Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain ...infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ≥1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (P
= 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A
and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.
Hormonal contraception has been associated with a reduced risk of vaginal dysbiosis, which in turn has been associated with reduced prevalence of sexually transmitted infections (STIs), including ...HIV. Vaginal rings are used or developed as delivery systems for contraceptive hormones and antimicrobial drugs for STI and HIV prevention or treatment. We hypothesized that a contraceptive vaginal ring (CVR) containing oestrogen enhances a lactobacilli-dominated vaginal microbial community despite biomass accumulation on the CVR's surface.
We enrolled 120 women for 12 weeks in an open-label NuvaRing® study at Rinda Ubuzima, Kigali, Rwanda. Vaginal and ring microbiota were assessed at baseline and each ring removal visit by Gram stain Nugent scoring (vaginal only), quantitative PCR for Lactobacillus species, Gardnerella vaginalis and Atopobium vaginae, and fluorescent in situ hybridization to visualize cell-adherent bacteria. Ring biomass was measured by crystal violet staining.
Bacterial vaginosis (BV) prevalence was 48% at baseline. The mean Nugent score decreased significantly with ring use. The presence and mean log10 concentrations of Lactobacillus species in vaginal secretions increased significantly whereas those of G. vaginalis and presence of A. vaginae decreased significantly. Biomass accumulated on the CVRs with a species composition mirroring the vaginal microbiota. This ring biomass composition and optical density after crystal violet staining did not change significantly over time.
NuvaRing® promoted lactobacilli-dominated vaginal microbial communities in a population with high baseline BV prevalence despite the fact that biomass accumulated on the rings.
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Maternal disorders are the third leading cause of sepsis globally, accounting for 5.7 million (12%) cases in 2017. There are increasing concerns about the emergence of antimicrobial resistance (AMR) ...in bacteria commonly causing maternal sepsis. Our aim is to describe the protocol for a clinical and microbiology laboratory study to understand risk factors for and the bacterial etiology of maternal sepsis in a tertiary Obstetrics and Gynaecology Hospital. This case-control study aims to recruit 100 cases and 200 controls at Tu Du Hospital in Ho Chi Minh City, Vietnam, which had approximately 55,000 births in 2022. Women aged greater than or equal to 18 years and greater than or equal to 28 weeks gestation having a singleton birth will be eligible for inclusion as cases or controls, unless they have an uncomplicated localised or chronic infection, or an infection with SARS-CoV-2. Cases will include pregnant or recently pregnant women with sepsis recognised between the onset of labour and/or time of delivery/cessation of pregnancy for up to 42 days post-partum. Sepsis will be defined as suspected or confirmed infection with an obstetrically modified Sequential Organ Failure Assessment score of greater than or equal to 2, treatment with intravenous antimicrobials and requested cultures of any bodily fluid. Controls will be matched by age, location, parity, mode of delivery and gestational age. Primary and secondary outcomes are risk factors associated with the development of maternal sepsis, the frequency of adverse outcomes due to maternal sepsis, bacterial etiology and AMR profiles of cases and controls. This study will improve understanding of the epidemiology and clinical implications of maternal sepsis management including the presence of AMR in women giving birth in Vietnam. It will help us to determine whether women in this setting are receiving optimal care and to identify opportunities for improvement.
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Adherence to combination antiretroviral therapy (cART) is vital for HIV-infected adolescents for survival and quality of life. However, this age group faces many challenges to remain adherent. We ...used multiple data sources (role-play, focus group discussions (FGD), and in-depth interviews (IDI)) to better understand adherence barriers for Rwandan adolescents. Forty-two HIV positive adolescents (ages 12-21) and a selection of their primary caregivers were interviewed. All were perinatally-infected and received (cART) for ≥ 12 months. Topics discussed during FGDs and IDIs included learning HIV status, disclosure and stigma, care and treatment issues, cART adherence barriers.
Median age was 17 years, 45% female, 45% orphaned, and 48% in boarding schools. We identified three overarching but inter-related themes that appeared to influence adherence. Stigma, perceived and experienced, and inadvertent disclosure of HIV status hampered adolescents from obtaining and taking their drugs, attending clinic visits, carrying their cARTs with them in public. The second major theme was the need for better support, in particular for adolescents with different living situations, (orphanages, foster-care, and boarding schools). Lack of privacy to keep and take medication came out as major barrier for adolescents living in congested households, as well the institutionalization of boarding schools where privacy is almost non-existent. The third important theme was the desire to be 'normal' and not be recognized as an HIV-infected individual, and to have a normal life not perturbed by taking a regimen of medications or being forced to disclose where others would treat them differently.
We propose better management of HIV-infected adolescents integrated into boarding school, orphanages, and foster care; training of school-faculty on how to support students and allow them privacy for taking their medications. To provide better care and support, HIV programs should stimulate caregivers of HIV-infected adolescents to join them for their clinic visits.
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Introduction of contraceptive vaginal rings (CVRs) could expand the contraceptive method mix reducing the unmet need for family planning in Rwanda, but data on acceptability of CVRs from low and ...middle-income countries are lacking.
This study explores acceptability of contraceptive vaginal ring (NuvaRing) use in Kigali, Rwanda using a mixed methods approach. We collected quantitative and qualitative data before, during and after conducting a clinical trial, using Case Report Forms, Interviewer Administered Questionnaires, In Depth Interviews and Focus Group Discussions. We analyzed the data using an existing theoretical framework including product attributes, relationship attributes and sexual encounter attributes as well as the contextual environment.
Our data showed that initial worries reduced over time with actual ring use and ring insertions and removals were described as easy. Most women did not feel the ring during daily activities, appreciated the lack of perceived negative side effects and the increased lubrication. Relationship attributes and sexual encounter attributes such as sexual comfort played a significant role in ring acceptability of the participants and their partners. The contextual environment including Rwandan cultural norms around sexuality positively influenced the acceptance of the NuvaRing. Overall satisfaction was high.
Acceptability of the Nuvaring was high among study participants and represents a promising option that could contribute to lowering the unmet need for family planning in Rwanda.
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Gestational Diabetes Mellitus (GDM) is common in South East Asia, occurring at relatively lean Body Mass Index (BMI). Outside pregnancy, cardiometabolic risks increase at lower BMI in Asian ...populations, justifying Asian-specific thresholds for overweight and obesity. We aimed to explore the effects of GDM and obesity on perinatal outcomes using a WHO expert consultation-recommended Asian-specific definition of obesity.
This is a secondary analysis of a prospective, hospital-based, cohort study in Ho Chi Minh City. Participants were recruited from antenatal clinics between 19
-22
weeks gestation and followed until delivery. GDM screening occurred between 24 and 28 weeks using WHO criteria. Obesity was defined as BMI ≥ 27.5 kg/m
, based on weight and height at recruitment. We assessed associations between GDM (singly, and in combination with obesity) and perinatal outcomes. Participants were categorised into four groups: no GDM/non-obese (reference group), GDM/non-obese, no GDM/obese and GDM/obese. Outcomes included primary caesarean section, hypertensive disorders of pregnancy (HDP), large-for-gestational-age (LGA), birth weight, preterm birth, and composite adverse neonatal outcome. Logistic and linear regressions were performed with adjustment for differences in baseline characteristics.
Among 4,970 participants, 908 (18%) developed GDM. Compared to women without GDM, GDM increased risks for preterm birth (OR: 1.40, 95% CI: 1.09-1.78), higher birthweight (birthweight z-score 0.16 versus 0.09, p = 0.027), and LGA (OR 1.14, 0.89-1.46). GDM without obesity was associated with an increased risk of preterm birth (OR 1.35, 1.04-1.74). Obese women without GDM were more likely to deliver by caesarean section and have an LGA baby (1.80, 1.33-2.44 and 2.75, 1.88-4.03). The highest risks were observed amongst women with both GDM and obesity: caesarean Sect. (2.43, 1.49-3.96), LGA (3.36, 1.94-5.80) and preterm birth (2.42, 1.32-4.44).
GDM was associated with an increased risk of preterm birth and larger newborn size. Using an Asian-specific definition of obesity, we demonstrate obese women with GDM are at the highest risk of adverse outcomes. Using a BMI threshold in pregnancy of 27.5 kg/m
(between 19 and 22 weeks gestation) for Asian women can identify women who will benefit from intensified diabetes, nutritional, and obstetric care. This has relevance for obstetric service delivery within Asia, and other health systems providing pregnancy care for Asian expatriate women.
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Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with ...amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.
Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first 2 weeks - or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031.
Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (-0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference -0.005log10CFU/ml/day, 95% CI: -0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation.
High-dose tamoxifen does not increase the clearance rate of
from CSF. Novel, affordable therapies are needed.
The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.
Contraceptive vaginal rings could play a role in expanding the contraceptive method mix and in preparing communities for the introduction of HIV prevention and multipurpose rings.
We conducted an ...open label single-centre randomised clinical trial of intermittent versus continuous use of NuvaRing® in Kigali, Rwanda, in 2013-2014. We randomised 120 HIV-negative women 1:1 to intermittent use (three rings with a ring-free week in between rings) or continuous use (four rings without ring-free weeks). Women underwent an interview, counselling, and a speculum examination, and were tested for pregnancy, bacterial vaginosis (BV) by Nugent scoring, yeasts and trichomonads on wet mount, and sexually transmitted infections.
Only one woman withdrew early. Deliberate ring removals were rare, but spontaneous ring expulsions occurred during 14% of ring use periods. There were no incident pregnancies, serious adverse events, serious social harms, or early discontinuations for safety reasons. Systemic side effects were uncommon, and local side effects were not significantly differently distributed between groups except for lower abdominal pain (P = 0.013). The incidence of vaginal yeasts during ring use was high: 22% of intermittent users and 27% of continuous users had incident vaginal yeasts at one or multiple ring removal visits (P = 0.666), and symptomatic vaginal yeast cases were more common in the continuous than intermittent users (P = 0.031). In contrast, mean Nugent scores improved over time in both groups.
Intermittent and continuous NuvaRing® use were safe in Rwandan women and improved Nugent scores over time. However, attention should be paid to ring expulsions and to a potential increased risk of vaginal candidiasis.
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The informed consent process in clinical trials has been extensively studied to inform the development processes which protect research participants and encourage their autonomy. However, ensuring a ...meaningful informed consent process is still of great concern in many research settings due to its complexity in practice and interwined socio-cultural factors.
This study explored the practices and meaning of the informed consent process in two clinial trials conducted by Oxford University Clinical Research Unit in collaboration with the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
We used multiple data collection methods including direct observervations, in-depth interviews with study physicians and trial participants, review of informed consent documents from 2009 to 2018, and participant observation with patients' family members. We recruited seven physicians and twenty-five trial participants into the study, of whom five physicians and thirteen trial participants completed in-depth interviews, and we held twenty-two direct observation sessions.
We use the concept "fragmented understanding" to describe the nuances of understanding about the consent process and unpack underlying reasons for differing understandings.
Our findings show how practices of informed consent and different understanding of the trial information are shaped by trial participants' characteristics and the socio-cultural context in which the trials take place.
Direct acting antiviral treatment to cure hepatitis C virus (HCV) is becoming more accessible yet the experiences of those accessing care and treatment and the contexts under which care seeking takes ...place are largely unknown in low- and middle-income countries. These experiences are important for insight into the challenges people encounter and the support/structures they utilize. The study objective was to explore the experiences of care seeking and treatment for participants enrolled in a clinical trial in Ho Chi Minh City, Vietnam.
We used in-depth interviews, home visits, mobile interviews, at both the clinic and in the home as we explored how participants experienced health and illness within their social worlds over time.
We enrolled 20 participants, of whom 20 completed the first interview, 16 the second, and 18 completed the last interview. Findings explore four themes: (1) navigating uncertainty, (2) proactivity in the face of challenges, (3) living in fear with faith, and (4) dynamic support systems.
Understanding how participants envision and act upon their lived experiences can help to develop public health programmes that effectively address barriers and promote access to care and treatment for people with HCV in Vietnam.
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