Quantifying changes in ambient NOx, O3 and PM10 concentrations in Austria during the COVID-19 related lockdown in spring 2020.

During spring 2020, unprecedented changes in local and regional emissions have occurred around the globe due to governmental restrictions associated with COVID-19. Many European countries including Austria issued partial curfews or stay-at-home order policies, which have impacted ambient air quality through reductions in non-essential transportation and energy consumption of industrial sites and work places. Here, we analyse the effect of these measures on ambient concentrations of nitrogen oxides (NOx), ozone (O3) and particulate matter (PM10) during the first nationwide lockdown in Austria (16.03.2020 to 14.04.2020). To ensure a robust analysis, the Austrian domain is divided into four individual subsectors contingent on regional climate. For air quality analysis a novel method is applied for filtering days with comparable weather conditions during the 2020 lockdown and spring 2017 to 2019. In general, our analysis shows decreasing pollutant concentrations, although in magnitude dependent on pollutant and regional subdomain. Largest reductions are found for NOx reaching up to -68% at traffic sites reflecting the substantial decrease in non-essential transport. Changes in the O3 concentrations at background sites show a rather weak response to NOx declines varying between roughly -18 to +8% for both the median and the upper tail of the distribution. Occasional site level increases in O3 concentrations can be attributed to comparably weak titration during night-time. PM10 concentrations show the smallest response among air pollutants, attributable to manifold precursor sources not affected by the lockdown measures. However, our analysis indicates also a shift of PM10 distributions at traffic sites closer to distributions observed at background sites. Supplementary Information: The online version contains supplementary material available at 10.1007/s11869-022-01232-w.

When to start treatment? Dilemma illustrated by a paediatric case of extensively drug-resistant tuberculosis of the central nervous system.

An HIV-positive mother infected her daughter with extensively drug-resistant Mycobacterium tuberculosis. Despite adhering to the then current guidelines for prevention, the infant was diagnosed with extensively drug-resistant pulmonary tuberculosis at the age of 4 months and developed tuberculous meningitis. After a short delay, appropriate treatment was initiated, followed by an inhospital stay at a specialised hospital. The infant became generally well, but had delayed neurological development. Secondary hydrocephalus due to tuberculous meningitis required a ventriculoperitoneal shunt. After 2 years of microbiologically and clinically effective tuberculosis treatment and several shunt complications, the HIV-negative child died at the age of 28 months ‒ with radiological signs of a shunt infection. The reason for the fatal outcome was probably related to inadequate risk reduction of airborne mother-to-child transmission, inappropriate chemoprophylaxis and delayed initiation of adequate treatment.

Gatifloxacin is superior to levofloxacin and moxifloxacin in shorter treatment regimens for multidrug-resistant TB.

SETTING: Data were collected from patients starting one of the shorter treatment regimens (STRs) for multidrug-resistant tuberculosis (MDR-TB) in Bangladesh, Niger or Cameroon.OBJECTIVE: To estimate the effect of either a gatifloxacin (GFX), moxifloxacin (MFX) or levofloxacin (LVX) based STR on bacteriological effectiveness.DESIGN: Retrospective study of prospectively collected data.RESULTS: Among 1530 patients, bacteriological effectiveness was 96.7% overall. Stratified by treatment with a GFX-, LVX- or MFX-based regimen effectiveness was respectively 97.5%, 95.5% and 94.7%. Compared to those on a GFX-based regimen, the estimated summary odds ratio of having an adverse outcome was more than double (OR 2.05, 95% CI 1.09-3.90) in patients treated with either an LVX-based or MFX-based regimen. After adjusting for initial resistance, patients treated with an LVX-based regimen and MFX-based regimen had respectively a 4.5- and 8.4-fold times larger odds of an adverse bacteriological outcome. None among 859 patients at risk treated with a GFX-based compared to at least 4 of 228 among those on an MFX-based regimen acquired fluoroquinolone resistance.CONCLUSION: GFX-based regimens had superior bacteriological effectiveness than MFX-based or LVX-based regimens. As GFX is currently unavailable in most MDR-TB programs, its reintroduction should be prioritised.

Outcome definitions for multidrug-resistant tuberculosis treated with shorter treatment regimens.

To assess whether the revised 2013 World Health Organization (WHO) definitions for multidrug-resistant tuberculosis (MDR-TB) treatment outcomes apply to shorter treatment regimens in low- and middle-income countries and to propose modified criteria. Criteria for 'failure' and 'cure' outcomes were assessed using data on 1006 patients enrolled in an observational study on the standardised 9-11 month shorter MDR-TB regimen in Africa. Absence of conversion in the intensive phase, a WHO criteria for failure, was the worst performing criterion; reversion had low sensitivity and other criteria provided limited added value. Based on our study results, we propose new definitions for 'treatment failure' as treatment termination or the permanent discontinuation of 2 anti-tuberculosis drugs due to 1) positive culture after 6 months of treatment (except for one isolated positive culture) or 2) at least two consecutive grade 2+ positive sputum smears after 6 months of treatment if culture is not available; and for 'cure' as treatment completion without proof of failure AND two consecutive negative cultures taken 30 days apart, one of which should be after 6 months of treatment. The proposed new definitions are applicable to shorter regimens in low- and middle-income countries, and should also work for the newly recommended longer regimens. .

Sputum smear microscopy in the Xpert® MTB/RIF era.

A balanced perspective is advocated for the assessment and application of the most recent and the oldest diagnostic methods for pulmonary tuberculosis (TB)-the molecular Xpert® MTB/RIF assay and microscopy for acid-fast bacilli. We discuss their respective merits and shortcomings and identify threats that may hamper their use in TB control. Neither test on its own provides all the information needed for diagnosis and treatment monitoring. Considering all aspects important for both individual patient care and disease control, neither seems 'better' than the other. The required advancement of microscopy had already been hampered before the introduction of the GeneXpert technology by unsuccessful and probably misguided attempts to decentralise culture-based diagnosis and drug susceptibility testing. It seems evident that systematic replacement of microscopy by Xpert is not a viable option for the foreseeable future. Instead, the two methods should complement each other to arrive at a comprehensive, accessible and continuous service for a maximum number of patients. This will intrinsically prioritise targeting the most potent transmitters with the worst prognosis, simultaneously offering optimised prospects for efficient TB control. New microscopy and Xpert applications are expected to ultimately make control programmes independent of culture-based methods in diagnosis, treatment monitoring and outcome assessment.

Principles for constructing a tuberculosis treatment regimen: the role and definition of core and companion drugs.

Current World Health Organization guidelines for the formulation of treatment regimens for multidrug-resistant tuberculosis (MDR-TB) pay too little attention to the microbiological activity of anti-tuberculosis drugs. Here, we draw lessons from the pioneering work done on shorter MDR-TB treatment regimens and the current knowledge of the bactericidal and sterilizing properties of the drugs to inform the composition of treatment regimens for MDR-TB. We propose to reserve the term 'core drug' for the one drug in a regimen that contributes most to relapse-free cure. The core drug has both moderate to high bactericidal and sterilizing activity, is given throughout treatment, is well tolerated, and has no cross-resistance with the core drug used in the previous regimen. Currently used core drugs include rifampicin in the first-line 6-month regimen, and fourth-generation fluoroquinolones and bedaquiline in regimens for drug-resistant TB. All other drugs are 'companion drugs', used to avert treatment failure due to acquired drug resistance against the core drug. Some also help further reduce the risk of relapse. Moreover, toxic drugs should be avoided if there is an alternative. A regimen must always include the core drug, plus at least one companion drug with high bactericidal activity, a second bactericidal companion drug, plus two sterilizing companion drugs.

Impact of quality improvement in tuberculosis laboratories in low- and lower-middle-income countries: a systematic review.

BACKGROUND: The effect of quality improvement measures on the performance of diagnostic tuberculosis (TB) laboratories in low- and lower-middle-income countries is not known, and is the subject of this review. METHODS: Three databases were searched for quality improvement studies presenting data on performance parameters before and after the implementation of quality improvement interventions. RESULTS: Twenty-one studies were included in this review. Quality improvement measures were most frequently implemented by an external organization; settings targeted ranged from microscopy centers, hospitals, districts, regional and national reference laboratories. Quality improvement interventions and outcome measurements were highly heterogeneous. Most studies investigated interventions aimed at improving smear microscopy (n = 17). Two studies evaluated comprehensive quality improvement measures (n = 2) and another three studies focused on mycobacterial culture and drug susceptibility testing. Most studies showed an improvement in outcomes measured on before-after or time trend analysis. CONCLUSION: Quality improvement measures implemented in TB laboratories showed a positive impact on various outcomes. Due to the high heterogeneity of outcome reporting and interventions and the low quality of the studies, the effect size was not clear. Identification of standardized quality indicators and their link to the quality of patient care would improve knowledge in this field.

Treatment outcome with a short multidrug-resistant tuberculosis regimen in nine African countries.

SETTING: Nine countries in West and Central Africa. OBJECTIVE: To assess outcomes and adverse drug events of a standardised 9-month treatment regimen for multidrug-resistant tuberculosis (MDR-TB) among patients never previously treated with second-line drugs. DESIGN: Prospective observational study of MDR-TB patients treated with a standardised 9-month regimen including moxifloxacin, clofazimine, ethambutol (EMB) and pyrazinamide (PZA) throughout, supplemented by kanamycin, prothionamide and high-dose isoniazid during an intensive phase of a minimum of 4 to a maximum of 6 months. RESULTS: Among the 1006 MDR-TB patients included in the study, 200 (19.9%) were infected with the human immunodeficiency virus (HIV). Outcomes were as follows: 728 (72.4%) cured, 93 (9.2%) treatment completed (81.6% success), 59 (5.9%) failures, 78 (7.8%) deaths, 48 (4.8%) lost to follow-up. The proportion of deaths was much higher among HIV-infected patients (19.0% vs. 5.0%). Treatment success did not differ by HIV status among survivors. Fluoroquinolone resistance was the main cause of failure, while resistance to PZA, ethionamide or EMB did not influence bacteriological outcome. The most important adverse drug event was hearing impairment (11.4% severe deterioration after 4 months). CONCLUSIONS: The study results support the use of the short regimen recently recommended by the World Health Organization. Its high level of success even among HIV-positive patients promises substantial improvements in TB control.

Gatifloxacin for short, effective treatment of multidrug-resistant tuberculosis.

The 9-month regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) piloted in Bangladesh and used, with modifications, in Cameroon and Niger, has achieved treatment success in a very large proportion of patients; gatifloxacin (GFX) is likely to have played a critical role in this success. Two months after the publication of a study reporting that GFX and not moxifloxacin (MFX) was associated with dysglycaemia, the manufacturer announced the withdrawal of GFX from the market. The findings of that study may have less significance for the majority of MDR-TB patients living in high-incidence countries who are much younger, have a lower risk of dysglycaemia and suffer from a highly fatal condition. The problem of dysglycaemia is not limited to GFX use and may occur with other fluoroquinolones; furthermore, GFX-associated dysglycemia was manageable among those MDR-TB patients in Bangladesh and Niger in whom it occurred. GFX has now become unavailable in Bangladesh, Cameroon, Niger and other countries piloting the shorter MDR-TB regimens, depriving resource-poor countries of an efficacious, effective and inexpensive drug with a demonstrated good safety profile for the given indication. There is little reason not to make GFX available for MDR-TB treatment as long as the superiority of non-GFX-based MDR-TB regimens is not demonstrated.

Specific gyrA gene mutations predict poor treatment outcome in MDR-TB.

OBJECTIVES: Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second-line treatment outcomes in M. tuberculosis patients treated with fourth-generation fluoroquinolones. METHODS: We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs. RESULTS: The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4-13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs. CONCLUSIONS: Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective.

High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon.

SETTING: Two specialised multidrug-resistant tuberculosis (MDR-TB) treatment units in Cameroon. OBJECTIVE: To assess outcome and adverse drug events with a standardised 12-month regimen for MDR-TB among second-line drug naïve patients. DESIGN: Prospective observational study of MDR-TB patients treated with a standardised 12-month regimen including gatifloxacin, clofazimine, prothionamide, ethambutol and pyrazinamide throughout, supplemented by kanamycin and isoniazid during an intensive phase of a minimum of 4 months. Progress was monitored monthly until treatment completion and twice over one year after treatment cessation. RESULTS: Eighty-seven potentially eligible patients were lost and never treated due to delayed availability of test results. Among the 150/236 eligible and treated patients, 134 (89%) successfully completed treatment, 10 died, 5 were lost, 1 failed and none relapsed. The patients' mean age was 33.7 years (range 17-68), 73 (49%) were females, 120 (80%) had failed on previous treatment, 30 (20%) were human immunodeficiency virus seropositive, 62 (43%) had a body mass index <18.5 kg/m(2) and 41 (27%) had radiographic involvement of five or six of the six lung zones. The most important adverse drug event was hearing impairment, which occurred in 46 of 106 (43%) patients. CONCLUSIONS: These results add further evidence for the usefulness of shorter, standardised regimens among patients without second-line drug resistance.

Molecular epidemiology of tuberculosis in Cambodian children.

SUMMARY We analysed Mycobacterium tuberculosis strains from children, hospitalized from January 2004 to July 2008 in the largest paediatric hospital complex in Cambodia. Specimens were tested for drug susceptibility and genotypes. From the 260 children, 161 strains were available. The East African-Indian genotype family was the most common (59.0%), increasing in frequency with distance from the Phnom Penh area, while the frequency of the Beijing genotype family strains decreased. The drug resistance pattern showed a similar geographical gradient: lowest in the northwest (4.6%), intermediate in the central (17.1%), and highest in the southeastern (30.8%) parts of the country. Three children (1.9%) had multidrug-resistant tuberculosis. The Beijing genotype and streptomycin resistance were significantly associated (P < 0.001). As tuberculosis in children reflects recent transmission patterns in the community, multidrug resistance levels inform about the current quality of the tuberculosis programme.

Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients.

SETTING: Tuberculosis (TB) program, Damien Foundation Projects, Bangladesh. OBJECTIVE: To summarize the outcome and its determinants of the first treatment for multidrug-resistant TB using a standardized regimen consisting of a minimum 9 months. DESIGN: This was a prospective, observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initial hospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients were monitored using culture for up to 2 years after treatment completion. RESULTS: Of the 515 patients who met the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had a bacteriologically favorable outcome. Due to extensive disease with delayed sputum conversion, only half of the patients completed treatment within 9 months; however, 95% were able to complete treatment within 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who were successfully treated completed at least 12 months post-treatment follow-up. The strongest risk factor for a bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ) resistance, particularly when compounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effect on treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine. CONCLUSION: The excellent outcome of the Bangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare, except among patients with high-level GFX resistance, notably in the presence of PZA resistance.

Changes in body weight and tuberculosis treatment outcome in Viet Nam.

SETTING: National Tuberculosis Programme, Viet Nam, 2008. OBJECTIVE: To assess the relationship between changes in body weight and tuberculosis (TB) treatment outcome. METHODS: All treatment cards of patients from a sample of 30 randomly selected treatment units in the country were analysed. RESULTS: Of 2609 patients, 2506 (96.1%) had a successful treatment outcome. The median body weight of all patients at diagnosis was 46.0 kg (25th and 75th percentiles 41-51). New sputum smear-positive TB patients with a successful treatment outcome gained an average of 2.6 kg during treatment. Patients with weight loss during the first 2 months of treatment were more likely to have an unsuccessful outcome than patients without (OR 4.9, 95%CI 3.0-7.9). Patients weighing <40 kg at treatment start who gained more than 5% of their body weight after 2 months of treatment had a significantly smaller risk of an unsuccessful treatment outcome than patients who did not (OR 0.2, 95%CI 0.05-0.96). CONCLUSIONS: Patients failing to gain weight or losing weight, particularly during the first 2 months of treatment, require particular attention, as they appear to be at an increased risk of unsuccessful treatment outcome.

Efficient, quality-assured data capture in operational research through innovative use of open-access technology.

Ensuring quality of data during electronic data capture has been one of the most neglected components of operational research. Multicentre studies are also challenged with issues about logistics of travel, training, supervision, monitoring and troubleshooting support. Allocating resources to these issues can pose a significant bottleneck for operational research in resource-limited settings. In this article, we describe an innovative and efficient way of coordinating data capture in multicentre operational research using a combination of three open access technologies-EpiData for data capture, Dropbox for sharing files and TeamViewer for providing remote support.

La garantie de la qualité des données au cours de la capture des données électroniques a constitué une des composantes les plus négligées de la recherche opérationnelle. De plus, les défis des études multicentriques comportent des problèmes concernant les logistiques du voyage, la formation, la supervision, le suivi et le soutien au dépannage. Une allocation de ressources à ces problèmes peut constituer un goulot significatif pour les recherches opérationnelles dans les contextes à ressources limitées. Dans cet article, nous décrivons une façon innovatrice et efficiente pour la capture des données de coordination dans la recherche opérationnelle multicentrique au moyen d'une combinaison de trois technologies libres d'accès­EpiData pour la capture des données, Dropbox pour le partage des dossiers et TeamViewer pour procurer un soutien à distance.

Garantizar la calidad de los datos durante la captura electrónica ha sido uno de los componentes más desatendidos de la investigación operativa. Los estudios multicéntricos afrontan además dificultades relacionadas con la logística del desplazamiento, la capacitación, la supervisión el seguimiento y de la asistencia técnica para la resolución de los problemas. La atribución de recursos a estas esferas puede representar un cuello de botella de la investigación operativa en los entornos con escasos recursos. En el presente artículo se describe un método innovador y eficaz de coordinar la captura de datos en investigación operativa mediante la aplicación de tres tecnologías de acceso abierto, a saber: EpiData en la captura de datos, Dropbox en la puesta en común de los archivos y TeamViewer en la prestación de asistencia técnica a distancia.

Laboratory diagnosis of tuberculosis in a large pediatric hospital in Cambodia.

SETTING: Tuberculosis laboratory in the Jayavarman VII Children's Hospital in Siem Reap, part of the Kantha Bopha Hospitals, the largest pediatric hospital complex in Cambodia. OBJECTIVE: To determine the efficiency of on-site microscopy and rRNA amplification in children with a clinical diagnosis of tuberculosis (TB) and specimen sampling for culture. RESULTS: From 1 July 2005 to 31 March 2006, 52,400 children were admitted to the hospital. Among these, 405 children had tuberculosis, including 91 (22.5%) laboratory-confirmed cases, or respectively 7.7 and 1.7 per 1000 admissions. Among cases confirmed by microscopy or rRNA assay, rRNA identified 91.2%. Among all culture-confirmed cases, rRNA identified 90.5%. Culture alone contributed 7.1% to all laboratory confirmed cases. The yield of culture from preserved specimens was not affected by shipment delay. For 97.4% of the children, the maximum turnaround time for the on-site laboratory result was 48 h. CONCLUSION: Implementation of a mycobacteriology service in a referral hospital is feasible, as the molecular technique is highly efficient. Storage of specimen aliquots allows subsequent culture without loss of viability due to shipment delay.

Adequacy of anti-tuberculosis drug prescriptions in Viet Nam.

SETTING: National Tuberculosis Program, Viet Nam, 2008. OBJECTIVES: To determine drug prescription adherence to national guidelines, to examine factors associated with an erroneous dosage of rifampin (RMP) and to evaluate the impact of an insufficient RMP dosage on treatment outcome. METHODS: A representative sample of 30 treatment units was randomly selected. All patient treatment cards enrolled in these units were obtained, and data were double-entered and validated before calculating the adequacy of the individual drug prescriptions. RESULTS: Of 3412 tuberculosis treatment cards, 3225 (94.5%) had information on treatment regimen and the patient's weight. Treatment was successful in 89.4%. Prescriptions of tablets/vials conforming to recommendations were found for respectively 91.2%, 89.9%, 92.3% and 94.6% of the patients for RMP/isoniazid, pyrazinamide, ethambutol and streptomycin. Patients in the 25-39 kg weight bracket received insufficient dosages. This was almost entirely attributable to patients at the end of the weight bracket. Nevertheless, no significant association was found between treatment failure and death, body weight and insufficient RMP dosage. CONCLUSIONS: Adherence to national recommendations was high. RMP was given in insufficient dosage for patients at the end of a weight range bracket, but the under-dosage was small and did not measurably affect treatment outcome.