Dengue fever is the most important mosquito-borne viral disease of humans with more than 50 million cases estimated annually in more than 100 countries. Disturbingly, the geographic range of dengue ...is currently expanding and the severity of outbreaks is increasing. Control options for dengue are very limited and currently focus on reducing population abundance of the major mosquito vector, Aedes aegypti. These strategies are failing to reduce dengue incidence in tropical communities and there is an urgent need for effective alternatives. It has been proposed that endosymbiotic bacterial Wolbachia infections of insects might be used in novel strategies for dengue control. For example, the wMelPop-CLA Wolbachia strain reduces the lifespan of adult A. aegypti mosquitoes in stably transinfected lines. This life-shortening phenotype was predicted to reduce the potential for dengue transmission. The recent discovery that several Wolbachia infections, including wMelPop-CLA, can also directly influence the susceptibility of insects to infection with a range of insect and human pathogens has markedly changed the potential for Wolbachia infections to control human diseases. Here we describe the successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion. Under semi-field conditions, the wMel strain increased from an initial starting frequency of 0.65 to near fixation within a few generations, invading A. aegypti populations at an accelerated rate relative to trials with the wMelPop-CLA strain. We also show that wMel and wMelPop-CLA strains block transmission of dengue serotype 2 (DENV-2) in A. aegypti, forming the basis of a practical approach to dengue suppression.
Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases ...where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency <30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation.
The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.
To assess the association of prior ...randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials.
Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.
In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration.
The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.
Among 27 347 postmenopausal women who were randomized in both trials (baseline mean SD age, 63.4 years 7.2 years), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio HR, 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11).
In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.
Using femtosecond time-resolved x-ray diffraction, we directly monitor the coherent lattice dynamics through an ultrafast charge-density-wave-to-metal transition in the prototypical Peierls system ...K(0.3)MoO(3) over a wide range of relevant excitation fluences. While in the low fluence regime we directly follow the structural dynamics associated with the collective amplitude mode; for fluences above the melting threshold of the electronic density modulation we observe a transient recovery of the periodic lattice distortion. We can describe these structural dynamics as a motion along the coordinate of the Peierls distortion triggered by the prompt collapse of electronic order after photoexcitation. The results indicate that the dynamics of a structural symmetry-breaking transition are determined by a high-symmetry excited state potential energy surface distinct from that of the initial low-temperature state.
Background and objectives
Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of ...alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis.
Methods
Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases.
Results
We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system.
Conclusions
Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.
A chronic mismatch of caregiver responsiveness to infant-feeding cues, such as feeding when the infant is not hungry, is hypothesized to have a role in the development of overweight by impairing an ...infant's response to internal states of hunger and satiation. Although this concept of mismatch or discordance has long been acknowledged in scholarly writings, a systematic assessment of the evidence supporting the role of discordant responsiveness during infant feeding in the early origins of overweight is lacking. This review was undertaken to assess evidence for this hypothesized relationship between discordant responsiveness in feeding and overweight in infancy and toddlerhood, framed within the larger social-environmental context of the infant–caregiver dyad. A systematic method was used to extract articles from three databases of the medical, psychology and nursing fields. The quality of evidence collected was assessed using Oxford University Centre for Evidence Based Medicine's level of evidence and through a narrative review. The systematic search resulted in only nine original research studies, which met a priori inclusion/exclusion criteria. Several studies provide support for the conceptual model, but most were cross-sectional or lower quality prospective studies. The need for consistent definitions, improved measures and longitudinal work is discussed. In conclusion, this review reveals preliminary support for the proposed role of discordant responsiveness in infant/child overweight and at the same time highlights the need for rigorous investigation of responsive feeding interactions in the first years of life.
AIM: Granite outcrops are prominent throughout the world and harbour many endemic species. Their topographic complexity and range of environments have led to the hypothesis that they act as refugia ...facilitating the persistence of species through climate change. We evaluate this hypothesis by investigating the phylogeographic patterns in a common granite endemic shrub. LOCATION: Granite outcrops of the Southwest Australian Floristic Region. METHODS: Chloroplast haplotypes of 89 Kunzea pulchella individuals from 16 granite outcrops were determined from sequences of three chloroplast intergenic spacer regions. Phylogenetic reconstruction and divergence dating was inferred using Bayesian and Parsimony analyses and phylogenetic relationships between haplotypes were examined in relation to geographic distributions. Nuclear diversity and differentiation of populations were assessed through analysis of 11 nuclear microsatellite loci across 384 individuals from the 16 granite outcrops. RESULTS: Kunzea pulchella exhibited low haplotype and allelic diversity within outcrops and high levels of divergence among outcrops, indicating an ancient restriction to specific outcrops with genetic drift as the main driver of evolution. Two divergent lineages were revealed in the chloroplast phylogeny dating to the Pliocene and potentially reflecting the initial impact of increased aridity prior to isolation on individual outcrops. MAIN CONCLUSIONS: Rather than uncovering the typical pattern for Pleistocene refugia with contraction to, and expansion from particular granite outcrops, we observed persistence, prolonged isolation and divergence of populations. We suggest the persistence of K. pulchella on multiple outcrops through a period of considerable climatic change may be a result of broad climatic tolerances or contraction and expansion dynamics operating at microrefugial scales within outcrops. Our observations of low haplotype and allelic diversity within populations of K. pulchella provide some support for the latter. The enduring nature of K. pulchella and evolutionary potential of populations on individual outcrops accentuates the value of these environments for biodiversity conservation planning in a changing climate.
In topological quantum materials the conduction and valence bands are connected at points or along lines in the momentum space. A number of studies have demonstrated that several materials are indeed ...Dirac/Weyl semimetals. However, there is still no experimental confirmation of materials with line nodes, in which the Dirac nodes form closed loops in the momentum space. Here we report the discovery of a novel topological structure--Dirac node arcs--in the ultrahigh magnetoresistive material PtSn4 using laser-based angle-resolved photoemission spectroscopy data and density functional theory calculations.
Substantial evidence suggests that people with type 2 diabetes have an increased risk of developing several types of cancers. These associations may be due to a number of direct and indirect ...mechanisms. Observational studies of these associations, including the potential role for glucose-lowering therapy, are being increasingly reported, but face a number of methodological challenges. This paper is the first of two review papers addressing methodological aspects underpinning the interpretations of links between diabetes and cancer, and suggests potential approaches to study designs to be considered in observational studies. This paper reviews factors related to cancer incidence in the diabetic population; the second paper relates to studies of cancer mortality.
Aim
To determine whether using HbA1c for screening and management could be confounded by age differences, whether age effects can be explained by unrecognized diabetes and prediabetes, insulin ...resistance or postprandial hyperglycaemia, and whether the effects of aging have an impact on diagnostic accuracy.
Methods
We conducted a cross‐sectional analysis in adults without known diabetes in the Screening for Impaired Glucose Tolerance (SIGT) study 2005–2008 (n=1573) and the National Health and Nutrition Examination Survey (NHANES) 2005–2006 (n=1184).
Results
Both glucose intolerance and HbA1c levels increased with age. In univariate analyses including all subjects, HbA1c levels increased by 0.93 mmol/mol (0.085%) per 10 years of age in the SIGT study and by 1.03 mmol/mol (0.094%) per 10 years in the NHANES; in both datasets, the HbA1c increase was 0.87 mmol/mol (0.08%) per 10 years in subjects without diabetes, and 0.76 mmol/mol (0.07%) per 10 years in subjects with normal glucose tolerance, all P<0.001. In multivariate analyses of subjects with normal glucose tolerance, the relationship between age and HbA1c remained significant (P<0.001) after adjustment for covariates including race, BMI, waist circumference, sagittal abdominal diameter, triglyceride/HDL ratio, and fasting and 2‐h plasma glucose and other glucose levels, as assessed by an oral glucose tolerance test. In both datasets, the HbA1c of an 80‐year‐old individual with normal glucose tolerance would be 3.82 mmol/mol (0.35%) greater than that of a 30‐year‐old with normal glucose tolerance, a difference that is clinically significant. Moreover, the specificity of HbA1c‐based diagnostic criteria for prediabetes decreased substantially with increasing age (P<0.0001).
Conclusions
In two large datasets, using different methods to measure HbA1c, the association of age with higher HbA1c levels: was consistent and similar; was both statistically and clinically significant; was unexplained by features of aging; and reduced diagnostic specificity. Age should be taken into consideration when using HbA1c for the diagnosis and management of diabetes and prediabetes.
What's new?
Measures of HbA1c are used for screening and management, but HbA1c levels rise with increasing age.
Higher HbA1c levels with increasing age cannot be attributed to unrecognized diabetes or prediabetes, postprandial hyperglycaemia or insulin resistance.
Differences in HbA1c levels with age are substantial: levels are 3.82 mmol/mol (0.35%) greater for an 80‐year‐old than for a 30‐year‐old individual, with the same glucose levels.
The specificity of HbA1c‐based criteria for prediabetes decreases with increasing age.
Screening with HbA1c will tend to overdiagnose diabetes and prediabetes in older patients.
Guiding management based only on HbA1c levels might increase hypoglycaemia in older patients.
Practitioners should monitor glucose as well as HbA1c levels.
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