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Altering the microstructure in order to improve the tensile properties of bow shackles resulted in inconsistency in the fatigue performance. This raises the question whether the inconsistency in fatigue life can be attributed to microstructural changes along the profile of the shackle or to decarburization at the surface. Bow shackles forged from 080M40 (EN8) material were subjected to different heat treatments in order to alter the microstructure. The shackles were subjected to five different fatigue load cases, which represented typical loads experienced at termination points for an overhead power line with a span length of 400 m, with changes in conductor type, configuration, wind, and ice loading. Although the change in microstructure does improve both the tensile and fatigue performance, we found that the depth of the decarburization layer has a greater effect on the high cycle fatigue life of bow shackles than the non-homogeneous microstructure.

Immune checkpoint inhibitor (ICI) therapy is an emerging option for advanced endometrial cancer (EC). Mismatch repair (MMR) status is widely regarded as a biomarker predictive of response to ICIs. The predictive value of MMR based on small, single-arm trials, however, is conflicting. In this meta-analysis, we aimed to assess the activity of single-agent ICI in advanced EC, and compared the magnitude of treatment benefit in MMR deficient (dMMR) and MMR proficient (pMMR) EC.We carried out an electronic search to identify prospective trials of single-agent ICI in advanced EC. Data on objective response rate (ORR) and progression-free survival (PFS) were extracted and pooled. ORR was estimated using the inverse variance method and subgroup difference by MMR status was examined. PFS difference according to MMR status was summarized using the Kaplan-Meier approach.From eight trials with 492 women, the pooled ORR was 19% [95% confidence interval (CI) 16% to 22%]. ORR was significantly greater in dMMR (n = 281) than pMMR EC (n = 211) (dMMR: 46%, pMMR: 8%; risk ratio 5.74, 95% CI 3.58-9.21; interaction P0.001). Complete response was 11% and 0.05% and median PFS was 8.3 and 2.1 months in dMMR and pMMR EC, respectively (hazard ratio PFS 0.58, 95% CI 0.38-0.89; P = 0.01). The 12-month PFS rates were 42.0% and 20.7%, respectively.Single-agent ICI is associated with a 5.74 times greater objective response and 42% reduction in risk of disease progression or death in dMMR compared with pMMR EC. MMR status should be determined prospectively and be used as a stratification factor in future trials of advanced EC. Further translational analysis is urgently required to identify the cause of dMMR and allow subclassification of EC into different dMMR molecular subtypes.

Land subsidence is increasingly recognised as a complex and costly challenge, especially in urban subsidence-prone areas. Often caused by overextraction of groundwater in order to meet increasing drinking and irrigation water demand, the expected damage from subsidence across the globe runs in the billions of dollars annually. Economic cost assessment can support the development of policies for dealing with subsidence, e.g. in problem analysis and evaluation of strategies. However, research on economic cost assessment of subsidence is limited and a standardized framework is lacking: this is an important basis for sound, comparable and consistent decision making and knowledge transfer across studies. Results from a review of existing literature indicate that that there is a (i) high variability in the literature in terms of subsidence characteristics and geographical origin, (ii) variation in addressed effects and applied economic assessment approaches and (iii) lack of a standardized assessment framework. This complicates comparison and value transfer of results across settings. In this context, we propose a standardized framework for economic cost assessment of land subsidence along the lines of direct and indirect, market and non-market effects

In a bid to minimise the cost of electrical energy production through the reduction in the quantity of coal usage, the power generation companies resolved to operate different daily cycles characterized by peak and off-peak energy demand periods. These daily operational cycles have left the power plant components operating in a possible creep-fatigue regime. As such, earlier failure of the plant’s components such as the steam pipes due to creep, fatigue, or the combination of both failure modes became inevitable. This study employed finite element (FE) technique to determine the dominant failure mechanism and useful life of P92 power generation steam piping subjected to one of the daily operational cycles. The outcome of the study showed that the failure of the piping when subjected to the daily cycle is creep dominated, and failure due to fatigue or possible creep-fatigue interaction was impossible since the daily cycle was insufficient to induce the extensive plastic strain required for the initiation and propagation of fatigue failure. Hence, the best form of operating steam pipe/piping is steady-state, since subjecting them to daily cycles significantly reduce their useful life.

ObjectiveUterine fibroids can cause a variety of symptoms in women, from heavy menstrual bleeding and dysmenorrhea to bulk symptoms. The Uterine Fibroid Symptom and health-related Quality Of Life questionnaire (UFS-QOL) is a patient-reported outcome measure developed for assessing fibroid-related symptoms in a standardised way. Our aim was to translate and validate the UFS-QOL in Dutch.DesignValidation study.SettingPatients were recruited by a gynaecologist at the outpatient clinic.ParticipantsWomen with uterine fibroids.MethodsThe UFS-QOL was translated into Dutch (UFS-QOL NL) and validated through testing construct validity (comprising of structural validity and hypotheses testing), reliability, responsiveness and interpretability, assessing floor and ceiling effects and minimal important change. An option to answer ‘not applicable’ was added to the translated questionnaire.Results191 women with uterine fibroids completed the UFS-QOL NL at baseline, after 2 weeks and after 3 months. The questionnaire retained the same factor structure after translation (Comparative Fit Index 0.94–0.95; Tucker-Lewis fit Index 0.93–0.95; Root Mean Square Error of Approximation 0.10–0.11) and correlations to other questionnaires (RAND 36, Hospital Anxiety and Depression Scale and Golombok Rust Inventory of Sexual Satisfaction) were generally moderate, as hypothesised (Pearson’s r 0.3–0.7). We found a sufficient reliability with intraclass correlation coefficients of approximately 0.8–0.9 for all subscales. Responsiveness was sufficient when testing hypotheses comparing women who had surgery with those who did not. Cronbach’s alpha was higher than 0.7 for all subscales, indicating sufficient internal consistency and there were no concerns about floor or ceiling effects. Minimal important change could not be calculated due to low correlation between the different subscales and the anchor question.ConclusionsThe results support the measurement properties of the Dutch UFS-QOL for assessing fibroid-related symptoms and health-related quality of life in Dutch women with uterine fibroids.

Objective To evaluate if immediate catheter removal (ICR) after laparoscopic hysterectomy is associated with similar retention outcomes compared with delayed removal (DCR). Study design Non‐inferiority randomised controlled trial. Population Women undergoing laparoscopic hysterectomy in six hospitals in the Netherlands. Methods Women were randomised to ICR or DCR (between 18 and 24 hours after surgery). Primary outcome The inability to void within 6 hours after catheter removal. Results One hundred and fifty‐five women were randomised to ICR (n = 74) and DCR (n = 81). The intention‐to‐treat and per‐protocol analysis could not demonstrate the non‐inferiority of ICR: ten women with ICR could not urinate spontaneously within 6 hours compared with none in the delayed group (risk difference 13.5%, 5.6–24.8, P = 0.88). However, seven of these women could void spontaneously within 9 hours without additional intervention. Regarding the secondary outcomes, eight women from the delayed group requested earlier catheter removal because of complaints (9.9%). Three women with ICR (4.1%) had a urinary tract infection postoperatively versus eight with DCR (9.9%, risk difference −5.8%, −15.1 to 3.5, P = 0.215). Women with ICR mobilised significantly earlier (5.7 hours, 0.8–23.3 versus 21.0 hours, 1.4–29.9; P ≤ 0.001). Conclusion The non‐inferiority of ICR could not be demonstrated in terms of urinary retention 6 hours after procedure. However, 70% of the women with voiding difficulties could void spontaneously within 9 hours after laparoscopic hysterectomy. It is therefore questionable if all observed urinary retention cases were clinically relevant. As a result, the clinical advantages of ICR may still outweigh the risk of bladder retention and it should therefore be considered after uncomplicated laparoscopic hysterectomy. Tweetable abstract The advantages of immediate catheter removal after laparoscopic hysterectomy seem to outweigh the risk of bladder retention., Tweetable abstract The advantages of immediate catheter removal after laparoscopic hysterectomy seem to outweigh the risk of bladder retention.

Aim: To evaluate the effect of graft preparation and organ-culture storage on endothelial cell density (ECD) and viability of Descemet membrane endothelial keratoplasty (DMEK) grafts. Materials and methods: DMEK grafts (n = 27) were prepared at Amnitrans EyeBank Rotterdam from 27 corneas (15 donors) that were eligible for transplantation but could not be allocated due to the Covid-19-related cancellation of elective surgeries. Cell viability (by Calcein-AM staining) and ECD of five grafts originally scheduled for transplantation were evaluated on the originally planned surgery day, whereas 22 grafts from paired donor corneas were evaluated either directly post-preparation or after 3-7 days of storage. ECD was analyzed by light microscopy (LM ECD) and Calcein-AM staining (Calcein-ECD). Results: Light microscopy (LM) evaluation of all grafts showed an unremarkable endothelial cell monolayer directly after preparation. However, median Calcein-ECD for the five grafts initially allocated for transplantation was 18% (range 92-73%) lower than median LM ECD. For the paired DMEK grafts, Calcein-ECD determined by Calcein-AM staining on the day of graft preparation and after 3-7 days of graft storage showed a median decrease of 1% and 2%, respectively. Median percentage of central graft area populated by viable cells after preparation and after 3-7 days of graft storage was 88% and 92%, respectively. Conclusion: Cell viability of most of the grafts will not be affected by preparation and storage. Endothelial cell damage may be observed for some grafts within hours after preparation, with insignificant additional ECD changes during 3-7 days of graft storage. Implementing an additional post-preparation step in the eye bank to evaluate cell density before graft release for transplantation may help to reduce postoperative DMEK complications.

Background An enriched environment for residents with dementia may have a positive effect on the rest-activity rhythm. A small scaled homelike special care unit might be such an enriched environment. The present study shows whether the rest-activity rhythm of residents with moderate to severe dementia responds positively to a transfer from a regular Special Care Unit (SCU) to a small scaled homelike SCU. Methods Initially, a group of 145 residents living in a regular SCU participated. Out of this group, 77 residents moved to a small scaled homelike SCU. This group was compared to the group of 68 residents that remained at the regular SCU. Rest-activity rhythm was assessed by means of actigraphy and observation scales before and after relocation. Results No significant main effects nor significant interaction effects in intradaily and interdaily activity were found for the data of 38 residents in the small scaled homelike SCU and 20 residents of the regular SCU. The effect sizes, however, ranged from small to large. Conclusions Considering the effect sizes, a new study with a larger number of participants is necessary before firm conclusions can be drawn. Trial registration Current Controlled Trials ISRCTN11151241 . registration date: 21–06-2017. Retrospectively registered.

Background In women with abnormal uterine bleeding, fibroids are a frequent finding. In case of heavy menstrual bleeding and presence of submucosal type 0–1 fibroids, hysteroscopic resection is the treatment of first choice, as removal of these fibroids is highly effective. Hysteroscopic myomectomy is currently usually performed in the operating theatre. A considerable reduction in costs and a higher patient satisfaction are expected when procedural sedation and analgesia with propofol (PSA) in an outpatient setting is applied. However, both safety and effectiveness – including the necessity for re-intervention due to incomplete resection – have not yet been evaluated. Methods This study is a multicentre randomised controlled trial with a non-inferiority design and will be performed in the Netherlands. Women > 18 years with a maximum of 3 symptomatic type 0 or 1 submucosal fibroids with a maximum diameter of 3.5 cm are eligible to participate in the trial. After informed consent, 205 women will be randomised to either hysteroscopic myomectomy using procedural sedation and analgesia with propofol in an outpatient setting or hysteroscopic myomectomy using general anaesthesia in a clinical setting in the operating theatre. Primary outcome will be the percentage of complete resections, based on transvaginal ultrasonography 6 weeks postoperatively. Secondary outcomes are cost effectiveness, menstrual blood loss (Pictorial blood assessment chart), quality of life, pain, return to daily activities/work, hospitalization, (post) operative complications and re-interventions. Women will be followed up to one year after hysteroscopic myomectomy. Discussion This study may demonstrate comparable effectiveness of hysteroscopic myomectomy under procedural sedation and analgesia versus general anaesthesia in a safe and patient friendly environment, whilst achieving a significant cost reduction. Trial registration Dutch trial register, number NTR5357. Registered 11th of August 2015. Electronic supplementary material The online version of this article (10.1186/s12905-019-0742-1) contains supplementary material, which is available to authorized users.

Objectives: Over the past decade, a trend has been noticed in the Netherlands to replace large-scaled special care units (SCUs) caring for 20–30 residents with dementia by small-scaled SCUs caring for up to 8 residents. Systematic evaluations, however, have yielded a differentiated picture of the effects. As the impact on psychotropic drug use has hardly been addressed thus far, we examined the (potential) impact of psychotropic drug use when moving residents with dementia from large-scaled to small-scaled SCUs. Methods: We conducted a non-randomized, controlled study with a six-month follow-up. Among 145 residents with dementia living a large-scaled SCUs for dementia caring for 20–30 residents per unit, a total of 77 residents were moved to small-scaled SCUs caring for up to 8 residents per unit. Psychotropic drug use, classified according to the Anatomical Therapeutic Chemical Classification (ATC) system was monitored at 2 months before replacement, as well as at 3 and 6 months thereafter. Repeated measures ANOVAs were conducted for the mean Defined Daily Doses (DDDs) of both groups. Results: No significant differences between both groups in psychotropic medication use were found over a period of 8 months. Conclusion: Prescription of psychotropic drugs does not change after a transfer from a large-scaled SCU to a small-scaled SCU of patients with moderate to severe dementia. Current Controlled Trials: ISRCTN11151241.

The possibility of accurately inferring the external forces applied to a vehicle can directly contribute to better safety systems and thus lowers the chance of injury or loss of life. These external forces are applied to a vehicle through the tyres and are challenging to measure directly. Still, it is possible to measure acceleration, deformation, or strain on the inner surface of a tyre. These measurements are theorized to be strongly linked to the forces produced by the tyre. However, it is still unknown whether or not one can always identify external forces from internal measurements in this way. Research has mainly focused on obtaining estimates of tyre forces rather than establishing to what extent these tyre forces are identifiable. This paper investigates this by conducting a virtual experiment that simulates known external forces applied to the tyre and computes the strains and displacements inside the tyre. A virtual inverse simulation then recovers the external forces from either the deformation or strain computed on the inside of the tyre. The identifiability of the forces recovered by the virtual inverse simulation is investigated by adding artificial measurement noise and initial guess perturbations to quantify the variance in the identified forces.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).

Gram-negative bacteria naturally produce and secrete nanosized outer membrane vesicles (OMVs). In the human gastrointestinal tract, OMVs produced by commensal Gram-negative bacteria can mediate interactions amongst host cells (including between epithelial cells and immune cells) and maintain microbial homeostasis. This OMV-mediated pathway for host-microbe interactions could be exploited to deliver biologically active proteins to the body. To test this we engineered the Gram-negative bacterium Bacteroides thetaiotaomicron (Bt), a prominent member of the intestinal microbiota of all animals, to incorporate bacteria-, virus- and human-derived proteins into its OMVs. We then used the engineered Bt OMVs to deliver these proteins to the respiratory and gastrointestinal (GI)-tract to protect against infection, tissue inflammation and injury. Our findings demonstrate the ability to express and package both Salmonella enterica ser. Typhimurium-derived vaccine antigens and influenza A virus (IAV)-derived vaccine antigens within or on the outer membrane of Bt OMVs. These antigens were in a form capable of eliciting antigen-specific immune and antibody responses in both mucosal tissues and systemically. Furthermore, immunisation with OMVs containing the core stalk region of the IAV H5 hemagglutinin from an H5N1 strain induced heterotypic protection in mice to a 10-fold lethal dose of an unrelated subtype (H1N1) of IAV. We also showed that OMVs could express the human therapeutic protein, keratinocyte growth factor-2 (KGF-2), in a stable form that, when delivered orally, reduced disease severity and promoted intestinal epithelial repair and recovery in animals administered colitis-inducing dextran sodium sulfate. Collectively, our data demonstrates the utility and effectiveness of using Bt OMVs as a mucosal biologics and drug delivery platform technology.

No Abstract

While we were preparing another paper, we were surprised not to find an existing peer-reviewed overview of the Dutch development of conflict archaeology. Though a vast number of publications, theoretical debates and conferences on this topic does exist, nothing has appeared in academic journals. We argue that Dutch archaeology of modern conflict is primarily a community-driven development and that this is the cause for the current gap. To set the record straight we provide a review of this development up to 2015 and we argue that conflict archaeology might be the best example of community archaeology in the Netherlands yet because it started with the public. To illustrate how the results of conflict archaeology in archaeological heritage management can have an impact on local, national and army communities, we discuss the case of the 1940 battlefield ‘Grebbeberg Mount’.

Background Quality of life is a clinical highly relevant outcome for residents with dementia. The question arises whether small scaled homelike facilities are associated with better quality of life than regular larger scale nursing homes do. Methods A sample of 145 residents living in a large scale care facility were followed over 8 months. Half of the sample (N = 77) subsequently moved to a small scaled facility. Quality of life aspects were measured with the QUALIDEM and GIP before and after relocation. Results We found a significant Group x Time interaction on measures of anxiety meaning that residents who moved to small scale units became less anxious than residents who stayed on the regular care large-scale units. No significant differences were found on other aspects of quality of life. Conclusions This study demonstrates that residents who move from a large scale facility to a small scale environment can improve an aspect of quality of life by showing a reduction in anxiety. Trial registration Current Controlled Trials ISRCTN11151241. registration date: 21–06-2017. Retrospectively registered.

Arsenic (As) contamination of communal tubewells in Prey Veng, Cambodia, has been observed since 2000. Many of these wells exceed the WHO As in drinking water standard of 10 μg/L by a factor of 100. The aim of this study was to assess how cooking water source impacts dietary As intake in a rural community in Prey Veng. This aim was fulfilled by (1) using geostatistical analysis techniques to examine the extent of As contaminated groundwater in Prey Veng and identify a suitable study site, (2) conducting an on-site study in two villages to measure As content in cooked rice prepared with water collected from tubewells and locally harvested rainwater, and (3) determining the dietary intake of As from consuming this rice. Geostatistical analysis indicated that high risk tubewells (>50 μg As/L) are concentrated along the Mekong River's east bank. Participants using high risk tubewells are consuming up to 24 times more inorganic As daily than recommended by the previous FAO/WHO provisional tolerable daily intake value (2.1 μg/kg BW/day). However, As content in rice cooked in rainwater was significantly reduced, therefore, it is considered to be a safer and more sustainable option for this region.

Background: Special care facilities for patients with dementia gain increasing attention. However, an overview of studies examining the differences between care facilities with respect to their effects on behavior, cognition, functional status and quality of life is lacking. Results: Our literature search resulted in 32 studies published until October 2012. Overall, patients with dementia who lived at special care units (SCUs) showed a significantly more challenging behavior, more agitation/aggression, more depression and anxiety, more cases of global cognitive impairment and a better psychosocial functioning. There was a tendency towards a better functional status in specialized care facilities, and a better quality of life was found in favor of the SCU group compared to the traditional nursing home (n-SCU) group. Longitudinal studies showed an increased number of neuropsychiatric cases, more patients displaying deteriorating behavior and resistance to care as well as less decline in activities of daily living (ADL) in the SCU group compared to the n-SCU group. Patients in small-scale, homelike SCUs showed more agitation and less ADL decline compared to SCU patients. Conclusion: This review shows that the patient characteristics in SCU and n-SCU settings and, to a minor extent, in SCU and small-scale, homelike SCU settings are different. Over time, there are differences between n-SCU, SCU and small-scale, homelike SCU facilities for some variables.

Background:Eustachian tube dysfunction is a disorder for which there are limited medical and surgical treatments. Recently, eustachian tube balloon dilation has been proposed as a potential solution.Method:A systematic literature review was performed. Abstracts were selected for relevance, and pooled data analysis and qualitative analysis was conducted.Results:Nine prospective studies, describing 713 eustachian tube balloon dilations in 474 patients (aged 18–86 years), were identified. Follow-up duration ranged from 1.5 to 18 months. Ability to perform a Valsalva manoeuvre improved from 20 to 177 out of 245 ears following eustachian tube balloon dilation and, where data were reported in terms of patient numbers, from 15 to 189 out of 210 patients. Tympanograms were classified as type A in 7 out of 141 ears pre-operatively and in 86 out of 141 ears post-operatively.Conclusion:Prospective case series can confirm the safety of eustachian tube balloon dilation. As a potential solution for chronic eustachian tube dysfunction, further investigations are warranted to establish a higher level of evidence of efficacy.

Lion populations in West and Central Africa are small and fragmented. In areas where park management is weak, threats will likely facilitate the extinction of the lion. Wildlife management requires knowledge of the population estimate. The population of lions in Waza National Park (Waza NP) was assessed by individual identification of members in the population. The population was assessed to comprise of 14‐21 adult individual lions. The age structure was skewed towards adults; cubs comprised 22% of all lions identified while the sex ratio was 1 : 3. Two out of four collared lions were lost to illegal, retaliatory killings within 1 year; and probably two more males and one more female were also killed during this period. The lion population appears to have declined during the last 5 years with six lions dying per year, which is at a much higher rate than observed in the previous decades. Human-livestock pressure has increased tremendously in this period, resulting to frequent human-lion conflicts. To ensure the survival of the lion in Waza NP and in the entire region, management needs to intensify efforts to mitigate the pressure from humans and their livestock.

Internet of Things (IoT) has been implemented in most advance technologies as part of the emerging 4th industrial revolution, and recently, blockchain technology is being welcomed. These rapid growing technologies giving a big challenge to the students. As such, learning these new technologies should be made easy and simple. However, current education does not specifically offer a curriculum to empower skills and knowledge in IoT and blockchain technology. The aim of this research is to develop learning kit that can provide suitable training to understand concept of IoT and blockchain technology. The kit consists of three parts namely “brain”, “muscle” and “cloud”. Raspberry Pi is used as “brain” of operation that will be interact with the Caiser Cloud platform. A testbox operates as “muscle” to provide simple data input. The input from testbox will be sent, stored and displayed on a platform created using Xojo software. The results show that the learning kit is successfully interact with Caiser Cloud platform and can be used as a training tools for education purpose.

Summary. Background: Accurate diagnosis of acute recurrent deep vein thrombosis (DVT) is relevant to avoid improper diagnosis and unnecessary life-long anticoagulant treatment. Compression ultrasound has high accuracy for a first episode of DVT, but is often unreliable in suspected recurrent disease. Magnetic resonance direct thrombus imaging (MR DTI) has been shown to accurately detect acute DVT. The purpose of this prospective study was to determine the MR signal change during 6 months follow-up in patients with acute DVT. Patients/methods: This study was a prospective study of 43 consecutive patients with a first episode of acute DVT demonstrated by compression ultrasound. All patients underwent MR DTI. Follow-up was performed with MR-DTI and compression ultrasound at 3 and 6 months respectively. All data were coded, stored and assessed by two blinded observers. Results: MR direct thrombus imaging identified acute DVT in 41 of 43 patients (sensitivity 95%). There was no abnormal MR-signal in controls, or in the contralateral extremity of patients with DVT (specificity 100%). In none of the 39 patients available at 6 months follow-up was the abnormal MR-signal at the initial acute DVT observed, whereas in 12 of these patients (30.8%) compression ultrasound was still abnormal. Conclusion: Magnetic resonance direct thrombus imaging normalizes over a period of 6 months in all patients with diagnosed DVT, while compression ultrasound remains abnormal in a third of these patients. MR-DTI may potentially allow for accurate detection in patients with acute suspected recurrent DVT, and this should be studied prospectively.

Background: Evidence shows that living in small scale homelike Special Care Units (SCU) has positive effects on behavioural and psychological symptoms of patients with dementia. Effects on cognitive functioning in relation to care facilities, however, are scarcely investigated. The purpose of this study is to gain more insight into the effects of living in small scale homelike Special Care Units, compared to regular SCU's, on the course of cognitive functioning in dementia.Methods: A group of 67 patients with dementia who moved from a regular SCU to a small scale homelike SCU and a group of 48 patients with dementia who stayed in a regular SCU participated in the study. Cognitive and behavioural functioning was assessed by means of a neuropsychological test battery and observation scales one month before (baseline), as well as 3 (post) and 6 months (follow-up) after relocation.Results: Comparing the post and follow-up measurement with the baseline measurement, no significant differences on separate measures of cognitive functioning between both groups were found. Additional analyses, however, on 'domain clusters' revealed that global cognitive functioning of the small scale homelike SCU group showed significantly less cognitive decline three months after the transfer (p Conclusions: While there is no significant longitudinal effect on the progression of cognitive decline comparing small scaled homelike SCU's with regular SCU's for patients with dementia, analyses on the domain clusters and effect sizes cautiously suggest differences in favour of the small scaled homelike SCU for different aspects of cognition.

OBJECTIVES The purpose of this study was to investigate whether a harmful cardiovascular risk profile accelerates menopause. BACKGROUND Women with an early menopause are at an increased risk of cardiovascular disease. Although increased cardiovascular risk has been proposed as consequence of menopause, the alternative hypothesis, that increased premenopausal cardiovascular risk promotes early menopause, needs to be examined. METHODS We used data from the Framingham Heart Study cohort. This study started in 1948 and has followed up participants biennially since then. Women who were premenopausal at study entry and who reached natural menopause after at least two examination rounds were included in the study (n = 695). Premenopausal age-independent levels of serum total cholesterol, relative weight, blood pressure, and Framingham risk score were determined, as well as premenopausal changes in cholesterol, body weight, and blood pressure. RESULTS A higher premenopausal serum total cholesterol level was statistically significantly associated with an earlier age at menopause, as were increases in total serum cholesterol, relative weight, and blood pressure in the premenopausal period. A decrease in total serum cholesterol during premenopause was statistically significantly associated with later age at menopause. Decreasing blood pressure was associated with a later menopausal age, but this association was not statistically significant. A decrease in relative weight was associated with a significant earlier age at menopause. Each 1% higher premenopausal Framingham risk score was associated with a decrease in menopausal age of 1.8 years (95% confidence interval -2.72 to -0.92). CONCLUSIONS The findings support the view that heart disease risk determines age at menopause. This offers a novel explanation for the inconsistent findings on cardiovascular disease rate and its relationship to menopausal age and effects of hormone replacement therapy. (J Am Con Cardiol 2006;47:1976 - 83) (c) 2006 by the American College of Cardiology Foundation

Four institutes, all of which are involved in nuclear-emergency management in the Dutch-German border region, have compared their short-range dispersion and radiological dose models using scenarios consisting of single-station meteorology and two dispersed radionuclides. After adjustment of some of the parameters, the consequence of the differences in parameters on the effective dose was quantified at several stages from source to exposure. Results for the neutral stability class agreed within a factor of four. Variations in wet deposition of radioactive material, giving rise to external radiation from the ground, can cause significant variations to the effective dose. Furthermore, the way the different emergency-management tools model the atmospheric dispersion for a stable stability class in the horizontal plane can generate large differences. Finally, the methodology of calculating cloudshine is not comparable among the models, which causes the effective dose near the source to show large deviations for high emission sources.

Menopausal age is important as a retrospective marker for ovarian senescence, an early menopausal age is associated with an increased risk of cardiovascular diseases and osteoporosis, whereas a later menopausal age has been associated with an increased risk of breast cancer. The worldwide average for age at natural menopause is approximately 51 years and is more or less normally distributed with a range roughly between 40 and 60 years. Environmental factors explain only a small part of the variance and it has been proposed that genetic factors are the main source of variation. Menopausal age may be considered a continuous complex trait. Complex traits are defined as traits that are influenced by both multiple genetic and environmental factors. A category of complex traits comprises those that are measured on a continuous scale. The genomic loci that make up the genetic component are called 'quantitative trait loci' or QTLs. The first linkage study on menopausal age suggests that the involvement of the X-chromosome may not be limited to premature ovarian failure (POF), but may influence the broader spectrum of menopausal age. A potentially new locus for variation in menopausal age was allocated to chromosome 9. Further studies need to identify new candidate genes to help unravel the pathophysiology of menopausal age. It is becoming increasingly clear that, in any speciality, it should be acknowledged that genetic factors are involved in many traits and that uncovering these factors may provide insight into pathogenesis and ultimately advance prevention and treatment of disease. In this review we discuss methods and basic principles of gene finding for such traits, exemplified by menopausal age as phenotype. Furthermore, we give an overview of the state of the art of candidate gene studies and linkage studies.

Background: Age at menopause is under strong genetic control. So far, genetic variations of only one gene, the PvuII polymorphism of the estrogen receptor alpha (ERalpha) gene, have been shown to be associated with age at onset of menopause. This study aims to investigate whether PvuII, XbaI and B-variant polymorphisms of the ERalpha gene, and the MspAI polymorphism of the cytochrome P450c17alpha (CYP17) gene are associated with age at menopause in a Dutch cohort. Methods: DNA was isolated from urine samples of 385 Caucasian women with natural menopause and the genotypes of the four polymorphisms were determined. A questionnaire was used for background characteristics. The genotypes of PvuII, XbaI, MspAI were obtained by PCR restriction fragment length polymorphism analysis. The B-variant was determined with an allele-specific oligonucleotide hybridization method. Two-sided t-tests were performed to assess the association between the four polymorphisms and menopausal age. The PvuII and XbaI polymorphisms were analysed separately as well as in a combined score. Results: The results show that none of the polymorphisms independently, nor the combined genotypes for PvuII and XbaI, were associated with age at natural menopause. Conclusion: No evidence was found for a relationship between common variants of the ERalpha gene and the CYP17 gene with age at natural menopause

Objective: To determine the heritability of age at natural menopause from mother-daughter pairs. Design: Two-generation families were selected to study heritability of menopausal age. Setting: Subjects were drawn from a population-based study. Patient(s): One hundred sixty-four mother-daughter pairs with a natural menopausal age. Intervention(s): None. Main Outcome Measure(s): The heritability of age at natural menopause estimated by a random-effects model. Result(s): A heritability of 44% (95% confidence interval, 36%, 50%) was estimated. Conclusion(s): This study confirms that heritable components largely determine the natural age at menopause. Reasons for the differences between heritability estimates based on sibling pairs and parent-child comparisons are discussed. (C) 2004 by American Society for Reproductive Medicine

Objective Studies have shown that age at natural menopause is heritable. Mutations in the FSH-receptor have been identified in women with premature ovarian failure (POF) and the FSH-receptor gene may, therefore, be considered a candidate gene for (early) menopausal age. This study investigates whether there is linkage between genetic markers in the FSH-receptor region and (early) age at menopause using a sib-pair design. Design Sib-pair based linkage analysis. Setting Sister pairs and their first-degree family members from The Netherlands. Patient(s) The inclusion criteria for a family were natural menopause in upper or lower tail of the distribution of menopausal age in at least two sisters. A total of 126 families with at least one sib-pair were included in this study. Six polymorphic markers encompassing the FSH-receptor gene were genotyped. Intervention(s) None. Main outcome measure(s) Single point and multipoint logarithm of the odds (LOD) scores. Result(s) None of the markers showed evidence in favor of linkage with overall age at natural menopause or early age at natural menopause. Conclusion(s) Possibly, age at natural menopause in the more or less normal range is not part of the spectrum of phenotypes determined by mutations in the FSH-receptor gene. Alternatively, our results might be explained by genetic heterogeneity in the left tail of the distribution of menopausal age. This can limit the chance of finding a genetic locus, especially if this factor has a modest contribution to the phenotype.

Background: Smoking has frequently been associated with early menopause. However, studies of this association have been inconclusive with regard to duration and intensity of smoking. A major problem in analyzing the effect of smoking duration on menopausal age is that both exposure and outcome are age-dependent. Methods: We calculated age-specific rates for categories of smoking duration and subsequently computed the rate ratios for occurrence of menopause. We were thus able to model the effect of smoking duration on 2 time scales without assumptions of linearity. We used data from a Dutch population-based cohort comprising 5544 women age 49-70 years who had experienced natural menopause. Results: The rate ratio (RR) for occurrence of menopause was increased in women who smoked in the year of menopause (RR = 1.41; 95% confidence interval = 1.32-1.50). The rate ratio of former smokers was similar to women who never smoked (0.95; 0.89-1.02). Prolonged exposure of smoking did not materially affect the risk of menopause, although the daily number of cigarettes currently smoked could increase the risk. Conclusion: Perimenopausal smoking is apparently more important than smoking history in explaining an earlier age of onset of menopause among women who smoke

Objective: Smoking is consistently associated with a younger age for menopause. Although this may be because of the direct toxic effects of tobacco smoke on follicles, we hypothesize that there may also be a relationship between smoking and a vascular origin of early menopausal onset. Several lifestyle factors have been investigated, but never factors of the clotting cascade. The objective of this study, then, was to determine the effect of factor V Leiden mutation and smoking with respect to age at menopause. Design: Data were used from a subset of 373 postmenopausal participants of a Dutch population-based cohort, born between 1911 and 1925. All women had experienced natural menopause, without use of hormone replacement therapy. Results: Female carriers of the factor V Leiden mutation (n = 14) reported the onset of menopause at an earlier age than noncarriers (n = 359; difference, 3.1 years; 95% CI: 0.3, 5.9). Smoker carriers (n = 5) were 4.3 years younger at menopause than smoker noncarriers (n = 92; 95% Cl: 0.9,7.6). In nonsmokers, this relationship was less strong. Conclusions: We found that the factor V Leiden mutation was related, but not statistically significant, to an earlier age at menopause; smoking possibly enhances this effect. The mutation can be one of the genetic determinants of menopausal age operating through a vascular mechanism

BACKGROUND: The aim of the study was to explore the extent to which accelerated ovarian ageing may lead to subfertility early in reproductive life and eventually cause early menopause. METHODS: The population studied (n = 2393) never used oral contraceptives, hormone replacement therapy or an intrauterine device. Logistic regression analyses were performed using age at menopause as proxy for accelerated ovarian ageing. Measures of ovarian ageing and subfertility were menstrual cycle irregularity, ever consulted a physician for fertility problems, nulliparity, uniparity, miscarriage(s) and time interval >5 years between birth of first and second child. RESULTS: For every 5 years later menopause, the probability of reporting menstrual cycle irregularity was reduced by 26% (OR = 0.74, 95% CI: 0.63‐0.86); the probability of ever consulting a physician for fertility problems was reduced by 18% (OR = 0.82, 95% CI: 0.71‐0.95); the probability of staying nulliparous was reduced by 22% (OR = 0.78, 95% CI: 0.64‐0.96); the probability of being uniparous was reduced by 22% (OR = 0.78, 95% CI: 0.66‐0.91); the probability of having a miscarriage was reduced by 11% (OR = 0.89, 95% CI: 0.79‐1.01); the probability of a large time interval between birth of first two children was reduced by 27% (OR = 0.73, 95% CI: 0.61‐0.89). CONCLUSIONS: Fertility problems are frequently followed by early menopause. The findings support the view that both are an expression of accelerated ovarian ageing.

Attempts to reproduce malabsorption syndrome (MAS) by oral inoculation with several different combinations including intestinal homogenate, reovirus, and hemolytic Escherichia coli obtained from MAS-affected chickens and intestinal homogenate from healthy chickens (healthy homogenate) were performed in 1-day-old specific-pathogen-free (SPF) broilers. The MAS homogenate, serving as a positive control, induced weight gain depression and intestinal lesions such as cystic crypts of Lieberkuhn, villus atrophy, and lymphoid and/or granulocytic infiltration. The healthy homogenate, the formalin-treated MAS homogenate, the formalin-treated healthy homogenate, and phosphate-buffered saline caused neither weight gain depression nor intestinal lesions. We were able to reproduce both weight gain depression and intestinal lesions by inoculation of reovirus either combined with the formalin-treated MAS homogenate or combined with healthy homogenate. Surprisingly, when hemolytic E. coli was added to the combination of reovirus with formalin-treated MAS homogenate, this did not cause weight gain depression although this combination caused the described intestinal lesions. Identical results were obtained with the combination of formalin-treated MAS homogenate with hemolytic E coli or the combination of reovirus with hemolytic E. coli. The intestinal lesions were more severe and developed faster by combinations including reovirus and formalin-treated MAS homogenate. This study indicates that a combination of enteropathogenic reovirus with other agents or substances that are present in an intestinal homogenate from MAS-affected and healthy chickens can induce MAS in SPF broilers. Escherichia coli is not essential for induction of weight gain depression but can play a role in development of intestinal lesions. Furthermore, intestinal lesions alone will not always result in weight gain depression.