https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60438-8.pdf

Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study

Background 
Xpert MTB/RIF (Xpert) is a promising new rapid diagnostic technology for tuberculosis (TB) that has characteristics that suggest large-scale roll-out. However, because the test is expensive, there are concerns among TB program managers and policy makers regarding its affordability for low- and middle-income settings.


Methods and Findings 
We estimate the impact of the introduction of Xpert on the costs and cost-effectiveness of TB care using decision analytic modelling, comparing the introduction of Xpert to a base case of smear microscopy and clinical diagnosis in India, South Africa, and Uganda. The introduction of Xpert increases TB case finding in all three settings; from 72%–85% to 95%–99% of the cohort of individuals with suspected TB, compared to the base case. Diagnostic costs (including the costs of testing all individuals with suspected TB) also increase: from US$28–US$49 to US$133–US$146 and US$137–US$151 per TB case detected when Xpert is used “in addition to” and “as a replacement of” smear microscopy, respectively. The incremental cost effectiveness ratios (ICERs) for using Xpert “in addition to” smear microscopy, compared to the base case, range from US$41–$110 per disability adjusted life year (DALY) averted. Likewise the ICERS for using Xpert “as a replacement of” smear microscopy range from US$52–$138 per DALY averted. These ICERs are below the World Health Organization (WHO) willingness to pay threshold.


Conclusions 
Our results suggest that Xpert is a cost-effective method of TB diagnosis, compared to a base case of smear microscopy and clinical diagnosis of smear-negative TB in low- and middle-income settings where, with its ability to substantially increase case finding, it has important potential for improving TB diagnosis and control. The extent of cost-effectiveness gain to TB programmes from deploying Xpert is primarily dependent on current TB diagnostic practices. Further work is required during scale-up to validate these findings.



Please see later in the article for the Editors' Summary

/pdf/rapid-diagnosis-of-tuberculosis-with-the-xpert-mtb-rif-assay-l6tdvf1j8t.pdf

Rapid diagnosis of tuberculosis with the Xpert MTB/RIF assay in high burden countries: a cost-effectiveness analysis.

Congenital Clubfoot: Fundamentals of Treatment

Objective
Congenital talipes equinovarus (CTEV), or clubfoot, is a structural malformation that develops early in gestation. Birth prevalence of clubfoot is reported to vary both between and within low- and middle-income countries (LMICs), and this information is needed to plan treatment services. This systematic review aimed to understand the birth prevalence of clubfoot in LMIC settings.

Methods
Six databases were searched for studies that reported birth prevalence of clubfoot in LMICs. Results were screened and assessed for eligibility using pre-defined criteria. Data on birth prevalence were extracted and weighted pooled estimates were calculated for different regions. Wilcoxon rank-sum test was used to examine changes in birth prevalence over time. Included studies were appraised for their methodological quality, and a narrative synthesis of findings was conducted.

Results
Forty-eight studies provided data from 13 962 989 children in 20 countries over 55 years (1960–2015). The pooled estimate for clubfoot birth prevalence in LMICs within the Africa region is 1.11 (0.96, 1.26); in the Americas 1.74 (1.69, 1.80); in South-East Asia (excluding India) 1.21 (0.73, 1.68); in India 1.19 (0.96, 1.42); in Turkey (Europe region) 2.03 (1.54, 2.53); in Eastern Mediterranean region 1.19 (0.98, 1.40); in West Pacific (excluding China) 0.94 (0.64, 1.24); and in China 0.51 (0.50, 0.53).

Conclusion
Birth prevalence of clubfoot varies between 0.51 and 2.03/1000 live births in LMICs. A standardised approach to the study of the epidemiology of clubfoot is required to better understand the variations of clubfoot birth prevalence and identify possible risk factors.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/tmi.12833

Birth prevalence of congenital talipes equinovarus in low- and middle-income countries: a systematic review and meta-analysis.

Author(s): Walter, Nicholas D; Dolganov, Gregory M; Garcia, Benjamin J; Worodria, William; Andama, Alfred; Musisi, Emmanuel; Ayakaka, Irene; Van, Tran T; Voskuil, Martin I; de Jong, Bouke C; Davidson, Rebecca M; Fingerlin, Tasha E; Kechris, Katerina; Palmer, Claire; Nahid, Payam; Daley, Charles L; Geraci, Mark; Huang, Laurence; Cattamanchi, Adithya; Strong, Michael; Schoolnik, Gary K; Davis, John Lucian | Abstract: BackgroundTreatment initiation rapidly kills most drug-susceptible Mycobacterium tuberculosis, but a bacterial subpopulation tolerates prolonged drug exposure. We evaluated drug-tolerant bacilli in human sputum by comparing messenger RNA (mRNA) expression of drug-tolerant bacilli that survive the early bactericidal phase with treatment-naive bacilli.MethodsM. tuberculosis gene expression was quantified via reverse-transcription polymerase chain reaction in serial sputa from 17 Ugandans treated for drug-susceptible pulmonary tuberculosis.ResultsWithin 4 days, bacterial mRNA abundance declined g98%, indicating rapid killing. Thereafter, the rate of decline slowed g94%, indicating drug tolerance. After 14 days, 16S ribosomal RNA transcripts/genome declined 96%, indicating slow growth. Drug-tolerant bacilli displayed marked downregulation of genes associated with growth, metabolism, and lipid synthesis and upregulation in stress responses and key regulatory categories-including stress-associated sigma factors, transcription factors, and toxin-antitoxin genes. Drug efflux pumps were upregulated. The isoniazid stress signature was induced by initial drug exposure, then disappeared after 4 days.ConclusionsTranscriptional patterns suggest that drug-tolerant bacilli in sputum are in a slow-growing, metabolically and synthetically downregulated state. Absence of the isoniazid stress signature in drug-tolerant bacilli indicates that physiological state influences drug responsiveness in vivo. These results identify novel drug targets that should aid in development of novel shorter tuberculosis treatment regimens.

Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis

Background: Drug resistance among tuberculosis patients in sub-Saharan Africa is increasing, possibly due to association with HIV infection. We studied drug resistance and HIV infection in a representative sample of 533 smear-positive tuberculosis patients diagnosed in Kampala, Uganda. Methods/Principal Findings: Among 473 new patients, multidrug resistance was found in 5 (1.1%, 95% CI 0.3-2.5) and resistance to any drug in 57 (12.1%, 9.3-15.3). Among 60 previously treated patients this was 7 (11.7%, 4.8-22.6) and 17 (28.3%; 17.5-41.4), respectively. Of 517 patients with HIV results, 165 (31.9%, 27.9-36.1) tested positive. Neither multidrug (adjusted odds ratio (ORadj) 0.7; 95% CI 0.19-2.6) nor any resistance (ORadj 0.7; 0.43-1.3) was associated with HIV status. Primary resistance to any drug was more common among patients who had worked in health care (ORadj 3.5; 1.0-12.0). Conclusion/Significance: Anti-tuberculosis drug resistance rates in Kampala are low and not associated with HIV infection, but may be associated with exposure during health care

https://pure.uva.nl/ws/files/1184815/117967_364465.pdf

Rates of Anti-Tuberculosis Drug Resistance in Kampala-Uganda Are Low and Not Associated with HIV Infection

Background: While the congenital clubfoot deformity is a common deformity recorded in Uganda, the incidence of the condition had never been accurately determined. The objective of this study was to measure the overall incidence of congenital clubfoot deformity in a representative sample of births. Methods: A study of all babies born with foot anomalies took place from March 2006 to October 2007. The study was based at 8 Regional Hospitals with active maternity units and a functioning clubfoot clinic. All babies with foot deformities at birth at any of eight centres as detected by the delivery room staff were referred to the respective centre’s clubfoot clinic. The children were examined by clubfoot clinic orthopedic officers who diagnosed the specific deformity. Children referred to the clinic from any source and born at the maternity unit were included in the study. The denominator was all live births at the centre during the study period. Results: The total number of live births during the study period was 110,336. The maternity units of the centres identified 290 infants with a foot deformity. One hundred and thirty infants born during the study period were diagnosed in the clubfoot clinic as having a congenital clubfoot deformity. The proportion of infants with a clubfoot deformity was 1.2 per 1000 births over the 20-month period. The male to female ratio was 2.4:1. Recommendation: The rate of clubfoot deformities in the newborn can be used to estimate the numbers of children who should be treated and to estimate resource needs for the identification and management of this treatable congenital malformation. By comparing the number of those treated with the expected number of cases, the numbers of children with neglected clubfoot can be calculated. Key words: Clubfoot; incidence; gender ratio

/pdf/incidence-of-clubfoot-in-uganda-52kcli5jxa.pdf

Joseph Konde Lule

Papers

Rates of Anti-Tuberculosis Drug Resistance in Kampala-Uganda Are Low and Not Associated with HIV Infection

Incidence of clubfoot in Uganda.