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Comparison of children hospitalized with enterovirus or human parechovirus (HPeV) detected in their cerebrospinal fluid revealed that HPeV infections presented with more persistent fever, irritability and feeding problems, more frequent leukopenia and lymphopenia and higher admission rates to high dependency or intensive care units. Few HPeV cases were followed up, further studies on long-term outcomes are needed.

Background: Norovirus is the commonest cause of infectious intestinal disease (IID) worldwide. In the UK community incidence of norovirus has been estimated at 59/1000 population, equating to four million cases a year. Whilst norovirus infects people of all ages, a substantial burden occurs in infants and young children. The population of viruses found in sporadic cases among infants has been observed to be more diverse than that associated with outbreaks. In this study, we analysed norovirus-positive specimens collected during the second study of infectious intestinal diseases (IID2 Study) a national community cohort study conducted between April 2008 and August 2009 We examined the data for differences in circulating norovirus strains between two arms of a community cohort, and differences between genotypes and disease outcomes such as illness duration and symptom profiles., Methods: Analysis was conducted to assess genetic diversity of noroviruses in the community. We also assessed differences in the cycle threshold (Ct) value, as a proxy for viral load, between norovirus genogroups and genotypes, and differences in reported symptoms or length of illness in relation to genogroup and genotype., Results: There were 477 samples where norovirus was detected. Whilst 85% of people recovered within two days for vomiting; diarrhoea symptoms were reported to day 4 for 83% of the cases, and 10% of people reported symptoms of diarrhoea lasting between five and six days. Both diarrhoea and vomiting symptoms lasted longer in children aged < 5 years compared to adults. There was a significantly higher proportion of GII.4 in samples obtained from the GP arm of the study (chi-square = 17.8, p < 0.001) compared to samples received via post in the self-reporting arm. In the latter group, the prevalence of GII.6 was significantly higher (chi-square = 7.5, p < 0.001)., Conclusions: We found that there is a difference in disease severity by age group. Children aged < 5 years had longer duration of illness, with 10% still having diarrhoea at seven days, and vomiting of between four and five days. The duration of illness reported is higher overall than one might expect for cases in the community in otherwise healthy individuals which has implications for infection control. No differences were observed in relation to duration of vomiting and or diarrhoea by genotype.

Background: The monovalent oral rotavirus vaccine Rotarix® was introduced into the UK infant immunisation programme in 2013. We estimated vaccine effectiveness (VE) in the first two years of the programme., Methods: We used a test-negative case-control design and enhanced national surveillance data for 1869 vaccine-eligible children tested for rotavirus infection to obtain adjusted odds ratios and VE against laboratory-confirmed rotavirus infections. Linked anonymised UK primary care and hospitalisation data from the Clinical Practice Research Datalink (40,723 children) and random-effects Poisson regression were used in a cohort study to estimate VE against all-cause acute gastroenteritis (AGE) and AGE hospitalisations., Results: VE against laboratory-confirmed infection was 69% (95% Confidence Interval: 40-84%) for one dose and 77% (95%CI: 66-85%) for two doses. Two-dose VE in children aged <12 months and ≥12 months was 85% (95%CI: 74-91%) and 54% (95%CI: 15-75%), respectively. In contrast, we found no evidence that the vaccine was effective against all-cause AGE (VE = -20%, 95%CI: -36% to -5%), or against AGE hospitalisations (VE = 35%, 95% CI: -86% to 77%)., Conclusions: In this first detailed assessment of VE of the Rotarix® vaccine in the English national programme, we show that Rotarix® was highly effective in preventing laboratory-confirmed rotavirus infection in young children. This provides reassurance about the vaccine's performance in real-life settings and gives key information for future cost-effectiveness analyses. The high VE against rotavirus-specific AGE, and the exceptionally successful implementation of the national rotavirus vaccine programme (with >90% vaccine coverage), explains the lack of VE against all-cause AGE because most AGE in the post-vaccine era would not have been due to rotavirus, although some underestimation of VE could also have occurred due to differential healthcare utilisation by vaccinated and unvaccinated infants. This highlights the importance of using specific vaccine-preventable endpoints for these scenarios.

Background: Norovirus places a substantial burden on healthcare systems, arising from infected patients, disease outbreaks, beds kept unoccupied for infection control, and staff absences due to infection. In settings with high rates of bed occupancy, opportunity costs arise from patients who cannot be admitted due to beds being unavailable. With several treatments and vaccines against norovirus in development, quantifying the expected economic burden is timely., Methods: The number of inpatients with norovirus-associated gastroenteritis in England was modeled using infectious and noninfectious gastrointestinal Hospital Episode Statistics codes and laboratory reports of gastrointestinal pathogens collected at Public Health England. The excess length of stay from norovirus was estimated with a multistate model and local outbreak data. Unoccupied bed-days and staff absences were estimated from national outbreak surveillance. The burden was valued conventionally using accounting expenditures and wages, which we contrasted to the opportunity costs from forgone patients using a novel methodology., Results: Between July 2013 and June 2016, 17.7% (95% confidence interval [CI], 15.6%‒21.6%) of primary and 23.8% (95% CI, 20.6%‒29.9%) of secondary gastrointestinal diagnoses were norovirus attributable. Annually, the estimated median 290000 (interquartile range, 282000‒297000) occupied and unoccupied bed-days used for norovirus displaced 57800 patients. Conventional costs for the National Health Service reached £107.6 million; the economic burden approximated to £297.7 million and a loss of 6300 quality-adjusted life-years annually., Conclusions: In England, norovirus is now the second-largest contributor of the gastrointestinal hospital burden. With the projected impact being greater than previously estimated, improved capture of relevant opportunity costs seems imperative for diseases such as norovirus.

Background: The development of a vaccine for norovirus requires a detailed understanding of global genetic diversity of noroviruses. We analysed their epidemiology and diversity using surveillance data from the NoroNet network., Methods: We included genetic sequences of norovirus specimens obtained from outbreak investigations and sporadic gastroenteritis cases between 2005 and 2016 in Europe, Asia, Oceania, and Africa. We genotyped norovirus sequences and analysed sequences that overlapped at open reading frame (ORF) 1 and ORF2. Additionally, we assessed the sampling date and country of origin of the first reported sequence to assess when and where novel drift variants originated., Findings: We analysed 16 635 norovirus sequences submitted between Jan 1, 2005, to Nov 17, 2016, of which 1372 (8·2%) sequences belonged to genotype GI, 15 256 (91·7%) to GII, and seven (<0·1%) to GIV.1. During this period, 26 different norovirus capsid genotypes circulated and 22 different recombinant genomes were found. GII.4 drift variants emerged with 2-3-year periodicity up to 2012, but not afterwards. Instead, the GII.4 Sydney capsid seems to persist through recombination, with a novel recombinant of GII.P16-GII.4 Sydney 2012 variant detected in 2014 in Germany (n=1) and the Netherlands (n=1), and again in 2016 in Japan (n=2), China (n=8), and the Netherlands (n=3). The novel GII.P17-GII.17, first reported in Asia in 2014, has circulated widely in Europe in 2015-16 (GII.P17 made up a highly variable proportion of all sequences in each country [median 11·3%, range 4·2-53·9], as did GII.17 [median 6·3%, range 0-44·5]). GII.4 viruses were more common in outbreaks in health-care settings (2239 [37·2%] of 6022 entries) compared with other genotypes (101 [12·5%] of 809 entries for GI and 263 [13·5%] of 1941 entries for GII non-GII.Pe-GII.4 or GII.P4-GII.4)., Interpretation: Continuous changes in the global norovirus genetic diversity highlight the need for sustained global norovirus surveillance, including assessment of possible immune escape and evolution by recombination, to provide a full overview of norovirus epidemiology for future vaccine policy decisions., Funding: European Union's Horizon 2020 grant COMPARE, ZonMw TOP grant, the Virgo Consortium funded by the Dutch Government, and the Hungarian Scientific Research Fund., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Noise after ceramic-on-ceramic (CoC) total hip arthroplasty (THA) is a well-recognized problem. Computer navigation has been shown to achieve desired implant orientation. Our aim was (1) to compare the incidence of noise between navigated and conventional CoC THAs and (2) to determine the factors associated with noise., Methods: All patients undergoing CoC THA between March 2009 and August 2012 were considered for this study. Information regarding hip noise was obtained via telephone or postal interview. A comparable cohort of patients in navigated and conventional groups was used to evaluate the incidence of noise., Results: A total of 375 CoC THAs using the same implant (202 navigated and 173 conventional) were evaluated. Patients <65 years of age had significantly greater incidence of noise (22.4% vs 6.1%; P < .001). To ensure similarity, a subgroup of cohort <65 years and a 32-mm head size was used to compare the incidence of noise between the navigated (68 THAs) and conventional (118 THAs) groups. Overall incidence of noise was significantly greater in the conventional group (28%) as compared with the navigated group (10%; P = .005). The relative risk of noise for the conventional vs the navigated group was 2.7 (P = .01), and for squeaking was 1.9 (P = .2). Squeaking THAs had significantly lower cup anteversion (13.4° ± 5.2°) as compared with the silent THAs (17.6° ± 6.9°; P = .01)., Conclusion: Navigated CoC THAs were 2.7× less likely to have noise as compared with the conventional ones. Squeaking THAs had significantly lower cup anteversion as compared with the silent ones. Patients of age <65 years had significantly greater incidence of noise after CoC THA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: People with hip osteoarthritis are likely to limit physical activity (PA) engagement due to pain and lack of function. Total hip arthroplasty (THA) reduces pain and improves function, potentially allowing increased PA. PA of THA patients was quantified to 12 months postoperation. The hypothesis was that postoperatively levels of PA would increase., Methods: PA of 30 THA patients (67 ± 7 years) was objectively measured preoperatively and 3 and 12 months postoperation. Harris Hip Score (HHS), Oxford Hip Score (OHS), and 6-minute walk test (6MWT) were recorded. Mixed linear modelling was used to examine relationships of outcomes with time, baseline body mass index (BMI), age, gender, and baseline HHS., Results: Time was not a significant factor in predicting volume measures of PA, including sit-to-stand transitions, upright time, and steps. Notably, baseline BMI was a significant predictor of upright time, steps, largest number of steps in an upright bout, HHS, and 6MWT. Baseline HHS helped predict longest upright bout, cadence of walking bouts longer than 60 seconds, and OHS. The significant effect of participant as a random intercept in the model for PA outcomes suggested habituation from presurgery to postsurgery., Conclusion: Volume measures of PA did not change from presurgery to 12 months postsurgery despite improvement in HHS, OHS, and 6MWT. Baseline BMI was a more important predictor of upright activity and stepping than time. Preoperative and postoperative PA promotion could be used to modify apparently habitual low levels of PA to enable full health benefits of THA to be gained., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: This randomized controlled trial validated a redesigned version of navigated total knee arthroplasty software with a streamlined registration (Smart) against the previous version (Classic). The objectives were to determine if Smart software had the same accuracy of component positioning and whether registration and operative time were reduced., Methods: A total of 220 patients were recruited and had a navigated total knee arthroplasty performed. With the exception of the software, all patients had the same perioperative care. At 6-week follow-up with an independent arthroplasty service, all patients had a computerized tomography scan. This was assessed by an independent radiologist to measure the mechanical alignment of the components., Results: The mean postoperative mechanical femorotibial angles were equivalent between groups (mean difference -0.2°, 95% confidence interval -0.7° to 0.3°, P  = .407). Component positions were similar in both groups. Mean registration time was significantly shorter for the Smart group (2 minutes 30 seconds ± 54 seconds) than the Classic group (3 minutes 23 seconds ± 39 seconds), P < .001. The mean operative time was 72 ± 12 minutes in both groups ( P  = .855). At 6-week follow-up, both groups had similar clinical outcomes with 96.5% of patients being satisfied or very satisfied., Conclusions: The study verified that a reduced registration time did not alter the accuracy of component placement. However, despite a shorter registration time, the overall surgical time was not reduced.

Background: Although early mobilization in hospital is a key element of post-total hip arthroplasty rehabilitation, it is poorly documented., Methods: To gain quantitative insight into inhospital mobilization, upright times and sit-to-stand transitions (STS) were measured using a thigh-mounted movement sensor in 44 participants (13 males and 31 females), age 50 to 82 years, in an observational, postsurgery, inhospital, longitudinal study., Results: Some participants performed no activity in the first 24 hours after surgery. However, in the last 24 hours before discharge, participants performed a median of 40 (interquartile range [IQR], 15) STS and spent 134 minutes (IQR, 74 minutes) upright. Activity in rehabilitation constituted 19.4% (IQR, 15.8%) of STS and 13.3% (IQR, 5.5%) of upright time. Females spent longer in hospital (80 hours; IQR, 24) compared to males (54 hours; IQR, 26)., Conclusion: Although there was considerable activity within rehabilitation periods, a large majority of STS and upright time occurred outside rehabilitation. Within the last 24 hours in hospital, all participants were upright for prolonged periods and completed numerous STS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction., Methods: We extracted data on laboratory-confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE-associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013-2014 rotavirus season to the rate during the prevaccination era., Results: In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16-.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65-.84) in all-cause AGE-associated hospitalizations in 2013-2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE-associated hospital admissions were averted in 2013-2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014-2015 season., Conclusions: The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Depolarization of mitochondrial inner transmembrane potential (ΔΨm) is a key biochemical manifestation of the intrinsic apoptosis pathway in anucleate platelets. Little is known, however, about the relationship between ΔΨm depolarization and downstream morphological manifestations of platelet apoptosis, cell shrinkage and microparticle (MP) formation., Objectives: To elucidate this relationship in human platelets., Materials and Methods: Using flow cytometry, we analyzed ΔΨm depolarization, platelet shrinkage and MP formation in platelets treated with BH3-mimetic ABT-737 and calcium ionophore A23187, well-known inducers of intrinsic platelet apoptosis., Results: We found that at optimal treatment conditions (90min, 37°C) both ABT-737 and A23187 induce ΔΨm depolarization in the majority (88-94%) of platelets and strongly increase intracellular free calcium. In contrast, effects of A23187 and ABT-737 on platelet shrinkage and MP formation are quite different. A23187 strongly stimulates cell shrinkage and MP formation, whereas ABT-737 only weakly induces these events (10-20% of the effect seen with A23187, P<0.0001)., Conclusions: These data indicate that a high level of ΔΨm depolarization and intracellular free calcium does not obligatorily ensure strong platelet shrinkage and MP formation. Since ABT-737 efficiently induces clearance of platelets from the circulation, our results suggest that platelet clearance may occur in the absence of the morphological manifestations of apoptosis., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Aim: To understand the interaction of human IQGAP1 and CDC42, especially the effects of phosphorylation and a cancer-associated mutation., Methods: Recombinant CDC42 and a novel C-terminal fragment of IQGAP1 were expressed in, and purified from, Escherichia coli. Site directed mutagenesis was used to create coding sequences for three phosphomimicking variants (S1441E, S1443D and S1441E/S1443D) and to recapitulate a cancer-associated mutation (M1231I). These variant proteins were also expressed and purified. Protein-protein crosslinking using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide was used to investigate interactions between the C-terminal fragment and CDC42. These interactions were quantified using surface plasmon resonance measurements. Molecular modelling was employed to make predictions about changes to the structure and flexibility of the protein which occur in the cancer-associated variant., Results: The novel, C-terminal region of human IQGAP1 (residues 877-1558) is soluble following expression and purification. It is also capable of binding to CDC42, as judged by crosslinking experiments. Interaction appears to be strongest in the presence of added GTP. The three phosphomimicking mutants had different affinities for CDC42. S1441E had an approximately 200-fold reduction in affinity compared to wild type. This was caused largely by a dramatic reduction in the association rate constant. In contrast, both S1443D and the double variant S1441E/S1443D had similar affinities to the wild type. The cancer-associated variant, M1231I, also had a similar affinity to wild type. However, in the case of this variant, both the association and dissociation rate constants were reduced approximately 10-fold. Molecular modelling of the M1231I variant, based on the published crystal structure of part of the C-terminal region, revealed no gross structural changes compared to wild type (root mean square deviation of 0.564 Å over 5556 equivalent atoms). However, predictions of the flexibility of the polypeptide backbone suggested that some regions of the variant protein had greatly increased rigidity compared to wild type. One such region is a loop linking the proposed CDC42 binding site with the helix containing the altered residue. It is suggested that this increase in rigidity is responsible for the observed changes in association and dissociation rate constants., Conclusion: The consequences of introducing negative charge at Ser-1441 or Ser-1443 in IQGAP1 are different. The cancer-associated variant M1231I exerts its effects partly by rigidifying the protein.

Using data for 25,780 species categorized on the International Union for Conservation of Nature Red List, we present an assessment of the status of the world's vertebrates. One-fifth of species are classified as Threatened, and we show that this figure is increasing: On average, 52 species of mammals, birds, and amphibians move one category closer to extinction each year. However, this overall pattern conceals the impact of conservation successes, and we show that the rate of deterioration would have been at least one-fifth again as much in the absence of these. Nonetheless, current conservation efforts remain insufficient to offset the main drivers of biodiversity loss in these groups: agricultural expansion, logging, overexploitation, and invasive alien species.

The role of the mitochondrial permeability transition pore (MPTP) in apoptosis of nucleated cells is well documented. In contrast, the role of MPTP in apoptosis of anucleated platelets is largely unknown. The aim of this study was to elucidate the contribution of MPTP in the control of different manifestations of platelet apoptosis by analyzing the effect of cyclosporin A (CsA), a potent inhibitor of MPTP formation. Using flow cytometry, we studied the effect of pretreatment of platelets with CsA on apoptotic responses in human platelets stimulated with calcium ionophore A23187. We found that CsA inhibited A23187-stimulated platelet apoptosis, completely preventing (i) depolarization of mitochondrial inner membrane potential (DeltaPsim), (ii) activation of cytosolic apoptosis executioner caspase-3, (iii) platelet shrinkage, and (iv) fragmentation of platelets to microparticles, but (v) only partially (approximately 25%), inhibiting phosphatidylserine (PS) exposure on the platelet surface. This study shows that MPTP formation is upstream of DeltaPsim depolarization, caspase-3 activation, platelet shrinkage and microparticle formation, and stringently controls these apoptotic events in A23187-stimulated platelets but is less involved in PS externalization. These data also indicate that CsA may rescue platelets from apoptosis, preventing caspase-3 activation and inhibiting the terminal cellular manifestations of platelet apoptosis, such as platelet shrinkage and degradation to microparticles. Furthermore, the results suggest a novel potentially useful application of CsA as an inhibitor of platelet demise through apoptosis in thrombocytopenias associated with enhanced platelet apoptosis.

Traditional metal-on-polyethylene total hip replacements are prone to wear with secondary osteolysis and aseptic loosening, especially in younger, more active patients. Metal-on-metal represents an alternative bearing surface that offers much lower wear rates with the aim of improving longevity and the use of larger femoral heads that confer increased inherent stability, resulting in fewer patient restrictions and improved patient satisfaction. This article discusses the science and clinical evidence in support of choosing metal-on-metal as a bearing as well as its limitations.