Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

A case series of post-partum haemorrhage managed using Ellavi uterine balloon tamponade in a rural regional hospital.

Uterine balloon tamponade (UBT) should be attempted once emergency measures have been applied and medical treatment for post-partum haemorrhage (PPH) resulting from an atonic uterus has failed. Sinapi Biomedical (Pty) Ltd developed the Ellavi UBT, a free-flow pressure-controlled UBT unit. The device is affordable for use in lesser-resourced countries. A case series of Ellavi UBT used by medical officers in a rural regional hospital without specialist supervision was conducted. This case series was conducted in St Elizabeth's Hospital in Lusikisiki, South Africa. The hospital serves as the regional hospital for the Ingquza Hill Subdistrict in the Eastern Cape Province. The Nelson Mandela Academic Hospital (NMAH) in Mthatha is the tertiary referral hospital. Workshops were conducted on the use of Ellavi UBT, and devices were made freely available to the hospital. The case series included 10 patients. Six patients delivered by caesarean section, and four had normal vertex deliveries. All patients had additional oxytocin infusions, and eight patients received misoprostol. Following the insertion and inflation of the Ellavi UBT, the PPH stopped in seven patients, was much reduced in one patient and reduced in one patient. In one case, the Ellavi UBT had no effect on the bleeding. All 10 patients were referred to the NMAH. All patients in the case series had good outcomes. The insertion of the Ellavi UBT and subsequent referral proved to be feasible in a rural regional hospital. All patients included in the case series arrived at the referral hospital and had a good outcome.

Gamifying Parenting Education Using an App Developed for Pacific and Other New Zealand Families (Play Kindly): Qualitative Study.

BACKGROUND: Play Kindly is a gamified animated app designed to address common behavioral problems in childhood. The interface is designed to appeal to Pacific people, a population group with a higher risk of developing clinically significant behavioral problems than most other ethnic groups in New Zealand. OBJECTIVE: The aim of this study is to explore the opinions of parents and professionals about the acceptability, usability, and content of Play Kindly. METHODS: We used qualitative and Pacific and Maori research methodologies. A total of five focus groups with 45 parents and 12 individual interviews with professionals were conducted. The five focus groups consisted of 2 pan-Pacific groups, 1 Maori group, 1 open group, and 1 group of young Pacific adults or prospective parents. The professionals were from a range of disciplines, and the majority had expertise in early childhood, parenting interventions, or research in this field. RESULTS: Play Kindly appealed to both parents and professionals. Participants related to the scenarios, which were created in collaboration with a playwright and animator. Although most participants liked the Pacific feel, there was some disagreement about how culturally specific the app should be. A range of issues with usability and gamification techniques were highlighted, likely attributed to the low budget and lack of initial co-design with parents as well as professionals with specific expertise in parenting. A number of parents and professionals felt that the parenting strategies were overly simplified and did not take into account the context in which the behavior occurred. Professionals suggested narrowing the focus of the app to deliver two important parenting messages: playing with your child and positively reinforcing desired behaviors. CONCLUSIONS: Play Kindly is the first culturally adapted parenting app of its kind designed for Pacific parents and other New Zealanders with children 2-5 years of age. This app has potential in Pacific communities where there are limited culturally specific parenting resources. The results of this study will guide improvements of the app prior to testing it in an open trial.

Intrapartum human immunodeficiency virus transmission rate in a central hospital in the Western Cape province after universal antiretroviral therapy roll-out.

The national human immunodeficiency virus (HIV) mother-to-child transmission rate at 6-10 weeks post-partum was 0.9% in 2016. There is a paucity of data about the intrapartum transmission rate after lifelong antiretroviral therapy was implemented in 2015. We assessed all pregnant women living with HIV who delivered at Tygerberg Hospital in 2017. Positive polymerase chain reactions (PCRs) at birth indicated an in utero transmission rate of 0.8%. One infant with a negative PCR at birth tested positive at 6-10 weeks. The intrapartum transmission rate was low (0.08%). About 25% of infants were lost to follow-up after birth.

Price dispersion of generic medications.

Generic pharmaceuticals should have very little price dispersion. Economics' Law of One Price suggests that identical goods, in the absence of trade frictions and under conditions of free competition and price flexibility, should sell for the same price, and the FDA ensures that generics are identical. In this study, we examine whether generic pharmaceuticals indeed have the low price dispersion that theory predicts, and if not, whether the dispersion seen for pharmaceuticals used to treat neuropsychiatric conditions is substantially higher than that of other drugs. Such a difference may offer an explanation for the price dispersion seen: namely, a strategy that takes advantage of buyers' cognitive constraints and impaired ability to comparison shop. We thus assembled a list of generic pharmaceuticals and their prices using www.GoodRx.com, based on a convenience sample of the 5 most popular drugs for 10 common medical conditions listed there. Three neuropsychiatric diagnoses were used: Alzheimer's disease, depression and schizophrenia. Seven other diagnoses served as controls: asthma; diabetes mellitus-type II; high cholesterol; hypertension; osteoarthritis; osteoporosis; and urinary tract infection. For each drug, we identified the highest and lowest prices and calculated the mean, median and coefficient of variation (CV). We further calculated the ratios of the highest price to the median price and of the highest to lowest price. We found that the mean price CV was 43%. For neuropsychiatric drugs and controls, it was 61% and 35%, respectively. The mean high-to-median ratio was3.7 for neuropsychiatric drugs and 1.9 for controls. The mean high-to-low ratio was 5.9 for neuropsychiatric drugs and 2.8 for controls. In short, generic medications have high price dispersion, despite public availability of prices. Although our study did not examine why this price dispersion is present, the especially large high-to-low price ratio for neuropsychiatric medications suggests a strategy that exploits vulnerable patients.

A blueprint to establish a four-bed obstetric critical care unit in the labor ward of a central hospital.

Patients at risk of organ dysfunction or with established organ dysfunction should be referred to central or tertiary-level hospitals. However, even in central hospitals, intensive care unit (ICU) beds are often unavailable, which may contribute to maternal deaths. One pragmatic solution is to establish obstetric critical care units (OCCUs) in the labor wards of central hospitals; however, specific guidance on how to do this is limited. In addition, globally applicable standards of care are lacking, with uncertainty regarding who should lead obstetric critical care. In this article the specific OCCU infrastructure, equipment and human resources required to establish such units in central hospitals in low- and middle-income countries are described in sufficient detail for easy replication. Admission and discharge guidelines and operational recommendations that include quality indicators are also provided.

Delphi consensus statement on intrapartum fetal monitoring in low-resource settings.

OBJECTIVE: To determine acceptable and achievable strategies of intrapartum fetal monitoring in busy low-resource settings. METHODS: Three rounds of online Delphi surveys were conducted between January 1 and October 31, 2017. International experts with experience in low-resource settings scored the importance of intrapartum fetal monitoring methods. RESULTS: 71 experts completed all three rounds (28 midwives, 43 obstetricians). Consensus was reached on (1) need for an admission test, (2) handheld Doppler for intrapartum fetal monitoring, (3) intermittent auscultation (IA) every 30 minutes for low-risk pregnancies during the first stage of labor and after every contraction for high-risk pregnancies in the second stage, (4) contraction monitoring hourly for low-risk pregnancies in the first stage, and (5) adjunctive tests. Consensus was not reached on frequency of IA or contraction monitoring for high-risk women in the first stage or low-risk women in the second stage of labor. CONCLUSION: There is a gap between international recommendations and what is physically possible in many labor wards in low-resource settings. Research on how to effectively implement the consensus on fetal assessment at admission and use of handheld Doppler during labor and delivery is crucial to support staff in achieving the best possible care in low-resource settings.

Esomeprazole to treat women with preterm preeclampsia: a randomized placebo controlled trial.

BACKGROUND: Preterm preeclampsia has a high rate of fetal death or disability. There is no treatment to slow the disease, except delivery. Preclinical studies have identified proton pump inhibitors as a possible treatment. OBJECTIVE: The purpose of this study was to examine whether esomeprazole could prolong pregnancy in women who have received a diagnosis of preterm preeclampsia. STUDY DESIGN: We performed a double-blind, randomized controlled trial at Tygerberg Hospital in South Africa. Women with preterm preeclampsia (gestational age 26 weeks+0 days to 31 weeks+6 days) were assigned randomly to 40-mg daily esomeprazole or placebo. The primary outcome was a prolongation of gestation of 5 days. Secondary outcomes were maternal and neonatal outcomes. We compared circulating markers of endothelial dysfunction that was associated with preeclampsia and performed pharmacokinetic studies. RESULTS: Between January 2016 and April 2017, we recruited 120 participants. One participant was excluded because of incorrect randomization, which left 59 participants in the esomeprazole and 60 participants in the placebo group. Median gestational age at enrolment was 29+4 weeks gestation. There were no between-group differences in median time from randomization to delivery: 11.4 days (interquartile range, 3.6-19.7 days) in the esomeprazole group and 8.3 days (interquartile range, 3.8-19.6 days) in the placebo group (3 days longer in the esomeprazole arm; 95% confidence interval, -2.9-8.8; P=.31). There were no placental abruptions in the esomeprazole group and 6 (10%) in the placebo group (P=.01, P=.14 adjusted). There were no differences in other maternal or neonatal outcomes or markers of endothelial dysfunction. Esomeprazole and its metabolites were detected in maternal blood among those treated with esomeprazole, but only trace amounts in the umbilical cord blood. CONCLUSION: Daily esomeprazole (40 mg) did not prolong gestation in pregnancies with preterm preeclampsia or decrease circulating soluble fms-like tyrosine kinase 1 concentrations. Higher levels in the maternal circulation may be needed for clinical effect.

Calmodulin Regulated Spectrin Associated Protein 1 mRNA is Directly Regulated by miR-126 in Primary Human Osteoblasts.

Vascularization is essential for bone development, fracture healing, and bone tissue engineering. We have previously described that coculture of primary human osteoblasts (hOBs) and human umbilical vein endothelial cells (HUVECs) improves differentiation of both cell types. Investigating the role of microRNAs (miRNAs) in this system, we found that miR-126 is highly upregulated in hOBs following coculturing with HUVECs. In this study we performed miR-126 gain-of-function and loss-of-function experiments in hOBs followed by microarray analysis in order to identify targets of miR-126. The transcript cluster IDs were sieved by applying cut-off criteria and by selecting transcripts which were upregulated following miR-126 downregulation and vice versa. The calmodulin regulated spectrin associated protein 1 (CAMSAP1) mRNA was confirmed to be differentially regulated by miR-126. Using the luciferase reporter assay it was demonstrated that CAMSAP1 is directly targeted by miR-126. In this study, we show that miR-126 and CAMSAP1 directly interact in hOBs. This finding has potential implications for tissue engineering applications. J. Cell. Biochem. 118: 1756-1763, 2017. © 2016 Wiley Periodicals, Inc.

Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.

BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).

Acceptability and feasibility of mHealth and community-based directly observed antiretroviral therapy to prevent mother-to-child HIV transmission in South African pregnant women under Option B+: an exploratory study.

OBJECTIVE: To examine the acceptability and feasibility of mobile health (mHealth)/short message service (SMS) and community-based directly observed antiretroviral therapy (cDOT) as interventions to improve antiretroviral therapy (ART) adherence for preventing mother-to-child human immunodeficiency virus (HIV) transmission (PMTCT). DESIGN AND METHODS: A mixed-method approach was used. Two qualitative focus group discussions with HIV-infected pregnant women (n=20) examined the acceptability and feasibility of two ART adherence interventions for PMTCT: 1) SMS text messaging and 2) patient-nominated cDOT supporters. Additionally, 109 HIV-infected, pregnant South African women (18-30 years old) receiving PMTCT services under single-tablet antiretroviral therapy regimen during pregnancy and breastfeeding and continuing for life ("Option B+") were interviewed about mobile phone access, SMS use, and potential treatment supporters. SETTING: A community primary care clinic in Cape Town, South Africa. PARTICIPANTS: HIV-infected pregnant women. MAIN OUTCOMES: Acceptability and feasibility of mHealth and cDOT interventions. RESULTS: Among the 109 women interviewed, individual mobile phone access and SMS use were high (>90%), and 88.1% of women were interested in receiving SMS ART adherence support messages such as reminders, motivation, and medication updates. Nearly all women (95%) identified at least one person close to them to whom they had disclosed their HIV status and would nominate as a cDOT supporter. Focus group discussions revealed that cDOT supporters and adherence text messages were valued, but some concerns regarding supporter time availability and risk of unintended HIV status disclosure were expressed. CONCLUSION: mHealth and/or cDOT supporter as interventions to improve ART adherence are feasible in this setting. However, safe HIV status disclosure to treatment supporters and confidentiality of text messaging content about HIV and ART were deemed crucial.

The Potato Nucleotide-binding Leucine-rich Repeat (NLR) Immune Receptor Rx1 Is a Pathogen-dependent DNA-deforming Protein.

Plant nucleotide-binding leucine-rich repeat (NLR) proteins enable cells to respond to pathogen attack. Several NLRs act in the nucleus; however, conserved nuclear targets that support their role in immunity are unknown. Previously, we noted a structural homology between the nucleotide-binding domain of NLRs and DNA replication origin-binding Cdc6/Orc1 proteins. Here we show that the NB-ARC (nucleotide-binding, Apaf-1, R-proteins, and CED-4) domain of the Rx1 NLR of potato binds nucleic acids. Rx1 induces ATP-dependent bending and melting of DNA in vitro, dependent upon a functional P-loop. In situ full-length Rx1 binds nuclear DNA following activation by its cognate pathogen-derived effector protein, the coat protein of potato virus X. In line with its obligatory nucleocytoplasmic distribution, DNA binding was only observed when Rx1 was allowed to freely translocate between both compartments and was activated in the cytoplasm. Immune activation induced by an unrelated NLR-effector pair did not trigger an Rx1-DNA interaction. DNA binding is therefore not merely a consequence of immune activation. These data establish a role for DNA distortion in Rx1 immune signaling and define DNA as a molecular target of an activated NLR.

Initial feasibility and acceptability of a comprehensive intervention for methamphetamine-using pregnant women in South Africa.

The purpose of the present study was to determine the feasibility, acceptability, and initial efficacy of a women-focused intervention addressing methamphetamine use and HIV sexual risk among pregnant women in Cape Town, South Africa. A two-group randomized pilot study was conducted, comparing a women-focused intervention for methamphetamine use and related sexual risk behaviors to a psychoeducational condition. Participants were pregnant women who used methamphetamine regularly, had unprotected sex in the prior month, and were HIV-negative. Primary maternal outcomes were methamphetamine use in the past 30 days, frequency of unprotected sexual acts in the past 30 days, and number of antenatal obstetrical appointments attended. Primary neonatal outcomes were length of hospital stay, birth weight, and gestational age at delivery. Of the 57 women initially potentially eligible, only 4 declined to participate. Of the 36 women who were eligible and enrolled, 92% completed all four intervention sessions. Women in both conditions significantly reduced their methamphetamine use and number of unprotected sex acts. Therefore, delivering comprehensive interventions to address methamphetamine use and HIV risk behaviors among methamphetamine-using pregnant women is feasible in South Africa. Further testing of these interventions is needed to address methamphetamine use in this vulnerable population.

Prevalence of HIV among women entering labor who accepted or declined voluntary counseling and testing.

OBJECTIVE: To assess whether there was a difference in HIV seroprevalence between eligible women who declined and those who agreed to participate in a study of voluntary counseling and testing among women entering labor with unknown HIV status in South Africa. METHODS: Anonymous cord blood specimens were collected-as dried blood spots-from all women approached for participation in a cluster-randomized trial. No patient identifiers were included on the cord blood specimens. The dried blood spots were analyzed for HIV antibody via enzyme immunoassay and western blotting. RESULTS: Of 7238 women screened for study participation, 1041 (14.4%) had undocumented HIV status; of these women, 542 were eligible for inclusion and 343 enrolled. Based on 513 evaluable samples, the overall seroprevalence was 13.3% (95% confidence interval [CI], 10.4-16.5), which was similar to the 13.1% (95% CI, 9.7-17.2) seroprevalence among the 343 enrolled women. CONCLUSION: Seroprevalence among eligible women was similar to that among enrolled women, which indicates that study participation did not select for a group with an HIV seroprevalence substantially different from that among women who declined to enroll.