Timing of treatment interruption among latently infected tuberculosis cases treated with a nine-month course of daily isoniazid: findings from a time to event analysis.

BACKGROUND: Treatment of latent tuberculosis infection (LTBI) in high-risk groups is an effective strategy for TB control and elimination in low incidence settings. A nine-month course of daily isoniazid (INH) has been the longest prescribed therapy; however, completion rates are suboptimal. We need data to guide TB program outreach efforts to optimize LTBI treatment completion rates. METHODS: We pooled seven (2009-2015) years of LTBI treatment outcome data. We computed the probability of INH treatment disruption over time by patient demographic and clinical risk factors. We used log-rank tests and Cox proportional hazards models to assess the risk factors for treatment disruption. RESULTS: We analyzed data from 12,495 persons with complete data on INH treatment initiation. Pediatric cases (0-17 years), recent contacts of active TB patients, and non-U.S.-born adults living in the United States ≤5 years represented 25.2, 13.0, and 59.2% of the study population, respectively. Overall, 48.4% failed to complete therapy. The median treatment duration was 306 days (95% CI: 297, 315). A significant drop in adherence could be observed around day 30 of treatment initiation. Indeed, by day 30 of treatment, 17.0% (95% CI: 16.4, 17.7) of patients had defaulted on therapy. Pediatric patients (HR = 0.83, 95% CI: 0.78, 0.89), recent contacts (HR = 0.74, 95% CI: 0.68, 0.81), patients with diabetes (HR = 0.77, 95% CI: 0.60, 0.98), and patients with HIV (HR = 0.39, 95% CI: 0.30, 0.51) had a lower risk of treatment default. However, black patients (HR = 1.57, 95% CI: 1.44, 1.70), Hispanic patients (HR = 1.54, 95% CI: 1.43, 1.66), and non-U.S.-born persons living in the United States ≤5 years (HR = 1.25, 95% CI: 1.18, 1.32) were significantly more likely to default on therapy. CONCLUSIONS: In this analysis of INH treatment outcome, we see high levels of treatment discontinuation. On average, patients defaulted on their prescribed nine-month daily INH therapy within 30 days of initiating treatment, and those at increased risk of progression to active disease were most likely to do so. We highlight the need to introduce patient-centered programs to increase treatment adherence in this population.

The endoderm indirectly influences morphogenetic movements of the zebrafish head kidney through the posterior cardinal vein and VegfC.

Integration of blood vessels and organ primordia determines organ shape and function. The head kidney in the zebrafish interacts with the dorsal aorta (DA) and the posterior cardinal vein (PCV) to achieve glomerular filtration and definitive hematopoiesis, respectively. How the head kidney co-develops with both the axial artery and vein remains unclear. We found that in endodermless sox32-deficient embryos, the head kidney associated with the PCV but not the DA. Disrupted convergent migration of the PCV and the head kidney in sox32-deficient embryos was rescued in a highly coordinated fashion through the restoration of endodermal cells. Moreover, grafted endodermal cells abutted the host PCV endothelium in the transplantation assay. Interestingly, the severely-disrupted head kidney convergence in the sox32-deficient embryo was suppressed by both the cloche mutation and the knockdown of endothelial genes, indicating that an interaction between the endoderm and the PCV restricts the migration of the head kidney. Furthermore, knockdown of either vegfC or its receptor vegfr3 suppressed the head kidney convergence defect in endodermless embryos and perturbed the head kidney-PCV association in wild-type embryos. Our findings thus underscore a role for PCV and VegfC in patterning the head kidney prior to organ assembly and function.

Arterial and venous vessels are required for modulating developmental relocalization and laterality of the interrenal tissue in zebrafish.

During zebrafish embryogenesis, the endothelium signals to emergent bilateral interrenal primordia to converge toward the midline, yet the merged interrenal tissue has been found to be situated lateral to the midline. We show in this study that bilateral interrenal tissue clusters fused at the central midline, before relocating laterally to be juxtaposed between the dorsal aorta and the posterior cardinal vein. In ets1b morphants where the midtrunk vasculature failed to assemble, various degrees of interrenal fusion defects were displayed, and the interrenal laterality was lost. As either arterial or venous endothelium was specifically reduced, the interrenal tissue was defective in its relocalization and laterality, yet remained closely associated with the malformed vasculature. Our results showed evidence to support that assembly of the axial artery and vein, and its resulting vascular topology at the midtrunk, is required for patterning relocalization and laterality of the interrenal tissue after the initial medial fusion.