Frontier Science & Technology Research Foundation

BackgroundThere are no published data on clofazimine pharmacokinetics during pregnancy, and safety data are limited. We present data from pregnant and postpartum women receiving clofazimine for treatment of rifampicin-resistant tuberculosis (RR-TB).MethodsIMPAACT P1026s was an observational study to assess the pharmacokinetics of tuberculosis and/or antiretroviral drugs during pregnancy. Between 2017 and 2019, pregnant women receiving ≥2 second-line antituberculosis drugs in routine care were enrolled in the second or third trimester and had intensive pharmacokinetic sampling at least once during pregnancy, and 2–8 weeks postpartum. Pharmacokinetic parameters were estimated using noncompartmental methods and compared between the antepartum and postpartum periods using geometric mean ratios (GMR) with 90% confidence intervals (CIs) and the Wilcoxon signed rank test for paired data.ResultsEleven pregnant women from South Africa, 7 (64%) with HIV, were receiving clofazimine (100 mg daily) at enrollment, of which 82% received clofazimine for more than 8 weeks prior to pharmacokinetic evaluation. Nine (82%) women continued treatment postpartum. Peak plasma concentrations and area-under-the-concentration–time-curve over 12 hours were comparable to historical clofazimine pharmacokinetic data in nonpregnant women with RR-TB but were approximately 30% higher in the third trimester of pregnancy compared to the postpartum period. Eight women and 8 infants experienced at least one severe adverse event while on study but direct relatedness to clofazimine was considered unlikely.ConclusionsOverall, antepartum and postpartum clofazimine exposures were comparable to those reported in nonpregnant women with RR-TB. Exposures were lower than expected in the postpartum period, particularly compared with the third trimester of pregnancy.

Background:Diagnosing tuberculosis in children remains challenging due to the paucibacillary nature of the disease, non-specific symptoms, and difficulty collecting samples. New tests are urgently needed. We evaluated the diagnostic accuracy of FujiLAM version 1 urine test in children under 5 years with presumptive tuberculosis in Uganda.Methods:This was a cross-sectional evaluation nested in the NOD-pedFEND diagnostic study. Children under 5 years with signs or symptoms of tuberculosis were recruited from three hospitals in Uganda. All participants underwent comprehensive baseline investigations, including culture and Xpert MTB/RIF Ultra on reference samples and chest X-ray. Culture and Xpert MTB/RIF Ultra results were used to define a microbiological reference standard. FujiLAM version 1 testing was performed on fresh urine at the baseline visit.Results:Seventy-nine children were included in the study. Fifteen participants (19%) were classified as having microbiologically confirmed TB, 44 (56%) as unconfirmed TB, thirteen (16%) as unlikely TB, and seven participants (9%) were unclassifiable. Only one participant (with unlikely TB) had a positive FujiLAM test. Culture and Xpert MTB/RIF Ultra on reference samples were negative in this child, indicating poor diagnostic accuracy with a sensitivity of 0% (95% CI: 0 – 21.8) of FujiLAM version 1 against the microbiological reference standard.Conclusion:The poor diagnostic accuracy of FujiLAM version 1 in children under five years of age makes it unsuitable as a diagnostic test in this age group. Further evaluation with the optimized version 2 of this test is needed.

This study provides the end-of-study results on the durability of seroprotection response in a trial comparing 2- and 3-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG) vs 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant.

To investigate whether hormone receptor-positive, human epidermal growth factor receptor 2-low (HR+HER2-low) versus HR+HER2-zero early breast cancers have distinct genomic and clinical characteristics. This study included HR+, HER2-negative early breast cancers from patients enrolled in the phase III, randomized BIG 1-98 and SOFT clinical trials that had undergone tumor genomic sequencing. Tumors were classified HR+HER2-low if they had a centrally reviewed HER2 immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization and HR+HER2-zero if they had an HER2 IHC score of 0. A total of 1,795 tumors were evaluable for this study (BIG 1-98 n = 520, SOFT n = 1,275). The frequency of HER2-low tumors was 37% and 21% in the postmenopausal BIG 1-98 and premenopausal SOFT cohorts, respectively. There were no significant differences in clinicopathologic variables between HER2-low and HER2-zero groups which was consistent across both trials. There was no significant difference in risk of distant recurrence for patients with HER2-low tumors versus HER2-zero tumors (5-year % distant recurrence-free 94.0% v 92.8%, P = .61, in BIG 1-98; 89.4% v 92.7%, P = .31, in SOFT, respectively). Somatic genomic profiles were similar with the exception of MAP3K1 mutations which were more frequent in HER2-zero tumors (BIG 1-98 19% v 5%, SOFT 11% v 6%). Both ERBB2 copy number and ERBB2 gene expression abundance were significantly higher in HER2-low tumors compared with HER2-zero tumors; however, the absolute difference was small. Correlation between ERBB2 copy number values and gene expression was modest (r = 0.17). In two large clinical trials with centrally reviewed HER2 IHC, our findings do not support HER2-low breast cancer as a distinct clinical or biologic entity among HR+HER2- early breast cancers. Absolute differences in median ERBB2 copy number levels or gene expression are small and of unclear biologic relevance.

Tenofovir alafenamide (TAF)-based antiretroviral therapy (ART) regimens have been associated with adverse changes in lipid and glucose profiles compared with tenofovir disoproxil fumarate (TDF)-based ART, but data in pregnancy are limited. We evaluated metabolic markers in pregnant women with human immunodeficiency virus (HIV) after starting TAF- versus TDF-based ART. We analyzed data within the IMPAACT 2010/VESTED trial, which demonstrated better pregnancy outcomes in pregnant women randomized to initiate TAF/Emtricitabine/Dolutegravir (TAF/FTC + DTG; n = 217) or TDF/FTC + DTG (n = 215). We measured non-fasting plasma concentrations of glucose, total-cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), lipoprotein (a), and triglycerides from samples collected 8 weeks after enrollment. We employed linear regression models to estimate by-arm mean differences. In total, 219 participants enrolled in the DTG arms in Zimbabwe and Uganda: 109 in the TAF/FTC + DTG and 110 in the TDF/FTC + DTG arms. At study entry, mean gestational age was 22.6 weeks, median HIV-1 RNA was 711 copies/mL, and mean age was 25.8 years. By 8 weeks, mean total cholesterol was 12 mg/dL higher in women randomized to TAF/ FTC + DTG versus TDF/FTC + DTG (95% confidence interval [CI]: 3.8, 21.1). Pregnant women in the TAF/FTC + DTG arm had higher mean LDL-C (7.1 mg/dL, 95% CI: .2, 14.0), triglycerides (12.3 mg/dL, 95% CI: 1.8, 22.7), lipoprotein (a) (7.3 mg/dL, 95% CI: 1.1, 13.6), and lower mean HDL-C (2.8 mg/dL, 95% CI: .1, 5.6) compared to the TDF/FTC + DTG arm. Pregnant women randomized to start TAF/FTC + DTG had higher lipids than those randomized to TDF/FTC + DTG within 8 weeks of ART initiation. However, lipid levels were within normal reference ranges.

To evaluate whether infectious illness symptoms (IIS) are associated with generalized anxiety symptoms during the COVID-19 pandemic in sexual/gender (SGM) minority young adults assigned male at birth (AMAB). Four hundred eighteen participants (median age = 25; range, 20-40) were recruited through RADAR, an ongoing Chicago-based cohort study of SGM-AMAB between September 2020 and February 2021. Participants completed online surveys. A subset (n = 145) provided dried blood spot samples to assess SARS-CoV-2 serostatus. One hundred twenty participants (28.7%) had GAD-7 scores of 10 or greater, which indicates generalized anxiety symptoms that may be clinically significant. In a binomial logistic regression model adjusting age, gender identity, race/ethnicity, substance use, and HIV status, the authors found that having a higher IIS count since March 1, 2020, was associated with greater odds of having a GAD-7 score of 10 or greater (OR = 1.14; 95% CI, 1.04, 1.25; P = 0.007). This effect was more pronounced in a binomial logistic regression model adjusting for the same covariates but using current IIS count as the independent variable (OR = 1.39; 95% CI, 1.13, 1.74; P = 0.002). Among SGM-AMAB young adults, those who experienced ISS reported higher scores on the GAD-7, a widely used and validated screening measure for generalized anxiety symptoms. These findings highlight the importance of screening for anxiety disorders when patients present with IIS in clinical settings and psychobehavioral health follow-ups when indicated.

Considering the time spent in early childhood development centre vs. at home – parents/caregivers play bigger role in optimizing children’s growth and development. Ironically, upon entering school, parents were as if “handing over the responsibility” to teachers – considered to be more knowledgeable. Additionally, interaction between teachers and parents was cold, insufficient to do problem solving together, moreover sharing about good parenting practice.This project has been implemented in 3 districts (Bogor, West Lombok, and East Lombok) in Indonesia, involving 120 teachers and 60 school leaders from rural/suburb areas. During the project period, more than 250 parenting sessions were held, with average attendance of 40 parents per session. Most teachers agreed that the project has been helpful in building their understanding of early childhood development, and skills in interacting with children and parents. Most parents admitted that the session was educational and fun. The distinctive features of this project are: First, focus on family instead of child/service. Most teachers’ training focused on curriculum and pedagogy, overlooking family/parenting. Secondly, the andragogy approach, using adult education principles, which includes active participation in discussions, games, and problem solving. This is unlike the conventional one-direction communication and lacking dialogue. Third, introduction of play as part of facilitation methods in parenting class, to help parents realize about fun-learning concept.