Haptoglobin polymorphism affects its N-glycosylation pattern in serum.

Introduction: Haptoglobin (Hp) is an abundant acute-phase protein secreted mainly by the liver into the bloodstream. There are three Hp protein phenotypes (Hp type 1-1, 2-1, and 2-2), which differ in the number of α- and ß-chains, type of α-chain (the ß-chain type remains the same in all the Hp phenotypes), and the polymers that they form via disulfide bonds. Hp has four N-glycosylation sites on the ß-chain. Glycosylation of Hp has been reported frequently as a potential glycobiomarker for many diseases; however, whether Hp polymorphism affects its glycosylation has not yet been addressed extensively or in depth. Objectives: This study investigated the differences between the glycosylation patterns of Hp phenotypes using serum from 12 healthy individuals (four for each Hp phenotype). Method: An efficient method for isolating Hp from serum was established and subsequently the Hp phenotype of each sample was characterized by immunoblotting. Then, LC-MS/MS analysis of isolated Hp after treatment with three exoglycosidases (sialidase, α2-3 neuraminidase, Endo F3) was performed to characterize the glycosylation pattern of Hp for each individual sample. Results: The data reveal significant differences among the branching, sialylation, and fucosylation of Hp types, documenting the effect of Hp polymorphism on its glycosylation. Conclusion: Overall, the study suggests that Hp phenotype characterization should be considered during the investigation of Hp glycosylation.

Severe acute respiratory infections surveillance for early signals in the community.

BACKGROUND: Surveillance of acute respiratory infections (ARI) in the Netherlands and other European countries is based mostly on primary care data, with little insight into the severe spectrum of the disease. We compared time-trends for ARI in secondary care with influenza-like illness (ILI), ARI and pneumonia in primary care, and crude mortality, in order to assess the value of routinely collected data on respiratory infections in hospitals and the added value of severe acute respiratory infections (SARI) surveillance. METHODS: We calculated incidence of ARI in secondary care, ILI, ARI, and pneumonia in primary care, and crude mortality using five historical databases (2008-2016). RESULTS: Over eight years, seasonal incidence peaks of ARI in secondary care occurred earlier than ILI and ARI incidence peaks in primary care, except during the 2009 influenza A(H1N1) pandemic and post-pandemic season. The median time-lag between ARI in secondary care and ILI, ARI and pneumonia in primary care was 6.5 weeks, 7 weeks, and 1 week, respectively. Crude mortality lagged a median 5 weeks behind ARI in secondary care. CONCLUSION: This observational study demonstrates that routinely collected data can be used for describing trends of ARI in secondary care and may be suitable for near real-time SARI surveillance. In most seasons, the incidence peaks for ARI in secondary care preceded the peaks in primary care and crude mortality with a considerable time-lag. It would be of great value to add microbiological test results to the incidence data to better explain the difference in time-lag between these surveillance systems.

Intrauterine fundal anaesthesia during endometrial ablation in the office: A randomised double-blind, non-inferiority trial.

OBJECTIVE: To evaluate the effect of intrauterine fundal anaesthesia during outpatient endometrial ablation. STUDY DESIGN: A randomised, double-blinded non-inferiority trial was performed in one hospital and one independent treatment center in the Netherlands. A total of 96 women who were planned for a NovaSure® endometrial ablation under local anaesthesia between December 2015 and February 2018 were included in this trial. These women were randomised to paracervical anaesthesia combined with hysteroscopic fundal infiltration with anaesthestics or paracervical anaesthesia combined with hysteroscopic fundal infiltration with saline. The primary outcome was pain during ablation. To study non-inferiority of paracervical anaesthesia without fundal anaesthesia, we assessed the co-primary endpoints Faces Pain Score and Numeric Rating Score. Secondary outcomes included pain scores at other moments during and after the procedure, postoperative use of analgesics, satisfaction, side-effects and complications. The primary outcomes were tested with a non-inferiority margin (2.0 points on changes in pain), and the secondary outcomes were compared using conventional statistical methods. RESULTS: Paracervical anaesthesia without fundal anaesthesia did not establish non-inferiority to the combination of paracervical anaesthesia and fundal infiltration with anaesthetics when both primary outcome variables of pain were taken into account (Numeric Rating Scale 5.0 versus 3.9 (mean difference 1.2 (95% CI 0.1-2.2)) and Faces Pain Score 5.4 versus 4.8 (mean difference 0.6 (95% CI -0.3-1.5))). Secondary pain scores measured during the procedure were higher or similar in women receiving fundal infiltration with saline as compared to women who received fundal infiltration with anaesthetics. After the procedure, there were no differences in reported pain scores, satisfaction, and side-effects. In the group who received fundal infiltration with saline, more women were admitted to the hospital because of severe pain (3 versus 0 women) and endometritis (1 versus 0 women). CONCLUSION: This study did not confirm non-inferiority of paracervical anaesthesia without fundal anaesthesia to the combination of paracervical anaesthesia with fundal anaesthesia in the reduction of pain during endometrial ablation and therefore provides no reason to leave out fundal anaesthesia. We recommend to use fundal anaesthesia combined with paracervical anaesthesia to reduce pain during endometrial ablation in the office.

Notification data and criteria during a large Q-fever epidemic reassessed.

From 2007 to 2010, the largest reported Q-fever epidemic occurred in the Netherlands with 4026 notified laboratory-confirmed cases. During the course of the epidemic, health-seeking behaviour changed and awareness among health professionals increased. Changes in laboratory workflows were implemented. The aim of this study was to analyse how these changes instigated adjustments of notification criteria and how these adjustments affected the monitoring and interpretation of the epidemic. We used the articles on laboratory procedures related to the epidemic and a description of the changes that were made to the notification criteria. We compared the output of a regional laboratory with notifications to the regional Public Health Service and the national register of infectious diseases. We compared the international notification criteria for acute Q-fever. Screening with ELISA IgM phase II and PCR was added to the diagnostic workflow. In the course of the epidemic, serology often revealed a positive IgG/IgM result although cases were not infected recently. With increasing background seroprevalence, the presence of IgM antibodies can only be suggestive for acute Q-fever and has to be confirmed either by seroconversion of IgG or a positive PCR result. Differences in sero-epidemiology make it unlikely that full harmonisation of notification criteria between countries is feasible.

Evaluating the impact of an insulin pump discontinuation action plan on patient or caregiver confidence and anxiety.

AIMS: Insulin pump failure and adverse events are common and therefore anticipatory education is recommended. Research in other chronic diseases shows written action plans improve confidence and adherence during an acute deterioration. However, no similar data exists for patients with type one diabetes mellitus provided with anticipatory education via an insulin pump action plan. This study evaluates whether an insulin pump action plan improves patient and caregiver confidence in managing a potential pump failure without a subsequent increase in anxiety. METHODS: Adults with type one diabetes mellitus and caregivers of children with type 1 diabetes on continuous subcutaneous insulin infusions across four New Zealand diabetes services participated. Participants completed a questionnaire examining pump-related adverse events and self-reported confidence and anxiety in managing pump failure. An insulin pump action plan and focused education by their diabetes team was provided, with a follow-up questionnaire at least 3 months later. RESULTS: 174/270 pump patients participated initially, with a follow-up response rate of 84.5% (147/174). Despite prior provision, many could not recall having an insulin pump action plan at study commencement (101/174, 58%), and of these 92% stated they would have liked one. Patients had good levels of confidence in the reliability of their pump and infusion sets/sites (Likert scores of 4.4/5 and 3.95/5) which was not undermined by the insulin pump action plan. Confidence in managing a potential pump failure showed a small but significant increase (3.66/5 to 3.95/5, p = 0.004) present in both adults and parents, with anxiety also showing a small increase (2.16/5 to 2.38/5, p = 0.012). CONCLUSION: Patient recall of prior insulin pump action plan education is poor, with the vast majority of patients interested in further written anticipatory education regarding potential pump failure. The provision of an insulin pump action plan increases self-reported confidence in managing unexpected pump failure with a small associated increase in anxiety.

European all-cause excess and influenza-attributable mortality in the 2017/18 season: should the burden of influenza B be reconsidered?

OBJECTIVES: Weekly monitoring of European all-cause excess mortality, the EuroMOMO network, observed high excess mortality during the influenza B/Yamagata dominated 2017/18 winter season, especially among elderly. We describe all-cause excess and influenza-attributable mortality during the season 2017/18 in Europe. METHODS: Based on weekly reporting of mortality from 24 European countries or sub-national regions, representing 60% of the European population excluding the Russian and Turkish parts of Europe, we estimated age stratified all-cause excess morality using the EuroMOMO model. In addition, age stratified all-cause influenza-attributable mortality was estimated using the FluMOMO algorithm, incorporating influenza activity based on clinical and virological surveillance data, and adjusting for extreme temperatures. RESULTS: Excess mortality was mainly attributable to influenza activity from December 2017 to April 2018, but also due to exceptionally low temperatures in February-March 2018. The pattern and extent of mortality excess was similar to the previous A(H3N2) dominated seasons, 2014/15 and 2016/17. The 2017/18 overall all-cause influenza-attributable mortality was estimated to be 25.4 (95%CI 25.0-25.8) per 100,000 population; 118.2 (116.4-119.9) for persons aged 65. Extending to the European population this translates into over-all 152,000 deaths. CONCLUSIONS: The high mortality among elderly was unexpected in an influenza B dominated season, which commonly are considered to cause mild illness, mainly among children. Even though A(H3N2) also circulated in the 2017/18 season and may have contributed to the excess mortality among the elderly, the common perception of influenza B only having a modest impact on excess mortality in the older population may need to be reconsidered.

The incidence of symptomatic infection with influenza virus in the Netherlands 2011/2012 through 2016/2017, estimated using Bayesian evidence synthesis.

Due to differences in the circulation of influenza viruses, distribution and antigenic drift of A subtypes and B lineages, and susceptibility to infection in the population, the incidence of symptomatic influenza infection can vary widely between seasons and age-groups. Our goal was to estimate the symptomatic infection incidence in the Netherlands for the six seasons 2011/2012 through 2016/2017, using Bayesian evidence synthesis methodology to combine season-specific sentinel surveillance data on influenza-like illness (ILI), virus detections in sampled ILI cases and data on healthcare-seeking behaviour. Estimated age-aggregated incidence was 6.5 per 1000 persons (95% uncertainty interval (UI): 4.7-9.0) for season 2011/2012, 36.7 (95% UI: 31.2-42.8) for 2012/2013, 9.1 (95% UI: 6.3-12.9) for 2013/2014, 41.1 (95% UI: 35.0-47.7) for 2014/2015, 39.4 (95% UI: 33.4-46.1) for 2015/2016 and 27.8 (95% UI: 22.7-33.7) for season 2016/2017. Incidence varied substantially between age-groups (highest for the age-group <5 years: 23 to 47/1000, but relatively low for 65+ years: 2 to 34/1000 over the six seasons). Integration of all relevant data sources within an evidence synthesis framework has allowed the estimation - with appropriately quantified uncertainty - of the incidence of symptomatic influenza virus infection. These estimates provide valuable insight into the variation in influenza epidemics across seasons, by virus subtype and lineage, and between age-groups.

[Effectiveness of influenza vaccine in the Netherlands: predominant circulating virus type and vaccine match are important conditions]. / Effectiviteit van influenzavaccinatie in Nederland.

OBJECTIVE: To investigate the relationship between circulating influenza virus A types and subtypes and influenza B lineages, their match with the vaccine and the effectiveness of the influenza vaccine (IVE). DESIGN: Test negative case control study. METHOD: We used data from the Dutch Sentinel Practices of the Netherlands Institute for Health Services Research (NIVEL) Primary Care Database. Participating general practitioners took nose and throat swabs for viral studies from patients with influenza-like illness or another acute respiratory infection. Cases were those patients whose samples were positive for an influenza virus and controls were those whose samples were negative for influenza virus. We determined the IVE of 11 influenza seasons 2003/2004 to 2013/2014, for all seasons together and stratified by influenza virus type and to vaccine match or mismatch. RESULTS: Over all seasons, the IVE was 29% (95% CI:11-43). In seven of the 11 seasons there was a mismatch between vaccine and circulating virus type. The IVE was 40% (95% CI: 18-56) for those seasons in which there was a vaccine match, and 20% (95% CI: - 5-38) for seasons with a mismatch. When the influenza A/H3N2 virus was dominant, the IVE was 38% (95% CI: 14-55). The IVE against the influenza virus A/H1N1, A/H1N1/pdm09 and against both influenza B lineages was 77% (95% CI: 37-92), 47% (95% CI: 22-64) and 64% (95% CI: 50-74), respectively. CONCLUSION: The IVE was particularly low when there was a mismatch between the vaccine and the circulating virus type and when A/H3N2 was the dominant influenza subtype.

Local anaesthesia during endometrial ablation: a systematic review.

BACKGROUND: Endometrial ablation has been widely implemented in the outpatient setting. Many different protocols of local anaesthesia during endometrial ablation are used and described. However, prospective studies to assess and evaluate these protocols appear to be scarce. OBJECTIVES: To evaluate systematically the different local anaesthesia techniques in relation to pain perception during endometrial ablation. SEARCH STRATEGY: Medline and Embase were systematically searched and reference lists of selected articles were checked for missed publications. SELECTION CRITERIA: All types of studies reporting the performance of endometrial ablation under local anaesthesia in ten or more women were included. DATA COLLECTION AND ANALYSIS: Data about the procedure, the protocol of local anaesthesia, the acceptability and side-effects were extracted. MAIN RESULTS: Twenty-five studies, involving 2013 women, were included. Applied anaesthesia techniques included intracervical, paracervical and intrauterine anaesthesia or a combination of these techniques. Women who received a combination of either intra- or paracervical anaesthesia and intrauterine injections reported significantly lower pain scores than those who received no local anaesthesia or intra- or paracervical anaesthesia alone (P = 0.000), but the quality of evidence is low. The acceptability of endometrial ablation under local anaesthesia was high (77-94%). CONCLUSION: Endometrial ablation under local anaesthesia is a safe, feasible and acceptable procedure. The combination of either intra- or paracervical anaesthesia with intrauterine injections seems to be promising, but has to be investigated more thoroughly. TWEETABLE ABSTRACT: Systematic review of local anaesthesia techniques during endometrial ablation.

Evidence for a chemical clock in oscillatory formation of UiO-66.

Chemical clocks are often used as exciting classroom experiments, where an induction time is followed by rapidly changing colours that expose oscillating concentration patterns. This type of reaction belongs to a class of nonlinear chemical kinetics also linked to chaos, wave propagation and Turing patterns. Despite its vastness in occurrence and applicability, the clock reaction is only well understood for liquid-state processes. Here we report a chemical clock reaction, in which a solidifying entity, metal-organic framework UiO-66, displays oscillations in crystal dimension and number, as shown by X-ray scattering. In rationalizing this result, we introduce a computational approach, the metal-organic molecular orbital methodology, to pinpoint interaction between the tectonic building blocks that construct the metal-organic framework material. In this way, we show that hydrochloric acid plays the role of autocatalyst, bridging separate processes of condensation and crystallization.

Excess mortality among the elderly in European countries, December 2014 to February 2015.

Since December 2014 and up to February 2015, the weekly number of excess deaths from all-causes among individuals ≥ 65 years of age in 14 European countries have been significantly higher than in the four previous winter seasons. The rise in unspecified excess mortality coincides with increased proportion of influenza detection in the European influenza surveillance schemes with a main predominance of influenza A (H3N2) viruses seen throughout Europe in the current season, though cold snaps and other respiratory infections may also have had an effect.

Coxiella burnetii seroprevalence and risk factors on commercial sheep farms in The Netherlands.

Coxiella burnetii seroprevalence was assessed on Dutch dairy and non-dairy sheep farms using ELISA. Risk factors for seropositivity on non-dairy sheep farms were identified at farm and sheep level by univariate and multivariate multilevel analyses. Based on 953 dairy and 5671 non-dairy serum samples, sheep seroprevalences were 18.7 per cent and 2.0 per cent, respectively, and 78.6 per cent and 30.5 per cent at farm level. Significant risk factors for non-dairy sheep farms were farm location in the south of the country, sheep kept on marginal grounds, one or several supply addresses for ewes during 2007-2009 and wearing farm boots and/or outfit by professional visitors. On sheep level, risk factors included among others farm location in the south of the country, lamb breeding as main farm purpose, goat density within 10 km farm radius, use of windbreak curtain or windshields, and presence of ≥6 stillborn lambs in 2009. Farm location in the south of the country and goat density suggests that infected goats have played a role in the transmission to non-dairy sheep. Other risk factors suggest introduction of the bacterium through sheep supply and professional visitors. Biosecurity measures should be strengthened, including avoiding infection during handling of stillborn lambs and birth products in the lambing period.

Coxiella burnetii seroprevalence and risk factors in sheep farmers and farm residents in The Netherlands.

SUMMARY: In this study, Coxiella burnetii seroprevalence was assessed for dairy and non-dairy sheep farm residents in The Netherlands for 2009-2010. Risk factors for seropositivity were identified for non-dairy sheep farm residents. Participants completed farm-based and individual questionnaires. In addition, participants were tested for IgG and IgM C. burnetii antibodies using immunofluorescent assay. Risk factors were identified by univariate, multivariate logistic regression, and multivariate multilevel analyses. In dairy and non-dairy sheep farm residents, seroprevalence was 66·7% and 51·3%, respectively. Significant risk factors were cattle contact, high goat density near the farm, sheep supplied from two provinces, high frequency of refreshing stable bedding, farm started before 1990 and presence of the Blessumer breed. Most risk factors indicate current or past goat and cattle exposure, with limited factors involving sheep. Subtyping human, cattle, goat, and sheep C. burnetii strains might elucidate their role in the infection risk of sheep farm residents.

[Orthodontics and vertical distraction osteogenesis of the maxilla]. / Orthodontie en verticale distractieosteogenese van de maxilla.

A female patient (age 26) visited the orthodontist for correction of the reduced exposure of the upper incisors during laughing. She also reported crowding of the lower incisors and an association between lisping and her open bite. The diagnosis in this case: a Class III malocclusion case with incisor crowding and an open bite. Because her main complaint was reduced upper incisor exposure while talking and laughing, which would not be corrected with orthodontic appliances only, the position of the maxilla was corrected during orthodontic treatment by means of vertical intra-oral maxillary distraction. An acceptable and relatively stable result was achieved.

The heritability of plasma homocysteine, and the influence of genetic variation in the homocysteine methylation pathway.

BACKGROUND: The extent of genetic influence on plasma homocysteine, a risk factor for ischaemic heart disease, is uncertain. Many association studies have investigated common polymorphisms and their role in hyperhomocysteinaemia, but only the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) has shown an association (small but robust). AIM: To estimate the heritability of plasma homocysteine and the contributions of well-studied common SNPs in the three main candidate genes in the homocysteine methylation pathway. DESIGN: Twin study. METHODS: We studied 216 monozygotic and 790 dizygotic pairs of twins; all were women. Blood was collected after overnight fasting for measurement of homocysteine, folate, vitamin B12, and extraction of DNA. Heritability was estimated by structural modelling, including correction for known environmental influences, particularly serum folate. The frequency of a common coding SNP in MTHFR and methionine synthase (MTR), and two coding SNPs in methionine synthase reductase (MTRR) were measured in dizygotic twins by ABI 7700 Sequence Detection, and the contribution of each to homocysteine variance was determined. RESULTS: The heritability of homocysteine was 57% (95%CI 51-63%). The highest contribution to homocysteine was serum folate, accounting for 10.13% of variance. This was twice the total genetic contribution of 4.56%, and only the C1763T SNP of MTRR showed significant association with homocysteine. DISCUSSION: Homocysteine has one of the highest heritabilities of common risk factors for ischaemic heart disease. This is not accounted for by the commonly studied SNPs in MTHFR, MTR and MTRR.

Genetic variation in bone mineral density and calcaneal ultrasound: a study of the influence of menopause using female twins.

The aim of the study was to determine whether the genetic variance in bone mineral density (BMD) and calcaneal ultrasound differs in pre- and postmenopausal women and to establish whether the genes operating before the menopause are the same as those after the menopause. Twins aged 18-75 years were recruited from the St Thomas' UK Adult Twin Registry. Quantitative model fitting techniques were used to test for differences in genetic influences in pre- and postmenopausal twins of several BMD sites and calcaneal ultrasound measures accounting for age. BMD and heel ultrasound variables were measured in 2490 female twins: 360 monozygotic pairs and 885 dizygotic pairs. The heritability in the group overall ranged from 19% to 76%. A significant increase in total variance was seen for most BMD sites after the menopause. The proportion of total variance explained by genetic influence was higher premenopausally at all sites except the femoral neck. For example, the genetic proportion of total variance for spine BMD was 88% premenopausally and 77% postmenopausally. In contrast there was no significant difference in total variance of ultrasound measures with menopause. There was no indication that traits are influenced by different genes before and after menopause. This study demonstrates that genetic and environmental influences differ significantly in pre- and postmenopausal groups for BMD, but not for calcaneal ultrasound. The total variance in BMD is greater postmenopausally, but there is evidence that the same genes are involved. These data stress the importance of accounting for menopause-gene interactions in the genetic analysis of data on osteoporosis.

Water law and human rights--roles and responsibilities.

This paper focuses on the experience of South Africa in introducing water legislation based on human rights principles (in particular the National Water Act of 1998) and reflects on some practical implications for the implementation of water management in a country with limited water and financial resources.

The genetics of haemostasis: a twin study.

BACKGROUND: The concentrations of fibrinogen, factor VII and VIII, von Willebrand factor, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator have been associated with coronary-heart disease. In addition, polymorphisms in the genes coding for fibrinogen, factor VII, PAI-1, and factor XIII have been reported to affect both protein concentrations and cardiovascular disease risk. METHODS: We did a classic twin study to assess heritabilities of these haemostatic factors. We enrolled 1002 female twins; 149 pairs of monozygotic and 352 pairs of dizygotic twins. 89 monozygotic and 196 dizygotic twin pairs were analysed for factor VII. FINDINGS: Quantitative genetic model fitting showed that genetic factors contributed to about 41-75% of the variation in concentrations of fibrinogen, factor VII, factor VIII, PAI-1, tissue plasminogen activator, factor XIII A-subunit and B-subunit, and von Willebrand factor. Factor XIII activity showed higher (82%) and factor XIIa lower (38%) heritability. INTERPRETATION: We have shown that genetic factors have a major effect on plasma concentrations of haemostatic proteins. Our results stress the importance of research into the genetic regulation of proteins involved in haemostasis and atherothrombotic disorders, including myocardial infarction and stroke.