- Completion Rates, Adverse Effects, and Costs of a 3-Month and 9-Month Treatment Regimen for Latent Tuberculosis Infection in California Inmates, 2011-2014. [Journal Article]
- PHPublic Health Rep 2019 May/Jun; 134(1_suppl):71S-79S
- CONCLUSIONS: In an incarcerated population, the 3HP regimen had a higher completion rate, lower hepatotoxicity, and lower cost per fully treated patient than the 9H regimen. If coupled with a high treatment initiation rate, the high rate of LTBI treatment completion with 3HP may contribute to reducing tuberculosis morbidity in California.
- Controlling latent TB tuberculosis infection in high-burden countries: A neglected strategy to end TB. [Journal Article]
- PMPLoS Med 2019; 16(4):e1002787
- In a Perspective, Gavin Churchyard and Sue Swindells discuss the importance of strategies to target latent tuberculosis infection in high risk populations and thus disrupt a reservoir for new infecti…
In a Perspective, Gavin Churchyard and Sue Swindells discuss the importance of strategies to target latent tuberculosis infection in high risk populations and thus disrupt a reservoir for new infections in high burden countries.
- Addressing tuberculosis among Inuit in Canada. [Journal Article]
- CCCan Commun Dis Rep 2018 Mar 01; 44(3-4):82-85
- The average annual rate of tuberculosis (TB) among Inuit in Canada is now more than 290 times higher than Canadian born non-Indigenous people. How did this happen? Using the Territory of Nunavut as a…
The average annual rate of tuberculosis (TB) among Inuit in Canada is now more than 290 times higher than Canadian born non-Indigenous people. How did this happen? Using the Territory of Nunavut as a case example, the roots of this situation can largely be traced back to social determinants of health and challenges in access to health care. Half (52%) of all Nunavut residents live in social housing, often under overcrowded conditions. Many experience food insecurity, with food prices in Nunavut that are twice those in southern Canada. Sixty percent of Nunavut residents smoke. Challenges in health care delivery include the small isolated communities, with few roads and difficult weather conditions during the long winters, which impede the ability to reach or provide healthcare, staff that arrive with little TB experience or cultural knowledge, multiple competing health care demands, limited resources and high staff turnover. The housing shortage is not only a social determinant of health, it also impacts the ability to hire new staff or mount an effective response in the event of an outbreak. Yet despite these challenges, progress has been made. Tuberculosis care in Nunavut includes active case finding, contact tracing for all cases of infectious TB, and screening of school age children. Rapid testing with the GeneXpert© platform has resulted in a quicker diagnosis of active TB, earlier treatment (preventing progression of disease) and less transmission. Progressively, there has been a switch from plain film to digital x-rays reducing x-ray turnaround time from as long as two to three weeks to one or two days. Standard treatment protocols include quadruple therapy until sensitivities are known, the use of home isolation for active cases and directly observed treatment (DOT) for both latent and active TB. Special access to rifapentine (Priftin), and its use in combination therapy (3HP), requires only once weekly treatments that can be completed in 12 visits instead of 78 visits for isoniazid (INH) or 120 visits for rifampin, which increases adherence and greatly reduces the health care resources needed to treat TB. In October 2017, the Honourable Jane Philpott, then Minister of Health and now Minister of Indigenous Services, and Natan Obed, president of Inuit Tapiriit Kanatami (ITK) announced the establishment of a Task Force to develop an Inuit TB Elimination Action Framework, accompanied by regional action plans. It is hoped that the task force, and current efforts in Nunavut, will lead to the long term changes needed to ultimately eliminate TB among Inuit in Canada.
- The Transcriptome and Flux Profiling of Crabtree-Negative Hydroxy Acid-Producing Strains of Saccharomyces cerevisiae Reveals Changes in the Central Carbon Metabolism. [Journal Article]
- BJBiotechnol J 2019 Apr 10; :e1900013
- Saccharomyces cerevisiae (S. cerevisiae) is the yeast cell factory of choice for the production of many biobased chemicals. However, it is a Crabtree-positive yeast and so shuttles a large portion of…
Saccharomyces cerevisiae (S. cerevisiae) is the yeast cell factory of choice for the production of many biobased chemicals. However, it is a Crabtree-positive yeast and so shuttles a large portion of carbon into ethanol. Ethanol formation can be eliminated by deleting pyruvate decarboxylase (PDC) activity. It is not yet well understood how PDC-negative yeasts are affected when engineered to produce other products than ethanol. In this study, pathways are introduced for the production of three hydroxy acids (lactic, malic, or 3-hydroxypropionic acid [3HP]) into an evolved PDC-negative strain. These strains are characterized via transcriptome and flux profiling to elucidate the effects that the production of these hydroxy acids has on the host strain. Expression of lactic and malic acid biosynthesis pathways improved the maximum specific growth rate (μmax) of the strain by 64% and 20%, respectively, presumably due to nicotinamide adenine dinucleotide regeneration. All strains show a very high flux (> 90% of glucose uptake) into the oxidative pentose phosphate pathway under batch fermentation conditions. The study, for the first time, directly compares the flux and transcriptome profiles of several hydroxy acid-producing strains of an evolved PDC-negative S. cerevisiae and suggests directions for future metabolic engineering.
- Treatment of latent Mycobacterium tuberculosis infection with 12 once weekly directly-observed doses of isoniazid and rifapentine among persons experiencing homelessness. [Journal Article]
- PlosPLoS One 2019; 14(3):e0213524
- CONCLUSIONS: This study demonstrates the feasibility of administering the 3HP/DOT LTBI regimen to persons experiencing homelessness, a high-risk population.
- Identification of a novel advanced glycation end product derived from lactaldehyde. [Journal Article]
- BBBiosci Biotechnol Biochem 2019; 83(6):1136-1145
- Advanced glycation end products (AGEs) are implicated in the development of diabetic complications via the receptor for AGEs (RAGE). We have reported that the 3-hydroxypyridinium (3HP)-containing AGE…
Advanced glycation end products (AGEs) are implicated in the development of diabetic complications via the receptor for AGEs (RAGE). We have reported that the 3-hydroxypyridinium (3HP)-containing AGEs derived from α-hydroxyaldehydes physically interact with RAGE and show cytotoxicity. Lactaldehyde (LA) is formed from a reaction between threonine and myeloperoxidase, but no LA-derived AGEs have been characterized. Here, we identify the structure and physiological effects of an AGE derived from LA. We isolated a novel 3HP derivative, 2-acetamido-6-(3-hydroxy-5-methyl-pyridin-1-ium-1-yl)hexanoate, named as N-acetyl-LAPL (lactaldehyde-derived pyridinium-type lysine adduct), from a mixture of LA with Nα-acetyl-L-lysine. LAPL was also detected in the LA-modified protein. LAPL elicited toxicity in PC12 neuronal cells, but the effect was suppressed by the soluble form of RAGE as a decoy receptor. Moreover, surface plasmon resonance-based analysis revealed that LAPL specifically binds to recombinant RAGE. These results indicate that LA generates an AGE containing the 3HP moiety and contributes to RAGE-dependent cytotoxicity. Abbreviations: AGEs: advanced glycation end products; RAGE: receptor for advanced glycation end products; 3HP: 3-hydroxypyridinium; LA: lactaldehyde; LAPL: lactaldehyde-derived pyridinium-type lysine adduct; BSA: bovine serum albumin; GLAP: glyceraldehyde-derived pyridinium; MPO: myeloperoxidase; HFBA: heptafluorobutyric acid; TFA: trifluoroacetic acid; HPLC: high performance liquid chromatography; LC-ESI-QTOF-MS: liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry; NMR: nuclear magnetic resonance; LA-BSA: lactaldehyde-modified bovine serum albumin; PBS: phosphate buffered saline, GST, glutathione S-transferase; SPR: surface plasmon resonance; OP-lysine: 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate; GLO1: glyoxalase 1; MG, methylglyoxal.
- Three-month weekly rifapentine plus isoniazid for tuberculosis preventive treatment: a systematic review. [Journal Article]
- IJInt J Tuberc Lung Dis 2018 12 01; 22(12):1422-1428
- CONCLUSIONS: HP was shown to have a preventive effect similar to that of INH monotherapy, with fewer adverse events and higher completion rates. 3HP can contribute significantly to the scale-up of preventive treatment.
- Magnesium starvation improves production of malonyl-CoA-derived metabolites in Escherichia coli. [Journal Article]
- MEMetab Eng 2019; 52:215-223
- Starvation of essential nutrients, such as nitrogen, sulfur, magnesium, and phosphorus, leads cells into stationary phase and potentially enhances target metabolite production because cells do not co…
Starvation of essential nutrients, such as nitrogen, sulfur, magnesium, and phosphorus, leads cells into stationary phase and potentially enhances target metabolite production because cells do not consume carbon for the biomass synthesis. The overall metabolic behavior changes depend on the type of nutrient starvation in Escherichia coli. In the present study, we determined the optimum nutrient starvation type for producing malonyl-CoA-derived metabolites such as 3-hydroxypropionic acid (3HP) and naringenin in E. coli. For 3HP production, high production titer (2.3 or 2.0 mM) and high specific production rate (0.14 or 0.28 mmol gCDW-1 h-1) was observed under sulfur or magnesium starvation, whereas almost no 3HP production was detected under nitrogen or phosphorus starvation. Metabolic profiling analysis revealed that the intracellular malonyl-CoA concentration was significantly increased under the 3HP producing conditions. This accumulation should contribute to the 3HP production because malonyl-CoA is a precursor of 3HP. Strong positive correlation (r = 0.95) between intracellular concentrations of ATP and malonyl-CoA indicates that the ATP level is important for malonyl-CoA synthesis due to the ATP requirement by acetyl-CoA carboxylase. For naringenin production, magnesium starvation led to the highest production titer (144 ± 15 μM) and specific productivity (127 ± 21 μmol gCDW-1). These results demonstrated that magnesium starvation is a useful approach to improve the metabolic state of strains engineered for the production of malonyl-CoA derivatives.
- Using Video Technology to Increase Treatment Completion for Patients With Latent Tuberculosis Infection on 3-Month Isoniazid and Rifapentine: An Implementation Study. [Journal Article]
- JMJ Med Internet Res 2018 Nov 20; 20(11):e287
- CONCLUSIONS: The NYC TB program observed higher treatment completion with VDOT than that previously seen with clinic DOT among patients on 3HP. Expanding the use of VDOT may improve treatment completion and corresponding outcomes for patients with LTBI.
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- Improved treatment completion with shorter treatment regimens for latent tuberculous infection. [Journal Article]
- IJInt J Tuberc Lung Dis 2018 11 01; 22(11):1344-1349
- CONCLUSIONS: Most patients were placed on shorter regimens for LTBI treatment, and higher treatment completion was observed. Encouraging community providers to use shorter regimens for LTBI treatment would reduce the TB disease burden in NYC.