Zeatin- and polyamine-induced nitric oxide biosynthesis in Arabidopsis thaliana seedlings and its role in signal transduction

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Mass drug administration for the acceleration of malaria elimination in a region of Myanmar with artemisinin-resistant falciparum malaria: a cluster-randomised trial

Background: To contain multidrug-resistant Plasmodium falciparum, malaria elimination in the Greater Mekong subregion needs to be accelerated while current antimalarials remain effective. We evaluated the safety, effectiveness, and potential resistance selection of dihydroartemisinin–piperaquine mass drug administration (MDA) in a region with artemisinin resistance in Myanmar. Methods: We did a cluster-randomised controlled trial in rural community clusters in Kayin (Karen) state in southeast Myanmar. Malaria prevalence was assessed using ultrasensitive quantitative PCR (uPCR) in villages that were operationally suitable for MDA (villages with community willingness, no other malaria control campaigns, and a population of 50–1200). Villages were eligible to participate if the prevalence of malaria (all species) in adults was greater than 30% or P falciparum prevalence was greater than 10% (or both). Contiguous villages were combined into clusters. Eligible clusters were paired based on P falciparum prevalence (estimates within 10%) and proximity. Community health workers provided routine malaria case management and distributed long-lasting insecticidal bed-nets (LLINs) in all clusters. Randomisation of clusters (1:1) to the MDA intervention group or control group was by public coin-flip. Group allocations were not concealed. Three MDA rounds (3 days of supervised dihydroartemisinin–piperaquine [target total dose 7 mg/kg dihydroartemisinin and 55 mg/kg piperaquine] and single low-dose primaquine [target dose 0·25 mg base per kg]) were delivered to intervention clusters. Parasitaemia prevalence was assessed at 3, 5, 10, 15, 21, 27, and 33 months. The primary outcomes were P falciparum prevalence at months 3 and 10. All clusters were included in the primary analysis. Adverse events were monitored from the first MDA dose until 1 month after the final dose, or until resolution of any adverse event occurring during follow-up. This trial is registered with ClinicalTrials.gov, NCT01872702. Findings: Baseline uPCR malaria surveys were done in January, 2015, in 43 villages that were operationally suitable for MDA (2671 individuals). 18 villages met the eligibility criteria. Three villages in close proximity were combined into one cluster because a border between them could not be defined. This gave a total of 16 clusters in eight pairs. In the intervention clusters, MDA was delivered from March 4 to March 17, from March 30 to April 10, and from April 27 to May 10, 2015. The weighted mean absolute difference in P falciparum prevalence in the MDA group relative to the control group was −10·6% (95% CI −15·1 to −6·1; p=0·0008) at month 3 and −4·5% (−10·9 to 1·9; p=0·14) at month 10. At month 3, the weighted P falciparum prevalence was 1·4% (0·6 to 3·6; 12 of 747) in the MDA group and 10·6% (7·0 to 15·6; 56 of 485) in the control group. Corresponding prevalences at month 10 were 3·2% (1·5 to 6·8; 34 of 1013) and 5·8% (2·5 to 12·9; 33 of 515). Adverse events were reported for 151 (3·6%) of 4173 treated individuals. The most common adverse events were dizziness (n=109) and rash or itching (n=20). No treatment-related deaths occurred. Interpretation: In this low-transmission setting, the substantial reduction in P falciparum prevalence resulting from support of community case management was accelerated by MDA. In addition to supporting community health worker case management and LLIN distribution, malaria elimination programmes should consider using MDA to reduce P falciparum prevalence rapidly in foci of higher transmission. Funding: The Global Fund to Fight AIDS, Tuberculosis and Malaria

Effect of point-of-care C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar : an open-label, randomised, controlled trial

Background In southeast Asia, antibiotic prescription in febrile patients attending primary care is common, and a probable contributor to the high burden of antimicrobial resistance. The objective of this trial was to explore whether C-reactive protein (CRP) testing at point of care could rationalise antibiotic prescription in primary care, comparing two proposed thresholds to classify CRP concentrations as low or high to guide antibiotic treatment. Methods We did a multicentre, open-label, randomised, controlled trial in participants aged at least 1 year with a documented fever or a chief complaint of fever (regardless of previous antibiotic intake and comorbidities other than malignancies) recruited from six public primary care units in Thailand and three primary care clinics and one outpatient department in Myanmar. Individuals were randomly assigned using a computer-based randomisation system at a ratio of 1:1:1 to either the control group or one of two CRP testing groups, which used thresholds of 20 mg/L (group A) or 40 mg/L CRP (group B) to guide antibiotic prescription. Health-care providers were masked to allocation between the two intervention groups but not to the control group. The primary outcome was the prescription of any antibiotic from day 0 to day 5 and the proportion of patients who were prescribed an antibiotic when CRP concentrations were above and below the 20 mg/L or 40 mg/L thresholds. The primary outcome was analysed in the intention-to-treat and per-protocol populations. The trial is registered with ClinicalTrials.gov, number NCT02758821, and is now completed. Findings Between June 8, 2016, and Aug 25, 2017, we recruited 2410 patients, of whom 803 patients were randomly assigned to CRP group A, 800 to CRP group B, and 807 to the control group. 598 patients in CRP group A, 593 in CRP group B, and 767 in the control group had follow-up data for both day 5 and day 14 and had been prescribed antibiotics (or not) in accordance with test results (per-protocol population). During the trial, 318 (39%) of 807 patients in the control group were prescribed an antibiotic by day 5, compared with 290 (36%) of 803 patients in CRP group A and 275 (34%) of 800 in CRP group B. The adjusted odds ratio (aOR) of 0·80 (95% CI 0·65–0·98) and risk difference of −5·0 percentage points (95% CI −9·7 to −0·3) between group B and the control group were significant, although lower than anticipated, whereas the reduction in prescribing in group A compared with the control group was not significant (aOR 0·86 [0·70–1·06]; risk difference −3·3 percentage points [–8·0 to 1·4]). Patients with high CRP concentrations in both intervention groups were more likely to be prescribed an antibiotic than in the control group (CRP ≥20 mg/L: group A vs control group, p<0·0001; CRP ≥40 mg/L: group B vs control group, p<0·0001), and those with low CRP concentrations were more likely to have an antibiotic withheld (CRP <20 mg/L: group A vs control group, p<0·0001; CRP <40 mg/L: group B vs control group, p<0·0001). 24 serious adverse events were recorded, consisting of 23 hospital admissions and one death, which occurred in CRP group A. Only one serious adverse event was thought to be possibly related to the study (a hospital admission in CRP group A). Interpretation In febrile patients attending primary care, testing for CRP at point of care with a threshold of 40 mg/L resulted in a modest but significant reduction in antibiotic prescribing, with patients with high CRP being more likely to be prescribed an antibiotic, and no evidence of a difference in clinical outcomes. This study extends the evidence base from lower-income settings supporting the use of CRP tests to rationalise antibiotic use in primary care patients with an acute febrile illness. A key limitation of this study is the individual rather than cluster randomised study design which might have resulted in contamination between the study groups, reducing the effect size of the intervention

Observational study of adult respiratory infections in primary care clinics in Myanmar: understanding the burden of melioidosis, tuberculosis and other infections not covered by empirical treatment regimes.

BACKGROUND: Lower respiratory infections constitute a major disease burden worldwide. Treatment is usually empiric and targeted towards typical bacterial pathogens. Understanding the prevalence of pathogens not covered by empirical treatment is important to improve diagnostic and treatment algorithms. METHODS: A prospective observational study in peri-urban communities of Yangon, Myanmar was conducted between July 2018 and April 2019. Sputum specimens of 299 adults presenting with fever and productive cough were tested for Mycobacterium tuberculosis (microscopy and GeneXpert MTB/RIF [Mycobacterium tuberculosis/resistance to rifampicin]) and Burkholderia pseudomallei (Active Melioidosis Detect Lateral Flow Assay and culture). Nasopharyngeal swabs underwent respiratory virus (influenza A, B, respiratory syncytial virus) polymerase chain reaction testing. RESULTS: Among 299 patients, 32% (95% confidence interval [CI] 26 to 37) were diagnosed with tuberculosis (TB), including 9 rifampicin-resistant cases. TB patients presented with a longer duration of fever (median 14 d) and productive cough (median 30 d) than non-TB patients (median fever duration 6 d, cough 7 d). One case of melioidosis pneumonia was detected by rapid test and confirmed by culture. Respiratory viruses were detected in 16% (95% CI 12 to 21) of patients. CONCLUSIONS: TB was very common in this population, suggesting that microscopy and GeneXpert MTB/RIF on all sputum samples should be routinely included in diagnostic algorithms for fever and cough. Melioidosis was uncommon in this population

Non-contact tests for identifying people at risk of primary angle closure glaucoma

BACKGROUND: Primary angle closure glaucoma (PACG) accounts for 50% of glaucoma blindness worldwide. More than three-quarters of individuals with PACG reside in Asia. In these populations, PACG often develops insidiously leading to chronically raised intraocular pressure and optic nerve damage, which is often asymptomatic. Non-contact tests to identify people at risk of angle closure are relatively quick and can be carried out by appropriately trained healthcare professionals or technicians as a triage test. If the test is positive, the person will be referred for further specialist assessment. OBJECTIVES: To determine the diagnostic accuracy of non-contact tests (limbal anterior chamber depth (LACD) (van Herick test); oblique flashlight test; scanning peripheral anterior chamber depth analyser (SPAC), Scheimpflug photography; anterior segment optical coherence tomography (AS-OCT), for identifying people with an occludable angle. SEARCH METHODS: We searched the following bibliographic databases 3 October 2019: CENTRAL; MEDLINE; Embase; BIOSIS; OpenGrey; ARIF and clinical trials registries. The searches were limited to remove case reports. There were no date or language restrictions in the searches. SELECTION CRITERIA: We included prospective and retrospective cross-sectional, cohort and case-control studies conducted in any setting that evaluated the accuracy of one or more index tests for identifying people with an occludable angle compared to a gonioscopic reference standard. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and quality assessment using QUADAS2 for each study. For each test, 2 x 2 tables were constructed and sensitivity and specificity were calculated. When four or more studies provided data at fixed thresholds for each test, we fitted a bivariate model using the METADAS macro in SAS to calculate pooled point estimates for sensitivity and specificity. For comparisons between index tests and subgroups, we performed a likelihood ratio test comparing the model with and without the covariate. MAIN RESULTS: We included 47 studies involving 26,151 participants and analysing data from 23,440. Most studies were conducted in Asia (36, 76.6%). Twenty-seven studies assessed AS-OCT (analysing 15,580 participants), 17 studies LACD (7385 participants), nine studies Scheimpflug photography (1616 participants), six studies SPAC (5239 participants) and five studies evaluated the oblique flashlight test (998 participants). Regarding study quality, 36 of the included studies (76.6%) were judged to have a high risk of bias in at least one domain.The use of a case-control design (13 studies) or inappropriate exclusions (6 studies) raised patient selection concerns in 40.4% of studies and concerns in the index test domain in 59.6% of studies were due to lack of masking or post-hoc determination of optimal thresholds. Among studies that did not use a case-control design, 16 studies (20,599 participants) were conducted in a primary care/community setting and 18 studies (2590 participants) in secondary care settings, of which 15 investigated LACD. Summary estimates were calculated for commonly reported parameters and thresholds for each test; LACD ≤ 25% (16 studies, 7540 eyes): sensitivity 0.83 (95% confidence interval (CI) 0.74, 0.90), specificity 0.88 (95% CI 0.84, 0.92) (moderate-certainty); flashlight (grade1) (5 studies, 1188 eyes): sensitivity 0.51 (95% CI 0.25, 0.76), specificity 0.92 (95% CI 0.70, 0.98) (low-certainty); SPAC (≤ 5 and/or S or P) (4 studies, 4677 eyes): sensitivity 0.83 (95% CI 0.70, 0.91), specificity 0.78 (95% CI 0.70, 0.83) (moderate-certainty); Scheimpflug photography (central ACD) (9 studies, 1698 eyes): sensitivity 0.92 (95% CI 0.84, 0.96), specificity 0.86 (95% CI 0.76, 0.93) (moderate-certainty); AS-OCT (subjective opinion of occludability) (13 studies, 9242 eyes): sensitivity 0.85 (95% CI 0.76, 0.91); specificity 0.71 (95% CI 0.62, 0.78) (moderate-certainty). For comparisons of sensitivity and specificity between index tests we used LACD (≤ 25%) as the reference category. The flashlight test (grade 1 threshold) showed a statistically significant lower sensitivity than LACD (≤ 25%), whereas AS-OCT (subjective judgement) had a statistically significant lower specificity. There were no statistically significant differences for the other index test comparisons. A subgroup analysis was conducted for LACD (≤ 25%), comparing community (7 studies, 14.4% prevalence) vs secondary care (7 studies, 42% prevalence) settings. We found no evidence of a statistically significant difference in test performance according to setting. Performing LACD on 1000 people at risk of angle closure with a prevalence of occludable angles of 10%, LACD would miss about 17 cases out of the 100 with occludable angles and incorrectly classify 108 out of 900 without angle closure. AUTHORS' CONCLUSIONS: The finding that LACD performed as well as index tests that use sophisticated imaging technologies, confirms the potential for this test for case-detection of occludable angles in high-risk populations. However, methodological issues across studies may have led to our estimates of test accuracy being higher than would be expected in standard clinical practice. There is still a need for high-quality studies to evaluate the performance of non-invasive tests for angle assessment in both community-based and secondary care settings

Implementation of Finite Field Arithmetic Operations for Large Prime and Binary Fields Using java BigInteger class

Many cryptographic protocols are based on thedifficulty of factoring large composite integers or a relatedproblem. Therefore, we implement the finite field arithmeticoperations for large prime and binary fields by using javaBigInteger class to study our research under large integers forpublic key cryptosystems and elliptic curve

Attack Experiments on Elliptic Curves of Prime and Binary Fields

At the beginning the paper describes the basic properties of finite fieldarithmetic and elliptic curve arithmetic over prime and binary fields. Then it discussesthe elliptic curve discrete logarithm problem and its properties. We study the BabyStep, Giant-Step method, Pollard’s rho method and Pohlig–Hellman method, knownas general methods that can exploit the elliptic curve discrete logarithm problem,and describe in detail attack experiments using these methods over prime and binaryfields. Finally, the paper discusses the expected running time of these attacks andsuggests the strong elliptic curves that are not vulnerable to these attacks

Experiments on Implementation of Elliptic Curve Arithmetic over Complex Fields Using java BigInteger Class

Elliptic curve cryptosystems are nowadays widelyused in public communication channels for network security.Their security depends on the complexity of solving the ellipticcurve discrete logarithm problem. But, there are several generalattacks in them. Elliptic curve arithmetic is implemented overcomplex fields to improve the security of elliptic curvecryptosystems. This paper begins the characteristics of ellipticcurve cryptosystems and their security services. Then wediscuss finite field arithmetic and its properties, prime fieldarithmetic, binary field arithmetic and complex numberarithmetic, and elliptic curve arithmetic over prime field andbinary field. This paper proposes how to implement complexnumber arithmetic under prime field and binary field using javaBigInteger class and we implement elliptic curve arithmetic andelliptic curve cryptosystems using complex numbers over primefield and binary field and discuss the experiments that got fromour implementations

A Complex Number Approach to Elliptic Curve Cryptosystems over Finite Fields: Implementations and Experiments

Network security is a general idea to ensureinformation transmission over PC and portable systems. Ellipticcurve cryptosystems are nowadays widely used in publiccommunication channels for network security. Their securityrelies upon the complexity of clarifying the elliptic curve discretealogarithm issue. But, there are several general attacks in them.Elliptic bend number juggling is actualized over complex fields toenhance the security of elliptic curve cryptosystems. This paperstarts with the qualities of elliptic curve cryptosystems and theirsecurity administrations. At that point we talk about limited fieldnumber-crunching and its properties, prime field numbercrunching, twofold field math and complex number-crunching,and elliptic bend number-crunching over prime field and parallelfield. This paper proposes how to execute the unpredictablenumber of math under prime field and double field utilizing javaBigInteger class. also, we actualize elliptic bend math and ellipticbend cryptosystems utilizing complex numbers over prime fieldand double field and talk about our trials that got from the usage