[Show abstract][Hide abstract] ABSTRACT: Sparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use. We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis.
The Lancet Infectious Diseases 10/2015; DOI:10.1016/S1473-3099(15)00318-7 · 22.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P 37.5 degrees C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.
[Show abstract][Hide abstract] ABSTRACT: Amodiaquine (AQ) is a 4-aminoquinoline widely used in the treatment of malaria as part of the artemisinin combination therapy (ACT). AQ is metabolised towards its main metabolite desethylamodiaquine mainly by cytochrome P450 2C8 (CYP2C8). CYP1A1 and CYP1B1 play a minor role in the metabolism but they seem to be significantly involved in the formation of the short-lived quinine-imine. To complete the genetic variation picture of the main genes involved in AQ metabolism in the Zanzibar population, previously characterised for CYP2C8, we analysed in this study CYP1A1 and CYP1B1 main genetic polymorphisms. The results obtained show a low frequency of the CYP1A1*2B/C allele (2.4%) and a high frequency of CYP1B1*6 (approximately 42%) followed by CYP1B1*2 (approximately 27%) in Zanzibar islands. Genotype data for CYP1A1 and CYP1B1 show a low incidence of fast metabolisers, revealing a relatively safe genetic background in Zanzibar’s population regarding the appearance of adverse effects.
L’amodiaquine (AQ) est une 4-aminoquinoléine largement utilisée dans le traitement du paludisme dans le cadre de la thérapie de combinaison à base d’artémisinine (TCA). AQ est métabolisée vers son métabolite majeur, la desethylamodiaquine principalement par le cytochrome P450 2C8 (CYP2C8). Les protéines CYP1A1 et CYP1B1 jouent un rôle mineur dans le métabolisme, mais elles semblent être fortement impliquées dans la formation de quinine-imine transitoire. Afin de compléter le tableau de variation génétique des principaux gènes impliqués dans le métabolisme de l’AQ dans la population de Zanzibar, précédemment caractérisé pour CYP2C8, nous avons analysé dans cette étude les principaux polymorphismes génétiques de CYP1A1 et CYP1B1. Les résultats obtenus montrent une faible fréquence de l’allèle CYP1A1*2B/C (2,4%) et une fréquence élevée de CYP1B1*6 (∼ 42%) suivie par CYP1B1*2 (∼ 27%) dans les îles de Zanzibar. Les données sur le génotype de CYP1A1 et CYP1B1 montrent une faible incidence de métaboliseurs rapides, révélant une base génétique relativement sûre dans la population de Zanzibar pour ce qui concerne l’apparition d’effets indésirables.
La amodiaquina (AQ) es una 4-aminoquinolina ampliamente utilizada en el tratamiento de la malaria como parte de la terapia de combinación basada en la artemisinina (ACT). La AQ se metaboliza hacia la desetilamodiaquina - su principal metabolito - principalmente a través del citocromo P450 2C8 (CYP2C8). CYP1A1 y CYP1B1 juegan un papel menor en el metabolismo, pero parecen estar significativamente implicados en la formación de quinina-iminas de corta vida. En este estudio hemos analizado los principales polimorfismos genéticos de CYP1A1 y CYP1B1 para completar el panorama de variación genética de los principales genes involucrados en el metabolismo de la AQ en la población de Zanzíbar, previamente caracterizada para CYP2C8. Los resultados obtenidos muestran una baja frecuencia, en las islas Zanzíbar, del alelo CYP1A1*2B/C (2.4%) y una alta frecuencia de CYP1B1*6 (∼42%) seguido por CYP1B1*2 (∼27%). Los datos de genotipaje de CYP1A1 y CYP1B1 muestran una baja incidencia de metabolitos rápidos, revelando un contexto genético relativamente seguro con respecto a la aparición de efectos adversos en la población de Zanzíbar.
Tropical Medicine & International Health 05/2012; 17(7):854-7. DOI:10.1111/j.1365-3156.2012.03011.x · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In Honduras, chloroquine and primaquine are recommended and still appear to be effective for treatment of Plasmodium falciparum and Plasmodium vivax malaria. The aim of this study was to determine the proportion of resistance associated genetic polymorphisms in P. falciparum and P. vivax collected in Honduras.
Blood samples were collected from patients seeking medical attention at the Hospital Escuela in Tegucigalpa from 2004 to 2006 as well as three regional hospitals, two health centres and one regional laboratory during 2009. Single nucleotide polymorphisms in P. falciparum chloroquine resistance transporter (pfcrt), multidrug resistance 1 (pfmdr1), dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes and in P. vivax multidrug resistance 1 (pvmdr1) and dihydrofolate reductase (pvdhfr) genes were detected using PCR based methods.
Thirty seven P. falciparum and 64 P. vivax samples were collected. All P. falciparum infections acquired in Honduras carried pfcrt, pfmdr1, pfdhps and pfdhfr alleles associated with chloroquine, amodiaquine and sulphadoxine-pyrimethamine sensitivity only. One patient with parasites acquired on a Pacific Island had pfcrt 76 T and pfmdr1 86Y alleles. That patient and a patient infected in West Africa had pfdhfr 51I, 59 R and 108 N alleles. Pvmdr1 976 F was found in 7/37 and two copies of pvmdr1 were found in 1/37 samples. Pvdhfr 57 L + 58 R was observed in 2/57 samples.
The results indicate that P. falciparum from Honduras remain sensitive to chloroquine and sulphadoxine-pyrimethamine. This suggests that chloroquine and sulphadoxine-pyrimethamine should be efficacious for treatment of uncomplicated P. falciparum malaria, supporting current national treatment guidelines. However, genetic polymorphisms associated with chloroquine and sulphadoxine-pyrimethamine tolerance were detected in local P. vivax and imported P. falciparum infections. Continuous monitoring of the prevalence of drug resistant/tolerant P. falciparum and P. vivax is therefore essential also in Honduras.
[Show abstract][Hide abstract] ABSTRACT: In Zanzibar, the Ministry of Health and partners accelerated malaria control from September 2003 onwards. The impact of the scale-up of insecticide-treated nets (ITN), indoor-residual spraying (IRS) and artemisinin-combination therapy (ACT) combined on malaria burden was assessed at six out of seven in-patient health facilities.
Numbers of outpatient and inpatient cases and deaths were compared between 2008 and the pre-intervention period 1999-2003. Reductions were estimated by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period.
In 2008, for all age groups combined, malaria deaths had fallen by an estimated 90% (95% confidence interval 55-98%)(p < 0.025), malaria in-patient cases by 78% (48-90%), and parasitologically-confirmed malaria out-patient cases by 99.5% (92-99.9%). Anaemia in-patient cases decreased by 87% (57-96%); anaemia deaths and out-patient cases declined without reaching statistical significance due to small numbers. Reductions were similar for children under-five and older ages. Among under-fives, the proportion of all-cause deaths due to malaria fell from 46% in 1999-2003 to 12% in 2008 (p < 0.01) and that for anaemia from 26% to 4% (p < 0.01). Cases and deaths due to other causes fluctuated or increased over 1999-2008, without consistent difference in the trend before and after 2003.
Scaling-up effective malaria interventions reduced malaria-related burden at health facilities by over 75% within 5 years. In high-malaria settings, intensified malaria control can substantially contribute to reaching the Millennium Development Goal 4 target of reducing under-five mortality by two-thirds between 1990 and 2015.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: We assessed the efficacy, effectiveness and safety of artemether-lumefantrine, which is the most widely used artemisinin-based combination therapy in Africa, against Plasmodium falciparum malaria during an extended follow-up period after initial and repeated treatment. METHODS: We performed an open-label randomized trial of artemether-lumefantrine with supervised (n=180) and unsupervised intake (n=179) in children 5 years of age with uncomplicated falciparum malaria in rural Tanzania. Recurrent infections between day 14 and day 56 were retreated within the same study arm. Main end points were polymerase chain reaction (PCR)-corrected cure rates by day 56 and day 42 after initial and repeated treatment, respectively, as estimated by survival analysis. RESULTS: The PCR-corrected cure rate after initial treatment was 98.1% (95% confidence interval [CI], 94.2%-99.4%) after supervised and 95.1% (95% CI, 90.7%-98.1%) after unsupervised intake (P=.29). After retreatment of recurrent infections, the cure rates were 92.9% (95% CI, 81.8%-97.3%) and 97.6% (95% CI, 89.3%-98.8%), respectively (P=.58). Reinfections occurred in 46.9% (82 of 175) versus 50.9 % of the patients (relative risk [RR], 0.92 [95% CI, 0.74-1.14]; P=.46) after initial therapy and 32.4% (24 of 74) versus 39.0% (32 of 82) (RR, 0.83 [95% CI, 0.54-1.27]; P=.39) after retreatment. Median blood lumefantrine concentrations in supervised and unsupervised patients on day 7 were 304 versus 194 ng/mL (P.001) after initial treatment and 253 versus 164 ng/mL (P=.001) after retreatment. Vomiting was the most commonly reported drug-related adverse event (in 1% of patients) after both initial and repeated treatment. CONCLUSIONS: Artemether-lumefantrine was highly efficacious even after unsupervised administration, despite significantly lower lumefantrine concentrations, compared with concentration achieved with supervised intake, and was well-tolerated and safe after initial and repeated treatment. CLINICAL TRIAL REGISTRATION: ISRCTN69189899.
[Show abstract][Hide abstract] ABSTRACT: Prescribing antimalarial medicines based on parasite confirmed diagnosis of malaria is critical to rational drug use and optimal outcome of febrile illness. The impact of microscopy-based versus clinical-based diagnosis of childhood malaria was assessed at primary health care (PHC) facilities using a cluster randomized controlled training intervention trial.
Sixteen PHC facilities in rural Tanzania were randomly allocated to training of health staff in clinical algorithm plus microscopy (Arm-I, n = 5) or clinical algorithm only (Arm-II, n = 5) or no training (Arm-III, n = 6). Febrile under-five children presenting at these facilities were assessed, treated and scheduled for follow up visit after 7 days. Blood smears on day 0 were only done in Arm-I but on Day 7 in all arms. Primary outcome was antimalarial drug prescription. Other outcomes included antibiotic prescription and health outcome. Multilevel regression models were applied with PHC as level of clustering to compare outcomes in the three study arms.
A total of 973, 1,058 and 1,100 children were enrolled in arms I, II and III, respectively, during the study period. Antimalarial prescriptions were significantly reduced in Arm-I (61.3%) compared to Arms-II (95.3%) and III (99.5%) (both P < 0.001), whereas antibiotic prescriptions did not vary significantly between the arms (49.9%, 54.8% and 34.2%, respectively). In Arm-I, 99.1% of children with positive blood smear readings received antimalarial prescriptions and so did 11.3% of children with negative readings. Those with positive readings were less likely to be prescribed antibiotics than those with negative (relative risk = 0.66, 95% confidence interval: 0.55, 0.72). On day 7 follow-up, more children reported symptoms in Arm-I compared to Arm-III, but fewer children had malaria parasitaemia (p = 0.049). The overall sensitivity of microscopy reading at PHC compared to reference level was 74.5% and the specificity was 59.0% but both varied widely between PHCs.
Microscopy based diagnosis of malaria at PHC facilities reduces prescription of antimalarial drugs, and appears to improve appropriate management of non-malaria fevers, but major variation in accuracy of the microscopy readings was found. Lack of qualified laboratory technicians at PHC facilities and the relatively short training period may have contributed to the shortcomings.
This study is registered at Clinicaltrials.gov with the identifier NCT00687895.
[Show abstract][Hide abstract] ABSTRACT: The indications for prescribing malaria chemoprophylaxis lack a solid evidence base that results in subjectivity and wide variation of practice across countries and among professionals.
European experts in travel medicine, who are members of TropNetEurop, participated in a survey conducted using the Delphi method. This technique aims at evaluating and developing a consensus through iterations of questionnaires, controlled feedback, and statistical group responses.
A first questionnaire, including questions about controversial issues in prescribing malaria prophylaxis, required responses on a visual scale between 1 and 10. The questionnaire included issues on problematic prescribing, characteristics of drugs, relevance of geography, and importance of insect bite prevention. The repeat questionnaire with the group response from the first round revealed an increasing consensus on most issues. A second survey considered 14 practical scenarios (including two internal standards) and investigated preferred choice of prophylaxis. A significant consensus was noted in 8 of 14 scenarios, which did not increase after a second round. The analysis revealed a wide variation in prescribing choices with preferences grouped by region of practice, and a greater willingness to prescribe in northern and southern Europe than in central Europe. The second round showed a 9.5% change of opinion.
The study shows that improving the evidence base on efficacy and tolerability and risk of malaria for prescribing chemoprophylaxis is needed as is further discussion across Europe to achieve harmonization of prescribing practice.
Journal of Travel Medicine 09/2008; 15(5):294-301. DOI:10.1111/j.1708-8305.2008.00226.x · 1.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malaria-associated anaemia is a major public-health problem. Although the treatment of uncomplicated, Plasmodium falciparum malaria aims to clear the parasites, relieve the symptoms and permit haematological recovery, data on the impact of antimalarial treatment on haematological recovery are few. Haematological recovery and the prevalence of anaemia were therefore evaluated in 600 Kenyan children with uncomplicated malaria who were randomly assigned to one of three treatment groups. The children were given sulfadoxine-pyrimethamine (SP) on day 0, SP plus artesunate on day 0 (AS1), or SP on day 0 and artesunate on each of days 0-2 (AS3). Haemoglobin (Hb) concentrations were measured on days 0, 7, 14, 21 and 28, with haematological recovery defined as a day-28 Hb concentration of at least 11 g/dl. Only 96 (18%) of the 543 children who were anaemic (i.e. with <11.0 g Hb/dl) at enrolment achieved haematological recovery. The prevalence of anaemia fell from 91% on day 0 to 74% (252/340) by day 28 (P=0.065). Compared with SP alone, neither artesunate regimen resulted in higher Hb concentrations on day 28 (with means of 10.2, 9.9 and 10.2 g/dl for AS3, AS1 and SP, respectively; P=0.254), a higher frequency of haematological recovery (19%, 14% and 20% for AS3, AS1 and SP, respectively; P=0.301) or a greater reduction in the prevalence of anaemia (prevalences in the AS3, AS1 and SP arms falling from 90%, 89% and 93%, respectively, on day 0, to corresponding values of 71%, 82% and 69% on day 28; P=0.40). In fact, between days 0 and 7, the children in the AS3 arm showed a larger drop in mean Hb than the children in the other two treatment arms. In general, haematological recovery was most likely in older children who had mild anaemia at presentation and were parasitologically cured. Overall, the frequencies of haematological recovery were modest and not influenced by the artesunate treatments. Other factors contributing to anaemia need to be explored more fully.
Pathogens and Global Health 07/2007; 101(4):281-95. DOI:10.1179/136485907X176337 · 1.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We assessed the influence that consecutive-day blood sampling, compared with single-day blood sampling, had on polymerase chain reaction (PCR)-adjusted parasitological cure after stepwise genotyping of merozoite surface proteins 2 (msp2) and 1 (msp1) in 106 children in Tanzania who had uncomplicated falciparum malaria treated with either sulfadoxine-pyrimethamine or artemether-lumefantrine; 78 of these children developed recurrent parasitemia during the 42-day follow-up period. Initial msp2 genotyping identified 27 and 33 recrudescences by use of single- and consecutive-day sampling, respectively; in subsequent msp1 genotyping, 17 and 21 of these episodes, respectively, were still classified as recrudescences; these results indicate a similar sensitivity of the standard single-day PCR protocol--that is, 82% (27/33) and 81% (17/21), in both genotyping steps. Interpretation of PCR-adjusted results will significantly depend on methodology.
The Journal of Infectious Diseases 03/2007; 195(4):597-601. DOI:10.1086/510910 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anaemia among small children in tropical Africa is common and often caused by infection with Plasmodium falciparum. The diagnosis of anaemia is difficult without a laboratory estimation of haemoglobin. The aim of this study was to examine if clinical findings related to malaria and anaemia would help to detect moderate and/or severe anaemia in children in rural Tanzania.
Children between 6 and 36 months were examined by health workers in an Out Patient Department (OPD) to detect severe anaemia (packed cell volume, PCV< or =20%) and in a cross sectional survey at village level to identify moderate anaemia (PCV 21-25%). History of recent fever and treatments was recorded and a clinical examination was performed.
In the survey, comparison of 65 moderately anaemic children with 373 mild/non anaemic children revealed no differences in history of fever or in the clinical examination. In the OPD comparison of 100 severely anaemic children with 116 non-severely anaemic control children revealed that pallor, respiratory rate, number of fever days last week, deteriorated general condition, heart rate, age, splenomegaly, low body weight and elevated body temperature were all indicators of severe 'anaemia, only pallor, respiratory rate, fever days and palpable spleen however, remained associated with severe anaemia in multiple regression analysis. The combination of any pallor and either respiratory rate >55/min or fever >3 days, could predict severe anaemia with a sensitivity of 96% and a specificity of 71%. This was better than the currently recommended signs of severe pallor or an approximation of the Integrated Management of Childhood Illness (IMCI) criteria's for referral of children.
At primary health care level detection of severe anaemia can be improved by information about fever duration and determination of respiratory rate in children with pallor.
[Show abstract][Hide abstract] ABSTRACT: Anaemia is a major complication of Plasmodium falciparum malaria among small children in sub-Saharan Africa. We studied the performance of the Integrated Management of Childhood Illness (IMCI) recommended assessment of no/some/severe pallor as predictor of anaemia in health surveys at community level and in clinical practice in an out patient department (OPD) and in a hospital ward in rural Tanzania.
The study was undertaken among 6-36 months old children. Pallor was evaluated as a combined assessment of conjunctiva, tongue and palms and categorised as no, some or severe pallor. Packed cell volume (PCV) was measured and related to pallor.
A total of 740 examinations were performed at village, OPD and in the hospital ward. The prevalences of severe pallor were 0%, 1.5% and 7% respectively. The prevalences of any pallor were 14%, 41% and 86%. The prevalences of severe anaemia (PCV<21%) were 1%, 5% and 81% and of any anaemia (PCV<33%) 68%, 73% and 98%. Severe pallor could not detect severe anaemia. The sensitivities were only 0%, 0% and 8%. The sensitivities of any pallor to detect severe anaemia were however 86% and 98% for children at the health care facility level, but still of relatively poor predictive values since the specificities were only 61% and 68%.
Division of pallor into some or severe degrees was of no use at any health care level. The identification of any pallor was of no use at village level, but it may possibly be of some value as a screening test for severe anaemia at health care facilities, if additional assessment is included in view of the low specificity and positive predictive value of the finding.
[Show abstract][Hide abstract] ABSTRACT: The determination of the prevalence of the CYP2C8 main alleles in a typical set of malaria patients in Zanzibar, as these patients represent a typical population exposed to amodiaquine, an antimalarial mainly metabolized by CYP2C8. Also, to determine for the first time the frequencies of CYP2C8 alleles in native African populations.
Polymerase chain reaction-restriction fragment polymorphism for the identification of CYP2C8*1, CYP2C8*2, CYP2C8*3 and CYP2C8*4 on a random population of 165 unrelated malaria patients.
The allele frequencies found were: CYP2C8*1 (wild type, 83.4%), CYP2C8*2 (13.9%), CYP2C8*3 (2.1%) and CYP2C8*4 (0.6%). In terms of genotypes, 70.4% of the patients showed the CYP2C8*1/ CYP2C8*1 genotypes, while heterozygous between the wild type and other minor alleles were seen in 26.0%. Finally, 3.6% of the patients were homozygous for slow metabolizer alleles. The frequencies observed are equivalent to those documented for African-Americans.
CYP2C8 non-wild type alleles have a significant prevalence in the East African population studied. The consequent frequency of 3.6% of patients homozygous for slow metabolizer alleles represent a significant fraction of the population potentially in higher risk of adverse effects due to a less efficient metabolism of amodiaquine. As approximately 10(6) first-line treatments are currently performed in Zanzibar per year, this represents a non-negligible absolute number of amodiaquine exposures. This information constitutes a background for the pharmacovigilance programs presently being employed in Zanzibar.
European Journal of Clinical Pharmacology 04/2005; 61(1):15-8. DOI:10.1007/s00228-004-0871-8 · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute haemolysis associated with clinical episodes of high-level Plasmodium falciparum parasitaemia was studied in 20 children from an holoendemic area (coastal Tanzania). The change in blood haemoglobin (Hb)
concentration ranged from −46 to +5 g/L during the 72-h observation period and was linearly related to maximum parasitaemia.
Balance studies between loss of blood Hb, increase in plasma Hb and appearance of Hb in the urine indicated that extravascular
clearance of red cells was the predominant mode of erythrocyte clearance. Most subjects, however, showed minor signs of intravascular
haemolysis. The plasma Hb was ⪡1% of blood Hb and haemoglobinuria was detected in 14/20 children but the excretion of Hb in
urine was <0·5% of total Hb loss. Haemoglobinuria was, however, a marker of severe haemolysis, since the maximum blood Hb
loss in children without haemoglobinuria was 10 g/L. Erythrocyte-bound opsonins known to induce erythrophagocytosis i.e.,
complement C3c fragments and autologous IgG, were increased in all patients. In the patients with major haemolysis, the changes
correlated to the haemolysis over time. Hence, a similar mechanism for predominantly extravascular erythrocyte clearance may
be operative in acute malarial anaemia, normal erythrocyte senescence and other forms of acute haemolysis.
Transactions of the Royal Society of Tropical Medicine and Hygiene 11/2001; 95(6):611-7. DOI:10.1016/S0035-9203(01)90095-1 · 1.84 Impact Factor