bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROGRESS IN THE DEVELOPMENT OF SAFE AND EFFECTIVE TUBERCULOSIS VACCINES
Authors: Tait Dereck 
Published: February 2017

BackgroundTuberculosis (TB) is the largest cause of mortality due to a single infectious agent. There were ∼9.6 million cases of TB and ∼1.5 million TB deaths in 2014, of which over 80% occurred in low- and middle income countries. In 1993, TB was declared a public health emergency by the World Health Organisation. Multidrug- and extensively drug-resistant TB is becoming increasingly common and adding significantly to the burden of disease. We will not meet the target of the WHO End TB Strategy of TB elimination by 2035 unless new interventions, drugs, diagnostics, and vaccines, become available. Modelling has demonstrated that elimination of TB is most likely to be achieved with new and effective TB vaccines. Effective and safe TB vaccines will also address the global crisis of drug resistant TB. The development of safe and effective TB vaccines is achievable as the human immune response does control TB in some circumstances – the highest risk of TB disease is within two years of skin test conversion, 90% of people with latent TB infection never develop TB disease, and BCG vaccine does provide partial protection. The probability of success is improved by significant progress in the field and the availability of new tools such as the robust use of improved animal models, increased diversity of mechanisms of action, combination vaccines, use of alternative routes of administration and stringent stage gates to concentrate resources of those vaccines most likely to succeed. New tools such as a controlled human infection model are in development, and novel clinical trial designs and use of special populations allow more streamlined studies and potentially earlier proof of concept. Globally, there are currently 13 TB vaccines in various stages of clinical development and efficacy data will be available from some of these candidates within one to three years.
COMMUNITY ENGAGEMENT IN TB VACCINE RESEARCH AND DEVELOPMENT IN ZAMBIA
Authors: Sibusiso Hlatjwako , Manda Olga , Croucher Kristin , Westhuizen Anja Van Der , Mshanga Isaac 
Published: February 2017

BackgroundCommunity engagement (CE) is an essential component of clinical research. In 2000, the National Institute of General Medical Sciences recommended that researchers obtain community input into all phases of research, respect communities as partners, and establish appropriate community review procedures.Method:Aeras incorporated CE activities into all its studies and continues to seek input from communities into Aeras-conducted clinical trials.ResultsIn Zambia, Aeras conducts TB vaccine clinical trials in collaboration with Zambia AIDS Related Tuberculosis (ZAMBART) Project and the Centre for Infectious Disease Research in Zambia (CIDRZ). Through an established CE program communities have received information on, and provided input to, the design and conduct of clinical trials. CE has provided a very useful avenue for communication between communities where clinical trials are being conducted and researchers.ConclusionsThe presentation will highlight CE activities related to TB vaccine clinical trials and their impact, and will promote discussion on the utility of CE activities in Zambia and elsewhere. The impact of funding shortfalls for CE will be discussed. As CE is an essential component of clinical trials continuous evaluation, it is important to ensure it remains effective and addresses changing knowledge and beliefs.
OCCURRENCE OF DAY 3 SUBMICROSCOPICPLASMODIUM FALCIPARUMPARASITAEMIA BEFORE AND AFTER IMPLEMENTATION OF ARTEMETHER-LUMEFANTRINE TREATMENT POLICY IN TANZANIA
Authors: Ngasala Billy , Jovel Irina , Malmberg Maja , Mmbando Bruno , Björkman Anders , Premji Zul , Mårtensson Andreas , Mwaiswelo Richard 
Published: February 2017

BackgroundEmergence ofPlasmodium falciparumresistance against artemisinin in Southeast Asia raises a serious concern about the long-term efficacy of artemisinin-based combination therapy (ACT) globally. In Africa, ACT has remained highly efficacious with a microscopy determined asexual parasites clearance occurring within 48 hours post-treatment in most patients. However, submicroscopic parasitaemia has been reported on Day 3 after ACT treatment. We assessed the prevalence of patients with submicroscopic parasitaemia on Day 3 and its associated factors following treatment with artemether-lumefantrine (AL) from 2006 to 2014 in Bagamoyo district, Tanzania.MethodsCytochrome b-nested polymerase chain reaction (PCR) was used for screening of submicroscopic parasitaemia from blood samples collected on filter paper on Day 3 post-AL treatment for acute uncomplicatedP. falciparummalaria.Primary outcome was proportion of patients with submicroscopic parasitaemia on Day 3 from 2006 to 2014. Secondary outcomes included proportional difference in submicroscopic parasitaemia across years, association of pre-treatment characteristics with submicroscopic parasitaemia, and association of submicroscopic parasitaemia with recurrent infection.ResultsOnly 2/584 (0.34%) of the screened patients had microscopy determined parasitaemia on Day 3, whereas, 256/584 (43.8%) had submicroscopic parasitaemia. Submicroscopic parasitaemia prevalence increased from 28% (14/50) in 2006 to 74.2% (132/178) in 2007–8, and thereafter declined to 36% (50/139) in 2012–13 and 27.6% (60/217) in 2014, with the likelihood of being positive for submicroscopic parasitaemia decreasing by 14.7% (95% CI: 9.5–19.7%, p<0.001) for an increase in year by one. Pre-treatment parasitaemia >100,000/µL, haemoglobin <10 g/dL, fever, being aged <5 years and year of study 2007–8 and 2012–13 were associated with the presence of submicroscopic parasitaemia. There was no association between submicroscopic parasitaemia and recurrent infection.ConclusionsDay 3 submicroscopic parasitaemia was common in patients treated with AL before and after implementation of the policy, and changed considerably across years from 2006 to 2014, however, its presence was associated with pre-treatment characteristics.
EVIDENCE OFPLASMODIUM FALCIPARUMRESISTANCE TO SULPHADOXINE-PYRIMETHAMINE (SP) IN PREGNANT WOMEN ALONG THE SLOPE OF MOUNT CAMEROON
Authors: Agbor Lenshina , Apinjoh Tobias 
Published: February 2017

BackgroundMalaria in pregnancy (MiP) has debilitating effects for both mother and neonate, with intermittent preventive treatment in pregnancy (IPTp) central to successful malaria control and management in this vulnerable group. However, the effectiveness of IPTp with sulphadoxinepy-rimethamine (SP) is threatened by the emergence of drug resistantPlasmodium falciparumparasites vastly documented in some settings but not in south-western Cameroon. This study sought to ascertain the level of resistance of natural parasite populations to SP in this area.MethodsA total of 358 parturients were enrolled through a cross-sectional survey from May to October 2015. Malaria parasitaemia was determined by light microscopy using Giemsa-stained thick and thin smears of the peripheral blood, while DNA was extracted from dried blood spots ofP. falciparum-positive samples by the Chelex-PBS method. SNPs inpfdhpsandpfdhfrwere then genotyped by nested polymerase chain reaction followed by allele-specific restriction analysis (ASRA).ResultsA total of 47 women (13.1%) had MiP, with a geometric mean parasitaemia density of 1064 parasites/µl of blood. The weight (p=0.038), gestational age (p=0.001), IPTp-SP usage (p< 0.001) and IPTp-SP dosage (p=0.001) of parturients were identified as risk factors of malaria parasitaemia. Overall, 76.5% (274/358) and 60.3% (216/358) of the women took IPTp-SP and two or more SP doses, respectively. Participants who had taken IPTp-SP (p=0.009) and two or more SP doses (p<0.001) had lower parasite loads compared to non-IPTp-SP users and those who had taken one dose or less, respectively. The Pfdhps K540E substitution was absent in the area, the prevalence of Pfdhfr S108N and Pfdhps A581G was 97.6% and 51.1%, respectively.ConclusionsThese results show the value of IPTp-SP usage and dosage in malaria parasitaemia control, in spite of the high prevalence ofP. falciparumresistance to SP in the area, with implications for the control of malaria in this vulnerable group.
EFFICACY AND SAFETY OF ARTEMISININ-BASED COMBINATION THERAPIES IN PEOPLE WITHPLASMODIUM FALCIPARUMMALARIA RECEIVING ANTIRETROVIRAL THERAPY IN ZAMBIA
Authors: Chaponda Mike 
Published: February 2017

BackgroundThe coverage of Artemisinin-based Combination Therapies (ACTs) for treatment of malaria and antiretroviral therapy (ART) is increasing rapidly in Sub-Saharan Africa. Because of the geographical overlap in areas of high malaria and HIV prevalence, HIV-infected people receiving ART may become malaria-infected and will need ACTs.However, few studies have assessed the safety and efficacy of administering ACTs in people taking ART. The interactions might lead to high ACT drug levels which might cause toxicity or low drug levels which might adversely affect malaria parasite clearance, thereby fuelling resistance.MethodsWe conducted a phase IIIb single arm (non-comparative), open label clinical trial. We enrolled and followed up 155 patients at St. Paul's Hospital in Nchelenge district of Zambia. The patients were enrolled in the study after they consented to participate and met strict inclusion and exclusion criteria.ResultsPatient enrolment was completed in September 2015. The results of this study are currently being analysed.ConclusionsData on the safety and efficacy of ACTs in people taking different types of ART are lacking since previous regulatory trials have systematically excluded HIV-positive people, including those receiving ART. Thus, the results of our study will assist in the following ways: determine whether HIV-infected individuals receiving specific types of ART require a specific type of ACTs, inform clinical practitioners about what sort of adverse events they should expect and monitor in people taking different combinations of ACTs and ARTs, and provide evidence-based recommendations to the WHO and National Malaria Control Programmes on safe and effective ACTs that can be used in patients' EFV-based regimen. This study was part of a multicentre trial including centres in Malawi and Mozambique.
POLICY-DRIVEN INTERVENTIONS: TUBERCULOSIS
Authors: Walzl Gerhard , Chegou Novel , Malherbe Stephanus , Hatherill Mark , Scriba Thomas J. , Zak Daniel E. , Barry Clifton E. , Kaufmann Stefan H.E. 
Published: February 2017

Annual tuberculosis (Tb) rates decline by 1.7%, which is inadequate to reach WHO targets. We describe three host-biomarker developments that are entering clinical testing and that could accelerate progress against TB.Blood mRNA signatures with promising predictive ability for incident TB were recently described in African cohorts. Correlate of risk (COR) positive participants have 7 to 18 times increased risk for progression. A clinical trial is underway in South Africa under leadership of the South African Tuberculosis Vaccine Initiative to evaluate targeted chemoprophylaxis in COR positive people in an area with a very high prevalence of latent TB infection, where untargeted preventative treatment is not practical.Historical data suggests that 85% of patients are cured after 4 months of TB treatment but attempts to shorten treatment without an unacceptable relapse rate have failed. Treatment shortening criteria based on PET/CT imaging and microbiological criteria were developed. An EDCTP/Bill & Melinda Gates Foundation/NIH co-funded study, led by the Tuberculosis Research Section of the NIH, will start in South Africa and in China in 2017 to evaluate biomarker-driven treatment shortening to 4 months.To address diagnostic bottlenecks, a blood-based 7-host marker diagnostic signature was recently found with promising screening potential for active TB. An EDCTP-funded project with Africa and EU partners aims to develop a point-of-care, finger stick blood test that can simultaneously measure all 7 markers and rule out 75% of people with symptoms compatible of active TB in whom the diagnosis is subsequently ruled out. Such screening tests could speed up diagnostic work-up and save significant costs. Taken together, biomarker-driven interventions are now being actively tested and hold promise to provide important tools towards the eventual eradication of the TB scourge.
CXCL10 GENE PROMOTER POLYMORPHISM – 1447A>G IS ASSOCIATED WITH MALARIA IN GHANAIAN CHILDREN
Authors: Botchway Felix , Wilson Nana , Dickinson-Copeland Carmen M , Adjei Andrew A. , Wilson Michael , Stiles Jonathan K. 
Published: February 2017

BackgroundRecent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. We hypothesised malaria infection is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection.MethodsBasic demographics that may impact our assessments including age, gender, full blood count, sickle cell status and CXCL10 polymorphism were assessed. We assessed a single nucleotide polymorphism in the CXCL10 promoter (–1447A>G [rs4508917]) among 382 malaria and 117 non-malaria subjects using PCR-restriction fragment length polymorphism assay. Adjusted Odds Ratio (AOR) was used to find out if there was any association between CXC10 promoter polymorphism –1447 A>G and susceptibility to malaria.ResultsThe median age for malaria patients was 4 years and that for non-malaria was14 years. There was significant difference with regards to haemoglobin levels and White cell counts between malaria patients and non-malaria subjects ( p<0.0001). Individuals with the 21447(A/G) genotype were susceptible to malaria (adjusted odds ratio [AOR]=2.60, 95% CI: 1.51–5.85, p=0.021). Additionally, individuals with the 21447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the 21447(A/A) genotype. Stratifying patients according to gender, the observed association of malaria with over expression of CXCL10 were more pronounced in females than in male patients (AOR=5.47, 95% CI: 1.34–22.29, p=0.018).ConclusionsPolymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of malaria. These results suggest that the 21447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of malaria outcomes particularly in females.
GENE VARIATION AND SUSPECTEDPLASMODIUM FALCIPARUMHISTIDINE-RICH PROTEIN 2 GENE DELETION AND ITS IMPACT ON SENSITIVITY OF MALARIA RAPID DIAGNOSTIC TESTS IN SUDAN
Authors: Hamid Muzamil Abdel , Awad-Elgeid Mona , Nasr Awad 
Published: February 2017

BackgroundMalaria rapid diagnostic tests (RDTs) play a significant role in malaria case management and case investigations. Variability or absence of antigens targeted by PfHRP2-based RDTs have been reported worldwide. However, little data is available concerning genetic variability within SudanesePlasmodium falciparumisolates while variable sensitivity of PfHRP2 based RDTs has been observed. The objective was to find out the possible effect of PfHRP2 gene variation and suspected deletion on the performance of PfHRP2-based RDTs.MethodsSeventy-sevenP. falciparumisolates were selected from three geographical regions of Sudan. Malaria HRP2-RDTs and Giemsa-stained blood films data were included for analysis. Thepfhrp2exon 2 fragments were amplified to study genetic variation and suspected deletion. Chi-square test was used for testing significance of results.ResultsForty percent (31/77) ofP. falciparumisolates showed amplification for PfHRP2 (which revealed five alleles of different sizes), whereas 60% of isolates were PfHRP2 PCR-negative. There is a concordance of positive and negative rates on PfHRP2 RDT and gene amplification results of (35%) and (33%) respectively. Eighty-seven percent (78%) of RDTs positive isolates were PfHRP2 negative (p-value=0.001), while 4 out of 31pfhrp2positive isolates gave false negative results in RDT detection. Twenty out of 47 RDTs positive isolates were PfHRP2 negative (p-value=0.001).Plasmodium falciparumHRP2-RDTs showed higher sensitivity than microscopy in malaria detection (p-value=0.007).ConclusionsThe study provided baseline data on genetic variation and suspected deletion in PfHRP2 and its potential effect on RDT performance.
RE-EVALUATION OF MALARIA DIAGNOSIS BY MOLECULAR METHODS REVEALS MUTATIONS IN HRP-2 AND DRUG RESISTANCE MARKERS IN CAMEROON
Authors: Netongo Palmer , Kamdem Séverin , Velavan Thirumalaisamy , Kremsner Peter 
Published: February 2017

BackgroundAs the decline in malaria cases becomes obvious in most sub-Saharan African countries, a new major concern is accurate diagnosis of low parasitaemia which can cause sub-patent infections and false-negative Rapid Diagnostic Test (RDT) results. We assessed the accuracy malaria diagnosis by RDT and microscopy are currently been conducted in Cameroon, by re-evaluating some samples from patients who sought medical care at three health centres in Yaounde. The study would provide information which can help the national malaria control program to reorient interventions strategies to enhance accurate diagnosis within the country.MethodsWe undertook a research project within a period of six months to re-evaluate malaria confirmed cases by microscopy and RDT test (HRP2: SD BIOLINE Malaria Ag P.f/Pan: Optimal screening test forP. falciparumand otherPlasmodium species). We used molecular methods such as nested PCR, in-house tailored loop amplified isothermal amplification (LAMP) and GenoType MalariaDR molecular assay to revalidate these samples. DNA was directly extracted from the RDT cassettes using qiagen spin columns.ResultsResults showed discrepancies in malaria diagnosis by microscopy, RDT, PCR, LAMP and GenoType MalariaDR. Most false negatives results (RDT negative but positive by microscopy and molecular methods) are linked to low parasite density usually<150 asexual parasites/μl. However, there were some cases where higher parasite density >5,00/μl could lead to false negative results (linked to a deletion of about 870 bp in the HRP-2 gene). GenoType MalariaDR revealed the presence of mutations onPfmdr1 and Pfcrtassociated with resistance to ART.ConclusionsThe study provided factual information on the detectedP. falciparumisolates,HRP-2mutations and the performance of RDTs andPfmdr1, PfcrtandARTresistance markers present in the population. The first-line of ACT in Cameroon is artesunate+amodiaquine, yet possible resistance isolates of amodiaquine and artesunate could be circulating in the country.
FOSMIDOMYCIN-PIPERAQUINE AS NON-ARTEMISININ-BASED COMBINATION FOR ACUTE UNCOMPLICATEDPLASMODIUM FALCIPARUMMALARIA
Authors: Mombo-Ngoma Ghyslain , Remppis Jonathan , Sievers Moritz , Manego Rella Zoleko , Endamne Lilian , Lell Bertrand , Hutchinson David , Kremsner Peter 
Published: February 2017

BackgroundAs investment in research related to artemisinin resistance is a key objective of the Global Plan for Artemisinin Resistance Containment (GPARC), fosmidomycin and piperaquine are being developed to address the delay in parasite clearance following treatment with Artemisinin-based Combination Therapy (ACT). Though artemisinin resistance occurs principally in the Greater Mekong Region, there are concerns that it will emerge in sub-Saharan Africa.MethodsA proof-of-concept study has been conducted in Gabon to determine the efficacy, tolerance and safety of fosmidomycin and piperaquine when administered orally for three days. A total of 100 subjects, including 10 adults, 40 children aged 5–14 years and 50 children aged 1–5 years fulfilling the inclusion criteria of mono-infection withPlasmodium falciparumand initial parasite counts between 1,000 and 150,000/µL were enrolled and followed up for 63 days. The primary efficacy endpoint was per protocol, the PCR-corrected cure rate on Day 28. Safety endpoints included the incidence, severity, drug-relatedness and seriousness of adverse events and laboratory abnormalities. ClinicalTrials.gov Identifier:NCT02198807ResultsThe PCR-corrected 28-day cure rate in the older children was 100% (n=31). It was also 100% (n=38) in the younger children, a group deemed to be more therapeutically challenging on account of their lower immune status. Tolerance was excellent and there were no drug-related safety issues. Full results will be presented.ConclusionsFulfilling the WHO criteria for combination therapy, fosmidomycin as a rapidly acting blood schizonticide and piperaquine with its prolonged post-treatment prophylactic effect have been shown to be highly efficacious for the treatment of acute uncomplicated falciparum malaria in an area of intense malaria transmission. Dose optimisation studies with the dual aim of achieving a reduction in the dose of fosmidomycin within a therapeutic regimen of once daily dosing are planned.
LUMEFANTRINE DISPOSITION AFTER REPETITIVE TREATMENT OF UNCOMPLICATED MALARIA PATIENTS WITH ARTEMETHER-LUMEFANTRINE IN MALI
Authors: Tekete Mamadou , Burhenne Juergen , Fofana Bakary , Toure Sekou , Dama Souleymane , Dara Nianwalou , Traore Oumar , Sidibe Bouran , Djimde Abdoulaye , Haefeli Walter , Borrmann Steffen 
Published: February 2017

BackgroundSince 2006 the national malaria control program in Mali recommended artemether-lumefantrine (AL) as the first-line treatment of uncomplicated malaria. The role of lumefantrine in this combination is to eliminate remaining parasites after the action of artemether and to protect the patient against a new blood infection. Some studies showed a correlation between lumefantrine's day 7 concentration and the efficacy of AL after treatment of a single episode of malaria. The objective of this work is to validate this observation after repetitive treatment of uncomplicated malaria patients with AL.MethodsDuring a phase IIIb/IV comparative, randomised, multicentre, clinical study of artemisinin-based combination therapies, we collected plasma on Day 7 from patients treated with standard dose of AL in Sotuba, Bougoula Hameau, and Kolle (Mali). The age of the patients enrolled in this study was from 6 months old. The plasma samples were kept at – 80°C until lumefantrine analysis using high performance liquid chromatography was performed.ResultsWe included 1076 subjects, of which 595 were females and a mean age of 12 years old in this analysis.The median concentration was 66% higher (p<0.0001) in patients without recurrent parasite on day 28 compared to patients with recurrent parasitaemia: 509.1 ng/ml (inter quartile range: 329.6–723.2; n=919)vs372.5 (255.7–538.4; n=157). Day 7 concentrations increased with age; the difference between age group was statistically significant: 305.9 (207.3–491.5, n=140), 447 (290.7–622.9, n=399), 544.7 (383.9–738.5, n=254) and 571.1 (378.8–850.9), n=283) in patients under 5 years old, 5–9 years old, 10–14 years old and 15 years old and older, respectively. Girls under 5 years old had a lower lumefantrine concentration at day 7 compared to other age groups of 223.3 ng/ml (159.7–425.6, n=37).ConclusionsWe found a lower concentration of lumefantrine in patients with recurrent parasitaemia at day 28.