bluuebunny/crossref_metadata_2025 huggingface dataset:
OC 8469 REVIEWING INVESTIGATIONAL PRODUCT’S QUALITY ASSURANCE DOCUMENTATION IN MAJOR CLINICAL TRIAL REGISTRIES FOR POST-MARKETING CLINICAL TRIAL STUDIES
Authors: Doua Joachim , Dominicus Hanneke
Published: April 2019

Background

The proven worrisome quality of medicines marketed in developing countries also affects clinical trials (CTs) as they may be used as Investigational Medicinal Products (IMPs). By regulation, CT sponsors should assure IMP’s quality and describe their quality measures in CT protocols that should be registered in a CT Registry (CTR). To check compliance with this regulation, we reviewed major CTRs to assess the availabilities of data fields on IMP quality for post-marketing CTs.

Methods

Two reviewers independently assessed English versions of CTRs of International Committee of Medical Journal Editors (ICJME) and WHO platforms in July 2017. Each CTR was checked for availability of data fields on: brand name; manufacturer’s name; regulatory approval status; approving regulator; manufacturer’s compliance with Good Manufacturing Practices (cGMP); and quality testing (IMP appearance, impurities, microbial contamination, dosing). In case of discrepancy, consensus was sought.

Results

Of 19 CTRs identified, 8 and 6 belonged to WHO and ICMJE, respectively, and 5 were equally part of both platforms. All CTRs had an ‘intervention’ data field to capture data on IMPs and IMP comparators. Unlike all others, the Canadian CTR used ‘drug name’ rather than ‘intervention’. Only the EU CTR had data fields for ‘manufacturer’s name’, ‘product approval status’, and ‘approving authority’. None of the CTRs had data fields on ‘cGMP’ or ‘quality testing’.

Conclusion

None of the CTRs of ICMJE and ICTRP has adequate data fields to establish that the source of post-marketing IMPs is of assured quality. This is astonishing given the extensive requirements in WHO and ICMJE guidelines. The gap of quality assurance fields should be bridged by adding them to CTRs. Specifically, IMP quality testing should be conducted before, during, and after clinical trial completion. Until adoption of these measures, EU-CTR should be favoured for registration of CTs conducted in developing countries.
OC 8491 PREPVACC: A PHASE III, MAMS ADAPTIVE PROPHYLACTIC HIV VACCINE TRIAL WITH A SECOND RANDOMISATION TO COMPARE F/TAF WITH TDF/FTC PREP
Authors: Joseph Sarah , Kaleebu Pontiano , Ruzagira Eugene , Hansen Christian Holm , Seeley Janet , Basajja Vincent , Weber Jonathan , Fox Julie , Kingsley Cherry , Aboud Said , Lyamuya Eligius , Maganga Lucas , Pamba Doreen , Ramjee Gita , Yssel Justin , Viegas Edna , Jani Ilesh , Priddy Fran , Nilsson Charlotta , Kroidl Arne , Pantaleo Giuseppe , Robb Merlin , Crook Angela , Dunne David , Mccormack Sheena
Published: April 2019

Background

There remains an urgent need for a prophylactic HIV vaccine to control generalised epidemics. PrEP has demonstrated effectiveness of 86% and is recommended by WHO; uptake is generally high, but retention is disappointing in some settings. The EDCTP2 project PrEPVacc will assess the efficacy of two combination prophylactic vaccine regimens (DNA, MVA and Env protein/adjuvant) each compared to placebo and the proportion of infections averted by F/TAF in comparison to TDF/FTC. A Registration Cohort, recruiting HIV negative volunteers at risk of HIV will precede the trial.

Methods

The PrEPVacc partnership agreed that 70% vaccine efficacy had public health relevance. The trial usesnstagesoftware for multi-arm, multi-stage designs (MAMS) and the averted infections ratio (AIR) methodology with participants randomised (i) 1:1:1 to active product or placebo (ii) 1:1 to TDF/FTC : F/TAF until week 26 (presumed peak immunogenicity). Access to PrEP in the Registration Cohort and after week 26 will be standard of care. HIV seroconversions occurring between weeks 0–26 will inform the PrEP analysis, incorporating HIV incidence amongst those who do not take up PrEP locally in the Registration Cohort. Seroconversions after week 26 will inform vaccine analyses.

Results

Up to 556 participants per group affords 92% power to detect vaccine efficacy of 70% at the final analysis, assuming incidence of 4/100-person years and 10% loss with 81% and 97% power to conclude that F/TAF can avert half or more of the infections prevented by TDF/FTC if effectiveness of TDF/FTC is 70% and 80%, respectively.

Conclusion

PrEPVacc adopts a pragmatic approach to uncertainties around HIV incidence in settings where PrEP is increasingly available. This innovative adaptive trial design uses validated software to determine vaccine efficacy and a novel methodology to evaluate a new PrEP agent, overcoming the challenge of demonstrating non-inferiority when adherence to TDF/FTC is high and the number of outcome events very low.
OC 8521 PRELIMINARY REPORT ON SAFETY OF CO-ADMINISTERED HUMAN HOOKWORM VACCINE CANDIDATESNA-APR-1 (M74)/ALHYDROGEL®ANDNA-GST-1/ALHYDROGEL®IN GABONESE CHILDREN
Authors: Zinsou Jeannot Fréjus , Honpkehedji Josiane , Agobe Jean Claude Dejon , Adegbite Bayodé R , Ronald Edoa Jean , Van Leeuwen Remko , Diemert David , Elena Botazzi Maria , Kremsner Peter G , Yazdanbakhsh Maria , Hotez Peter , P Grobusch Martin , Akim Adegnika Ayola , De Vries Sophie
Published: April 2019

Background

Human hookworm infection is a major public health issue in tropical low and middle-income countries with severe consequences. To date, improvement of water supply, sanitation, and hygiene is the major contributor to disease control, and additional control tools are needed. Here, we assess a phase I trial of a new hookworm vaccine candidateNa-APR-1 (M74)/Alhydrogel andNa-GST-1/Alhydrogel in Gabonese school-age children.

Methods

A double-blind, randomised, controlled, dose-escalation phase I clinical trial that aims to evaluate safety, reactogenicity and immunogenicity ofNa-APR-1 (M74)/Alhydrogel co-administered withNa-GST-1/Alhydrogel hookworm vaccines in children aged 6 to 10 years living in hookworm-endemic area of Lambaréné, compared to the hepatitis B vaccine (ENGERIX-B). Children received three doses of assigned vaccines, delivered intramuscularly (deltoid) on Days 0, 56, and 112 or 180. Safety is measured from Day 0 through Day 14 by the occurrence of solicited injection site and systemic reactogenicity events. Clinical laboratory evaluations were performed approximately 14 days after each immunisation. Unsolicited adverse events were collected from Day 0 through approximately 1 month after each vaccination.

Results

A total of 135 children were screened, and 60, aged 6 to 10 years old, were randomised into 3 groups and received 10 µg, 30 µg or 100 µg ofNa-APR-1 (M74)/Alhydrogel andNa-GST-1 Alhydrogel, respectively, compared to ENGERIX-B. At baseline, the mean age of the study population was 7.4 years and the sex ratio 1.3 (male: female). From Day 0 up to Day 14 after vaccination, the main solicited adverse events were pain and swelling at injection sites with 135 (26 of grade 2 and 1 of grade 3) and 9 events, respectively. Regarding systemic adverse events, 3 occurrences of grade 1 headache were recorded. Immunogenicity analyses are underway.

Conclusion

The preliminary results confirm that co-administration of the two hookworm vaccine candidates is safe and well-tolerated in Gabonese children.
OC 8535 AN OVERVIEW OF RESEARCH ETHICS COMMITTEES OPERATING IN LUSOPHONE AFRICAN COUNTRIES
Authors: Rosário Oliveira Martins Maria , Schwalbach João , Sevene Esperança , Martins Antonieta , Candida Branco Fernandes Ema , Ines Araujo Isabel , Pereira De Melo Helena , Bernardo Tome Da Silva Amilcar , Catumbela Emanuel , Sacarlal Jahit , Seixas Jorge , Chimpolo Maria , Nala Rassul , Tazi Nimi Maria , Rodrigues Amabelia
Published: April 2019

Background

In 2017, a North-South partnership was created, to strengthen Bioethics Committees in African Lusophone African countries (LAC), by joining the forces of National and Institutional Research Ethics Committees (REC) and Universities in Angola, Cape Verde, Mozambique and Portugal. This study is part of an EDCTP2-funded project and aims to describe key RECs operating in LAC, its establishment dates and further characteristics.

Methods

Document analysis and interviews with REC representatives of five LAC were conducted in April 2018. Legal documents were obtained through official national sources.

Results

We identified four National Ethics Committees, created between 2000 and 2008 by ministerial or governmental decree; only S. Tomé e Principe does not have an established REC. In Angola, the National REC was created in 2000, and since 2007, seven Institutional Committees were implemented at faculty level. National REC in Cape Verde and Guinee-Bissau (CNES) are unique and were founded in 2007 and 2009 respectively. In Mozambique, National REC (CNBS) dates to 2002, and since 2011, 8 Institutional Committees were formed; they functioned as a network under the umbrella of CNBS. Most National REC have representatives from health professional associations, lawyers, civil society and religious communities and have regular meetings (usually monthly). The number of members ranges between 6 (CNES) and 13 (CNBS). In 2007, around 200 protocols were reviewed by CNBS and 29 by CNES. Most of the National REC members attended training activities in bioethics but at different levels.

Conclusion

Few publications described REC operating in LAC; this study fills this gap by reporting historical and functional characteristics of RECs in five Lusophone African countries. Additional tools based on quantitative and qualitative approaches are being developed to assess more in-depth REC operational characteristics and to identify their needs in order to target training and capacity building initiatives underlying our project.
OC 8552 EFFICACY OF THE CHAD63-MVC ME-TRAP VECTORED MALARIA VACCINE CANDIDATE IN 5–17 MONTHS OLD INFANTS AND CHILDREN IN BURKINA FASO
Authors: Tiono Alfred B , Nebie Issa , Anagnostou Nicholas , Coulibaly Sam A , Lawrie Alison , Bougouma Edith C , Ouedraogo Alphonse , Yaro Jean Baptist , Barry Aïssata , Roberts Rachel , Ouedraogo Amidou , Ewer Katie J , Viebig Nicola K , Diarra Amidou , Leroy Odile , Bejon Philip , Hill Adrian , Sirima Sodiomon B
Published: April 2019

Background

Heterologous prime-boost immunisation with chimpanzee adenovirus 63 (ChAd63) and Modified Vaccinia Virus Ankara (MVA)-vectored vaccines is a strategy previously shown to provide substantial protective efficacy againstP. falciparuminfection in a UK adult phase IIa sporozoite challenge study, and in a trial in Kenyan adults.

Methods

We conducted the first phase IIb clinical trial assessing the safety, immunogenicity and efficacy of ChAd63-MVA ME-TRAP in 700 healthy malaria exposed children aged 5–17 months in a highly malaria-endemic area of Burkina Faso.

Participants were randomly assigned to received either ChAd63 ME-TRAP followed eight weeks later by MVA ME-TRAP or 2 doses of rabies vaccine. Monitoring of solicited adverse events was performed for seven days after each vaccination. Unsolicited adverse events were recorded until one month post each vaccination. Serious adverse events and malaria episodes were monitored throughout the study duration. Blood samples were collected at predefined timepoints to assess vaccine immunogenicity.

Results

ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses [median 326 SFU/106 PBMC (95% CI 290–387)]. However, non-significant low efficacy was observed against clinical malaria during the follow-up period, with efficacy against primary endpoint estimated by proportional analysis being 10.7% (95% CI: −44.2 to 44.7%) at sixth months post MVA ME-TRAP and 3.1% (95% CI −15.0 to 18.3; p=0.72) by cox regression.

Conclusion

This study has confirmed ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in children and infants with prior exposure to malaria. No significant protective efficacy was observed in this highly endemic context.
OC 8568 A RANDOMISED CONTROLLED TRIAL OF ORAL IRON FOR TREATMENT OF POST-MALARIA ANAEMIA IN MALAWIAN CHILDREN COMPARING IMMEDIATE VERSUS DELAYED ADMINISTRATION
Authors: Phiri Kamija , Longwe Herbert , White Sarah , Esan Michael , Kuile Feiko Ter , Brabin Bernard
Published: April 2019

Background

Although universal provision of iron supplements to children is recommended by the WHO, it is not yet clear whether the administration of the supplements poses a risk in children in malaria-endemic areas. We investigate the effects of iron supplementation in children with post-malaria anaemia and haematological response with immediate and delayed (2weeks) iron administration.

Methods

A randomised double-blind clinical trial was conducted in Zomba and Blantyre between 2009 and 2013. All children aged 4 to 36 months with uncomplicated malaria and with iron deficiency were enrolled into the study. Malaria treatment was administered to all the children and they were randomly assigned to 3 groups as follows: immediate iron administration, delayed iron administration, or placebo. The children were followed up for 10 weeks, with their haematological recovery indices and adverse effects being monitored at 2, 4, 8 and 10 weeks. The primary outcome of the study was the proportion of children without anaemia (defined as Hb >10.9 g/dl) at the end of the iron supplementation period.

Results

A total of 538 participants were randomised to immediate iron administration (n=183), delayed iron administration (n=183), or placebo (n=172). The incidence rate ratio (IRR) of being non-anaemic at the end of the follow-up period (10 weeks post-malaria infection) was 1.51 (95% CI 1.17–1.94, p<0.001) among immediate group versus the placebo group. There was no significant difference between delayed and placebo group (IRR 1.18, 95% CI 0.91–1.55). Secondary analysis of risk of malaria and bacterial infection and iron markers at the end of the intervention period is underway and shall be presented at the conference.

Conclusion

The results so far support the administration of iron immediately after completing antimalarial treatment in anaemic children, however safety results will be needed to be reviewed before conclusive recommendations.
OC 8582 A PHASE IA/B STUDY TO ASSESS SAFETY AND IMMUNOGENICITY OF PLACENTAL MALARIA VACCINE CANDIDATE: PRELIMINARY RESULTS OF THE PRIMALVAC TRIAL
Authors: Konate Amadou , Richert Laura , Chêne Arnaud , Semblat Jean-Philippe , Roguet Gwenaelle , Benhamouda Nadine , Bahuaud Mathilde , Havelange Nicolas , Kuppers Alexis , Campion Cécilia , Boilet Valérie , Gueguen Sonia , Loulergue Pierre , Leroy Odile , Batteux Frederic , Tartour Eric , Viebig Nicola K , Thiebaut Rodolphe , Sirima Sodiomon B , Launay Odile , Gamain Benoit
Published: April 2019

Background

Adhesion ofP. falciparum-infected erythrocytes (PEs) to placental chondroitin-4-sulfate (CSA) has been linked to severe placental malaria (PM) outcomes. Evidence strongly supports the VAR2CSA variant surface antigen mediating PEs CSA-binding phenotype as the leading candidate for a PM vaccine. This study was conducted to assess the safety and immunogenicity of 3 different dosages (20 µg, 50 µg and 100 µg) of the recombinant VAR2CSA protein (PRIMVAC), formulated with Alhydrogel or GLA-SE administered at days 0, 28 and 56.

Methods

A randomised double-blind phase Ia/Ib dose-escalation vaccine trial was conducted in healthy adult women. Within 4 sequential cohorts, volunteers were randomised to 2 arms (PRIMVAC adjuvanted with Alhydrogel or GLA-SE) in the first phase conducted in France and then to 3 arms (PRIMVAC with Alhydrogel or GLA-SE or placebo) in Burkina Faso. Enrolled volunteers were observed for at least 1 hour following each vaccination then seen at 1 day and 7 days later for safety evaluations. Serious adverse events (SAE) were recorded throughout the study duration. Routine clinical laboratory safety analyses were performed prior to first injection and at each subsequent visit.

Results

A total of 68 subjects were recruited in the four study cohorts. No SAE was reported in any of the cohort A volunteers and enrolment in cohort B was started. A Data Safety Monitoring Board (DSMB) reviewed the safety data for cohorts A (20 µg) and B (50 µg) before the trial was initiated in Burkina Faso. The DSMB also reviewed the safety data in Burkina to authorise the progression from the cohort C (50 µg) to cohort D (100 µg). The last vaccination of the last subject occurred in September 2017.

Conclusion

This was the first placental malaria vaccine phase Ia/b clinical trial conducted in France and Burkina Faso. No serious adverse events have been recorded. Preliminary safety and immunogenicity results will be presented.
PO 8179 MEAN LEVELS OF ENDOPLASMIC RETICULUM STRESS CHAPERONE PROTEIN – BINDING IMMUNOGLOBULIN PROTEIN (BIP) DECREASES FOLLOWING SUCCESSFUL TB TREATMENT
Authors: Motaung Bongani , Loxton Andre G
Published: April 2019

Background

Mycobacterium tuberculosis(Mtb) infection is one of the leading causes of mortality worldwide. Even though treatment is readily available the emergence of drug resistance amongst Mtb strains highlights the need for new advances in the TB field such as host-directed therapies (HDT). Recent studies have highlighted the importance of BiP in cells, which can become a target in many diagnostic settings as it has been implicated in conditions including arthritis, cancer, bacterial infection and autoimmune diseases. In our studies, we are aiming to identify expression differences of BiP in different Mtb infection stages to help us understand the change of function in immune cells in relation to infection stress.

Method

BiP secretion levels were assessed in plasma samples using ELISA technique. This included participants at TB diagnosis (TBDx), TB treatment group (Week 1, Month 2 and Month 6) and healthy (unexposed) participants. BiP concentration results were analysed using GraphPad Prism 7.

Results

Secretion of BiP was comparable between newly diagnosed untreated TB cases and healthy unexposed controls, with levels obtained in healthy group (42.64 µg/ml) and in TBDx (40.88 µg/ml). Highest levels of plasma BiP during treated TB was observed by Week 1 (mean 68.57 µg/ml) and declined by Month 2 with 60.92 µg/ml and Month 6 with 51.40 µg/ml.

Conclusion

Detection of BiP in plasma samples indicated metabolic change in immune cells due to stress posed onto cells by Mtb burden. This is due to the amount of protein product required by the immune system to mitigate the spread of the pathogen. Even though not significant, we observed a decrease in the mean levels of BiP over the course of TB treatment which correlates with a reduction in the accumulation of unfolded polypeptides in the endoplasmatic reticulum. This observation requires further testing in larger prospective studies.
PO 8182 INVESTIGATING TREATMENT RESPONSE OF PATIENTS WITH CONFIRMED DRUG-RESISTANT TUBERCULOSIS IN AN HIV-1-ENDEMIC POPULATION IN WESTERN KENYA
Authors: Shiluli Clement , Ouma Collins , Khayumbi Jeremiah , Murithi Wilfred , Ochieng Albert , Musau Susan
Published: April 2019

Background

In 2015, 10.4 million people worldwide had tuberculosis (TB) and 1.4 million deaths occurred, 400 000 of whom were HIV-positive. Sub-Saharan Africa accounted for 81% of these cases. In western Kenya, current data on the distribution of rifampicin (RIF) and isoniazid (INH) mutations is not available. The association of gene mutations with HIVinfection and the treatment response of HIV-infected and -uninfected patients with TB are not known. This study determined the proportion of drug-resistantMycobacterium tuberculosisin sputum isolates and investigated the association of RIF and INH gene mutations with HIV status and monitored the treatment response of TB/HIV-co-infected patients.

Methods

The present study was longitudinal, and enrolment was done between 2012 and 2014 after the revision of the TB treatment regimen. Patients with confirmed drug-resistant TB were followed up for one year to establish the TB treatment response as confirmed by sputum smear microscopy.

Results

A total of 1381 new and 18 previously treated TB patients were enrolled. Sputum samples were cultured on Mycobacteria-growth indicator tubes; drug susceptibility tests and line probe assay were performed to identify drug resistance and specific mutations on the rpo B, kat G and inh Agenes. Discordant samples were sequenced. Conversion rate was calculated by finding the percentage of smear-negative and -positive patients at follow-up and initial visit, respectively. Regression analysis showed that RIF resistance was associated with HIV status (p=0.025). Mann-Whitney tests revealed that the conversion time of HIV-infected and -uninfected patients with TB drug mutations was comparable (p=0.180).

Conclusion

The study showed that INH mono-resistance was common. Detection of INH mono-resistance in TB-endemic areas should be scaled-up as well as TB contact investigation studies to increase early detection of resistant strains.
PO 8208 CYTOKINE PROFILES IN SUDANESE CHILDREN PRESENTED WITH SEVERE MALARIA, UNCOMPLICATED MALARIA COMPARED TO HEALTHY COMMUNITY CONTROLS ACCORDING TO WHO CRITERIA
Authors: Hamdan Hamdan , El-Misbah Muna , El-Awad Tasneem
Published: April 2019

Background

Immune system response toPlasmodium falciparum(P. falciparum) malaria infection outlines the disease course and outcome. This is attributed to variable production of cytokines that either promote (pro-inflammatory) or curtail (anti-inflammatory) the inflammatory process. Elucidating underlying immunological disease interactions may direct development of effective treatment and provide better understanding of the disease process.

Methods

A case control study was conducted in Mohamed Elamin Paediatrics Hospital (March- August 2016) in Omdurman in central Sudan, an area that is characterised by unstable malaria transmission. The study aims to investigate the role/interaction of cytokine profiles of gamma interferon (IFN-γ) and Interleukin-10 (IL-10) in children infected withP. falciparummalaria. Enzyme-linked immunosorbent assay was used to measure the concentrations of cytokines, IFN- γ and IL-10, in serum from Sudanese children. Thirty–five children with complicatedP. falciparummalaria were enrolled to the study; well-matched 35 uncomplicatedP. falciparummalaria and another 35 healthy children were controls. Informed written consent was obtained from the parents or guardian. Complete blood count, blood urea and random blood glucose were measured by using standard laboratory procedures.

Results

The concentrations of IFN-γ and IL-10 levels were significantly higher in children with severe malaria compared to uncomplicated malaria and healthy control. There was a strong positive correlation observed between IL-10 and IFN-γ (r=0.688 p=<0.001, as well as a strong positive correlation detected between IFN-γ and urea levels (r=0.73; p=0.010). There was moderate correlation between IL-10 and urea (r=0.386; p=<0.001). While negative moderate correlation was observed between IL-10 and haemoglobin levels (r=−0.316; p=0.003), no correlation was detected between IFN-γ and haemoglobin levels. All patients were discharged home in good condition.

Conclusion

These results indicate both IFN- γ and IL-10 are involved in shaping the course and outcome of the severe malaria in children.
OC 8277 IDENTIFICATION OF NEW CEREBROSPINAL FLUID AND BLOOD-BASED BIOMARKERS FOR THE DIAGNOSIS OF TUBERCULOUS MENINGITIS IN CHILDREN
Authors: Manyelo Masilo Charles , Solomons Regan S , Walzl Gerhard , Chegou Novel N
Published: April 2019

Background

Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB). It mostly affects young children and results in high morbidity and mortality, mainly due to diagnostic delay. There is an urgent need for new tests for the earlier and accurate diagnosis of the disease. We previously identified a 3-marker cerebrospinal fluid (CSF) biosignature (VEGF, IL-13, and LL-37) with potential to diagnose TBM. In the present study, we show that CSF and blood-based biosignatures may be useful in the diagnosis of TBM.

Methods

CSF and serum samples were consecutively collected from 47 children that were admitted to the Tygerberg Academic Hospital in Cape Town, South Africa, on suspicion of having TBM. Using a multiplex platform, the concentrations of 69 host markers were evaluated in the CSF and serum samples from all the study participants, followed by statistical analysis to ascertain the usefulness of these biomarkers as diagnostic candidates for TBM disease.

Results

Out of the 47 study participants, 23 (48.9%) were finally diagnosed with TBM and 6 (12.8%) were infected with HIV. Several CSF and serum biomarkers showed potential individually as diagnostic candidates for TBM as ascertained by area under the receiver operator characteristics curve (AUC). However, the main findings of our study were the identification of a four-marker CSF biosignature which diagnosed TBM with an AUC of 0.97 (95% CI, 0.92–1.00), and a 3-marker serum biosignature which diagnosed TBM with an AUC of 0.84 (95% CI, 0.73–0.96). We also validated a previously identified 3-marker CSF biosignature (VEGF, IL13 and LL37) in the study.

Conclusion

CSF and serum biosignatures may be useful in the diagnosis of TBM in children. Our findings require further validation in larger, multi-site studies after which the biosignatures may be incorporated into point-of-care diagnostic tests for TBM.
PO 8261 CYTOCHROME P450 (CYP2B6*6C.516G>T) VARIANTS IN CONGOLESE INDIVIDUALS WITH HIV AND TB MONO AND DUAL INFECTIONS
Authors: Peko Simon M , Koukouikila-Koussounda Félix , Etokabeka Madinga Kosso , Gampio Nerly Gueye , Kobawila Simon Ch , Vouvoungui Christevy , S Linguissi Ghoma Laure , Nderu David , Velavan Thirumalaisamy P , Ntoumi Francine
Published: April 2019

Background

The inter-individual genetic polymorphism of cytochrome P450 enzymes (CYP), involved in the metabolism of many drugs, partly modulates drug response and toxicity. Single nucleotide polymorphisms of CYP2B6 for example, G516T have been implicated in high- and sub-therapeutic plasma concentration of the current antimalarial, HIV and TB first-line drugs in various geographical regions and thus undermines effective disease management. At present, there is no data on the frequency of CYP2B6 c.516G>T among the Congolese population, despite a significant number of people undergoing antimalarial, HIV and TB treatment that relies on CYP2B6-based drug clearance or activation.

Methods

A total of 418 patients with HIV-1 mono-infection, HIV-1 +TB coinfection andP. falciparuminfection were genotyped for CYP2B6 c.516G>T polymorphism using PCR-RFLP. The frequencies of the alleles as well as the genotypes (GG, GT and TT) were determined.

Results

The frequency of CYP2B6 c.516G>T polymorphism was 69% and frequency of G and T alleles were 45% and 55%, respectively. 17.0% (49/288) of participants were GG (extensive metaboliser), 55.2% (159/288) of participants were GT (intermediate metaboliser) and 27.8% (80/288) of participants were TT (poor metabolisers).

Conclusion

This study highlights CYP2B6 c.G516T polymorphism as a potential determinant of drug response and toxicity among the Congolese population, particularly those undergoing antiretroviral, malaria and tuberculosis treatment within the current first-line drug policy framework.
PO 8275 HEPATITIS B VIRUS IMMUNE ESCAPE MUTANTS AMONG APPARENTLY HEALTHY INHABITANTS IN IBADAN, SOUTHWESTERN NIGERIA
Authors: Bakarey Adeleye S , Ifeorah Ijeoma M , Akere Adegboyega
Published: April 2019

Background

The documentation of circulation of immune escape mutants (IEMs) poses a risk on the continual success of HBV prevention and control. Therefore, this study aimed to determine the possible circulation of IEM among asymptomatic dwellers in southwestern Nigeria.

Methods

Blood samples collected from consenting 133 males and 305 female participants in Ibadan were tested for HBsAg, HBeAg, HBcIgM, HBcTotal and HBsAb by ELISA technique. Samples positive for HBsAg were further analysed for HBV DNA by amplifying and sequencing the S gene. Isolates were genotyped and subtyped based on amino acid residues at position 122, 127, 134, 160 of the S gene.

Results

Of the 438 subjects tested 31 (7.1%) were positive for HBsAg, 2 (6.5%) of which were HBeAg positive. Ninety-nine (22.8%) had detectable HBsAb, 3 (0.7%) were positive for HBcIgM and 195 (44.5%) were HBcTotal positive. HBV DNA was amplified and sequenced in 27 out of 31 and 4 could not be amplified due to low titres. After sequencing, 9 (33.3%) were not exploitable due to the presence of multiple peaks. Of the 18 exploitable isolates, only 15 showed significant similarity to HBV S-gene. Eleven of the 15 isolates were subtyped as ayw4 while others could not due to substitution at s122p. Phylogram showed that the 11 isolates were genotype E. Two of the 4 isolates with R122Q/P substitutions also belonged to genotype E while the other 2 which were >11% divergent from the reference genotype E sequence clustered with an isolate previously described as an Immune Escape Mutant.

Conclusion

This study identified high endemicity of HBV infection, presence of markers of infection even in non-detectable HBsAg levels and circulation of genotype E ayw4 and vaccine mutants in south-western Nigeria. It therefore emphasises the risk of development of an indigenous infected population that may not be protected by the current vaccine.
PO 8276 COMMUNITY INDEX CASE APPROACH AND HIV TESTING AND COUNSELING (HTC) FOR SEXUAL PARTNERS OF HIV-POSITIVE PATIENTS LOST TO FOLLOW-UP: THE EXPERIENCE OF WORLD VISION MOZAMBIQUE
Authors: Lisboa Miguelhete , Culuze Saraiva , Imputiua Saimado , Cambule Adolfo , Latif Christine
Published: April 2019

Background

HIV-positive patients lost to follow-up (HP-LTFU) represent a challenge for HIV/AIDS control efforts as they are associated with higher risk of HIV transmission to their sexual partners, low viral load suppression and higher risk of morbidity and mortality than adherent patients. The SCIP-Ogumaniha programme implemented by World Vision Mozambique, has been utilising the index case approach together with systematic home-based HIV testing and counseling (hHTC) since August 2016 in 7 districts of the Zambezia province. This abstract outlines an evaluation of the contribution of this approach to HIV/AIDS care and treatment (HACT) of sexual partners of HP-LTFU in alignment with the first and second targets of the 90–90–90 UNAIDS strategy.

Methods

The study involved HP-LTFU returned to HACT between October 2016 and September 2017. These patients reported to have sexual partners who had not been tested for HIV and provided informed, written consent for joint hHTC with these individuals. The hHTC package for sexual partners was offered by World Vision project counselors and those who tested HIV-positive were referred to HACT.

Results

Of 7.084 patients who returned to HACT and reported to have an untested sexual partner, 63% (4,471) provided informed, written consent for joint hHTC. Of 4264 sexual partners found and tested, 52% was female, 64% was in the 15–34 age groups, and 88% had never been tested for HIV. About 28% (1.205/4.264) was HIV-positive, 56% of the sexual partners who tested HIV-positive, was female and 98% of these was successfully referred to HACT.

Conclusion

The index case approach together with hHTC has contributed to the early diagnosis of 28% of new HIV infections among sexual partners of HP-LTFU and 98% of them ensured timely linkage to the HACT. Therefore, broader promotion and adoption of this approach would make a significant contribution to achievement of the first and second targets of the 90–90–90 UNAIDS strategy.
PO 8369 BURULI ULCER: PATTERN OF PRESENTATION IN A NIGERIAN HOSPITAL
Authors: Ogbuagu Chukwuanugo , Enweani Ifeoma , Maurice Agu , Ogbuagu Ekenechukwu , Emelumadu Obiageli
Published: April 2019

Background

Buruli ulcer is one of the neglected tropical diseases. It is a chronic, debilitating, necrotising disease of the skin and soft tissue caused byMycobacterium ulcerans. Most times, the pattern of presentation is neglected by the infected because it is regarded as a disease of the poor who have little or no access to healthcare. Living in rural often inaccessible areas and suffering from a triad of ignorance, stigma and poverty, this poor population fails to present early to a hospital.

Methods

A retrospective review of patients who accessed care at the infectious disease clinic of Nnewi Diocesan Hospital, Nnewi, Southeast Nigeria, between 1 January to 31 December 2017. To achieve a complete inference, the results of laboratory wound swab culture of all patients were collated and matched with the clinical presentation. All cultures were done by a trained scientist of the German Leprosy and TB Relief Association (GLRA).

Results

Review of data showed a total of 10 120 patients of which 6402 were outpatients and 3718 were inpatients; they were between 1 and 86 years of age. There were 60 cases of limb ulcers of which wound swab culture was done. Fifty-four (54) were diabetic foot ulcers while five (5) were venous ulcers. Acid-fast bacilli were detected with Ziehl-Neelsen staining in one specimen and confirmed by the reference center.

Conclusion

Most of the Buruli ulcer patients are found incidentally following late presentation at hospitals with a questionable ulcer/wound with a high index of suspicion on clinical examination. If Buruli ulcer is to be eradicated, an intensive rural epidemiological identification programme must be implemented to isolate the infected. The vicious cycle of ignorance, stigma and poverty needs to be broken by massive awareness and education campaigns.
PO 8408 DETECTION OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS AMONG MULTIDRUG-RESISTANTMYCOBACTERIUM TUBERCULOSISCLINICAL ISOLATES IN BOTSWANA
Authors: Mogashoa Tuelo , Mupfumi Lucy , Iketleng Thato , Melamu Pinkie , Kelentse Nametso , Zetola Nicola , Mokomane Margaret , Letsibogo Letsibogo , Streicher Elizabeth M , Ley Serej , Kasvosve Ishmael , Moyo Sikhulile , Warren Robin , Gaseitsiwe Simani
Published: April 2019

Background

The emergence and transmission of multidrug-resistant (MDR) and extensively drug-resistant (XDR)Mycobacterium tuberculosis(Mtb) strains is a serious threat to tuberculosis control in Botswana. Early detection of drug-resistant isolates is critical to ensure optimal treatment and thereby improve treatment outcomes. The objective of this study was to determine the extent of second-line drug resistance among drug-resistant Mtb-isolates from Botswana.

Methods

A total of 60 drug-resistant Mtb isolates received at Botswana National Tuberculosis Reference Laboratory between 2012 and 2013 were analysed. DNA was extracted from BD Mycobacterial Growth Indicator Tubes (MGIT) using GenoLyse DNA isolation kit (Hain Lifescience). Spoligotyping was done using a commercially available spoligotyping kit (Isogen Life Science). The spoligotype patterns were compared with existing patterns in the SITVIT2 Web database. GenoType MTBDRs assay (Hain Lifescience) was used for second-line drug susceptibility testing. Fisher’s exact test was used to test for association between drug resistance patterns and HIV status, lineage and geographical location.

Results

Seventeen distinct spoligotype patterns were detected amongst the 60 drug-resistant isolates. The most predominant lineages were Euro-American (58.3%), East Asian (25%) and Indo-Oceanic (15%). Fifty (83.3%) were MDR, 7 (11.7%) were resistant to fluoroquinolones (Pre-XDR) whereas 3 (5%) were resistant to both fluoroquinolones and second-line injectable drugs (XDR). Drug resistance profiles were significantly associated with Mtb lineage (p<0.001). There was no association between drug resistance profile and HIV status (p=0.057) and geographical location (p=0.372).

Conclusion

This study highlights the importance of including second-line drug susceptibility testing in a testing algorithm in Botswana. The detection of XDR isolates among MDR-TB isolates highlights the ongoing evolution of resistance and the need for strengthened treatment regimens to improve treatment outcomes and to prevent the spread of these highly resistant strains. Second-line testing will be essential if the 9 month MDR regimen is used in Botswana.
Effect of dose reduction of supplemental zinc for childhood diarrhoea: study protocol for a double-masked, randomised controlled trial in India and Tanzania
Authors: Somji Sarah S , Dhingra Pratibha , Dhingra Usha , Dutta Arup , Devi Prabhabati , Kumar Jitendra , Deb Saikat , Semwal Om Prakash , Sazawal Sunil , Manji Karim , Kisenge Rodrick , Bakari Mohamed , Aboud Said , Liu Enju , Sudfeld Christopher , Duggan Christopher P , Ashorn Per , Bahl Rajiv , Simon Jonathon L
Published: April 2019

Background

Diarrhoea-associated mortality and morbidity are highest in infants and young children in low-income and middle-income countries (LMICs). Zinc supplementation during acute diarrhoea has been shown to reduce the duration of illness and the risk of persistent diarrhoea. However, vomiting with zinc supplementation is a common side effect that may interfere with compliance and programmatic scale-up, and may be related to the dose prescribed.

Methods/design

The Zinc Therapeutic Dose Trial (ZTDT) is a two-centre (Tanzania and India), three-arm randomised, double-blind controlled non-inferiority trial. Children 6–59 months of age with acute diarrhoea are eligible to participate. Enrolled children (1500 per arm; 4500 total) will be randomly allocated to receive 5, 10 or 20 mg of zinc sulfate daily for 14 days and will be followed up for 60 days after enrolment. All children will receive WHO/Unicef Integrated Management of Childhood Illness standard of care (oral or intravenous rehydration and zinc as indicated and feeding advice). The primary efficacy outcomes of the trial are the percentage of subjects with diarrhoea duration >5 days, the mean total number of loose or watery stools after enrolment and the proportion of children vomiting within 30 min of zinc administration.

Discussion

The ZTDT trial will determine the optimal dose of therapeutic zinc supplements for treatment of acute diarrhoea in children aged 6–59 months in two LMICs. The results of the trial are likely to be generalisable to childhood acute diarrhoea in similar resource-limited settings and may influence global policy about zinc supplementation dosage during acute diarrhoea.

Trial registration number

NCT03078842.

Trial status

Enrolment began in January 2017 and follow-up is estimated to be completed by April 2019. As of 1 February 2019, 742 children are still contributing data to the ZTDT study.
Incidence and outcomes of unstable angina compared with non-ST-elevation myocardial infarction
Authors: Puelacher Christian , Gugala Mathias , Adamson Philip D , Shah Anoop , Chapman Andrew R , Anand Atul , Sabti Zaid , Boeddinghaus Jasper , Nestelberger Thomas , Twerenbold Raphael , Wildi Karin , Badertscher Patrick , Rubini Gimenez Maria , Shrestha Samyut , Sazgary Lorraine , Mueller Deborah , Schumacher Lukas , Kozhuharov Nikola , Flores Dayana , du Fay de Lavallaz Jeanne , Miro Oscar , Martín-Sánchez Francisco Javier , Morawiec Beata , Fahrni Gregor , Osswald Stefan , Reichlin Tobias , Mills Nicholas L , Mueller Christian
Published: April 2019

Objective

Assess the relative incidence and compare characteristics and outcome of unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI).

Design

Two independent prospective multicentre diagnostic studies (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] and High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]) enrolling patients with acute chest discomfort presenting to the emergency department. Central adjudication of the final diagnosis was done by two independent cardiologists using all clinical information including serial measurements of high-sensitivity cardiac troponin (hs-cTn). All-cause death and future non-fatal MI were assessed at 30 days and 1 year.

Results

8992 patients were enrolled at 11 centres. UA was adjudicated in 8.9%(95% CI 8.0 to 9.7) and 2.8% (95% CI 2.3 to 3.3) patients in APACE and High-STEACS, respectively, and NSTEMI in 15.1% (95% CI 14.0 to 16.2) and 13.4% (95% CI 12.4 to 14.3). Coronary artery disease was pre-existing in 73% and 76% of patients with UA. At 30 days, all-cause mortality in UA was substantially lower as compared with NSTEMI (0.5% vs 3.7%, p=0.002 in APACE, 0.7% vs 7.4%, p=0.004 in High-STEACS). Similarly, at 1 year in UA all-cause mortality was 3.3% (95% CI 1.2 to 5.3) vs 10.4% (95% CI 7.9 to 12.9) in APACE, and 5.1% (95% CI 0.7 to 9.5) vs 22.9% (95% CI 19.3 to 26.4) in High-STEACS, and similar to non-cardiac chest pain (NCCP). In contrast, future non-fatal MI in APACE was comparable in UA and NSTEMI (11.2%, 95% CI 7.8 to 14.6 and 7.9%, 95% CI 5.7 to 10.2), and higher than in NCCP (0.6%, 95% CI 0.2 to 1.0).

Conclusions

The relative incidence and mortality of UA is substantially lower than that of NSTEMI, while the rate of future non-fatal MI is similar.
Characterisation of corneal impression cytology in dogs and its application in the diagnosis of keratoconjunctivitis sicca
Authors: Lejarza‐Ilaro Mikel , Rodriguez‐Alvaro Alfonso , Sanchez‐Maldonado Belen , Gonzalez‐Alonso‐Alegre Elisa
Published: April 2019

Objective

Determine morphological and morphometric parameters of corneal epithelium in dogs, and determine the cellular alterations that occur in canine keratoconjunctivitis sicca (KCS) using impression cytology.

Study animals

60 dogs divided into two groups: dogs with Schirmer tear test (STT) at least 15 mm/minute and absence of ocular disease, and dogs with STT less than 15 mm/minute and clinical signs of KCS.

Procedures

Impression cytology was used to collect corneal samples. The percentage of eyes with cell changes, the number of such cells and the percentage of cells with structural alterations in each group were determined. The possible correlation between corneal epithelium alterations and decreased tear production was evaluated.

Results

A significant positive correlation existed between STT and the area of the cytoplasm and nucleus of corneal cells. A significant negative correlation was found between STT ​​and the nucleus/cytoplasm ratio, and the presence of cellular changes. A significant difference existed between the numbers of pyknotic nuclei, being higher among animals with all stages of KCS.

Conclusion

Corneal impression cytology can be used to assess the corneal epithelium in healthy eyes and eyes with KCS, demonstrating its usefulness as a diagnostic tool especially in mild and early cases.
Mortality and injury assessment for three species of fish exposed to simulated turbine blade strike
Authors: Bevelhimer Mark S. , Pracheil Brenda M. , Fortner Allison M. , Saylor Ryan , Deck Kendra L.
Published: April 2019

Injury and mortality of fish during downstream passage through hydropower turbines is among the leading direct impacts of hydropower. Understanding the relationships among various strike variables and injury and mortality rates are necessary for improvements in turbine design. We subjected three species of fish to simulated blade strike in laboratory studies with different blade thicknesses, impact velocities, and body orientations to develop relationships between these variables and probability of injury and mortality. Midbody strikes resulted in higher mortality than head strikes, and tail strikes produced the least mortality. Lateral strikes caused more mortality than dorsal and ventral strikes, and higher strike velocities and thinner blades contributed to increased mortality. Several injury types were significantly associated with increased mortality, including injuries to the operculum, gills, viscera, heart, liver, swim bladder, muscle, and bone fractures. Results from this study will be used to define biologically based design criteria that can be used by turbine designers to improve designs (e.g., increased leading-edge thickness and slower turbine speeds) to minimize the probability and impact of blade strike.
Collaborative fisheries research: the Canadian Fisheries Research Network experience
Authors: Thompson Susan A. , Stephenson Robert L. , Rose George A. , Paul Stacey D.
Published: April 2019

The Canadian Fisheries Research Network (CFRN) was a collaboration among fish harvesters, academic researchers, and government scientists that undertook research between 2010 and 2016 on questions about fisheries that were identified by fish harvesters and pertinent to management objectives. This paper provides a synthesis of the scope and results of the CFRN. It explores the link between the increasing challenges to fisheries sustainability and the need for increased research capacity and for a collaborative approach. It documents the creation of the collaboration, the research it accomplished, and its benefits and explores the need for ongoing collaboration. The papers in this special issue on the CFRN demonstrate the benefits of collaborative fisheries research that are of relevance internationally and support the need for a permanent collaborative platform to conduct research to support fisheries management capacity and decision-making in Canada.
A Unified Framework for Bug Report Assignment
Authors: Zhao Yuan , He Tieke , Chen Zhenyu
Published: April 2019

It is typically a manual, time-consuming, and tedious task of assigning bug reports to individual developers. Although some machine learning techniques are adopted to alleviate this dilemma, they are mainly focused on the open source projects, which use traditional repositories such as Bugzilla to manage their bug reports. With the boom of the mobile Internet, some new requirements and methods of software testing are emerging, especially the crowdsourced testing. Unlike the traditional channels, whose bug reports are often heavyweight, which means their bug reports are standardized with detailed attribute localization, bug reports tend to be lightweight in the context of crowdsourced testing. To exploit the differences of the bug reports assignment in the new settings, a unified bug reports assignment framework is proposed in this paper. This framework is capable of handling both the traditional heavyweight bug reports and the lightweight ones by (i) first preprocessing the bug reports and feature selections, (ii) then tuning the parameters that indicate the ratios of choosing different methods to vectorize bug reports, (iii) and finally applying classification algorithms to assign bug reports. Extensive experiments are conducted on three datasets to evaluate the proposed framework. The results indicate the applicability of the proposed framework, and also reveal the differences of bug report assignment between traditional repositories and crowdsourced ones.
Deep insecurities
Authors: Greengard Samuel
Published: April 2019

A more connected world sounds alluring, but without better protections, the Internet of Things could lead to disaster.
Countering the negative image of women in computing
Authors: Payton Fay Cobb , Berki Eleni
Published: April 2019

A positive image would inspire the capable but underrepresented who might otherwise give up on computing.
Gene and Induced Pluripotent Stem Cell Therapy for Retinal Diseases
Authors: Maeda Akiko , Mandai Michiko , Takahashi Masayo
Published: April 2019

Given the importance of visual information to many daily activities, retinal degenerative diseases—which include both inherited conditions (such as retinitis pigmentosa) and acquired conditions (such as age-related macular degeneration)—can have a dramatic impact on human lives. The therapeutic options for these diseases remain limited. Since the discovery of the first causal gene for retinitis pigmentosa almost three decades ago, more than 250 genes have been identified, and gene therapies have been rapidly developed. Simultaneously, stem cell technologies such as induced pluripotent stem cell–based transplantation have advanced and have been applied to the treatment of retinal degenerative diseases. Here, we review recent progress in these expanding fields and discuss the potential for precision medicine in ophthalmic care.