Summary Background Tuberculosis incidence in the UK has risen in the past decade. Disease control depends on epidemiological data, which can be difficult to obtain. Whole-genome sequencing can detect ...microevolution within Mycobacterium tuberculosis strains. We aimed to estimate the genetic diversity of related M tuberculosis strains in the UK Midlands and to investigate how this measurement might be used to investigate community outbreaks. Methods In a retrospective observational study, we used Illumina technology to sequence M tuberculosis genomes from an archive of frozen cultures. We characterised isolates into four groups: cross-sectional, longitudinal, household, and community. We measured pairwise nucleotide differences within hosts and between hosts in household outbreaks and estimated the rate of change in DNA sequences. We used the findings to interpret network diagrams constructed from 11 community clusters derived from mycobacterial interspersed repetitive-unit–variable-number tandem-repeat data. Findings We sequenced 390 separate isolates from 254 patients, including representatives from all five major lineages of M tuberculosis . The estimated rate of change in DNA sequences was 0·5 single nucleotide polymorphisms (SNPs) per genome per year (95% CI 0·3–0·7) in longitudinal isolates from 30 individuals and 25 families. Divergence is rarely higher than five SNPs in 3 years. 109 (96%) of 114 paired isolates from individuals and households differed by five or fewer SNPs. More than five SNPs separated isolates from none of 69 epidemiologically linked patients, two (15%) of 13 possibly linked patients, and 13 (17%) of 75 epidemiologically unlinked patients (three-way comparison exact p<0·0001). Genetic trees and clinical and epidemiological data suggest that super-spreaders were present in two community clusters. Interpretation Whole-genome sequencing can delineate outbreaks of tuberculosis and allows inference about direction of transmission between cases. The technique could identify super-spreaders and predict the existence of undiagnosed cases, potentially leading to early treatment of infectious patients and their contacts. Funding Medical Research Council, Wellcome Trust, National Institute for Health Research, and the Health Protection Agency.
Summary In 2001, the World Health Assembly (WHA) passed the landmark WHA 54.19 resolution for global scale-up of mass administration of anthelmintic drugs for morbidity control of schistosomiasis and ...soil-transmitted helminthiasis, which affect more than 1·5 billion of the world's poorest people. Since then, more than a decade of research and experience has yielded crucial knowledge on the control and elimination of these helminthiases. However, the global strategy has remained largely unchanged since the original 2001 WHA resolution and associated WHO guidelines on preventive chemotherapy. In this Personal View, we highlight recent advances that, taken together, support a call to revise the global strategy and guidelines for preventive chemotherapy and complementary interventions against schistosomiasis and soil-transmitted helminthiasis. These advances include the development of guidance that is specific to goals of morbidity control and elimination of transmission. We quantify the result of forgoing this opportunity by computing the yearly disease burden, mortality, and lost economic productivity associated with maintaining the status quo. Without change, we estimate that the population of sub-Saharan Africa will probably lose 2·3 million disability-adjusted life-years and US$3·5 billion of economic productivity every year, which is comparable to recent acute epidemics, including the 2014 Ebola and 2015 Zika epidemics. We propose that the time is now to strengthen the global strategy to address the substantial disease burden of schistosomiasis and soil-transmitted helminthiasis.
Abstract Background Epidemiological investigations into Mycobacterium tuberculosis outbreaks use 24-locus genotyping (MIRU-VNTR typing). Where no epidemiological link can be found between patients, ...the importance of shared genotypes remains unclear. This issue is especially problematic and time-consuming when tracing contacts within some social groups at high tuberculosis risk, in which unwillingness to volunteer information is common. We investigated whether whole-genome sequencing (WGS) could delineate outbreaks with greater resolution than MIRU-VNTR typing has done. Methods We sequenced 390 M tuberculosis isolates from 254 patients from the UK Midlands (1994–2011) using Illumina technology ( appendix ). We estimated the expected genomic diversity between isolates within a transmission chain by measuring pairwise nucleotide differences between genomes within hosts (79 individuals with pulmonary and extrapulmonary disease, or multiple pulmonary episodes) and between hosts within 25 household outbreaks (63 individuals). We then investigated 11 MIRU-VNTR-based community clusters (168 patients, 157 transmission events) to assess whether WGS could delineate outbreaks more effectively. For each cluster we reconstructed the most plausible transmission chain based on epidemiological data collected by tuberculosis nurses, pairwise nucleotide distances, and times of diagnosis, and compared the genomic diversity across these constructed links with that within individuals and within household outbreaks. Findings 109 (96%) of 114 isolates were within five SNPs of another isolate taken from the same individual or from an individual in the same household outbreak. On the basis of longitudinal isolates from individuals or households, we estimated an evolutionary rate of 0·5 SNPs per genome per year, consistent with a maximum of five SNPs between related isolates 3 years or less apart. Using a greater than five SNP threshold to assess 11 MIRU-VNTR-based community clusters, we found that none of 69 epidemiologically related pairs of MIRU-VNTR-matched cases plausibly related by transmission, two of 13 possibly related pairs, and 13 of 75 pairs with no known epidemiological relation were separated by more than five SNPs (p<0·0001). Seven MIRU-VNTR-matched pairs with no epidemiological relation had more than 30 SNPs, five of seven belonging to the same immigrant community cluster. WGS also showed that 62 of 75 MIRU-VNTR-matched pairs for which no epidemiological relation had been identified from contact tracing were highly likely to indicate transmission: in one substance misuse cluster, 38 individuals were linked by five or fewer SNPs without a single epidemiological link having been established previously. Further analysis suggested that microevolutionary divergence of lineages within outbreaks could signal possible super-spreaders, corroborated by clinical and epidemiological data in two clusters. Interpretation WGS can delineate tuberculosis outbreaks with greater resolution than has previously been possible. These findings offer public health teams the potential to limit outbreak investigations to patients who are likely to be linked by recent transmission, irrespective of whether it has been possible to identify epidemiological links, and to save resources where they are not, even in the context of matched MIRU-VNTR genotypes. Uniquely, WGS also provides information about the genetic structure of outbreak clusters, thereby providing the potential to direct public health resources towards individuals most likely to have infected the largest number of secondary cases. As a consequence, the Health Protection Agency is considering introduction of WGS technology for routine tuberculosis public health practice in England. Funding NIHR Oxford Biomedical Research Centre and the UKCRC Modernising Medical Microbiology Consortium (UKCRC Translational Infection Research Initiative supported by MRC, Biotechnology and Biological Sciences Research Council, and NIHR on behalf of the Department of Health grant G0800778 and the Wellcome Trust 087646/Z/08/Z ).
Abstract Background Autism spectrum disorder is a complex neurodevelopmental disorder characterized by impaired social interaction and communication, repetitive behaviors, and restricted interests. ...Gray matter differences linked to autism spectrum disorder have been studied using a variety of structural imaging methods, but yielded little consensus; the extent to which disparate results reflect differences in methodology or heterogeneity within autism spectrum disorder is not yet clear. Moreover, very few studies have examined gray matter changes as a function of age in autism spectrum disorder. Method A detailed investigation of gray matter structural development was performed via voxel-based morphometry, cortical thickness, and cortical surface area analyses in 38 autism spectrum disorder versus 46 typically developing children. Results Relative to typically developing children, the autism spectrum disorder group showed gray matter increases most prominently in the frontal and temporal lobes (including regions such as medial frontal gyrus, Broca's area and posterior temporal cortex), as well as certain parietal and occipital subcortical regions. Gray matter decreases were found only near the temporoparietal junction. Subcortical gray matter increases were found in the putamen and caudate nucleus, while decreases were found in cerebellum. There were age-dependent GM differences in distributed regions including prefrontal cortex, primary sensorimotor cortex, and temporoparietal junction. Conclusion The results underline the distributed nature of gray matter structural differences in autism spectrum disorder and provide a more comprehensive characterization of autism spectrum disorder–related cortical and subcortical gray matter structural differences during childhood and adolescent development.
Kidney age, not kidney disease Stevens, Richard J., PhD; Evans, Julie, MSc; Oke, Jason, DPhil ...
CMAJ. Canadian Medical Association journal,
04/2018, Volume:
190, Issue:
13
Journal Article
Peer reviewed
Open access
Stevens et al cite that chronic kidney disease (CKD) stages 1 to 4 are asymptomatic health states. According to previously proposed definitions of disease, they don't meet the criteria for "disease." ...Reduced levels of kidney function, currently called CKD, are not abnormal in older age groups. The label "chronic kidney disease" can be misinterpreted by patients and can be an obstacle to communication. Referring to the stages of "chronic kidney disease" as categories of "kidney age" could improve doctors' ability to communicate, and patients' understanding of, the degree of renal impairment and its implications for health.
Abstract Background Fewer than half of eligible hospitalized medical patients receive appropriate venous thromboembolism (VTE) prophylaxis. One reason for this low rate is the complexity of existing ...risk assessment models. A simple set of easily identifiable risk factors that are highly predictive of VTE among hospitalized medical patients may enhance appropriate thromboprophylaxis. Methods Electronic medical record interrogation was performed to identify medical admissions from January 1, 2000-December 31, 2007 (n = 143,000), and those patients with objectively confirmed VTE during hospitalization or within 90 days following discharge. Putative risk factors most predictive of VTE were identified, and a risk assessment model (RAM) was derived; 46,000 medicine admissions from January 1, 2008-December 31, 2009 served as a validation cohort to test the predictive ability of the RAM. The newly derived RAM was compared with a published VTE assessment tool (Kucher Score). Results Four risk factors: previous VTE; an order for bed rest; peripherally inserted central venous catheterization line; and a cancer diagnosis, were the minimal set most predictive of hospital-associated VTE (area under the receiver operating characteristic curve AUC = 0.874; 95% confidence interval CI, 0.869-0.880). These risk factors upon validation in a separate population (validation cohort) retained an AUC = 0.843; 95% CI, 0.833-0.852. The ability of the 4-element RAM to identify patients at risk of developing VTE within 90 days was superior to the Kucher Score. Conclusions The 4-element RAM identified in this study may be used to identify patients at risk for VTE and improve rates of thromboprophylaxis. This simple and accurate RAM is an alternative to more complicated published VTE risk assessment tools that currently exist.
Summary Background Alleles of the apolipoprotein E (APOE) gene modulate risk for Alzheimer's disease, with carriers of the ε4 allele being at increased risk and carriers of the ε2 allele possibly at ...decreased risk compared with non-carriers. Our aim was to determine whether possession of an ε4 allele would confer children with a neural substrate that might render them at risk for Alzheimer's disease, and whether carriers of the ε2 allele might have a so-called protective cortical morphology. Methods 239 healthy children and adolescents were genotyped and had repeated neuroanatomic MRI (total 530 scans). Mixed model regression was used to determine whether the developmental trajectory of the cortex differed by genotype. Findings Cortical thickness of the left entorhinal region was significantly thinner in ε4 carriers than it was in non-ε4 carriers (3·79 SE 0·06 mm, range 1·54–5·24 vs 3·94 0·03 mm, 2·37–6·11; p=0·03). There was a significant stepwise increase in cortical thickness in the left entorhinal regions, with ε4 carriers having the thinnest cortex and ε2 carriers the thickest, with ε3 homozygotes occupying an intermediate position (left β 0·11 SE 0·05, p=0·02). Neuroanatomic effects seemed fixed and non-progressive, with no evidence of accelerated cortical loss in young healthy ε4 carriers. Interpretation Alleles of the apolipoprotein E gene have distinct neuroanatomic signatures, identifiable in childhood. The thinner entorhinal cortex in individuals with the ε4 allele might contribute to risk of Alzheimer's disease.
Summary Background Despite a recent resurgence in the incidence of bovine tuberculosis in UK cattle herds, no associated rise in the number of cases in man has been noted. Disease due to human ...Mycobacterium bovis infection usually occurs in older patients, in whom drinking unpasteurised milk in the past is the probable source of infection. Person-to-person transmission is very rare. Methods After identification of two epidemiologically-linked cases of human M bovis infection through routine laboratory and surveillance activities, all patients identified with M bovis infection in the Midlands from 2001–05 (n=20) were assessed by DNA fingerprinting (MIRU-VNTR and spoligotyping), with additional interviews for patients with a clustered strain. Findings A cluster of six cases was identified. All clustered cases were young and UK-born; five patients had pulmonary disease, and one patient died due to M bovis meningitis, with four patients possessing factors predisposing to tuberculosis. All patients had common social links through visits to bars in two different areas. With the exception of the first case, there was an absence of zoonotic links or consumption of unpasteurised dairy products, suggesting that person-to-person transmission had occurred. Interpretation This report of several instances of M bovis transmission between people in a modern urban setting emphasises the need to maintain control measures for human and bovine tuberculosis. Transmission and subsequent disease was probably due to a combination of host and environmental factors. Prospective surveillance and DNA fingerprinting identified the cluster, enabling health protection teams to set up control measures and prevent further transmission.
Abstract Background Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography (18 FFDG PET), ...18 FFDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. Objectives This study tested the efficacy of gallium-68-labeled DOTATATE (68 Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2 )-binding PET tracer, for imaging atherosclerotic inflammation. Methods We confirmed68 Ga-DOTATATE binding in macrophages and excised carotid plaques.68 Ga-DOTATATE PET imaging was compared to 18 FFDG PET imaging in 42 patients with atherosclerosis. Results Target SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific68 Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo68 Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval CI: 0.28 to 0.99; p = 0.02).68 Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax ) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range IQR: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003).68 Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve ROC AUC: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and 18 FFDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). 18 FFDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial 18 FFDG spillover rendered coronary 18 FFDG scans uninterpretable in 27 patients (64%). Coronary68 Ga-DOTATATE PET scans were readable in all patients. Conclusions We validated68 Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that68 Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than 18 FFDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography VISION; NCT02021188 )
PDF
