227 research outputs found
Treatment of enteric fever (typhoid and paratyphoid fever) with cephalosporins
Background
Typhoid and paratyphoid (enteric fever) are febrile bacterial illnesses common in many lowâ and middleâincome countries. The World Health Organization (WHO) currently recommends treatment with azithromycin, ciprofloxacin, or ceftriaxone due to widespread resistance to older, firstâline antimicrobials. Resistance patterns vary in different locations and are changing over time. Fluoroquinolone resistance in South Asia often precludes the use of ciprofloxacin. Extensively drugâresistant strains of enteric fever have emerged in Pakistan. In some areas of the world, susceptibility to old firstâline antimicrobials, such as chloramphenicol, has reâappeared. A Cochrane Review of the use of fluoroquinolones and azithromycin in the treatment of enteric fever has previously been undertaken, but the use of cephalosporins has not been systematically investigated and the optimal choice of drug and duration of treatment are uncertain.
Objectives
To evaluate the effectiveness of cephalosporins for treating enteric fever in children and adults compared to other antimicrobials.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, the WHO ICTRP and ClinicalTrials.gov up to 24 November 2021. We also searched reference lists of included trials, contacted researchers working in the field, and contacted relevant organizations.
Selection criteria
We included randomized controlled trials (RCTs) in adults and children with enteric fever that compared a cephalosporin to another antimicrobial, a different cephalosporin, or a different treatment duration of the intervention cephalosporin. Enteric fever was diagnosed on the basis of blood culture, bone marrow culture, or molecular tests.
Data collection and analysis
We used standard Cochrane methods. Our primary outcomes were clinical failure, microbiological failure and relapse. Our secondary outcomes were time to defervescence, duration of hospital admission, convalescent faecal carriage, and adverse effects. We used the GRADE approach to assess certainty of evidence for each outcome.
Main results
We included 27 RCTs with 2231 total participants published between 1986 and 2016 across Africa, Asia, Europe, the Middle East and the Caribbean, with comparisons between cephalosporins and other antimicrobials used for the treatment of enteric fever in children and adults. The main comparisons are between antimicrobials in most common clinical use, namely cephalosporins compared to a fluoroquinolone and cephalosporins compared to azithromycin.
Cephalosporin (cefixime) versus fluoroquinolones
Clinical failure, microbiological failure and relapse may be increased in patients treated with cefixime compared to fluoroquinolones in three small trials published over 14 years ago: clinical failure (risk ratio (RR) 13.39, 95% confidence interval (CI) 3.24 to 55.39; 2 trials, 240 participants; lowâcertainty evidence); microbiological failure (RR 4.07, 95% CI 0.46 to 36.41; 2 trials, 240 participants; lowâcertainty evidence); relapse (RR 4.45, 95% CI 1.11 to 17.84; 2 trials, 220 participants; lowâcertainty evidence). Time to defervescence in participants treated with cefixime may be longer compared to participants treated with fluoroquinolones (mean difference (MD) 1.74 days, 95% CI 0.50 to 2.98, 3 trials, 425 participants; lowâcertainty evidence).
Cephalosporin (ceftriaxone) versus azithromycin
Ceftriaxone may result in a decrease in clinical failure compared to azithromycin, and it is unclear whether ceftriaxone has an effect on microbiological failure compared to azithromycin in two small trials published over 18 years ago and in one more recent trial, all conducted in participants under 18 years of age: clinical failure (RR 0.42, 95% CI 0.11 to 1.57; 3 trials, 196 participants; lowâcertainty evidence); microbiological failure (RR 1.95, 95% CI 0.36 to 10.64, 3 trials, 196 participants; very lowâcertainty evidence). It is unclear whether ceftriaxone increases or decreases relapse compared to azithromycin (RR 10.05, 95% CI 1.93 to 52.38; 3 trials, 185 participants; very lowâcertainty evidence). Time to defervescence in participants treated with ceftriaxone may be shorter compared to participants treated with azithromycin (mean difference of â0.52 days, 95% CI â0.91 to â0.12; 3 trials, 196 participants; lowâcertainty evidence).
Cephalosporin (ceftriaxone) versus fluoroquinolones
It is unclear whether ceftriaxone has an effect on clinical failure, microbiological failure, relapse, and time to defervescence compared to fluoroquinolones in three trials published over 28 years ago and two more recent trials: clinical failure (RR 3.77, 95% CI 0.72 to 19.81; 4 trials, 359 participants; very lowâcertainty evidence); microbiological failure (RR 1.65, 95% CI 0.40 to 6.83; 3 trials, 316 participants; very lowâcertainty evidence); relapse (RR 0.95, 95% CI 0.31 to 2.92; 3 trials, 297 participants; very lowâcertainty evidence) and time to defervescence (MD 2.73 days, 95% CI â0.37 to 5.84; 3 trials, 285 participants; very lowâcertainty evidence). It is unclear whether ceftriaxone decreases convalescent faecal carriage compared to the fluoroquinolone gatifloxacin (RR 0.18, 95% CI 0.01 to 3.72; 1 trial, 73 participants; very lowâcertainty evidence) and length of hospital stay may be longer in participants treated with ceftriaxone compared to participants treated with the fluoroquinolone ofloxacin (mean of 12 days (range 7 to 23 days) in the ceftriaxone group compared to a mean of 9 days (range 6 to 13 days) in the ofloxacin group; 1 trial, 47 participants; lowâcertainty evidence).
Authors' conclusions
Based on very lowâ to lowâcertainty evidence, ceftriaxone is an effective treatment for adults and children with enteric fever, with few adverse effects. Trials suggest that there may be no difference in the performance of ceftriaxone compared with azithromycin, fluoroquinolones, or chloramphenicol. Cefixime can also be used for treatment of enteric fever but may not perform as well as fluoroquinolones.
We are unable to draw firm general conclusions on comparative contemporary effectiveness given that most trials were small and conducted over 20 years previously. Clinicians need to take into account current, local resistance patterns in addition to route of administration when choosing an antimicrobial
Is late-life dependency increasing or not? A comparison of the Cognitive Function and Ageing Studies (CFAS)
Background: Little is known about how dependency levels have changed between generational cohorts of older people. We estimated years lived in different care states at age 65 in 1991 and 2011 and new projections of future demand for care. Methods: Two population-based studies of older people in defined geographical areas conducted two decades apart (the Cognitive Function and Ageing Studies) provided prevalence estimates of dependency in four states: high (24-hour care); medium (daily care); low (less than daily); independent. Years in each dependency state were calculated by Sullivanâs method. To project future demand, the proportions in each dependency state (by age group and sex) were applied to the 2014 England population projections. Findings: Between 1991 and 2011 there were significant increases in years lived from age 65 with low (men:1·7 years, 95%CI 1·0-2·4; women:2·4 years, 95%CI 1·8-3·1) and high dependency (men:0·9 years, 95%CI 0·2-1·7; women:1·3 years, 95%CI 0·5-2·1). The majority of menâs extra years of life were independent (36%) or with low dependency (36%) whilst for women the majority were spent with low dependency (58%), only 5% being independent. There were substantial reductions in the proportions with medium and high dependency who lived in care homes, although, if these dependency and care home proportions remain constant in the future, further population ageing will require an extra 71,000 care home places by 2025. Interpretation: On average older men now spend 2.4 years and women 3.0 years with substantial care needs (medium or high dependency), and most will live in the community. These findings have considerable implications for older peopleâs families who provide the majority of unpaid care, but the findings also supply valuable new information for governments and care providers planning the resources and funding required for the care of their future ageing populations
The CIPAZ study protocol: an open label randomised controlled trial of azithromycin versus ciprofloxacin for the treatment of children hospitalised with dysentery in Ho Chi Minh City, Vietnam
Background: Diarrhoeal disease remains a common cause of illness and death in children <5 years of age. Faecal-oral infection by Shigella spp. causing bacillary dysentery is a leading cause of moderate-to-severe diarrhoea, particularly in low and middle-income countries. In Southeast Asia, S. sonnei predominates and infections are frequently resistant to first-line treatment with the fluoroquinolone, ciprofloxacin. While resistance to all antimicrobials is increasing, there may be theoretical and clinical benefits to prioritizing treatment of bacillary dysentery with the azalide, azithromycin. In this study we aim to measure the efficacy of treatment with azithromycin compared with ciprofloxacin, the current standard of care, for the treatment of children with bacillary dysentery.
Methods and analysis: We will perform a multicentre, open-label, randomized controlled trial of two therapeutic options for the antimicrobial treatment of children hospitalised with dysentery. Children (6â60 months of age) presenting with symptoms and signs of dysentery at Childrenâs Hospital 2 in Ho Chi Minh City will be randomised (1:1) to treatment with either oral ciprofloxacin (15mg/kg/twice daily for 3 days, standard-of-care) or oral azithromycin (10mg/kg/daily for 3 days). The primary endpoint will be the proportion of treatment failure (defined by clinical and microbiological parameters) by day 28 (+3 days) and will be compared between study arms by logistic regression modelling using treatment allocation as the main variable.
Ethics and dissemination: The study protocol (version 1.2 dated 27th December 2018) has been approved by the Oxford Tropical Research Ethics Committee (47â18) and the ethical review boards of Children's Hospital 2 (1341/NÄ2-CÄT). The study has also been approved by the Vietnamese Ministry of Health (5044/QÄ-BYT).
Trial registration: Clinicaltrials.gov: NCT03854929 (February 26th 2019)
An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.
New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers.
A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles.
Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence.
New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact
Developing a predictive modelling capacity for a climate change-vulnerable blanket bog habitat: Assessing 1961-1990 baseline relationships
Aim: Understanding the spatial distribution of high priority habitats and
developing predictive models using climate and environmental variables to
replicate these distributions are desirable conservation goals. The aim of this
study was to model and elucidate the contributions of climate and topography to
the distribution of a priority blanket bog habitat in Ireland, and to examine how
this might inform the development of a climate change predictive capacity for
peat-lands in Ireland.
Methods: Ten climatic and two topographic variables were recorded for grid
cells with a spatial resolution of 1010 km, covering 87% of the mainland
land surface of Ireland. Presence-absence data were matched to these variables
and generalised linear models (GLMs) fitted to identify the main climatic and
terrain predictor variables for occurrence of the habitat. Candidate predictor
variables were screened for collinearity, and the accuracy of the final fitted GLM
was evaluated using fourfold cross-validation based on the area under the curve
(AUC) derived from a receiver operating characteristic (ROC) plot. The GLM
predicted habitat occurrence probability maps were mapped against the actual
distributions using GIS techniques.
Results: Despite the apparent parsimony of the initial GLM using only climatic
variables, further testing indicated collinearity among temperature and precipitation
variables for example. Subsequent elimination of the collinear variables and
inclusion of elevation data produced an excellent performance based on the AUC
scores of the final GLM. Mean annual temperature and total mean annual
precipitation in combination with elevation range were the most powerful
explanatory variable group among those explored for the presence of blanket
bog habitat.
Main conclusions: The results confirm that this habitat distribution in general
can be modelled well using the non-collinear climatic and terrain variables tested
at the grid resolution used. Mapping the GLM-predicted distribution to the
observed distribution produced useful results in replicating the projected
occurrence of the habitat distribution over an extensive area. The methods
developed will usefully inform future climate change predictive modelling for
Irelan
The chemical compound 'Heatin' stimulates hypocotyl elongation and interferes with the Arabidopsis NIT1-subfamily of nitrilases
Temperature passively affects biological processes involved in plant growth. Therefore, it is challenging to study the dedicated temperature signalling pathways that orchestrate thermomorphogenesis, a suite of elongation growth-based adaptations that enhance leaf-cooling capacity. We screened a chemical library for compounds that restored hypocotyl elongation in the pif4-2-deficient mutant background at warm temperature conditions in Arabidopsis thaliana to identify modulators of thermomorphogenesis. The small aromatic compound 'Heatin', containing 1-iminomethyl-2-naphthol as a pharmacophore, was selected as an enhancer of elongation growth. We show that ARABIDOPSIS ALDEHYDE OXIDASES redundantly contribute to Heatin-mediated hypocotyl elongation. Following a chemical proteomics approach, the members of the NITRILASE1-subfamily of auxin biosynthesis enzymes were identified among the molecular targets of Heatin. Our data reveal that nitrilases are involved in promotion of hypocotyl elongation in response to high temperature and Heatin-mediated hypocotyl elongation requires the NITRILASE1-subfamily members, NIT1 and NIT2. Heatin inhibits NIT1-subfamily enzymatic activity in vitro and the application of Heatin accordingly results in the accumulation of NIT1-subfamily substrate indole-3-acetonitrile in vivo. However, levels of the NIT1-subfamily product, bioactive auxin (indole-3-acetic acid), were also significantly increased. It is likely that the stimulation of hypocotyl elongation by Heatin might be independent of its observed interaction with NITRILASE1-subfamily members. However, nitrilases may contribute to the Heatin response by stimulating indole-3-acetic acid biosynthesis in an indirect way. Heatin and its functional analogues present novel chemical entities for studying auxin biology
Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies
A search for the decay
We search for the rare flavor-changing neutral-current decay in a data sample of 82 fb collected with the {\sl BABAR}
detector at the PEP-II B-factory. Signal events are selected by examining the
properties of the system recoiling against either a reconstructed hadronic or
semileptonic charged-B decay. Using these two independent samples we obtain a
combined limit of
at the 90% confidence level. In addition, by selecting for pions rather than
kaons, we obtain a limit of using only the hadronic B reconstruction method.Comment: 7 pages, 8 postscript figures, submitted to Phys. Rev. Let
High-reflectivity broadband distributed Bragg reflector lattice matched to ZnTe
We report on the realization of a high quality distributed Bragg reflector
with both high and low refractive index layers lattice matched to ZnTe. Our
structure is grown by molecular beam epitaxy and is based on binary compounds
only. The high refractive index layer is made of ZnTe, while the low index
material is made of a short period triple superlattice containing MgSe, MgTe,
and ZnTe. The high refractive index step of Delta_n=0.5 in the structure
results in a broad stopband and the reflectivity coefficient exceeding 99% for
only 15 Bragg pairs.Comment: 4 pages, 3 figure
- âŠ