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Recruitment strategies used to enrol healthy volunteers in the first pneumococcal human infection study in Africa: Lessons from Blantyre, Malawi.
Get PDFBackgroundHuman Infection Studies (HIS) also known as Controlled Human Infection Models (CHIM) are a relatively new concept in African countries to clinicians, scientists, and communities alike. We have introduced HIS/CHIM studies to Malawi during the last four years by developing an experimental human pneumococcal carriage model. This CHIM was used to test the efficacy of a licensed 13-valent Pneumococcal Conjugate Vaccine (PCV13) against experimental nasal pneumococcal carriage. Traditional and digital recruitment strategies into this novel trial were explored.ObjectivesTo describe various methods of recruitment in this first CHIM study in Malawi.MethodsThe clinical trial within the context of which these data were recorded was registered with the Pan African Clinical Trials Registry (REF: PACTR202008503507113) on 03 August 2020. The project was conducted at the Malawi Liverpool Wellcome Programme (MLW) in Blantyre, Malawi between April 2021, and September 2022. Source populations were college students and community members within Blantyre. Recruitment strategies included sharing study information in written or visual form, community sensitization meetings, snowball contacts (word of mouth from previous volunteers), branded clothing and participating in radio and television programs.Results299 volunteers attended screening clinic, of whom 278 were recruited. Sixty-six recruited volunteers (23.7%) were college students and 212 (76.3%) were from the community. Snowball word-of-mouth contacting was the most successful recruitment strategy, with 201 (72.3%) participants recruited using this method. 195 (70.1%) were men of whom 149 (76.4%) joined the study through snowballing.</p
Cascade testing effectively identifies undiagnosed Sickle Cell Disease in The Gambia: a quality improvement project
Get PDFObjective Sickle cell disease (SCD) has a high mortality during childhood in many low and middle-income countries (LMICs). Early diagnosis improves outcomes but newborn screening is not well established in LMICs. Cascade testing may be feasible and effective in identifying undiagnosed SCD and carriers of haemoglobin (Hb) S.Design Quality improvement project using existing clinic and laboratory resources.Setting The Haematology Clinic at the Edward Francis Small Teaching Hospital, Banjul, The Gambia.Participants Families of index cases with SCD.Methods Hb phenotype was determined in full or half-siblings of a SCD index case over a 6-week period using the HemoTypeSC test and confirmed by Hb electrophoresis.Main outcome measure Identifying undiagnosed SCD.Results Of 102 families invited, 31 (30%) attended during the study period and 53 siblings were tested. Except for one indeterminate test, HemoType SC agreed with Hb electrophoresis. Ten (19%; 95% CI 10 to 32) siblings were diagnosed with HbSS, 25 (47%; 34 to 60) as carriers (HbAS) and 18 (34%; 23 to 48) were unaffected (HbAA). Some symptoms and signs of SCD occurred significantly more frequently in HbSS than in HbAA and HbAS, but none was sufficiently common to help in identifying children for testing.Conclusions Cascade testing was effective in identifying undiagnosed HbSS as well as children carrying the sickle cell gene. In routine care settings in LMICs, cascade testing facilitated by point-of-care tests may be feasible and affordable in increasing the detection of SCD and improving outcomes through earlier diagnosis.</p
A Y chromosome-linked genome editor for efficient population suppression in the malaria vector Anopheles gambiae
Get PDFGenetic control – the deliberate introduction of genetic traits to control a pest or vector population – offers a powerful tool to augment conventional mosquito control tools that have been successful in reducing malaria burden but that are compromised by a range of operational challenges. Self-sustaining genetic control strategies have shown great potential in laboratory settings, but hesitancy due to their invasive and persistent nature may delay their implementation. Here, instead, we describe a self-limiting strategy, designed to have geographically and temporally restricted effect, based on a Y chromosome-linked genome editor (YLE). The YLE comprises a CRISPR-Cas9 construct that is always inherited by males yet generates an autosomal dominant mutation that is transmitted to over 90% of the offspring and results in female-specific sterility. To our knowledge, our system represents a pioneering approach in the engineering of the Y chromosome to generate a genetic control strain for mosquitoes. Mathematical modelling shows that this YLE technology is up to seven times more efficient for population suppression than optimal versions of other self-limiting strategies, such as the widely used Sterile Insect Technique or the Release of Insects carrying a Dominant Lethal gene.</p
Clinical and psychosocial context of HIV perinatally infected young mothers in Harare, Zimbabwe: A longitudinal mixed-methods study
Get PDFBackgroundThe lives of adolescents and young people living with HIV (LHIV) are dominated by complex psychological and social stressors. These may be more pronounced among those perinatally infected. This longitudinal mixed-methods study describes the clinical and psychosocial challenges faced by HIV perinatally infected young mothers in Harare, Zimbabwe to inform tailored support.MethodsHIV perinatally infected young mothers were recruited in 2013 and followed up in 2019. In 2013, they completed a structured interview, clinical examination, psychological screening and had viral load and drug resistance testing. A subset completed in-depth interviews (n = 10). In 2019, they were re-interviewed and had viral load testing. Data were analyzed using STATA 15.0. and thematic analysis.ResultsNineteen mothers aged 17–24 years were recruited in 2013. Eleven (57.9%) were successfully recontacted in 2019; 3 had died, 2 had relocated and 3 were untraceable. In 2013, all 19 mothers were taking antiretroviral therapy (median duration 8 years, range 2–11 years) and median CD4 count was 524 (IQR 272). In 2013, eight mothers (42.1%) had virological failure (≥1000 copies/ml) (3 of whom subsequently died) and 7 (36.8%) had evidence of drug resistance. In 2019, the proportion with virological failure was 2/11 (18.1%). Six of 11 (54.5%) had switched to second line therapy. In 2013, 64.3% were at risk of common mental disorder and this risk was higher at follow-up (72.7%). Qualitative data highlighted three pertinent themes: HIV status disclosure, adherence experiences and, social and emotional support.ConclusionsFindings from this study underscore the significant clinical, social and psychological challenges faced by perinatally infected young mothers. The high rates of virological failure, drug resistant mutations, mental health issues and mortality observed in this population indicate the need for tailored and comprehensive health and support services to assist these young mothers.</p
Effect of a spatial repellent on malaria incidence in an area of western Kenya characterised by high malaria transmission, insecticide resistance, and universal coverage of insecticide treated nets (part of the AEGIS Consortium): a cluster-randomised, controlled trial.
Get PDFBackgroundSpatial repellent products are used for prevention of insect bites, and a body of evidence exists on spatial repellent entomological efficacy. A new option for vector control, spatial repellent products are designed to release active ingredient into the air for disruption of human–vector contact thereby reducing human exposure to mosquito-borne pathogens. Clinical trials have shown spatial repellent epidemiological efficacy against Aedes-borne viruses but inconclusive outcomes against malaria. We aimed to show and quantify the protective efficacy of spatial repellents in reducing malaria infection incidence in Busia County, Kenya.MethodsA prospective, cluster-randomised, controlled trial in Busia County, western Kenya was done to quantify the efficacy of a transfluthrin-based spatial repellent against human malaria infection following mass distribution of insecticide treated nets. Investigators, staff, and study participants were masked to cluster allocation. Infection incidence was measured by microscopy in children aged 6 months to younger than 10 years during a 4-month baseline (March–July 2021) and 24-month follow-up period with intervention (October, 2021–October, 2023). From 58 clusters (29 intervention, 29 placebo), a total of 1526 and 1546 participants from two consecutive, 12-month cohorts were assessed for first-time malaria infection (primary endpoint) by survival analysis at interim and end-of-trial timepoints, respectively. This trial is registered with ClinicalTrials.gov, NCT04766879 and is complete.FindingsThe outcome of the primary endpoint indicated that spatial repellents significantly reduced the hazard rate of first-time malaria infection by 33·4% (95% CI 11·1–50·1; p=0·0058) and the hazard rate of overall new malaria infections by 32·1% (15·9–45·2; p=0·0004). No reported adverse events and serious adverse events were deemed to be associated with the spatial repellent.InterpretationOur trial provides the first evidence of a demonstrative spatial repellent protective efficacy in reducing risk of malaria infection in an African setting characterised by high malaria transmission, pyrethroid resistant malaria vectors, and high coverage of insecticide treated nets. Results support spatial repellent products as a beneficial component of malaria prevention.</p
Zika virus modulates human fibroblasts to enhance transmission success in a controlled lab-setting
Get PDFTransmission of Zika virus (ZIKV) has been reported in 92 countries and the geographical spread of invasive virus-borne vectors has increased in recent years. Arboviruses naturally survive between vertebrate hosts and arthropod vectors. Transmission success requires the mosquito to feed on viraemic hosts. There is little specific understanding of factors that may promote ZIKV transmission-success. Here we show that mosquito host-seeking behaviour is impacted by viral infection of the vertebrae host and may be essential for the effective transmission of arboviruses like ZIKV. Human skin fibroblasts produce a variety of metabolites, and we show that ZIKV immediately alters gene/protein expression patterns in infected-dermal fibroblasts, altering their metabolism to increase the release of mosquito-attractive volatile organic compounds (VOCs), which improves its transmission success. We demonstrate that at the invasion stage, ZIKV differentially altered the emission of VOCs by significantly increasing or decreasing their amounts, while at the transmission stage of the virus, all VOCs are significantly increased. The findings are complemented by an extensive meta-proteome analysis. Overall, we demonstrate a multifaceted role of virus-host interaction and shed light on how arboviruses may influence the behaviour of their vectors as an evolved means of improving transmission-success.</p
The utility of dynamic chest radiography in patients with asthma, COPD, COVID-19 and ILD: A pilot study
Get PDFIntroduction and ObjectivesAssessment of breathlessness requires a combination of imaging and lung function testing. Dynamic digital radiography (DDR) of the thorax is an imaging technique that allows physiological and anatomical information to be gathered at the time of chest X-ray and has the potential to significantly streamline diagnostic pathways. The aims of this study were to investigate the acceptability of DDR to patients and explore the correlation between DDR-derived measurements with lung volumes measured using full pulmonary function tests (PFT).Materials and MethodsWe conducted a single-centre, prospective, pilot study of patients with confirmed asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) or post-COVID-19 infection. Participants underwent DDR and paired PFT between March 2021 and August 2022. Dynamic digital radiography acceptability was measured using a 10-cm visual analogue scale (VAS). Point estimates and exact confidence intervals were used to evaluate participant preference. Digital dynamic radiography would be considered acceptable if the lower bound of the 95% confidence interval (exact) is greater than 50%. Pearson correlation (r) was used to explore associations between DDR measurements and PFT parameters.Results40 participants (asthma, n = 11; COPD, n = 9; ILD, n = 11; post-COVID, n = 9) had DDR with adequate image acquisition and PFT. Mean age of participants was 63.38 years (standard deviation 14.89) and 63% were male (25/40). The lower 95% confidence interval threshold for VAS acceptability was 92% for all groups combined and considered acceptable. The projected lung area at end inspiration (PLAinsp) closely correlated with total lung capacity across all disease cohorts (r = 0.80, p < 0.001) and projected lung area at end expiration (PLAexp) was strongly correlated with residual volume in airways disease (COPD: r = 0.87, p = 0.003; asthma: r = 0.85, p = 0.002).ConclusionDynamic digital radiography is an acceptable investigation for respiratory patients. DDR-derived measurements correlate with lung volumes obtained from PFTs. Larger studies are required to validate DDR as a possible method to identify and monitor air trapping in airways disease, allowing early detection and assessment of treatment effectiveness.</p
The impact of insecticide decay on the rate of insecticide resistance evolution for monotherapies and mixtures
Get PDFBackgroundThe problem of insecticide decay following their deployment in public health applications is frequently highlighted as an issue for sustained disease control. There are additional concerns that it also increases selection for insecticide resistance. Despite these concerns insecticide decay is largely absent from models evaluating insecticide resistance management strategies.MethodologyThe impact of insecticide decay is investigated using a model which assumes a polygenic basis of insecticide resistance. Single generation evaluations are conducted that cover the insecticide efficacy and insecticide resistance space for insecticides when deployed as monotherapies or mixtures to mechanistically investigate how insecticide decay impacts selection for resistance. The outcome is the between generation change in bioassay survival to the insecticides. The monotherapy sequence and mixture strategies were compared in multi-generation simulations incorporating insecticide decay, with the outcome being the difference in strategy lifespan.ResultsThe results demonstrate that as insecticides decay, they can apply a much greater selection pressure than that imposed by newly deployed, non-decayed insecticides; this applies to both monotherapies and mixtures. For mixtures, selection for resistance is highest when both insecticides have reduced decayed efficacies; this also occurs if reduced dosages are deliberately used in mixtures. Insecticide decay was found to reduce the benefit of mixtures compared to sequential monotherapies, especially when reduced-dose mixtures are used.ConclusionsInsecticide decay is often highlighted as an important consideration for mixtures and these results indicate its absence in previous modelling studies may be over-inflating the performance of full-dose mixtures. In summary: as insecticides decay, they can impose increasing selection pressures for resistance with reduced ability to control the target insect populations. The optimal frequency with which decaying insecticides should be replenished is an important policy consideration.</p
Description of four cases of male genital schistosomiasis (MGS) in children and adolescents, with a scoping review.
Get PDFWe present four cases of male genital schistosomiasis (MGS) within children and adolescents opportunistically encountered as part of a wider screening programme for imported schistosomiasis in Germany and community outreach screening in Mali. Such genital manifestations in young children and adolescents are often overlooked but can include hydrocele, hypogonadism, varicocele, cutaneous granulomata on the penis and scrotum, echogenic spots in the prostate and the epididymis, alongside testicular masses. Though these cases appear sporadic, from our scoping literature review, they draw fresh attention on MGS in young children and highlight wider confusion with other congenital, neoplastic and infectious disease. These might include an insufficient closure of the tunica vaginalis,malignancies or lymphatic filariasis. Frequently hematuria is not present. One typical sign indicating MGS in adults, i.e. hematospermia is not present before puberty. Another reason of missing MGS cases may be that screening with scrotal or transabdominal ultrasonography are not easily accepted unless the reason for it is not extensively explained beforehand and that transabdominal ultrasonography is less sensitive for revealing prostatic lesions thantransrectal ultrasonography.</p