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Background: Oral poliovirus vaccine (OPV) is less immunogenic in low- or middle-income than in high-income countries. We tested whether bacterial and viral components of the intestinal microbiota are associated with this phenomenon.Methods: We assessed the prevalence of enteropathogens using TaqMan array cards 14 days before and at vaccination in 704 Indian infants (aged 6-11 months) receiving monovalent type 3 OPV (CTRI/2014/05/004588). Nonpolio enterovirus (NPEV) serotypes were identified by means of VP1 sequencing. In 120 infants, the prevaccination bacterial microbiota was characterized using 16S ribosomal RNA sequencing.Results: We detected 56 NPEV serotypes on the day of vaccination. Concurrent NPEVs were associated with a reduction in OPV seroconversion, consistent across species (odds ratio [95% confidence interval], 0.57 [.36-.90], 0.61 [.43-.86], and 0.69 [.41-1.16] for species A, B, and C, respectively). Recently acquired enterovirus infections, detected at vaccination but not 14 days earlier, had a greater interfering effect on monovalent type 3 OPV seroresponse than did persistent infections, with enterovirus detected at both time points (seroconversion in 44 of 127 infants [35%] vs 63 of 129 [49%]; P = .02). The abundance of specific bacterial taxa did not differ significantly according to OPV response, although the microbiota was more diverse in nonresponders at the time of vaccination.Conclusion: Enteric viruses have a greater impact on OPV response than the bacterial microbiota, with recent enterovirus infections having a greater inhibitory effect than persistent infections. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Foodborne outbreaks associated with transmission of norovirus are increasingly becoming a public health concern. Foods can be contaminated with faecal material at the point of production or during food preparation, in both the home and in commercial premises. Transmission of norovirus occurs through the faecal-oral route, either via person-to-person contact or through faecal-contamination of food, water, or environmental surfaces. Understanding the role and pathways of norovirus transmission – either via food handlers' hands, contaminated foods or the environment – remains a key public health priority to reduce the burden of norovirus-associated gastroenteritis. However the proportion of norovirus that is typically transferred remains unknown. Understanding this is necessary to estimate the risk of infection and the burden of gastroenteritis caused by norovirus. In this paper we present a novel method of capture, concentration and molecular detection of norovirus from a wider range of complex food matrices than those demonstrated in existing published methods. We demonstrate that this method can be used as a tool to detect and quantify norovirus from naturally contaminated food, and for monitoring norovirus transfer between food handlers' gloved hands, food or the environment. We measure the effect of introducing contamination at different food production process stages, to the final food product, to determine whether this could cause infection and disease. Between 5.9 and 6.3 Log 10 cDNA copies/μl of norovirus GII were inoculated onto food handlers' gloved hands, food or the environment and 1.1–7.4% of norovirus contamination was recovered from all samples tested. When interpreted quantitatively, this percentage equates to levels predicted to be sufficient to cause infection and disease through consumption of the final food product, demonstrating a public health risk. Overall detection and quantification of norovirus from foods, food handlers' gloved hands and the environment, when suspected to be implicated in foodborne transmissions, is paramount for appropriate outbreak investigation. • Detection of norovirus from 13 ready-to-eat food categories; a wider range of food samples than previously published. • Norovirus RNA detection and quantification from hands, food and the environment can support public health responses. • Detection and quantification of norovirus RNA in the final food product can be used to assess risk to the consumer. [ABSTRACT FROM AUTHOR]

Enterovirus A71 (EV-A71) and coxsackievirus A6 (CVA6) primarily cause hand, foot and mouth disease and have emerged to cause potential fatal neurological and systemic manifestations. However, limited surveillance data collected through passive surveillance systems hampers characterization of their epidemiological dynamics. We fit a series of catalytic models to age-stratified seroprevalence data for EV-A71 and CVA6 collected in England at three time points (2006, 2011 and 2017) to estimate the force of infection (FOI) over time and assess possible changes in transmission. For both serotypes, model comparison does not support the occurrence of important changes in transmission over the study period, and we find that a declining risk of infection with age and / or seroreversion are needed to explain the seroprevalence data. Furthermore, we provide evidence that the increased number of reports of CVA6 during 2006-2017 is unlikely to be explained by changes in surveillance. Therefore, we hypothesize that the increased number of CVA6 cases observed since 2011 must be explained by increased virus pathogenicity. Further studies of seroprevalence data from other countries would allow to confirm this. Our results underscore the value of seroprevalence data to unravel changes in the circulation dynamics of pathogens with weak surveillance systems and large number of asymptomatic infections., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kamau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: This study presents minimum 6-year follow-up data on the survival and satisfaction of an uncemented modular revision femoral system, following on from our previously published earlier results., Methods: We retrospectively reviewed all revision hip arthroplasties performed at our institution between January 2005 and October 2012, using a single modular femoral revision system. Patient-reported outcomes were collected (satisfaction score and Oxford Hip Score). Preoperative and postoperative radiographs were reviewed for stem subsidence, and Kaplan-Meier analysis was performed for survival. A total of 115 femoral revisions were performed in 106 patients., Results: All-cause survival was 82% (95% confidence interval 74 to 91%) at 10.8 years, and 96% (95% confidence interval 90 to 100%) excluding septic failure. Of the 19 cases requiring reoperation, 16 were for infection, 2 for aseptic loosening, and 1 for mechanical failure. At final follow-up, 88.5% of patients were "satisfied" or "very satisfied"., Conclusions: This study showed excellent clinical results of a commonly used revision hip stem with at least 10 years follow-up. Satisfaction rates were high, with few aseptic failures. Stem subsidence was more common in revisions for infection, but did not correlate with lower satisfaction scores., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Human norovirus is the leading cause of acute gastroenteritis. Young children and the elderly bear the greatest burden of disease, representing more than 200,000 deaths annually. Infection prevalence peaks at younger than 2 years and is driven by novel GII.4 variants that emerge and spread globally. Using a surrogate neutralization assay, we characterize the evolution of the serological neutralizing antibody (nAb) landscape in young children as they transition between sequential GII.4 pandemic variants. Following upsurge of the replacement variant, antigenic cartography illustrates remodeling of the nAb landscape to the new variant accompanied by improved nAb titer. However, nAb relative avidity remains focused on the preceding variant. These data support immune imprinting as a mechanism of immune evasion and GII.4 virus persistence across a population. Understanding the complexities of immunity to rapidly evolving and co-circulating viral variants, like those of norovirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and dengue viruses, will fundamentally inform vaccine design for emerging pathogens., Competing Interests: Declaration of interests L.C.L. and R.S.B. hold patents on norovirus vaccine design and ongoing collaborations with Vaxart, Takeda Vaccines, HilleVax, and BioNTech that are unrelated and do not pose conflicts of interest with this report. R.S.B. is a member of the advisory committee for Vaxart and Invivyd., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The emergence of severe acute respiratory syndrome 2 (SARS-CoV-2) variants of concern (VOCs), with mutations linked to increased transmissibility, vaccine escape and virulence, has necessitated the widespread genomic surveillance of SARS-CoV-2. This has placed a strain on global sequencing capacity, especially in areas lacking the resources for large scale sequencing activities. Here we have developed three separate multiplex high-resolution melting assays to enable the identification of Alpha, Beta, Delta and Omicron VOCs. The assays were evaluated against whole genome sequencing on upper-respiratory swab samples collected during the Alpha, Delta and Omicron [BA.1] waves of the UK pandemic. The sensitivities of the eight individual primer sets were all 100%, and specificity ranged from 94.6 to 100%. The multiplex HRM assays have potential as a tool for high throughput surveillance of SARS-CoV-2 VOCs, particularly in areas with limited genomics facilities., (© 2023. The Author(s).)

Aims: Norovirus remains the most significant virological risk that is transmitted via food and the environment to cause acute gastroenteritis. This study aimed to investigate the hypothesis that the contamination of the commercial food production environment with norovirus will be higher in premises that have recently reported a foodborne norovirus outbreak than those that have not., Methods: Sampling of commercial food production environments was carried out across a 16-month period between January 2015 and April 2016 in the South East and the North West of England by local authority environmental health departments as part of routine surveillance visits to premises. A total of 2982 samples, 2038 virological and 944 bacteriological, were collected from 256 premises. Sixteen of these premises, six from South East and ten from North West England, were sampled as part of a public health outbreak investigation., Results & Conclusions: Overall, 2038 swabs were submitted for norovirus testing, with an average of eight swabs per premises (range 4 to 23) and a median of seven. Of the premises sampled, 11.7% (30/256) yielded at least one norovirus-positive sample (environmental, and/or food handler hand swab), and 2.5% of the swabs were positive for norovirus. A peak in the positivity rate was seen in the South East in April 2016. No associations were found between norovirus positivity and bacteriology indicators, or between bacteriology indicators and hygiene ratings., Significance and Impact of Study: This study demonstrates that food premises and food handlers remain a potential source of norovirus transmission and outbreaks., (© 2022 Crown copyright and The Authors. Journal of Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.)

Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity. IMPORTANCE In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree. Neither evades current adult immunity, yet young children are likely susceptible. By comparing serological responses, we demonstrate that population immunity varies by age/exposure, impacting predicted susceptibility to variants. Repeat exposure to antigenically similar variants broadens antibody responses, providing immunological coverage of diverse variants but compromising response to the infecting variant, allowing continued circulation. These data indicate norovirus GII.4 variant replacement is driven distally by virus evolution and proximally by immunity in adults.

Background: Navigated total knee arthroplasty (TKA) improves implant and limb alignment but outliers continue to exist. This study aimed to determine the technical and surgical causes of outliers., Methods: This retrospective cohort study included 208 patients who had undergone navigated TKA. Limb and implant alignment indices were measured on post-operative CT scans: mechanical femoro-tibial angle (MFTA); coronal femoral angle (CFA); coronal tibial angle (CTA); sagittal femoral angle (SFA); and sagittal tibial angle (STA). Values outside 0°±3° for MFTA and SFA, 90°±3° for CFA, CTA and STA were considered outliers. Intra-operative navigation data and CT scans were evaluated to categorize the causes of sagittal and coronal plane outliers into hip centre error; ankle centre error; heterogeneous tibial cement mantle; malalignment accepted by surgeon; suboptimal knee balance; and no obvious explanation., Results: Of the 1040 measurements (five per TKA), the overall incidence of outliers was 10.4% (n = 108). Femoral component outliers (CFA + SFA, n = 51) were all attributable to hip centre error. Tibial component outliers (CTA + STA, n = 43) were attributable to ankle centre error (n = 6), heterogeneous cement mantle (n = 20), malalignment accepted by the surgeon (n = 6) and no obvious cause (n = 11). MFTA outliers were attributable to hip centre error (n = 4) or suboptimal knee balance (n = 10)., Conclusions: Surgeon related errors can be minimized by a meticulous operative technique. These results indicate scope for additional technical improvement, especially in hip centre acquisition, which may further reduce the incidence of outliers., (© 2019 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

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: 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: 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.)

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.