A social network analysis model approach to understand tuberculosis transmission in remote rural Madagascar.

BACKGROUND: Quality surveillance data used to build tuberculosis (TB) transmission models are frequently unavailable and may overlook community intrinsic dynamics that impact TB transmission. Social network analysis (SNA) generates data on hyperlocal social-demographic structures that contribute to disease transmission. METHODS: We collected social contact data in five villages and built SNA-informed village-specific stochastic TB transmission models in remote Madagascar. A name-generator approach was used to elicit individual contact networks. Recruitment included confirmed TB patients, followed by snowball sampling of named contacts. Egocentric network data were aggregated into village-level networks. Network- and individual-level characteristics determining contact formation and structure were identified by fitting an exponential random graph model (ERGM), which formed the basis of the contact structure and model dynamics. Models were calibrated and used to evaluate WHO-recommended interventions and community resiliency to foreign TB introduction. RESULTS: Inter- and intra-village SNA showed variable degrees of interconnectivity, with transitivity (individual clustering) values of 0.16, 0.29, and 0.43. Active case finding and treatment yielded 67%-79% reduction in active TB disease prevalence and a 75% reduction in TB mortality in all village networks. Following hypothetical TB elimination and without specific interventions, networks A and B showed resilience to both active and latent TB reintroduction, while Network C, the village network with the highest transitivity, lacked resiliency to reintroduction and generated a TB prevalence of 2% and a TB mortality rate of 7.3% after introduction of one new contagious infection post hypothetical elimination. CONCLUSION: In remote Madagascar, SNA-informed models suggest that WHO-recommended interventions reduce TB disease (active TB) prevalence and mortality while TB infection (latent TB) burden remains high. Communities' resiliency to TB introduction decreases as their interconnectivity increases. "Top down" population level TB models would most likely miss this difference between small communities. SNA bridges large-scale population-based and hyper focused community-level TB modeling.

Trends in the severity of opioid use disorder during pregnancy over time.

OBJECTIVE: Characterize severity of opioid use disorder during pregnancy over time. STUDY DESIGN: A retrospective chart review of pregnant women presenting to MetroHealth's Mother and Child Dependency program from 2002-2019 was performed. Severity of opioid use disorder was assessed by multinomial multivariable logistic regression of five discrete measures. Term birth rates and MAT use were analyzed using univariate regression. RESULTS: 606 women were included in this study. Duration of use, age at first use, polysubstance use, and route of administration did not significantly change over time. Significantly more women reported high use (>1 g daily) over time compared to low use (<0.5 g daily) (RRR = 1.21, p < 0.01). Buprenorphine use increased compared to methadone use (RRR = 1.54, p < 0.001). Rate of full-term delivery increased (RRR = 1.14, p < 0.001). CONCLUSIONS: Severity of opioid use disorder during pregnancy did not change over time. An increase in term births and preference for buprenorphine were observed.

Latent tuberculosis infection prevalence in rural Madagascar.

BACKGROUND: Understanding latent Mycobacterium tuberculosis infection (LTBI) prevalence is crucial for the design of TB control strategies. There are no data on LTBI in rural Madagascar. METHODS: Tuberculin skin tests were performed in 98 adults aged >15 y in five rural villages in the Ifanadiana district, Madagascar. RESULTS: Of adults, 78.6% were positive for LTBI, ranging between 28.6% and 95.0% among villages. The majority (65.3%) showed an induration reaction of >15 mm. CONCLUSIONS: LTBI prevalence is high in rural Madagascar. Long-term TB control strategies including LTBI testing and treatment must account for high and heterogeneous prevalence in remote, underdeveloped areas.

Adeno-Associated Virus Mediated Gene Delivery: Implications for Scalable in vitro and in vivo Cardiac Optogenetic Models.

Adeno-associated viruses (AAVs) provide advantages in long-term, cardiac-specific gene expression. However, AAV serotype specificity data is lacking in experimental models relevant to cardiac electrophysiology and cardiac optogenetics. We aimed to identify the optimal AAV serotype (1, 6, or 9) in pursuit of scalable rodent and human models using genetic modifications in cardiac electrophysiology and optogenetics, in particular, as well as to elucidate the mechanism of virus uptake. In vitro syncytia of primary neonatal rat ventricular cardiomyocytes (NRVMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were infected with AAVs 1, 6, and 9 containing the transgene for eGFP or channelrhodopsin-2 (ChR2) fused to mCherry. In vivo adult rats were intravenously injected with AAV1 and 9 containing ChR2-mCherry. Transgene expression profiles of rat and human cells in vitro revealed that AAV1 and 6 significantly outperformed AAV9. In contrast, systemic delivery of AAV9 in adult rat hearts yielded significantly higher levels of ChR2-mCherry expression and optogenetic responsiveness. We tracked the mechanism of virus uptake to purported receptor-mediators for AAV1/6 (cell surface sialic acid) and AAV9 (37/67 kDa laminin receptor, LamR). In vitro desialylation of NRVMs and hiPSC-CMs with neuraminidase (NM) significantly decreased AAV1,6-mediated gene expression, but interestingly, desialylation of hiPSC-CMs increased AAV9-mediated expression. In fact, only very high viral doses of AAV9-ChR2-mCherry, combined with NM treatment, yielded consistent optogenetic responsiveness in hiPSC-CMs. Differences between the in vitro and in vivo performance of AAV9 could be correlated to robust LamR expression in the intact heart (neonatal rat hearts as well as adult human and rat hearts), but no expression in vitro in cultured cells (primary rat cells and hiPS-CMs). The dynamic nature of LamR expression and its dependence on environmental factors was further corroborated in intact adult human ventricular tissue. The combined transgene expression and cell surface receptor data may explain the preferential efficiency of AAV1/6 in vitro and AAV9 in vivo for cardiac delivery and mechanistic knowledge of their action can help guide cardiac optogenetic efforts. More broadly, these findings are relevant to future efforts in gene therapy for cardiac electrophysiology abnormalities in vivo as well as for genetic modifications of cardiomyocytes by viral means in vitro applications such as disease modeling or high-throughput drug testing.