.0 mA/W are measured at a 5 V reverse bias with an estimated internal quantum efficiency of 2.7 - 4.5%. The dark current is found to vary from a few microamps down to less than a nanoamp after a post-implantation annealing of 350°C. The measured photocurrent dependence on input power shows a linear correspondence over more than three decades, and the frequency response of a 250 µm-length p-i-n device is measured to be ~1.7 GHz for a wavelength of λ = 2.2 µm, thus potentially opening up new communication bands for photonic integrated circuits.

A 60 Gb/s MDM-WDM Si photonic link with < 0.7 dB power penalty per channel.

Mode-division-multiplexing (MDM) and wavelength-division-multiplexing (WDM) are employed simultaneously in a multimode silicon waveguide to realize on-chip MDM and MDM-WDM transmission. Asymmetric Y-junction MDM multiplexers and demultiplexers are utilized for low coherently suppressed demultiplexed crosstalk at the receiver. We demonstrate aggregate bandwidths of 20 Gb/s and 60 Gb/s for MDM and MDM-WDM on-chip links, respectively, with measured 10(-9) BER power penalties between 0.1 dB and 0.7 dB per channel.

Metal-semiconductor-metal ion-implanted Si waveguide photodetectors for C-band operation.

Metal-semiconductor-metal Si waveguide photodetectors are demonstrated with responsivities of greater than 0.5 A/W at a wavelength of 1550 nm for a device length of 1mm. Sub-bandgap absorption in the Si waveguide is achieved by creating divacancy lattice defects via Si(+) ion implantation. The modal absorption coefficient of the ion-implanted Si waveguide is measured to be ≈ 185 dB/cm, resulting in a detector responsivity of ≈ 0.51 A/W at a 50 V bias. The frequency response of a typical 1mm-length detector is measured to be 2.6 GHz, with simulations showing that a frequency response of 9.8 GHz is achievable with an optimized contact configuration and bias voltage of 15 V. Due to the ease with which these devices can be fabricated, and their potential for high performance, these detectors are suitable for various applications in Si-based photonic integrated circuits.

Concordance between molecular and phenotypic testing of Mycobacterium tuberculosis complex isolates for resistance to rifampin and isoniazid in the United States.

Multidrug-resistant (MDR) isolates of Mycobacterium tuberculosis complex (MTBC) are defined by resistance to at least rifampin (RMP) and isoniazid (INH). Rapid and accurate detection of multidrug resistance is essential for effective treatment and interruption of disease transmission of tuberculosis (TB). Overdiagnosis of MDR TB may result in treatment with second-line drugs that are more costly, less effective, and more poorly tolerated than first-line drugs. CDC offers rapid confirmation of MDR TB by the molecular detection of drug resistance (MDDR) for mutations associated with resistance to RMP and INH along with analysis for resistance to other first-line and second-line drugs. Simultaneously, CDC does growth-based phenotypic drug susceptibility testing (DST) by the indirect agar proportion method for a panel of first-line and second-line antituberculosis drugs. We reviewed discordance between molecular and phenotypic DST for INH and RMP for 285 isolates submitted as MTBC to CDC from September 2009 to February 2011. We compared CDC's results with those from the submitting public health laboratories (PHL). Concordances between molecular and phenotypic testing at CDC were 97.4% for RMP and 92.5% for INH resistance. Concordances between CDC's molecular testing and PHL DST results were 93.9% for RMP and 90.0% for INH. Overall concordance between CDC molecular and PHL DST results was 91.7% for RMP and INH collectively. Discordance was primarily attributable to the absence of known INH resistance mutations in isolates found to be INH resistant by DST and detection of mutations associated with low-level RMP resistance in isolates that were RMP susceptible by phenotypic DST. Both molecular and phenotypic test results should be considered for the diagnosis of MDR TB.

Pulse compression in adiabatically tapered silicon photonic wires.

We present a comprehensive analysis of pulse compression in adiabatically tapered silicon photonic wire waveguides (Si-PhWWGs), both at telecom (λ ∼ 1.55 µm) and mid-IR (λ ≳ 2.1 µm) wavelengths. Our theoretical and computational study is based on a rigorous model that describes the coupled dynamics of the optical field and photogenerated free carriers, as well as the influence of the physical and geometrical parameters of the Si-PhWWGs on these dynamics. We consider both the soliton and non-soliton pulse propagation regimes, rendering the conclusions of this study relevant to a broad range of experimental settings and practical applications. In particular, we show that by engineering the linear and nonlinear optical properties of Si-PhWWGs through adiabatically varying their width, one can achieve more than 10× pulse compression in millimeter-long waveguides. The inter-dependence between the pulse characteristics and compression efficiency is also discussed.

Morphology-dependent light trapping in thin-film organic solar cells.

The active layer materials used in organic photovoltaic (OPV) cells often self-assemble into highly ordered morphologies, resulting in significant optical anisotropies. However, the impact of these anisotropies on light trapping in nanophotonic OPV architectures has not been considered. In this paper, we show that optical anisotropies in a canonical OPV material, P3HT, strongly affect absorption enhancements in ultra-thin textured OPV cells. In particular we show that plasmonic and gap-mode solar cell architectures redistribute electromagnetic energy into the out-of-plane field component, independent of the active layer orientation. Using analytical and numerical calculations, we demonstrate how the absorption in these solar cell designs can be significantly increased by reorienting polymer domains such that strongly absorbing axes align with the direction of maximum field enhancement.

Integrated optical modulators and switches using coherent perfect loss.

We propose a new type of amplitude modulator for integrated optics based on phase-controllable coherent perfect loss (CPL) from a resonant cavity. Temporal coupled-mode theory is employed to derive a simple set of equations that describe the device operation, and finite-difference time-domain simulations are used to verify these equations. Two examples of CPL modulators are described with this formalism: a ring resonator and a 1D photonic crystal cavity. We show that internal resonator loss, and thus critical coupling, are not strict requirements for CPL operation. These devices are simple to design and can act as compact switches and modulators for integrated optics.

Generation of parabolic similaritons in tapered silicon photonic wires: comparison of pulse dynamics at telecom and mid-infrared wavelengths.

We study the generation of parabolic self-similar optical pulses in tapered Si photonic nanowires (Si-PhNWs) at both telecom (λ=1.55 µm) and mid-infrared (λ=2.2 µm) wavelengths. Our computational study is based on a rigorous theoretical model, which fully describes the influence of linear and nonlinear optical effects on pulse propagation in Si-PhNWs with arbitrarily varying width. Numerical simulations demonstrate that, in the normal dispersion regime, optical pulses evolve naturally into parabolic pulses upon propagation in millimeter-long tapered Si-PhNWs, with the efficiency of this pulse-reshaping process being strongly dependent on the spectral and pulse parameter regime in which the device operates, as well as the particular shape of the Si-PhNWs.

Asymmetric Y junctions in silicon waveguides for on-chip mode-division multiplexing.

Silicon waveguide asymmetric Y junction mode multiplexers and demultiplexers are demonstrated for applications in on-chip mode-division multiplexing (MDM). We measure demultiplexed crosstalk as low as -30 dB, <-9 dB over the C band, and insertion loss <1.5 dB for multimode links up to 1.2 mm in length. The frequency response of these devices is shown to depend upon Y junction angle and multimode interconnect length. Interference effects are shown to be advantageous for low-crosstalk MDM, even while using compact Y junctions designed to be outside the mode-sorting regime.

Molecular epidemiology of HIV-associated tuberculosis in Dar es Salaam, Tanzania: strain predominance, clustering, and polyclonal disease.

Molecular typing of Mycobacterium tuberculosis can be used to elucidate the epidemiology of tuberculosis, including the rates of clustering, the frequency of polyclonal disease, and the distribution of genotypic families. We performed IS6110 typing and spoligotyping on M. tuberculosis strains isolated from HIV-infected subjects at baseline or during follow-up in the DarDar Trial in Tanzania and on selected community isolates. Clustering occurred in 203 (74%) of 275 subjects: 124 (80%) of 155 HIV-infected subjects with baseline isolates, 56 (69%) of 81 HIV-infected subjects with endpoint isolates, and 23 (59%) of 39 community controls. Overall, 113 (41%) subjects had an isolate representing the East Indian "GD" family. The rate of clustering was similar among vaccine and placebo recipients and among subjects with or without cellular immune responses to mycobacterial antigens. Polyclonal disease was detected in 6 (43%) of 14 patients with multiple specimens typed. Most cases of HIV-associated tuberculosis among subjects from this study in Dar es Salaam resulted from recently acquired infection. Polyclonal infection was detected and isolates representing the East Indian GD strain family were the most common.

Width-modulation of Si photonic wires for quasi-phase-matching of four-wave-mixing: experimental and theoretical demonstration.

We experimentally demonstrate quasi-phase-matched (QPM) four-wave-mixing (FWM) in silicon (Si) nanowire waveguides with sinusoidally modulated width. We perform discrete wavelength conversion over 250 nm, and observe 12 dB conversion efficiency (CE) enhancement for targeted wavelengths more than 100 nm away from the edge of the 3-dB conversion bandwidth. The QPM process in Si nanowires is rigorously modeled, with results explaining experimental observations. The model is further used to investigate the dependence of the CE on key device parameters, and to introduce devices that facilitate wavelength conversion between the C-band and mid-IR. Devices based on a superposition of sinusoidal gratings are investigated theoretically, and are shown to provide CE enhancement over the entire C-band. Width-modulation is further shown to be compatible with zero-dispersion-wavelength pumping for broadband wavelength conversion. The results indicate that QPM via width-modulation is an effective technique for extending the spectral domain of efficient FWM in Si waveguides.

Self-phase modulation and nonlinear loss in silicon nanophotonic wires near the mid-infrared two-photon absorption edge.

We report an experimental study of picosecond pulse propagation through a 4-mm-long Si nanophotonic wire with normal dispersion, at excitation wavelengths from 1775 to 2250 nm. This wavelength range crosses the mid-infrared two-photon absorption edge of Si at ~2200 nm. Significant reduction in nonlinear loss due to two-photon absorption is measured as excitation wavelengths approach 2200 nm. At high input power, self-phase modulation is clearly demonstrated by the development of power-dependant spectral fringes. Asymmetry and blue-shift in the appearance of the spectral fringes at 1775 nm versus 2200 nm is further shown to originate from a strong reduction in the intra-pulse density of two-photon absorption-generated free carriers and the associated free-carrier dispersion. Analysis of experimental data and comparison with numerical simulations illustrates that the two-photon absorption coefficient ß(TPA) obtained here from nanophotonic wire measurements is in reasonable agreement with prior measurements of bulk silicon crystals, and that bulk Si values of the nonlinear refractive index n(2) can be confidently incorporated in the modeling of pulse propagation in deeply-scaled waveguide structures.

Directionally anisotropic Si nanowires: on-chip nonlinear grating devices in uniform waveguides.

Computational studies are used to show that the crystalline structure of Si causes the waveguide Kerr effective nonlinearity, γ, to vary by 10% for in-plane variation of the orientation of a silicon nanowire waveguide (SiNWG) fabricated on a standard silicon-on-insulator wafer. Our analysis shows that this angular dependence of γ can be employed to form a nonlinear Kerr grating in dimensionally uniform SiNWGs based on either ring resonators or cascaded waveguide bends. The magnitude of the nonlinear index variation in these gratings is found to be sufficient for phase matching in four-wave mixing and other optical parametric processes.

Weakly modulated silicon-dioxide-cladding gratings for silicon waveguide Fabry-Pérot cavities.

We show by theory and experiment that silicon-dioxide-cladding gratings for Fabry-Pérot cavities on silicon-on-insulator channel ("wire") waveguides provide a low-refractive-index perturbation, which is required for several important integrated photonics components. The underlying refractive index perturbation of these gratings is significantly weaker than that of analogous silicon gratings, leading to finer control of the coupling coefficient κ. Our Fabry-Pérot cavities are designed using the transfer-matrix method (TMM) in conjunction with the finite element method (FEM) for calculating the effective index of each waveguide section. Device parameters such as coupling coefficient, κ, Bragg mirror stop band, Bragg mirror reflectivity, and quality factor Q are examined via TMM modeling. Devices are fabricated with representative values of distributed Bragg reflector lengths, cavity lengths, and propagation losses. The measured transmission spectra show excellent agreement with the FEM/TMM calculations.

Conversion of 10 Gb/s NRZ-OOK to RZ-OOK utilizing XPM in a Si nanowire.

We have demonstrated for the first time to our knowledge, the conversion of 10 Gb/s non-return-to-zero (NRZ) on-off keying (NRZ-OOK) to RZ-OOK using cross-phase modulation (XPM) in a compact, Silicon (Si) nanowire and a detuned filter. The pulse format conversion resulted in a polarity-preserved, correctly-coded RZ-OOK signal, with no evidence of an error-floor for BER < 10(-11). The advantages of a passive Si nanowire can lead to a compact, power-efficient, highly simplified configuration, amenable to chip-level integration.

Spoligotyping for molecular epidemiology of the Mycobacterium tuberculosis complex.

Spacer oligonucleotide typing, or spoligotyping, is a rapid, polymerase chain reaction (PCR)-based method for genotyping strains of the Mycobacterium tuberculosis complex (MTB). Spoligotyping data can be represented in absolute terms (digitally), and the results can be readily shared among laboratories, thereby enabling the creation of large international databases. Since the spoligotype assay was standardized more than 10 yr ago, tens of thousands of isolates have been analyzed, giving a global picture of MTB strain diversity. The method is highly reproducible and has been developed into a high-throughput assay for large molecular epidemiology projects. In the United States, spoligotyping is employed on nearly all newly identified culture-positive cases of tuberculosis as part of a national genotyping program. The strengths of this method include its low cost, its digital data results, the good correlation of its results with other genetics markers, its fair level of overall differentiation of strains, its high-throughput capacity, and its ability to provide species information. However, the method's weaknesses include the inability of spoligotyping to differentiate well within large strain families such as the Beijing family, the potential for convergent evolution of patterns, the limited success in improving the assay through expansion, and the difficulty in obtaining the specialized membranes and instrumentation.

Large longitudinal electric fields (Ez) in silicon nanowire waveguides.

We demonstrate the presence of strong longitudinal electric fields (E(z)) in silicon nanowire waveguides through numerical computation. These waveguide fields can be engineered through choice of waveguide geometry to exhibit amplitudes as high as 97% that of the dominant transverse field component. We show even larger longitudinal fields created in free space by a terminated waveguide can become the dominant electric field component, and demonstrate E(z) has a large effect on waveguide nonlinearity. We discuss the possibility of controlling the strength and symmetry of E(z) using a dual waveguide design, and show that the resulting longitudinal field is sharply peaked beyond the diffraction limit.

The evolution of drug resistance in Mycobacterium tuberculosis: from a mono-rifampin-resistant cluster into increasingly multidrug-resistant variants in an HIV-seropositive population.

We describe the genotypic and phenotypic characteristics of a mono-rifampin-resistant (RIF(R)) Mycobacterium tuberculosis strain cluster (designated AU-RIF(R)) and the acquisition of additional drug resistance. Drug susceptibility, sequences of regions that determine drug resistance, and basic clinical data were examined. A rare codon duplication (514(TTC)) in rpoB conferring high levels of RIF(R) (minimum inhibitory concentration of >256 microg/mL) in 29 isolates was identified. AU-RIF(R) strains developed secondary resistance to isoniazid and 7 resistance combinations to 6 different antibiotics. Patients infected with AU-RIF(R) strains were primarily immunocompromised. These data suggest that host factors, such as HIV status, may allow dissemination of mono-RIF(R) strains and facilitate the accumulation of additional drug resistance.