Abstract
α-Thalassemia is a common inherited blood disorder manifested mainly by the deletions of α-globin genes. In geographical areas with high carrier frequencies, screening of α-thalassemia ...carrier state is therefore of vital importance. This study presents a novel method for identifying female carriers of common α-thalassemia deletions using samples routinely taken for non-invasive prenatal tests for screening of fetal chromosomal aneuploidies. A total of 68,885 Vietnamese pregnant women were recruited and α-thalassemia statuses were determined by gap-PCR, revealing 5344 women (7.76%) carried deletions including αα/−−
SEA
(4.066%), αα/−α
3.7
(2.934%), αα/−α
4.2
(0.656%), and rare genotypes (0.102%). A two-stage model was built to predict these α-thalassemia deletions from targeted sequencing of the HBA gene cluster on maternal cfDNA. Our method achieved F1-scores of 97.14–99.55% for detecting the three common genotypes and 94.74% for detecting rare genotypes (−α
3.7
/−α
4.2
, αα/−−
THAI
, −α
3.7
/−−
SEA
, −α
4.2
/−−
SEA
). Additionally, the positive predictive values were 100.00% for αα/αα, 99.29% for αα/−−
SEA
, 94.87% for αα/−α
3.7
, and 96.51% for αα/−α
4.2
; and the negative predictive values were 97.63%, 99.99%, 99.99%, and 100.00%, respectively. As NIPT is increasingly adopted for pregnant women, utilizing cfDNA from NIPT to detect maternal carriers of common α-thalassemia deletions will be cost-effective and expand the benefits of NIPT.
Abstract
Objectives
To investigate the risk of colonization with ESBL-producing Escherichia coli (ESBL-Ec) in humans in Vietnam associated with non-intensive chicken farming.
Methods
Faecal samples ...from 204 randomly selected farmers and their chickens, and from 306 age- and sex-matched community-based individuals who did not raise poultry were collected. Antimicrobial usage in chickens and humans was assessed by medicine cabinet surveys. WGS was employed to obtain a high-resolution genomic comparison between ESBL-Ec isolated from humans and chickens.
Results
The adjusted prevalence of ESBL-Ec colonization was 20.0% (95% CI 10.8%–29.1%) and 35.2% (95% CI 30.4%–40.1%) in chicken farms and humans in Vietnam, respectively. Colonization with ESBL-Ec in humans was associated with antimicrobial usage (OR = 2.52, 95% CI = 1.08–5.87) but not with involvement in chicken farming. blaCTX-M-55 was the most common ESBL-encoding gene in strains isolated from chickens (74.4%) compared with blaCTX-M-27 in human strains (47.0%). In 3 of 204 (1.5%) of the farms, identical ESBL genes were detected in ESBL-Ec isolated from farmers and their chickens. Genomic similarity indicating recent sharing of ESBL-Ec between chickens and farmers was found in only one of these farms.
Conclusions
The integration of epidemiological and genomic data in this study has demonstrated a limited contribution of non-intensive chicken farming to ESBL-Ec colonization in humans in Vietnam and further emphasizes the importance of reducing antimicrobial usage in both human and animal host reservoirs.
Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing ...co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance.
In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2–65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin–piperaquine or dihydroartemisinin–piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate–mefloquine or dihydroartemisinin–piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether–lumefantrine or artemether–lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete.
Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin–piperaquine (183 17%), dihydroartemisinin–piperaquine plus mefloquine (269 24%), artesunate–mefloquine (73 7%), artemether–lumefantrine (289 26%), or artemether–lumefantrine plus amodiaquine (286 26%). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin–piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin–piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin–piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin–piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin–piperaquine plus mefloquine (96% 68 of 71; 95% CI 88 to 99) was non-inferior to that of artesunate–mefloquine (95% 69 of 73; 95% CI 87 to 99) in three sites in Cambodia (risk difference 1%; 95% CI −6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether–lumefantrine plus amodiaquine (98% 281 of 286; 95% CI 97 to 99) was similar to that of artemether–lumefantrine (97% 279 of 289; 95% CI 94 to 98; risk difference 2%, 95% CI −1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin–piperaquine plus mefloquine (30 3·8% of 794) than after dihydroartemisinin–piperaquine (eight 1·5% of 543; p=0·012). Vomiting after artemether–lumefantrine plus amodiaquine (22 1·3% of 1703) and artemether–lumefantrine (11 0·6% of 1721) was infrequent. Adding amodiaquine to artemether–lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms SD 18·6 vs 0·9 ms 16·1; p<0·01) but adding mefloquine to dihydroartemisinin–piperaquine did not (mean increase of 22·1 ms SD 19·2 for dihydroartemisinin–piperaquine vs 20·8 ms SD 17·8 for dihydroartemisinin–piperaquine plus mefloquine; p=0·50).
Dihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance.
UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.
The emergence and spread of resistance in Plasmodium falciparum malaria to artemisinin combination therapies in the Greater Mekong subregion poses a major threat to malaria control and elimination. ...The current study is part of a multi-country, open-label, randomised clinical trial (TRACII, 2015–18) evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapies. A very high rate of treatment failure after treatment with dihydroartemisinin-piperaquine was observed in Thailand, Cambodia, and Vietnam. The immediate public health importance of our findings prompted us to report the efficacy data on dihydroartemisinin-piperaquine and its determinants ahead of the results of the overall trial, which will be published later this year.
Patients aged between 2 and 65 years presenting with uncomplicated P falciparum or mixed species malaria at seven sites in Thailand, Cambodia, and Vietnam were randomly assigned to receive dihydroartemisinin-piperaquine with or without mefloquine, as part of the TRACII trial. The primary outcome was the PCR-corrected efficacy at day 42. Next-generation sequencing was used to assess the prevalence of molecular markers associated with artemisinin resistance (kelch13 mutations, in particular Cys580Tyr) and piperaquine resistance (plasmepsin-2 and plasmepsin-3 amplifications and crt mutations). This study is registered with ClinicalTrials.gov, number NCT02453308.
Between Sept 28, 2015, and Jan 18, 2018, 539 patients with acute P falciparum malaria were screened for eligibility, 292 were enrolled, and 140 received dihydroartemisinin-piperaquine. The overall Kaplan-Meier estimate of PCR-corrected efficacy of dihydroartemisinin-piperaquine at day 42 was 50·0% (95% CI 41·1–58·3). PCR-corrected efficacies for individual sites were 12·7% (2·2–33·0) in northeastern Thailand, 38·2% (15·9–60·5) in western Cambodia, 73·4% (57·0–84·3) in Ratanakiri (northeastern Cambodia), and 47·1% (33·5–59·6) in Binh Phuoc (southwestern Vietnam). Treatment failure was associated independently with plasmepsin2/3 amplification status and four mutations in the crt gene (Thr93Ser, His97Tyr, Phe145Ile, and Ile218Phe). Compared with the results of our previous TRACI trial in 2011–13, the prevalence of molecular markers of artemisinin resistance (kelch13 Cys580Tyr mutations) and piperaquine resistance (plasmepsin2/3 amplifications and crt mutations) has increased substantially in the Greater Mekong subregion in the past decade.
Dihydroartemisinin-piperaquine is not treating malaria effectively across the eastern Greater Mekong subregion. A highly drug-resistant P falciparum co-lineage is evolving, acquiring new resistance mechanisms, and spreading. Accelerated elimination of P falciparum malaria in this region is needed urgently, to prevent further spread and avoid a potential global health emergency.
UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and National Institutes of Health.
Background IgE characterizes the humoral response of allergic sensitization but less is known about what modulates its function and why some patients present clinical symptoms for a given IgE level ...and others do not. An IgE response also occurs during helminth diseases, independently of allergic symptoms. This response could be a model of non-functional IgE. Objective To study the IgE response against environmental allergens induced during natural helminth infection. Methods In 28 non allergic subjects from the periphery of Ho Chi Minh city with (H+, n = 18) and without helminth infection (H-, n = 10), we measured IgE and IgG4 against several components of Dermatophagoïdes pteronyssinus (Dpt) and Ascaris (a marker of immunization against nematodes), and determined the IgE component sensitization profile using microarray ISAC biochips. The functional ability of IgE to induce degranulation of cultured mast cells was evaluated in the presence of Dpt. Results Non allergic H+ subjects exhibited higher levels of IgE against Dpt compared to H- subjects. Dpt IgE were not functional in vitro and did not recognize usual Dpt major allergens. IgE recognized other component allergens that belong to different protein families, and most were glycosylated. Depletion of IgE recognizing carbohydrate cross-reactive determinant (CCD) did not induce a reduction in Dpt IgE. The Dpt IgG4 were not significantly different. Conclusion Helminth infections induced IgE against allergens such as Dpt and molecular components that belong to different sources as well as against CCD (such as beta-1,2-xylose and/or âº-1,3-fucose substituted N-glycans). Dpt IgE were not able to induce degranulation of mast cells and were not explained by sensitization to usual major allergens or N-glycans.
Vietnam has a high thalassemia burden. We collected blood samples from 5880 pregnant Vietnamese women during prenatal health checks to assess thalassemia carrier frequency using combined ...gap-polymerase chain reaction (gap-PCR) and targeted next-generation sequencing (NGS). Thalassemia carriers were identified with prevalence of 13.13% (772), including 7.82% (460) carriers of α-thalassemia (α-thal), 5.31% (312) carriers of β-thalassemia (β-thal), and 0.63% (37) concurrent α-/β-thal carriers. Deletional mutations (368) accounted for 80.0% of α-thal carriers, of which, --
SEA
(Southeast Asian) (n = 254; 55.0%) was most prevalent, followed by the -α
3.7
(rightward) (n = 66; 14.0%) and -α
4.2
(leftward) (n = 45; 9.8%) deletions. Hb Westmead (HBA2: c.369C>G) (n = 53) and Hb Constant Spring (Hb CS or HBA2: c.427T>C) (in 28) are the two most common nondeletional α-globin variants, accounting for 11.5 and 6.0% of α-thal carriers. We detected 11 different β-thal genotypes. Hb E (HBB: c.79G>A) (in 211) accounted for 67.6% of β-thal carriers. The most common β-thal genotypes were associated with mutations at codon 17 (A>T) (HBB: c.52A>T), codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), and codon 71/72 (+A) (HBB: c.217_218insA) (prevalence 0.70%, 0.68%, and 0.2%, respectively). Based on mutation frequencies calculated in this study, estimates of 5021 babies in Vietnam are affected with clinically severe thalassemia annually. Our data suggest a higher thalassemia carrier frequency in Vietnam than previously reported. We established that combining NGS with gap-PCR creates an effective large-scale thalassemia screening method that can detect a broad range of mutations.
Background Like other helminths, hookworms (HW) induce a regulatory immune response able to modulate and dampen reactivity of the host to antigens. No data about the evolution of the immune response ...after treatment are available. We aim to phenotype the regulatory immune response during natural HW infection and its evolution after treatment. Methodology Twenty hookworm infected (HW+) and 14 non-infected subjects HW-from endemic area in the periphery of Ho Chi Minh City were included. Blood and feces samples were obtained before, 2 and 4 weeks after treatment with Albendazole 400mg. Additional samples were obtained at 3 and 12 months in the HW+ group. Hematological parameters, Treg (CD4+CD25.sup.hi FoxP3.sup.hi) and surface molecules (CD39, CD62L, ICOS, PD-1, CD45RA) were measured as well as inflammatory and lymphocytes differentiation cytokines such as IL-1beta, IL-6, IFNgamma, IL-4, IL-17, IL-10, IL-2 and TGFbeta. Results HW+ subjects showed higher Treg, TregICOS+, Treg PD1-, TregCD62L+ and CD45RA+FoxP3.sup.lo resting Treg (rTreg). CD45RA-FoxP3.sup.lo non-suppressive Treg cells were also increased. No preferential Th1/Th2 orientation was observed, nor difference for IL-10 between two groups. After treatment, Treg, TregICOS+, TregCD62L+, Treg PD1- and rTreg decreased while IL-4 and IL-6 cytokines increased. Conclusion During HW infection, Treg are increased and characterized by a heterogeneous population: a highly suppressive as well as a non-suppressive T cells phenotype. After treatment, Treg with immune-suppressive phenotype exhibited a decrease parallel to an inflammatory Th2 response.
PurposeWith the focus on the context of small and medium-sized enterprises (SMEs), this study aims to investigate the joint effects of entrepreneurial leadership, entrepreneurial orientation and ...dynamic capabilities and the mechanisms of how these factors influence firm performance.Design/methodology/approachA survey from 319 managers in information and communications technology SMEs in Vietnam was conducted, and structural equation modeling was adopted to analyze the collected data.FindingsThe results confirm that dynamic capabilities directly influence firm performance and serve as a mediator that connects entrepreneurial leadership and entrepreneurial orientation with firm performance. Additionally, entrepreneurial leadership was found to have a significant positive impact on entrepreneurial orientation.Originality/valueThis research augments the understanding of entrepreneurship and dynamic capabilities literature by examining the joint effects and mechanisms of how entrepreneurial leadership, entrepreneurial orientation and dynamic capabilities interact to enhance SMEs' performance. Furthermore, this study provides empirical evidence of the strategies that SMEs should pursue to attain favorable performance outcomes.
The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must ...be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivo MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparum malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparum malaria were allocated sequentially to treatment with a single 30-mg (n = 6), 20-mg (n = 5), 10-mg (n = 7), or 15-mg (n = 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivo MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.).
We investigated the consequences of colistin use in backyard chicken farms in Vietnam by examining the prevalence of mcr-1 in fecal samples from chickens and humans. Detection of mcr-1-carrying ...bacteria in chicken samples was associated with colistin use and detection in human samples with exposure to mcr-1-positive chickens.
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