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A hill tribe community advisory board in Northern Thailand: lessons learned one year on.
Northern Thailand and its neighbouring regions are home to several minority ethnic groups known as hill tribes, each with their own language and customs. Hill tribe communities live mostly in remote agricultural communities, face barriers in accessing health, and have a lower socio-economic status compared to the main Thai ethnic group. Due to their increased risk of infectious diseases, they are often participants in our research projects.To make sure our work is in line with the interests of hill tribe communities and respects their beliefs and customs, we set up a hill tribe community advisory board. We consult the members before, during, and after our projects are carried out. This manuscript recounts how we set up the community advisory board and our reflections following one year of activities. Our experience strongly supports engaging with community advisory boards when working with minority ethnic groups in lower and middle-income settings. In particular, we found that over time, as researchers and members familiarise with one another and their respective environments, exchanges gain meaning and benefits increase, stressing the advantages of long-term collaborations over short or project-based ones.
Comparison of WHO versus national COVID-19 therapeutic guidelines across the world: not exactly a perfect match
BackgroundThe COVID-19 pandemic affected all WHO member states. We compared and contrasted the COVID-19 treatment guidelines of each member state with the WHO COVID-19 therapeutic guidelines.MethodsMinistries of Health or accessed National Infectious Disease websites and other relevant bodies and experts were contacted to obtain national guidelines (NGs) for COVID-19 treatment. NGs were included only if they delineated specific pharmacological treatments for COVID-19, which were stratified by disease severity. We conducted a retrospective review using the adapted Reporting Checklist for Public Versions of Guidelines (RIGHT-PVG) survey checklist and a derived comparative metric based on the WHO guidelines was performed.ResultsCOVID-19 therapeutics NGs could be obtained from 109 of the 194 WHO member states. There was considerable variation in guidelines and in disease severity stratifications. Therapeutic recommendations in many NGs differed substantially from the WHO guidelines. Overall in late 2022, 93% of NGs were recommending at least one treatment which had proved to be ineffective in large randomised trials, and was not recommended by WHO. Corticosteroids were not recommended in severe disease in nearly 10% of NGs despite overwhelming evidence of their benefit. NGs from countries with low-resource settings showed the greatest divergence when stratified by gross domestic product per year, Human Development Index and the Global Health Security Index.DiscussionOur study is limited to NGs that were readily accessible, and it does not reflect the availability of recommended medicines in the field. Three years after the start of the SARS-CoV-2 pandemic, available COVID-19 NGs vary substantially in their therapeutic recommendations, often differ from the WHO guidelines, and commonly recommend ineffective, unaffordable or unavailable medicines.
Greater preservation of SARS-CoV-2 neutralising antibody responses following the ChAdOx1-S (AZD1222) vaccine compared with mRNA vaccines in haematopoietic cell transplant recipients.
Whilst SARS-CoV-2 mRNA vaccines generate high neutralising antibodies (nAb) in most individuals, haematopoietic stem cell transplant (HSCT) and chimeric antigen receptor T-cell (CAR-T) recipients respond poorly. HSCT/CAR-T treatment ablates existing immune memory, with recipients requiring revaccination analogous to being vaccine naive. An optimal revaccination strategy for this cohort has not been defined. Factors predicting immunogenicity following three ancestral SARS-CoV-2 vaccines were assessed in 198 HSCT/CAR-T recipients and 96 healthcare workers (HCWs) recruited to multicentre studies. Only 25% of HSCT/CAR-T recipients generated nAbs following one dose, with titres 167-fold and 7-fold lower than that in HCWs after the first and second doses, respectively. Lower post-second dose nAb titres were associated with older age, rituximab use, and previous HSCT. ChAdOx1-S recipients were more likely to generate nAbs compared with mRNA vaccines, with titres comparable to HCWs. In contrast, nAbs were significantly lower in HSCT/CAR-T recipients than HCWs after mRNA vaccination. The poor first-dose immunogenicity in HSCT/CAR-T recipients suggests a minimum licensed dosing interval could limit the period of vulnerability following HSCT/CAR-T. The relative preservation of nAbs with ChAdOx1-S vaccination highlights the importance of evaluating alternative platforms to mRNA vaccination within this highly vulnerable clinical cohort.
Outbreaks of COVID-19 in a tuberculosis treatment sanatorium on the Thailand-Myanmar border: a retrospective cohort analysis.
BackgroundTuberculosis (TB) is a chronic condition, with overlapping symptoms to those of coronavirus disease 2019 (COVID-19). There has been inconsistent evidence on whether TB is a predisposing factor for developing severe COVID-19. The aim of this report is to explore whether TB influences the severity of COVID-19.MethodsCOVID-19 cases at two TB sanatoria on the Thailand-Myanmar border were reviewed. Demographic, clinical and laboratory data including TB treatment and co-morbidities, were analyzed. Characteristics and COVID-19 clinical outcomes were compared between two groups of patients: TB and those without TB (the caretakers and the medical personnel). Multivariable ordered logistic regression was conducted to compare the risk of severe COVID-19 between the two groups.ResultsBetween September 2021 and March 2022, 161 COVID-19 cases were diagnosed. Over half of the COVID-19 patients were infected with TB (n= 104, 64.6%), and the rest were not (n=57, 35.4%). The median (interquartile range) age was 48 (33.5-57.0) and 27 (23-33) years in the TB and in the non-TB COVID-19 patients, respectively. Before COVID-19 infection, 67.1% (106/158) of patients had received at least one dose of COVID-19 vaccine. The median cycle threshold value at diagnosis was not different between TB (18.5, IQR 16.1-32.3) and non-TB patients (18.8, 15.1-30.0). Fever, gastrointestinal symptoms and ageusia were more common in non-TB patients. Six patients (3.8%, 6/156) all from the TB group became severe of which five (3.2%, 5/156) required oxygen therapy. One TB patient died (1/104, 0.96%) of lung cancer. After adjustment for potential confounders, the final clinical severity was not different between the two groups (adjusted odds ratio 1.40, 95% confidence interval 0.16-12.39).ConclusionsTB was not associated with severe outcomes in the two TB sanatoria. The high uptake of COVID-19 vaccination and active screening could have impacted on disease progression and prevented unfavorable outcomes.
Informed consent and risk communication challenges in antimicrobial clinical trials: a scoping review.
OBJECTIVES: Randomised trials for the management of drug-resistant infections are challenging to conduct as target patient populations often lack decision-making capacity, and enrolment windows are typically short. Improving informed consent and risk communication in these trials is especially crucial for protecting patient interests and maximising trial efficiency. This study aimed to understand challenges in risk communication and informed consent in antimicrobial clinical trials. DESIGN: Scoping review. DATA SOURCES: Searches were conducted in Embase, Medline, CINAHL and Web of Science Core for peer-reviewed English articles that were published from January 2000 to April 2023. ELIGIBILITY CRITERIA: Included articles were empirical studies or expert opinions that sought experts', patients' or representatives' opinions on informed consent in the context of clinical trials involving antibiotic/anti-infective agents. DATA EXTRACTION AND SYNTHESIS: Abstract screening, full-text review, data extraction and evidence rating were performed by two independent reviewers. Extracted data were summarised and reported qualitatively based on common themes. A total of 2330 records were retrieved, and 29 articles were included in the review. RESULTS: Half of the articles involving medical experts and one-third involving patients and representatives reported that full comprehension by patients and representatives was challenging or not achievable. Healthcare providers and consent takers were crucial for the quality of informed consent. The level of trust consent givers placed on healthcare providers had a critical influence on the consent rate. Emotional distress was pervasive among patients/representatives. CONCLUSION: The findings indicate that strengthening consent takers' communication skills in providing emotional support to patients and their representatives may improve informed consent. More research is needed to understand informed consent in low-income and middle-income and non-English-speaking countries.
Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis
Background The 8-aminoquinolines, primaquine and tafenoquine, are the only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. Methods and findings We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences. Conclusions For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity.
Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.
BackgroundHydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use.Methods and findingsHealthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507.InterpretationIn this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs.Trial registrationClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.