Ultra-sensitive refractive index sensor using CMOS plasmonic transducers on silicon photonic interferometric platform.

Optical refractive-index sensors exploiting selective co-integration of plasmonics with silicon photonics has emerged as an attractive technology for biosensing applications that can unleash unprecedented performance breakthroughs that reaps the benefits of both technologies. However, towards this direction, a major challenge remains their integration using exclusively CMOS-compatible materials. In this context, herein, we demonstrate, for the first time to our knowledge, a CMOS-compatible plasmo-photonic Mach-Zehnder-interferometer (MZI) based on aluminum and Si3N4 waveguides, exhibiting record-high bulk sensitivity of 4764 nm/RIU with clear potential to scale up the bulk sensitivity values by properly engineering the design parameters of the MZI. The proposed sensor is composed of Si3N4 waveguides butt-coupled with an aluminum stripe in one branch to realize the sensing transducer. The reference arm is built by Si3N4 waveguides, incorporating a thermo-optic phase shifter followed by an MZI-based variable optical attenuation stage to maximize extinction ratio up to 38 dB, hence optimizing the overall sensing performance. The proposed sensor exhibits the highest bulk sensitivity among all plasmo-photonic counterparts, while complying with CMOS manufacturing standards, enabling volume manufacturing.

Plasmonics co-integrated with silicon nitride photonics for high-sensitivity interferometric biosensing.

We demonstrate a photonic integrated Mach-Zehnder interferometric sensor, utilizing a plasmonic stripe waveguide in the sensing branch and a photonic variable optical attenuator and a phase shifter in the reference arm to optimize the interferometer operation. The plasmonic sensor is used to detect changes in the refractive index of the surrounding medium exploiting the accumulated phase change of the propagating Surface-Plasmon-Polariton (SPP) mode that is fully exposed in an aqueous buffer solution. The variable optical attenuation stage is incorporated in the reference Si3N4 branch, as the means to counter-balance the optical losses introduced by the plasmonic branch and optimize interference at the sensor output. Bulk sensitivity values of 1930 nm/RIU were experimentally measured for a Mach Zehnder Interferometer (MZI) with a Free Spectral Range of 24.8 nm, along with extinction ratio of more than 35 dB, demonstrating the functional benefits of the co-integration of plasmonic and photonic waveguides.

Increasing directly observed therapy related to improved tuberculosis treatment outcomes in Taiwan.

SETTING: Directly observed therapy (DOT) is a core element of tuberculosis (TB) care and control efforts. In Taiwan, DOT was implemented in 2006, when the Stop TB Strategy was adopted as a national policy. OBJECTIVE: To quantify DOT among patients on anti-tuberculosis treatment and measure the association between proportion of DOT and TB treatment outcomes at a national level in Taiwan. DESIGN: We analyzed data prospectively collected on all new pulmonary TB cases reported to the national web-based registry between 1 January 2007 and 30 June 2008. We compared treatment outcomes and proportion of DOT in multivariable analyses. RESULTS: Among 11,528 patients initiating anti-tuberculosis treatment, the proportion of days during which an official DOT observer witnessed treatment was >60% for 5150 (45%) patients and ≤60% for 4601 (40%) patients, whereas for 1777 (15%) patients no days of DOT were recorded. Being older, male, having positive bacteriology results and a non-World Health Organization recommended treatment regimen at baseline were independently related to unsuccessful treatment outcomes and mortality. A dose-response effect was found between proportion of DOT and these outcomes. CONCLUSION: These findings highlight the importance of ensuring universal DOT in improving treatment outcomes among new pulmonary TB patients.

Assessing spatiotemporal patterns of multidrug-resistant and drug-sensitive tuberculosis in a South American setting.

We examined the spatiotemporal distribution of laboratory-confirmed multidrug-resistant tuberculosis (MDR TB) cases and that of other TB cases in Lima, Peru with the aim of identifying mechanisms responsible for the rise of MDR TB in an urban setting. All incident cases of TB in two districts of Lima, Peru during 2005-2007 were included. The spatiotemporal distributions of MDR cases and other TB cases were compared with Ripley's K statistic. Of 11,711 notified cases, 1187 received drug susceptibility testing and 376 were found to be MDR. Spatial aggregation of patients with confirmed MDR disease appeared similar to that of other patients in 2005 and 2006; however, in 2007, cases with confirmed MDR disease were found to be more tightly grouped. Subgroup analysis suggests the appearance of resistance may be driven by increased transmission. Interventions should aim to reduce the infectious duration for those with drug-resistant disease and improve infection control.

Bacteriologic monitoring of multidrug-resistant tuberculosis patients in five DOTS-Plus pilot projects.

BACKGROUND: Multidrug-resistant tuberculosis programs in DOTS-Plus pilot sites in five countries. OBJECTIVES: To calculate sputum conversion time and its relationship to treatment outcome, document the frequency of culture reversions and examine concordance of smear and culture to assess the potential consequences of monitoring by smear microscopy alone. DESIGN: Retrospective cohort analysis of 1926 patients receiving individualized, second-line therapy. RESULTS: Among 1385 sputum culture-positive cases at baseline, 1146 (83%) experienced at least one culture conversion during treatment. Conversion, however, was not sustained in all patients: 201 (15%) experienced initial culture conversion and at least one subsequent culture reversion to positive; 1064 (77%) achieved sustained culture conversion. Median time to culture conversion was 3 months. Among 206 patients whose nal conversion occurred 7-18 months after the initiation of therapy, 71% were cured or had completed treatment. CONCLUSIONS: Prolonged treatment for patients with delayed conversion may be beneficial, as 71% of late converters still achieved cure or completed treatment. This has implications for programs with de ned end points for treatment failure. The interval between rst and nal conversion among patients whose initial con- version is not sustained raises concern with respect to the ongoing debate regarding duration of treatment and the definition of cure.

Electronic laboratory system reduces errors in National Tuberculosis Program: a cluster randomized controlled trial.

OBJECTIVE: To evaluate the impact of the e-Chasqui laboratory information system in reducing reporting errors compared to the current paper system. DESIGN: Cluster randomized controlled trial in 76 health centers (HCs) between 2004 and 2008. METHODS: Baseline data were collected every 4 months for 12 months. HCs were then randomly assigned to intervention (e-Chasqui) or control (paper). Further data were collected for the same months the following year. Comparisons were made between intervention and control HCs, and before and after the intervention. RESULTS: Intervention HCs had respectively 82% and 87% fewer errors in reporting results for drug susceptibility tests (2.1% vs. 11.9%, P = 0.001, OR 0.17, 95%CI 0.09-0.31) and cultures (2.0% vs. 15.1%, P < 0.001, OR 0.13, 95%CI 0.07-0.24), than control HCs. Preventing missing results through online viewing accounted for at least 72% of all errors. e-Chasqui users sent on average three electronic error reports per week to the laboratories. CONCLUSIONS: e-Chasqui reduced the number of missing laboratory results at point-of-care health centers. Clinical users confirmed viewing electronic results not available on paper. Reporting errors to the laboratory using e-Chasqui promoted continuous quality improvement. The e-Chasqui laboratory information system is an important part of laboratory infrastructure improvements to support multidrug-resistant tuberculosis care in Peru.

Factors associated with positive tuberculin skin test results among HIV-infected persons in Orel Oblast, Russia.

BACKGROUND: The treatment of persons living with human immunodeficiency virus/acquired immune-deficiency syndrome (PLWHAs) for latent tuberculosis infection (LTBI) reduces tuberculosis (TB) morbidity. Despite a high TB burden and an expanding human immunodeficiency virus epidemic, Russia had limited data on the utility of the tuberculin skin test (TST) for LTBI diagnosis in PLWHAs. OBJECTIVE: To determine the prevalence and predictors of positive TSTs in PLWHAs in Orel Oblast. METHODS: A total of 150 consenting PLWHAs being followed up at the AIDS Center were administered a TST and a questionnaire for risk factors for LTBI. A positive TST result was defined as >or=5 mm induration. RESULTS: Of the 150 subjects, 67% were male and 74% were aged <30 years. Of the PLWHAs tested, 26% had a positive TST result, while among PLWHAs with CD4(+) >500 cells/ml, 36% were TST-positive. TST positivity varied inversely with CD4(+) cell count. Among PLWHAs with a history of injection drug use, the primary risk factor for HIV, 29 (31.9%) were positive. CONCLUSIONS: A high proportion of tested PLWHAs had a positive TST and could benefit from preventive therapy (PT) to reduce the risk of TB. A TB control programme in Russia should therefore include TST screening among PLWHAs and PT, besides active TB case finding and treatment.

Programmatic implementation of rapid DST for Mycobacterium tuberculosis in Peru.

BACKGROUND: Performance characteristics of novel rapid drug susceptibility tests (DST) for Mycobacterium tuberculosis may change when moving from research to implementation in actual public health practice. We describe the performance characteristics of a direct, rapid DST when implemented in Lima, Peru. METHODS: A district laboratory validated conventional proportions and nitrate reductase methods. We collected data on samples submitted for DST from January 2005 to June 2007 and calculated frequency of testing and results, and median time to test results. RESULTS: A total of 4102 DSTs were performed by conventional DST and 895 by nitrate reductase. Results were obtained from 72.8% of samples by conventional DST and from 70.2% of those processed by Griess; respectively 26.4% and 31.5% were multidrug-resistant tuberculosis. The median time from sample collection to test result was 31 days for Griess vs. 99 days for conventional DST. CONCLUSIONS: Preliminary experience with the Griess method demonstrates favorable performance under program conditions.

Timely diagnosis of MDR-TB under program conditions: is rapid drug susceptibility testing sufficient?

Timely diagnosis and effective, safe treatment are essential to reduce transmission and improve outcomes for patients with tuberculosis. Aside from laboratory methods, many programmatic factors influence the overall turnaround time (TAT) in diagnosing multidrug-resistant tuberculosis (MDR-TB). We measured each step in the overall TAT required for MDR-TB in two of five health districts of Lima, Peru. The total TAT, from initial sputum specimen to diagnosis and appropriate treatment, was 5 months, almost twice as long as the bacteriological procedures per se. Expensive investments in laboratory technology may yield low returns unless the programmatic aspects of the diagnostic process are streamlined at the same time.

Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex.

We initiated a prospective noncomparative trial of treatment for lung disease due to Mycobacterium avium complex (MAC) in human immunodeficiency virus-negative patients, with a regimen of clarithromycin (1000 mg), rifabutin (300-600 mg), and ethambutol (25 mg/kg) administered 3 times per week. Fifty-nine patients were enrolled. Twelve (20%) were lost to follow-up, and 6 (10%) developed clarithromycin intolerance. The remaining 41 patients (69%) completed the initial 6 months of therapy. The sputum of 32 of these patients (78%) converted to negative. When results were compared with the sputum response rates at 6 months in previous studies with a regimen including daily clarithromycin and regimens including intermittent (3 times per week) azithromycin with the same companion drugs, no differences in treatment responses were evident. Adverse reactions related to rifabutin were a major problem, and for 24 (41%) of 59 patients the dosage was decreased or the drug was withdrawn. Intermittent (3 times per week) administration of clarithromycin appears to be as effective as daily administration in effecting sputum conversion in pulmonary MAC disease.

Agglutination of Plasmodium falciparum-infected erythrocytes from east and west African isolates by human sera from distant geographic regions.

Plasmodium falciparum-infected erythrocytes (PfE) were collected from acutely infected children in The Gambia and Tanzania and cultured for more than 30 hr until the parasites were mature trophozoites. Sera collected from these countries, other African countries, Asia, and South America were used in the PfE microagglutination test to determine whether PfE from East and West Africa share surface antigens. From the patterns of agglutination reactivity, we identified extensive antigenic diversity in surface antigens, but obtained no evidence for greater differences between isolates from East or West Africa and those within one region. The majority of sera from immune adults from The Gambia, Tanzania, Sudan, Nigeria, or Ghana were pan-agglutinating, and agglutinated all PfE isolates from The Gambia and Tanzania. Some sera from immune adults of Irian Jaya also agglutinated each of the seven African isolates, while others agglutinated many but not all of the isolates, similar to sera from immune adults of Flores, Indonesia. In contrast, sera from nonimmune adults from Colombia agglutinated few of the African isolates. It was remarkable, however, that sera from nonimmune Colombians agglutinated any African isolates. Our results are consistent with the following conclusions: some PfE surface antigen(s) are very diverse; this diversity is a feature of the parasite worldwide; the repertoire of isolate-specific surface antigens, although large, includes antigens that are either identical or antigenically cross-reactive in geographically very distant parasite populations; and African adults have pan-agglutinating antibodies that may contribute to protective immunity. Such pan-agglutinating antibodies could reflect the accumulation of a large repertoire of isolate-specific antibodies. The contribution of antibody against any shared PfE surface antigen to the pan-agglutinating reactivities is unknown and awaits development of the appropriate reagents.

In vitro rosetting, cytoadherence, and microagglutination properties of Plasmodium falciparum-infected erythrocytes from Gambian and Tanzanian patients.

To understand the molecular mechanisms that lead to sequestration of red blood cells infected with mature stages of Plasmodium falciparum and to examine the relevance of earlier studies on adherence properties of laboratory-derived P falciparum parasites to the natural parasite population, we analyzed Gambian and Tanzanian isolates for in vitro cytoadherence and antibody-mediated microagglutination. Eighteen cryopreserved isolates of ring-stage parasites were cultured for 20 to 30 hours in vitro, in the patients original erythrocytes, to the trophozoite and schizont stage. All parasites were positive in the microagglutination assay with at least one of four African hyperimmune sera. In a rosetting assay, only 2 of the 18 isolates were strongly positive (35% and 41% of parasitized erythrocytes with more than two uninfected cells bound). Thirteen isolates showed either intermediate (5% to 18%) or low (less than 5%) rosetting while three isolates did not form rosettes. Infected cell-binding of the different isolates to immobilized CD36 or thrombospondin, or C32 melanoma cells correlated with the percentage of mature parasites in the blood samples (r = .932 for CD36, r = .946 for thrombospondin, and r = .881 for C32 melanoma cells). There was a high correlation between binding to CD36 and thrombospondin (r = .982). The extent of infected cell rosetting with uninfected cells in these blood samples was not correlated with these other receptor properties. We also observed coexpression of rosetting and cytoadherence receptors on the same parasitized erythrocytes.