Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial

Background Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is diffi cult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. Method We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1–65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecifi ed in the protocol and the statistical analysis plan. All analyses were done on the intention-totreat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. Findings Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics within 14 days was 581 (64%) of 902 patients in the C-reactive protein group versus 738 (78%) of 947 patients in the control group (odds ratio [OR] 0·49, 95% CI 0·40–0·61; p<0·0001). Highly signifi cant diff erences were seen in both children and adults, with substantial heterogeneity of the intervention eff ect across the 10 sites (I²=84%, 95% CI 66–96). 140 patients in the C-reactive protein group and 137 patients in the routine care group missed the urine test on day 3, 4, or 5. Antibiotic activity in urine on day 3, 4, or 5 was found in 267 (30%) of 877 patients in the C-reactive protein group versus 314 (36%) of 882 patients in the routine treatment group (OR 0·78, 95% CI 0·63–0·95; p=0·015). Time to resolution of symptoms was similar in both groups. Adverse events were rare, with no deaths and a total of 14 hospital admissions (six in the C-reactive protein group and eight in the control group). Interpretation C-reactive protein point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients’ recovery in primary health care in Vietnam. Health-care providers might have become familiar with the clinical picture of low C-reactive protein, leading to reduction in antibiotic prescribing in both groups, but this would have led to a reduction in observed eff ect, rather than overestimation. Qualitative analysis is needed to address diff erences in context in order to implement this strategy to improve rational antibiotic use for patients with acute respiratory infection in low-income and middle-income countries

The N=14 shell closure in 22^{22}O viewed through a neutron sensitive probe

NESTER PTHInternational audienceTo investigate the behavior of the N=14 neutron gap far from stability with a neutron-sensitive probe, proton elastic and 2+1 inelastic scattering angular distributions for the neutron-rich nucleus 22O were measured with a secondary beam intensity of only 1200 particles per second using the MUST silicon strip detector array at the GANIL facility. A phenomenological analysis yields a deformation parameter bp;p' = 0.26 +- 0.04 for the 2+1 state, much lower than in 20O, showing a surprisingly weak neutron contribution to this state. A fully microscopic analysis was performed using optical potentials obtained from matter and transition densities generated by continuum Skyrme-HFB and QRPA calculations, respectively. When the present results and those from a 22O + 197Au scattering experiment are combined, the ratio of neutron to proton contributions to the 2+1 state is found close to the N/Z ratio, demonstrating a strong N=14 shell closure in the vicinity of the neutron drip-line

Inference of reticulate evolutionary histories by maximum likelihood: the performance of information criteria

Background: Maximum likelihood has been widely used for over three decades to infer phylogenetic trees from molecular data. When reticulate evolutionary events occur, several genomic regions may have conflicting evolutionary histories, and a phylogenetic network may provide a more adequate model for representing the evolutionary history of the genomes or species. A maximum likelihood (ML) model has been proposed for this case and accounts for both mutation within a genomic region and reticulation across the regions. However, the performance of this model in terms of inferring information about reticulate evolution and properties that affect this performance have not been studied. Results: In this paper, we study the effect of the evolutionary diameter and height of a reticulation event on its identifiability under ML. We find both of them, particularly the diameter, have a significant effect. Further, we find that the number of genes (which can be generalized to the concept of "non-recombining genomic regions") that are transferred across a reticulation edge affects its detectability. Last but not least, a fundamental challenge with phylogenetic networks is that they allow an arbitrary level of complexity, giving rise to the model selection problem. We investigate the performance of two information criteria, the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC), for addressing this problem. We find that BIC performs well in general for controlling the model complexity and preventing ML from grossly overestimating the number of reticulation events. Conclusion: Our results demonstrate that BIC provides a good framework for inferring reticulate evolutionary histories. Nevertheless, the results call for caution when interpreting the accuracy of the inference particularly for data sets with particular evolutionary features

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Modelling the COVID-19 pandemic in context : An international participatory approach

Funding RA is funded by the Bill and Melinda Gates Foundation (OPP1193472). LW is funded by the Li Ka Shing Foundation. CF is funded by grant #2017/26770-8, São Paulo Research Foundation (FAPESP). The CoMo Consortium has support from the Oxford University COVID-19 Research Response Fund (ref: 0009280). Scientific writing assistance and editorial support was provided by Adam Bodley, according to Good Publication Practice guidelines.Peer reviewedPublisher PD

ASEAN's unchanged melody? The theory and practice of 'non-interference' in Southeast Asia

This is an Author's Accepted Manuscript of an article published as Jones, Lee. (2010). ASEAN's unchanged melody? The theory and practice of 'non-interference' in Southeast Asia. Pacific Review 23:4, 479-502 as published in PACIFIC REVIEW 2010 © Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/09512748.2010.49599

Analysis of the dihydrofolate reductase-thymidylate synthase gene sequences in Plasmodium vivax field isolates that failed chloroquine treatment

<p>Abstract</p> <p>Background</p> <p>To use pyrimethamine as an alternative anti-malarial drug for chloroquine-resistant malaria parasites, it was necessary to determine the enzyme's genetic variation in dihydrofolate reductase-thymidylate syntase (DHFR-TS) among Korean strains.</p> <p>Methods</p> <p>Genetic variation of <it>dhfr-ts </it>genes of <it>Plasmodium vivax </it>clinical isolates from patients who did not respond to drug treatment (<it>n </it>= 11) in Korea were analysed. The genes were amplified using the polymerase chain reaction (PCR) with genomic DNA as a template.</p> <p>Results</p> <p>Sequence analysis showed that the open reading frame (ORF) of 1,857 nucleotides encoded a deduced protein of 618 amino acids (aa). Alignment with the DHFR-TS genes of other malaria parasites showed that a 231-residue DHFR domain and a 286-residue TS domain were seperated by a 101-aa linker region. This ORF shows 98.7% homology with the <it>P. vivax </it>Sal I strain (XM001615032) in the DHFR domain, 100% in the linker region and 99% in the TS domain. Comparison of the DHFR sequences from pyrimethamine-sensitive and pyrimethamine-resistant <it>P. vivax </it>isolates revealed that nine isolates belonged to the sensitive strain, whereas two isolates met the criteria for resistance. In these two isolates, the amino acid at position 117 is changed from serine to asparagine (S117N). Additionally, all Korean isolates showed a deletion mutant of THGGDN in short tandem repetitive sequences between 88 and 106 amino acid.</p> <p>Conclusions</p> <p>These results suggest that sequence variations in the DHFR-TS represent the prevalence of antifolate-resistant <it>P. vivax </it>in Korea. Two of 11 isolates have the Ser to Asn mutation in codon 117, which is the major determinant of pyrimethamine resistance in <it>P. vivax</it>. Therefore, the introduction of pyrimethamine for the treatment of chloroquine-resistant vivax malaria as alternative drug in Korea should be seriously considered.</p

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div

Shedding Light on The Role of Keratinocyte-Derived Extracellular Vesicles on Skin-Homing Cells

Extracellular vesicles (EVs) are secretory lipid membranes with the ability to regulate cellular functions by exchanging biological components between different cells. Resident skin cells such as keratinocytes, fibroblasts, melanocytes, and inflammatory cells can secrete different types of EVs depending on their biological state. These vesicles can influence the physiological properties and pathological processes of skin, such as pigmentation, cutaneous immunity, and wound healing. Since keratinocytes constitute the majority of skin cells, secreted EVs from these cells may alter the pathophysiological behavior of other skin cells. This paper reviews the contents of keratinocyte-derived EVs and their impact on fibroblasts, melanocytes, and immune cells to provide an insight for better understanding of the pathophysiological mechanisms of skin disorders and their use in related therapeutic approaches