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Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.
To develop a regime of care for patients with head and neck cancers undergoing intensity-modulated radiotherapy (IMRT), with the support of a health advisor (HA) and temporary access to the mouth care product Caphosol™.
Materials and methods
A HA was temporarily employed to assess, monitor and refer patients as appropriate and ensure patients received and utilised supplies of Caphosol™. A retrospective audit was undertaken to provide a gap analysis of current service. The data were used to develop a pro forma for documenting assessments and monitoring lifestyle factors for IMRT patients. Assessments referrals and compliance, plus hospital admissions owing to treatment-related issues, were documented during the baseline audit and the temporary HA service and provision of Caphosol™.
The presence of a HA facilitated 100% compliance with appropriate assessments, referrals and adherence to treatment. The data suggests that the additional provision of Caphosol™ may have reduced levels of mucositis and associated pain.
It is recommended that a HA role be established within radiotherapy departments to facilitate lifestyle assessments, referrals and compliance with positive behaviour changes (e.g., stopping smoking). The use of Caphosol™ as a routine part of mouth care regime for IMRT patients also warrants further investigation.
In a cross-sectional study, data from records of cattle slaughtered over a 1-year period at a large abattoir in South West England were analysed using an ordered category response model to investigate the inter-relationships between age, sex and breed on development of the permanent anterior (PA) teeth. Using the model, transition points at which there was a 50% probability of membership of each category of paired PA teeth were identified. Data from ∼60 000 animals were initially analysed for age and sex effect. The age transition was found to be ∼23 months moving from zero to two teeth; 30 months for two to four teeth; 37 months for four to six teeth and 42 months for six to eight teeth. Males were found to develop, on average, ∼22 days earlier than females across all stages. A reduced data set of ∼23 000 animals registered as pure-bred only was used to compare breed and type interactions and to investigate sex effects within the sub-categories. Breeds were grouped into dairy and beef-type and beef breeds split into native and continental. It was found that dairy-types moved through the transition points earlier than beef-types across all stages (interval varying between ∼8 and 12 weeks) and that collectively, native beef breeds moved through the transition points by up to 3 weeks earlier than the continental beef breeds. Interestingly, in contrast to beef animals, dairy females matured before dairy males. However, the magnitude of the difference between dairy females and males diminished at the later stages of development. Differences were found between breeds. Across the first three stages, Ayrshires and Guernseys developed between 3 and 6 weeks later than Friesian/Holsteins and Simmental, Limousin and Blonde Aquitaine 6 and 8 weeks later than Aberdeen Angus. Herefords, Charolais and South Devon developed later but by a smaller interval and Red Devon and Galloway showed the largest individual effect with transition delayed by 8 to 12 weeks.
Neurological soft signs (NSS) have been inconsistently reported in obsessive-compulsive disorder (OCD) but may make an impact on treatment response.
The current study examined the presence of NSS in two independent European samples of OCD patients (combined 85 patients and 88 matched healthy controls) using a standardized instrument and conducted a meta-analysis of all published studies identified in the literature with the aim to provide a more definitive answer to the question of whether OCD patients are characterized by increased NSS.
Both empirical studies found elevated NSS scores in patients compared with matched controls. The results of the meta-analysis, which included 15 studies (combined 498 patients and 520 controls) showed large effect sizes (Hedges' g=1.27, 95% confidence interval 0.80–1.75), indicating that OCD patients have significantly higher rates of NSS than matched controls on both sides of the body and in multiple domains (motor coordination, sensory integration and primitive reflexes). The results were robust and remained largely unchanged in our reliability analyses, which controlled for possible outliers. Meta-regression was employed to examine the role of potential variables of interest including sociodemographic variables, symptom severity, medication effects and the use of different instruments, but none of these variables was clearly associated with NSS.
As a group, OCD patients are characterized by increased rates of NSS, compared with healthy controls. However, their origins and potential clinical importance remain to be clarified. Future directions for research are discussed.
To understand amorphous and structurally disordered materials requires the application of a wide-range of advanced physical probe techniques and herein a combined methodology is outlined. The relatively short-range structural sensitivity of solid state NMR means that it is a core probe technique for characterizing such materials. The aspects of the solid state NMR contribution are emphasized here with examples given from a number of systems, with especial emphasis on the information available from 17O NMR in oxygen-containing materials. 17O NMR data for crystallization of pure sol-gel prepared oxides is compared, with new data presented from In2O3 and Sc2O3. Sol-gel formed oxide mixtures containing silica have been widely studied, but again the role and effect of the other added oxide varies widely. In a ternary ZrO2-TiO2-SiO2 silicate sol-gel the level of Q4 formation is dependent not only on the composition, as expected, but also the nature of the second added oxide. Sol-gel formed phosphates have been much less widely studied than silicates and some 31P NMR data from xerogel, sonogel and melt-quench glasses of the same composition are compared. The effect of small amounts of added antibacterial copper on phosphate glass networks is also explored.
The sequence of 165 nucleotides at the 3´ end of the 1D (VP1) gene of foot-and-mouth disease (FMD) virus was determined for 44 type Asia 1 strains isolated from throughout Asia between 1954–92. Analysis of the relationships between the virus genomes showed epidemiological links not previously evident. The possible origin of the only outbreak of FMD Asia 1 to have occurred in Europe, in Greece in 1984, was identified because the nucleotide sequence of this virus was closely-related to the sequences of those present in the Middle East between 1983–5.
Variation in the region sequenced was not as great as that seen in the other FMDV serotypes and all viruses shared greater than 85% nucleotide identity. Thus all the virus isolates examined were considered to belong to a single genotype.
A database of Asia 1 virus sequences has been established which will facilitate the rapid analysis of new outbreaks strains.
This paper compares strains of foot-and-mouth disease (FMD) serotype SAT (South African Territories) 2 viruses isolated from Zimbabwe and other African countries using monoclonal antibodies (MAb). A sandwich-ELISA was used to examine the relative binding of anti-SAT 2 MAb to the various viruses. The MAb-binding profiles of viruses isolated from field samples were compared using hierarchical cluster analysis. Viruses were obtained from game animals, mainly African buffalo (Syncerus caffer) which is the natural host and reservoir for SAT serotypes in Africa, and from cattle showing clinical signs of FMD, as well as from animals suspected of carrying the virus subclinically. Some isolates have been adapted for use as vaccine strains. The results showed that most of the Zimbabwe isolates collected between 1989 and 1992 were an antigenically closely-related group. Although differences were observed between Zimbabwe isolates collected between 1989 and 1992 and those collected in 1987, there was no correlation with the different MAb binding patterns within the 1987 group and the epidemiological information received from the field. Similar profiles were observed for many SAT 2 viruses, including viruses isolated over a 50-year period and from geographically distant areas. This indicates an inherent stability in antigenic profiles of SAT 2 viruses. The MAb panel was capable of assessing antigenic variation, since very different profiles were obtained for some isolates. The work also allowed comparison and characterization of anti-type SAT 2 MAb from different laboratories. The findings are discussed with reference to selection of vaccine strains.
Plaque purification of foot-and-mouth disease (FMD) type O viruses isolated from cattle in Saudi Arabia showed the presence of mixed serotype infections. Sixteen out of 31 samples collected between 1985 and 1991 also contained Asia 1 virus, a serotype which had previously only been isolated from a single outbreak in that country in 1980. Nucleotide sequences of the Asia 1 component of all these samples revealed little variation and showed that they were closely related to both a Russian lapinized vaccine virus strain (Asia 1/Tadzhikistan/64), and to a field isolate from Turkey (Asia 1/TUR/15/73). Although mixed FMD infections have been observed previously this is a first report of a serotype, considered to be exotic to a country, co-existing undetected for an extended period of time.
In 1986 and 1987 foot-and-mouth disease virus (FMDV) serotype A was isolated from outbreaks of disease in Saudi Arabia and Iran. Selected virus isolates were antigenically distinct from the prototype A22 virus strain (A22/Iraq/64), but were serologically related to each other. However, polyacrylamide gel electrophoresis showed that whilst the respective Saudi Arabian structural polypeptides were homogeneous, those from an Iran isolate were distinct. Direct sequencing of part of the P-1D (VP1) gene demonstrated considerable difference in nucleotide homology between the two groups of viruses; the Saudi Arabian viruses were closely related to each other but only distantly related to both the A22 prototype virus strain and the Iranian virus isolate. The latter viruses were only slightly more closely related to each other. Thus there appeared to be at least two distinct FMDV type A variants co-circulating in the Middle East, both of which differed considerably from the classical A22 subtype.
Sequencing of part of the 1D gene of foot-and-mouth disease virus was used to determine the relationships between SAT-2 viruses isolated from outbreaks which occurred in cattle in Zimbabwe and Namibia and in impala in South Africa between 1979 and 1989. The results demonstrated that the outbreaks in different countries were unrelated. Surprisingly close relationships were shown between all SAT-2 viruses isolated from cattle in Zimbabwe since 1983 but the two major epizootics which occurred in 1989 were caused by viruses which were clearly different. Conversely, two apparently unrelated outbreaks in impala in South Africa were caused by viruses which could not be distinguished.
The work described here concentrates on under-expanded, axisym-metric turbulent jets issuing into quiescent conditions. Under-expanded turbulent jets are applicable to most aircraft propulsion applications that use convergent nozzles. Experimental studies used laser doppler velocimetry (LDV) and pitot probe measurements along the jet centreline. These measurements were made for two nozzle pressure ratios (2·5 and 4·0) and at various streamwise positions up to 10 nozzle diameters downstream of the nozzle exit plane. A computational fluid dynamics (CFD) model was developed using the Fluent code and utilised the RNG K-ε two-equation turbulence model. A mesh resolution of approximately one hundredth of nozzle exit diameter was found to be sufficient to establish a mesh independent solution.
Comparison of the jet centreline axial velocity (LDV data) and pressure ratio (pitot probe data) showed good agreement with the CFD model. The correct number of shock cells had been predicted and the shock strength agreed well between the experiments and numerical model. The CFD model was, however, found to over-predict the shock cell length resulting in a longer supersonic core. There was some evidence, based on analysis of the LDV measurements that indicates the presence of swirl and jet unsteadiness, which could contribute to a shortening of the shock cell length. These effects were not modelled in the CFD. Correlation between the LDV and pitot probe measurements was generally good, however, there was some evidence that probe interference may have caused the premature decay of the jet. Overall, this work has indicated the good agreement between a CFD simulation using the RNG k-ε turbulence model and experimental data when applied to the prediction of the flowfield generated by under-expanded turbulent jets. The suitability of the LDV technique to jet flows with velocities up to 500ms-1 has also been demonstrated.
We investigated primary human herpesvirus-6 and -7 (HHV-6, HHV-7) infections as a cause of rashes incorrectly diagnosed as measles in Brazilian children. Sera from 124 patients, aged 4 months to 17 years, from the states of Rio de Janeiro and Espírito Santo, in whom measles, rubella and parvovirus B19 infections had been excluded, were studied using indirect immunofluorescence antibody avidity tests; 38 (31%) had evidence of primary HHV-6 and/or HHV-7 infections. Twenty four children had primary HHV-6 infection, either recent or coincident with the rash, and similarly 31 had primary HHV-7 infection. Remarkably, almost half (17) of primary infections were dual HHV-6 and HHV-7 infections with the majority, 12 (71%), in children less than 1 year old. HHV-7 infection occurred earlier than previously reported, perhaps due to socioeconomic and tropical conditions in this region of Brazil, and thus coincided with the HHV-6 infections. This study also highlights the difficulties of diagnosing a rash illness on clinical grounds alone.
In March 1999, a large community outbreak of Escherichia coli O157 infection occurred in North Cumbria. A total of 114 individuals were reported to the Outbreak Control Team (OCT); 88 had laboratory confirmed E. coli O157. Twenty-eight (32%) of the confirmed cases were admitted to hospital, including three children (3·4%) with haemolytic uraemic syndrome. There were no deaths. A case-control study found that illness was strongly associated with drinking pasteurized milk from a local farm (P=<0·0001) on single variable analysis. Microbiological investigations at the farm revealed E. coli O157 phage type (PT) 21/28 VT 2 which was indistinguishable from the human isolates by pulsed field gel electrophoresis. At the time of occurrence this was the largest E. coli O157 outbreak in England and Wales and the first E. coli O157 PT 21/28 VT 2 outbreak associated with pasteurized milk. This outbreak highlights lessons to be learnt regarding on-farm pasteurization.
A study investigating the causes of rash diseases using systematic laboratory testing was conducted in Niterói, Rio de Janeiro, between January 1994 to April 1998. Sera from 327 patients were tested for evidence of anti-rubella virus, measles virus, human parvovirus B19 and dengue fever virus specific immunoglobulin IgM and anti-human herpes virus type 6 (HHV-6) IgG antibodies. A laboratory confirmed diagnosis was achieved in 71·3% of the cases investigated: dengue fever (33·0%), rubella (20·2%), parvovirus B19 (9·2%), measles (6·7%) and HHV-6 (2·1%). No diagnosis was established for 94 cases (28·7%). An outbreak of measles was detected during 1997, with a peak in September and October. All of the diseases studied here presented with clinical features similar to measles and classical symptoms were found in all measles confirmed cases. The large overlap of combinations of signs and symptoms seen in this study highlights the difficulties of diagnosing a rash illness on clinical grounds alone.
Nine isolates from pigs persistently infected with a recent Italian isolate of swine vesicular disease (SVD) virus, ITL/9/93, were collected sequentially over 121 days and were characterized antigenically and biochemically. There was an accumulation of amino acid (aa) substitutions in the capsid proteins throughout the carrier state that could be correlated with alterations in antigenicity in virus isolates collected late stage in infection. The aa substitutions detected mainly occurred in VP1 and antigenic changes were detected in late isolates both at antigenic site 1, resulting in loss of binding of Mab 4GO7, and at a closely located site which has not yet been named, recognized by Mab C29. In further experiments groups of pigs were exposed to a range of SVD viruses, but no virus was isolated beyond 16 days post infection (dpi) nor viral RNA detected beyond 42 dpi. Attempts to transfer infection to sentinel pigs introduced some time after initial infection of the original pigs were largely unsuccessful. The carrier state was established in only one out of five experimental infections of pigs with SVD virus and can therefore be considered a rare sequel to infection with SVD virus and is of limited significance in the epidemiology of the disease.
Partial nucleotide sequence at the 3′ end of 1D (VP1-encoding) gene of 90 foot-and-mouth
disease virus type O isolates recovered from field outbreaks in India between 1993–9 were
determined. The sequences were compared with each other and reference viruses. The published
sequences of 15 type O isolates recovered from different parts of Asia and one isolate (O1BFS)
from Europe and one from Egypt (O1/Sharquia/Egypt/72) were also included in the analysis
for comparison. On the basis of phylogenetic analysis the viruses could be grouped into four
distinct genotypes (genotypes I–IV). All 90 isolates from India were genotype-I, as were the
reference isolates from Bangladesh, China, Egypt, Iran, Saudi Arabia, Syria and Turkey.
Genotype-I isolates were further subdivided into 16 sub-genotypes. The Indian isolates were
found to be extremely heterogeneous in nature and clustered into 12 different genetic groups.
In genotype-I, the nucleotide sequence difference seen between the isolates was 0–11·6%, while
among the Indian isolates it is 0–8·8%. Viruses of similar genetic groups are circulating in
India, Bangladesh and countries of the Middle East. Genotype-II and -III are represented by
isolates from Lebanon (O1/South Lebanon) and Europe (O1-BFS), respectively. Genotype-IV
is formed by isolates from China, Hong Kong and Taiwan. The present study reveals the
occurrence of viruses belonging to multiple genetic groups over a short period of time and
persistence of single genetic group in the same geographical area over several years. This is
consistent with the endemic nature of the disease in the country.
The nucleotide sequences of the 3′ end of the capsid-coding region were determined for 30
serotype O foot-and-mouth disease (FMD) viruses isolated between 1987 and 1994 from
outbreaks in North Africa and the Middle East. These sequences were compared with the
previously published sequences of 9 field virus isolates from the Middle East and 5 vaccine
virus strains, 3 of which originated from the Middle East (O1/Turkey/Manisa/69,
O1/Sharquia/Egypt/72 and O1/Israel/2/85) and 2
from Europe (O1/Lausanne/Switzerland/65
and O2/Brescia/Italy/47). Cluster analysis of these sequences
using the unweighted pair group
mean average (UPGMA) method showed: (i) that the FMD viruses isolated from North Africa
and the Middle East were very different from the classical European vaccine strains; (ii) that
all the viruses isolated during the 1989–92 North African epidemic formed a cluster differing
by no more than 6% from each other; (iii) a virus isolated in Libya in 1988 was unrelated to
the aforementioned epidemic; and (iv) viruses from a second, less extensive epidemic, occurring
in 1994, fell into yet another cluster.
Two groups of pigs were infected with a recent Italian isolate
of swine vesicular disease virus
(SVDV). Blood, nasal swabs and faeces were collected for up to 6 months
after exposure to
infection and animals were killed at regular intervals to
obtain tissues post-mortem. These
samples were examined for virus by conventional means and for viral RNA
(vRNA) by reverse
transcription-nested polymerase chain reaction (RT-nPCR). Virus was identified
from both clinically and subclinically infected animals in nasal swabs,
faeces and tonsillar
tissue by either virus isolation or RT-nPCR up to 63 days post infection
(dpi). Between 63 and
119 dpi virus was not detected in the secretions, excretions or tissues
of any pigs. Following
mixing of the two groups of animals at 119 dpi, SVDV was again identified
in faeces for up to
7 days suggesting that the stress of mixing reactivated the excretion
of virus in pigs from which
the agent could no longer be identified. Minor antigenic changes were identified
parental virus and isolates recovered late in the course of infection.
corresponded with deduced amino acid substitutions identified from differences
sequence between early and late isolates. This investigation demonstrates
that SVDV and
vRNA can be present in pigs for considerably longer after exposure to infection
previously been recognized and provides preliminary evidence for a carrier
state in swine