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Objectives: Belgium experienced multiple COVID-19 waves that hit various groups in the population, which changed the mortality pattern compared to periods before the pandemic. In this study, we investigated the geographical excess mortality trend in Belgium during the first year of the COVID-19 pandemic., Methods: We retrieved the number of deaths and population data in 2020 based on gender, age, and municipality of residence, and we made a comparison with the mortality data in 2017-2019 using a spatially discrete model., Results: Excess mortality was significantly associated with age, gender, and COVID-19 incidence, with larger effects in the second half of 2020. Most municipalities had higher risks of mortality with a number of exceptions in the northeastern part of Belgium. Some discrepancies in excess mortality were observed between the north and south regions., Conclusions: This study offers useful insight into excess mortality and will aid local and regional authorities in monitoring mortality trends., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To estimate the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound and MRI for giant cell arteritis (GCA)., Methods: PubMed, Embase, Cochrane and Web of Science databases were searched from inception till August 31, 2022. Studies were included if they involved patients with suspected GCA and assessed the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound or MRI with the final clinical diagnosis as reference standard., Results: Eleven (1578 patients), 3 (149 patients) and 0 studies were included for the diagnostic accuracy of ultrasound, PET/CT and MRI, respectively. Combined cranial and large vessel ultrasound had a sensitivity of 86% (76-92%) and specificity of 96% (92-98%). PET/CT of both cranial and large vessels yielded a sensitivity of 82% (61-93%) and specificity of 79% (60-90%). No studies assessed both PET/CT and ultrasound, which precluded head-to-head comparison. Addition of large vessel ultrasound to ultrasound of the temporal arteries (7 studies) significantly increased sensitivity (91% versus 80%, p < 0.001) without decrease in specificity (96% versus 95%, p = 0.57). Evaluating cranial arteries in addition to large vessels on PET/CT (3 studies) tended to increase the sensitivity (82% versus 68%, p = 0.07) without decrease in specificity (81% versus 79%, p = 0.70)., Conclusion: Combined cranial and large vessel ultrasound and PET/CT provided excellent accuracy for the diagnosis of GCA. Either PET/CT or ultrasound may be preferred depending on setting, expertise and clinical presentation. The diagnostic accuracy of combined cranial and large vessel MRI needs to be determined in future studies., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: A rise in the incidence of some autoimmune disorders has been described. However, contemporary estimates of the overall incidence of autoimmune diseases and trends over time are scarce and inconsistent. We aimed to investigate the incidence and prevalence of 19 of the most common autoimmune diseases in the UK, assess trends over time, and by sex, age, socioeconomic status, season, and region, and we examine rates of co-occurrence among autoimmune diseases., Methods: In this UK population-based study, we used linked primary and secondary electronic health records from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex and ethnicity. Eligible participants were men and women (no age restriction) with acceptable records, approved for Hospital Episodes Statistics and Office of National Statistics linkage, and registered with their general practice for at least 12 months during the study period. We calculated age and sex standardised incidence and prevalence of 19 autoimmune disorders from 2000 to 2019 and used negative binomial regression models to investigate temporal trends and variation by age, sex, socioeconomic status, season of onset, and geographical region in England. To characterise co-occurrence of autoimmune diseases, we calculated incidence rate ratios (IRRs), comparing incidence rates of comorbid autoimmune disease among individuals with a first (index) autoimmune disease with incidence rates in the general population, using negative binomial regression models, adjusted for age and sex., Findings: Among the 22 009 375 individuals included in the study, 978 872 had a new diagnosis of at least one autoimmune disease between Jan 1, 2000, and June 30, 2019 (mean age 54·0 years [SD 21·4]). 625 879 (63·9%) of these diagnosed individuals were female and 352 993 (36·1%) were male. Over the study period, age and sex standardised incidence rates of any autoimmune diseases increased (IRR 2017-19 vs 2000-02 1·04 [95% CI 1·00-1·09]). The largest increases were seen in coeliac disease (2·19 [2·05-2·35]), Sjogren's syndrome (2·09 [1·84-2·37]), and Graves' disease (2·07 [1·92-2·22]); pernicious anaemia (0·79 [0·72-0·86]) and Hashimoto's thyroiditis (0·81 [0·75-0·86]) significantly decreased in incidence. Together, the 19 autoimmune disorders examined affected 10·2% of the population over the study period (1 912 200 [13·1%] women and 668 264 [7·4%] men). A socioeconomic gradient was evident across several diseases, including pernicious anaemia (most vs least deprived area IRR 1·72 [1·64-1·81]), rheumatoid arthritis (1·52 [1·45-1·59]), Graves' disease (1·36 [1·30-1·43]), and systemic lupus erythematosus (1·35 [1·25-1·46]). Seasonal variations were observed for childhood-onset type 1 diabetes (more commonly diagnosed in winter) and vitiligo (more commonly diagnosed in summer), and regional variations were observed for a range of conditions. Autoimmune disorders were commonly associated with each other, particularly Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Individuals with childhood-onset type 1 diabetes also had significantly higher rates of Addison's disease (IRR 26·5 [95% CI 17·3-40·7]), coeliac disease (28·4 [25·2-32·0]), and thyroid disease (Hashimoto's thyroiditis 13·3 [11·8-14·9] and Graves' disease 6·7 [5·1-8·5]), and multiple sclerosis had a particularly low rate of co-occurrence with other autoimmune diseases., Interpretation: Autoimmune diseases affect approximately one in ten individuals, and their burden continues to increase over time at varying rates across individual diseases. The socioeconomic, seasonal, and regional disparities observed among several autoimmune disorders in our study suggest environmental factors in disease pathogenesis. The inter-relations between autoimmune diseases are commensurate with shared pathogenetic mechanisms or predisposing factors, particularly among connective tissue diseases and among endocrine diseases., Funding: Research Foundation Flanders., Competing Interests: Declaration of interests NC is funded by a personal fellowship from the Research Foundation Flanders (grant number 12ZU922N) and declares royalties from Oxford University Innovation. SM is funded by a Wellcome Trust Career Development Award (223024/Z/21/Z) and is supported by the NIHR Imperial Biomedical Research Centre. IBM declares honoraria from AbbVie; grant support paid to his university from AstraZeneca and Eli Lilly; participation on data safety monitoring boards or advisory boards of AstraZeneca, Bristol Myers Squibb, Eli Lilly, Novartis, Janssen, GlaxoSmithKline, AbbVie, Cabaletta, Compugen, Causeway, Gilead, Moonlake, Reflexion, UCB, and XinThera; patents from Novartis; leadership roles with Evelo, Versus Arthritis, and Greater Glasgow and Clyde Health Board; and stock or stock options with Evelo, Compugen, and Cabaletta. JJVM has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Alkem Metabolics, Eris Lifesciences, Lupin, ProAdWise Communications, Servier Director, and Global Clinical Trial Partners. NS declares consulting fees or speaker honoraria, or both, from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. KK is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands and the NIHR Leicester Biomedical Research Centre. KK has also acted as a consultant, speaker, or received grants for investigator-initiated studies for AstraZeneca, Abbott, Amgen, Napp, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, and Applied Therapeutics. PNT declares personal consulting fees from Immunovant and leadership roles in the Society for Endocrinology and British Thyroid Association. All other authors declare no competing interests. The views expressed are those of the authors and not necessarily those of the funder., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The rapid spread of COVID-19 worldwide led to the implementation of various non-pharmaceutical interventions to limit transmission and hence reduce the number of infections. Using telecom-operator-based mobility data and a spatio-temporal dynamic model, the impact of mobility on the evolution of the pandemic at the level of the 581 Belgian municipalities is investigated. By decomposing incidence, particularly into within- and between-municipality components, we noted that the global epidemic component is relatively more important in larger municipalities (e.g., cities), while the local component is more relevant in smaller (rural) municipalities. Investigation of the effect of mobility on the pandemic spread showed that reduction of mobility has a significant impact in reducing the number of new infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

To monitor the COVID-19 epidemic in Cuba, data on several epidemiological indicators have been collected on a daily basis for each municipality. Studying the spatio-temporal dynamics in these indicators, and how they behave similarly, can help us better understand how COVID-19 spread across Cuba. Therefore, spatio-temporal models can be used to analyze these indicators. Univariate spatio-temporal models have been thoroughly studied, but when interest lies in studying the association between multiple outcomes, a joint model that allows for association between the spatial and temporal patterns is necessary. The purpose of our study was to develop a multivariate spatio-temporal model to study the association between the weekly number of COVID-19 deaths and the weekly number of imported COVID-19 cases in Cuba during 2021. To allow for correlation between the spatial patterns, a multivariate conditional autoregressive prior (MCAR) was used. Correlation between the temporal patterns was taken into account by using two approaches; either a multivariate random walk prior was used or a multivariate conditional autoregressive prior (MCAR) was used. All models were fitted within a Bayesian framework., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Some autoimmune diseases are associated with an increased risk of cardiovascular disease. We aimed to determine whether or not this is true, and to what extent, for a broad range of autoimmune conditions., Methods: In this population-based study, we used linked primary and secondary care records from the Clinical Practice Research Datalink (CPRD), GOLD and Aurum datasets, to assemble a cohort of individuals across the UK who were newly diagnosed with any of 19 autoimmune diseases between Jan 1, 2000, and Dec 31, 2017, younger than 80 years at diagnosis, and free of cardiovascular diseases up to 12 months after diagnosis. We also assembled a matched cohort with up to five individuals matched on age, sex, socioeconomic status, region, and calendar year, who were free of autoimmune disease and free of cardiovascular diseases up to 12 months after study entry. Both cohorts were followed up until June 30, 2019. We investigated the incidence of 12 cardiovascular outcomes and used Cox proportional hazards models to examine differences in patients with and without autoimmune diseases., Findings: Of 22 009 375 individuals identified from the CPRD databases, we identified 446 449 eligible individuals with autoimmune diseases and 2 102 830 matched controls. In the autoimmune cohort, mean age at diagnosis was 46·2 years (SD 19·8), and 271 410 (60·8%) were women and 175 039 (39·2%) were men. 68 413 (15·3%) people with and 231 410 (11·0%) without autoimmune diseases developed incident cardiovascular disease during a median of 6·2 years (IQR 2·7-10·8) of follow-up. The incidence rate of cardiovascular disease was 23·3 events per 1000 patient-years among patients with autoimmune disease and 15·0 events per 1000 patient-years among those without an autoimmune disease (hazard ratio [HR] 1·56 [95% CI 1·52-1·59]). An increased risk of cardiovascular disease with autoimmune disease was seen for every individual cardiovascular disease and increased progressively with the number of autoimmune diseases present (one disease: HR 1·41 [95% CI 1·37-1·45]; two diseases: 2·63 [2·49-2·78]); three or more diseases: 3·79 [3·36-4·27]), and in younger age groups (age <45 years: 2·33 [2·16-2·51]; 55-64 years: 1·76 [1·67-1·85]; ≥75 years: 1·30 [1·24-1·36]). Among autoimmune diseases, systemic sclerosis (3·59 [2·81-4·59]), Addison's disease (2·83 [1·96-4·09]), systemic lupus erythematosus (2·82 [2·38-3·33]), and type 1 diabetes (2·36 [2·21-2·52]) had the highest overall cardiovascular risk., Interpretation: These findings warrant targeted cardiovascular prevention measures, in particular in younger patients with autoimmune diseases, and further research into pathophysiological mechanisms underlying these complications., Funding: Horizon 2020 Marie Skłodowska-Curie Actions and European Society of Cardiology., Competing Interests: Declaration of interests JJVM reports personal fees for lectures from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus; and fees paid to their university for steering committees and advisory board membership, trial planning, being principal investigator or co-principal investigator for trials, consulting and advising, and travel expenses from Cytokinetics, Amgen, AstraZeneca, Theracos, Ionis Pharmaceuticals, DalCor, Cardurion, Novartis, GSK, Bayer, KBP Biosciences, Boehringer Ingelheim, and Bristol-Myers Squibb. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: We estimated the effect of pneumococcal vaccination (PV) on acute lower respiratory tract infections (LRTIs) in various age and risk groups using different methods within a causal inference methodological framework., Study Design and Setting: We used data from a general practitioners' morbidity registry for the year 2019. Both traditional statistical methods (regression-based and propensity score methods) and machine learning techniques were deployed. Multiple imputation was used to account for missing data. Relative risks (RRs) with 95% confidence intervals were estimated. Sensitivity analyses were performed to account for the severity of LRTIs and differences in vaccination registration., Results: All methods showed a standardized mean difference below 0.1 for each covariate. No method was found to be superior to another. PV (combination of conjugate and polysaccharide vaccine) had an overall protective effect for severe LRTIs. PV was protective in different age and risk groups, especially in people aged 50-84 years with an intermediate risk group., Conclusion: Using several techniques, PV was found to prevent severe LRTIs and confirmed the recommendations of the Belgian Superior Health Council., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Starting from historic reflections, the current SARS-CoV-2 induced COVID-19 pandemic is examined from various perspectives, in terms of what it implies for the implementation of non-pharmaceutical interventions, the modeling and monitoring of the epidemic, the development of early-warning systems, the study of mortality, prevalence estimation, diagnostic and serological testing, vaccine development, and ultimately clinical trials. Emphasis is placed on how the pandemic had led to unprecedented speed in methodological and clinical development, the pitfalls thereof, but also the opportunities that it engenders for national and international collaboration, and how it has simplified and sped up procedures. We also study the impact of the pandemic on clinical trials in other indications. We note that it has placed biostatistics, epidemiology, virology, infectiology, and vaccinology, and related fields in the spotlight in an unprecedented way, implying great opportunities, but also the need to communicate effectively, often amidst controversy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Although COVID-19 has been spreading throughout Belgium since February, 2020, its spatial dynamics in Belgium remain poorly understood, partly due to the limited testing of suspected cases during the epidemic's early phase. We analyse data of COVID-19 symptoms, as self-reported in a weekly online survey, which is open to all Belgian citizens. We predict symptoms' incidence using binomial models for spatially discrete data, and we introduce these as a covariate in the spatial analysis of COVID-19 incidence, as reported by the Belgian government during the days following a survey round. The symptoms' incidence is moderately predictive of the variation in the relative risks based on the confirmed cases; exceedance probability maps of the symptoms' incidence and confirmed cases' relative risks overlap partly. We conclude that this framework can be used to detect COVID-19 clusters of substantial sizes, but it necessitates spatial information on finer scales to locate small clusters., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The evolution of kidney allograft survival remains insufficiently studied in the context of the changing donor and recipient demographics. Since European data are lacking we performed a cohort study (1986-2015) that, based on the Collaborative Transplant Study, included 108 787 recipients of brain-death kidney donors in 135 hospitals across 21 European countries. We analyzed the hazard rate of kidney failure after transplantation. Between 1986 and 1999, improvement in graft survival was more pronounced in the short term than in the long term: one-, five- and ten-year hazard rates after transplantation declined 64% (95% confidence interval, 61%-66%), 53% (49%-57%) and 45% (39%-50%), respectively. Between 2000 and 2015, hazard rates at one, five and ten years post-transplant declined respectively 22% (12-30%), 47% (36-56%) and 64% (45-76%). Improvement in graft survival in the first five years post-transplant was significantly less since 2000, while improvement after five years was comparable to before. During the 2000-2015 period improvement of graft survival was greater in the long than in the short term. These changes were independent of changing donor and recipient characteristics, and reflect the evolution in global kidney transplant management over the past decades. Unfortunately, after accounting for the evolution of donor and recipient characteristics, we found that short-term improvement in graft survival decreased since 2000, while long-term improvement remained unchanged in Europe. Thus, deceleration of short-term graft survival improvement in more recent years illustrates an unmet need for innovation., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Current approaches such as inspections, audits, and end product testing cannot detect the distribution and dynamics of microbial contamination. Despite the implementation of current food safety management systems, foodborne outbreaks linked to fresh produce continue to be reported. A microbial assessment scheme and statistical modeling were used to systematically assess the microbial performance of core control and assurance activities in five Kenyan fresh produce processing and export companies. Generalized linear mixed models and correlated random-effects joint models for multivariate clustered data followed by empirical Bayes estimates enabled the analysis of the probability of contamination across critical sampling locations (CSLs) and factories as a random effect. Salmonella spp. and Listeria monocytogenes were not detected in the final products. However, none of the processors attained the maximum safety level for environmental samples. Escherichia coli was detected in five of the six CSLs, including the final product. Among the processing-environment samples, the hand or glove swabs of personnel revealed a higher level of predicted contamination with E. coli , and 80% of the factories were E. coli positive at this CSL. End products showed higher predicted probabilities of having the lowest level of food safety compared with raw materials. The final products were E. coli positive despite the raw materials being E. coli negative for 60% of the processors. There was a higher probability of contamination with coliforms in water at the inlet than in the final rinse water. Four (80%) of the five assessed processors had poor to unacceptable counts of Enterobacteriaceae on processing surfaces. Personnel-, equipment-, and product-related hygiene measures to improve the performance of preventive and intervention measures are recommended.

Introduction: Maternal cardiovascular (CV) profiling is useful in the assessment of gestational hypertensive disorders (GHD)(1). The onset of GHD occurs during the first weeks of gestation(2)., Objective: To evaluate whether CV profiling can detect first trimester differences between women with uncomplicated pregnancies (UP) and those who will develop GHD or fetal growth restriction (FGR)., Methods: CV function was evaluated according to standardised protocols in 242 pregnant women around 12 weeks of gestation, using impedance cardiography (ICG) and combined ECG - Doppler ultrasonography. Outcome was evaluated after delivery and categorized as UP (n=218), GHD with or without proteinuria (n=13), and pregnancies complicated with FGR (n=11). Measurements were compared between groups using Mann-Whitney U test for continuous data or Fisher's Exact test for categorical variables., Results: As compared to UP, women destined to develop GHD showed increased systolic blood pressure, diastolic blood pressure and mean arterial pressure; and decreased ICG aortic velocity - and acceleration index. Pregnancies complicated with FGR showed decreased stroke volume and cardiac output when compared to UP. No differences were found concerning the maternal veins., Conclusion: First trimester maternal CV function differs between women with uncomplicated pregnancies and those destined to develop GHD or FGR. Non-invasive CV profiling enables the identification of these differences., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: Cardiovascular profiling is useful for gestational hemodynamic studies. Conflicting results of cardiac output evolution from third trimester pregnancy to term are frequently reported., Objectives: To stress the effect of maternal position in the assessment of maternal cardiac and arterial parameters during normal pregnancy., Methods: Impedance cardiography measurements were executed during 16 normal pregnancies using a standard protocol with known reproducibility. Gestational evolution of stroke volume, cardiac output, cardiac cycle time intervals, aortic flow parameters and total peripheral vascular resistance was measured in supine, standing and sitting positions. SAS procedure MIXED for linear mixed models was used for each parameter separately., Results: Evolution of stroke volume and cardiac output in supine position differed from standing (p<0.01) and sitting positions (p<0.05). Next to this, pre-ejection period, left ventricular ejection time index, systolic time ratio and total peripheral vascular resistance also showed a different evolution between supine and standing positions (p<0.05); no differences were observed between standing and sitting positions (p⩾0.19)., Conclusion: Next to the frequently reported cardiac output, gestational evolutions of other pre-load dependent parameters are influenced by maternal position. This study shows the importance of a standardized protocol for the measurement of cardiovascular parameters in pregnancy., (Copyright © 2013. Published by Elsevier B.V.)

Modern disease mapping commonly uses hierarchical Bayesian methods to model overdispersion and spatial correlation. Classical random-effects based solutions include the Poisson-gamma model, which uses the conjugacy between the Poisson and gamma distributions, but which does not model spatial correlation, on the one hand, and the more advanced CAR model, which also introduces a spatial autocorrelation term but without a closed-form posterior distribution on the other. In this paper, a combined model is proposed: an alternative convolution model accounting for both overdispersion and spatial correlation in the data by combining the Poisson-gamma model with a spatially-structured normal CAR random effect. The Limburg Cancer Registry data on kidney and prostate cancer in Limburg were used to compare the conventional and new models. A simulation study confirmed results and interpretations coming from the real datasets. Relative risk maps showed that the combined model provides an intermediate between the non-patterned negative binomial and the sometimes oversmoothed CAR convolution model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Pre-eclampsia (PE) has been categorised into subtypes depending on low or high cardiac output (CO) states. Are cardiac reflex responses (CRR) different between these two subtypes?, Objectives: Impedance cardiography (ICG) measurements of cardiac cycle time intervals (CCTI) before and after orthostatic challenge are evaluated in the clinical phase of PE with low and high CO (LPE and HPE, respectively)., Methods: Examinations were performed in 25 LPE (CO⩽7l/min) and 16 HPE (CO⩾9l/min). A third generation ICG device using a four electrode arrangement (NICCOMO, Medis, Germany) was used to measure CCTI in supine position and after moving to upright position. The pre-ejection period (PEP) is the time-interval between ventricular depolarisation and start of aortic flow. The left ventricular ejection time (LVET) is the time-interval between opening and closing of the aortic valve. Systolic time ratio (STR) is PEP/LVET. Diastolic time (DT) is the heart period duration - (PEP+LVET). Time intervals were expressed as a percentage of the heart period duration, i.e. PEPi, LVETi and DTi. Orthostatic-induced changes from supine to upright position (cardiac reflex response or CRR) were evaluated using One-sample Wilcoxon Signed Rank Tests. All CRRs were compared between LPE and HPE using Mann-Whitney U tests. Data are presented as medians (interquartile ranges)., Results: Maternal age was comparable between LPE and HPE [29 (26-34) vs 28 (26-33) years; p=0.55]. This was also true for gestational age [34 (30-38) vs 36 (31-39) weeks; p=0.50], and pre-gestational BMI [24 (22-30) vs 25 (24-32); p=0.21]. Birth weight percentiles were lower in LPE compared to HPE [18 (5-31) vs 44 (18-83); p<0.01]. CRRs within each group are shown in Table 1. CRRs of PEP, PEPi and DT were different between LPE and HPE [p⩽0.04], whereas changes in LVET, LVETi, DTi and STR were not [p⩾0.09]. Reflex-induced changes of diastolic blood pressure and heart rate (HR) were not significantly different between LPE and HPE [p⩾0.41]., Conclusion: Orthostasis does not change PEP in HPE, but induces a significant increase of PEP in LPE. PEP is dependent on HR, preload, afterload and sympathetic activity. There is no difference in the reflex-induced response of HR, DBP (∼afterload), and STR (∼sympathetic activity) between the two groups. This suggests that the orthostatic-induced change in the isovolumetric contraction time in LPE is preload-induced. Our observations suggest that hemodynamic background mechanisms behind LPE and HPE are different, and support the view that these subtypes are two different clinical entities., (Copyright © 2010. Published by Elsevier B.V.)

Introduction: Reflex responses of cardiac cycle time intervals (CCTI) can be measured by echocardiography, and are reported to differ between uneventful pregnancy (UP) and pre-eclampsia (PE). It is unknown whether impedance cardiography (ICG) is a useful method to measure CCTI during pregnancy., Objectives: ICG measurements of CCTI before and after orthostatic challenge are evaluated in UP and in the clinical phase of PE., Methods: Examinations were performed twice in 16 UP (30-36 weeks), and once in 30 early PE (EPE, <34 weeks) and in 32 late PE (LPE, ⩾34 weeks). A 3rd generation ICG device using a 4 electrode arrangement (NICCOMO, Medis, Germany) was used to measure CCTI in supine position and after moving to upright position. The pre-ejection period (PEP) is the time-interval between ventricular depolarisation and start of aortic flow. The left ventricular ejection time (LVET) is the time-interval between opening and closing of the aortic valve. Diastolic time (DT) is heart period duration - (PEP+LVET). Orthostatic-induced changes from supine to upright position (cardiac reflex response or CRR) were evaluated using One-sample Wilcoxon Signed Rank Tests. All CRRs in EPE and LPE were compared to UP using Mann-Whitney U tests. Data are represented as medians (interquartile ranges)., Results: Maternal age was comparable between all groups [29 (26-32) years; p⩾0.47]. Gestational age was comparable between both early [31 (28-32) vs 31 (27-33) weeks] and late [37 (36-39) vs 38 (36-39) weeks] third trimester UP and PE [p⩾0.38]. Pre-gestational BMI was higher in EPE compared to UP [26 (24-32) vs 23 (21-24); p<0.01]. This was not true for LPE [25 (23-28); p=0.06]. Birth weight percentiles were lower in both EPE and LPE compared to UP [UP: 44 (38-78), EPE: 18 (5-28), LPE: 31 (18-59); p<0.05], and also lower in EPE compared to LPE [p=0.03]. CRRs within each group are shown in Table 1. The CRRs of PEP were significantly different between UP and both EPE and LPE [p⩽0.01], due to orthostatic-induced increase in PE but not in UP ., Conclusion: Our study confirms that orthostasis does not change PEP in UP but induces a significant increase of PEP in PE. The increased reflex-induced duration of isovolumetric contraction time can be explained by a decreased left ventricular performance in the clinical phase of PE as compared to UP. ICG turns out to be a straightforward and useful method to evaluate these hemodynamic features., (Copyright © 2012. Published by Elsevier B.V.)

Background: Age is associated with immune dysregulation, which results in an increased infection rate and reduced effectiveness of vaccination., Objective: We assessed whether an intervention with Lactobacillus casei Shirota (LcS) in elderly nursing home residents reduced their susceptibility to respiratory symptoms and improved their immune response to influenza vaccination., Design: Between October 2007 and April 2008, a randomized, double-blind, placebo-controlled trial was conducted in 737 healthy people aged ≥ 65 y in 53 nursing homes in Antwerp, Belgium. Volunteers were randomly assigned to receive a probiotic (n = 375; 2 bottles of fermented milk that contained ≥ 6.5 × 10(9) live LcS/bottle) or a placebo (n = 362; similar drink with no bacteria) for 176 d. After 21 d, all subjects received an influenza vaccination. Primary outcome parameters were the number of days with respiratory symptoms, the probability of respiratory symptoms, and antiinfluenza antibody titer by hemagglutination inhibition after vaccination., Results: Univariate and multivariate modeling showed no effect of the probiotic on clinical outcome parameters. Generalized linear mixed modeling showed no effect of the probiotic itself on the probability of respiratory symptoms [OR of probiotic: 0.8715; 95% CI: 0.6168, 1.2887). No significant difference regarding the influenza-vaccination immune response was shown., Conclusion: The results of this study show that daily consumption of a fermented milk drink that contains LcS has no statistically or clinically significant effect on the protection against respiratory symptoms. This trial was registered at clinicaltrials.gov as NCT00849277.

Rationale: Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available., Objective: To obtain better insight into the phenomenon of premature discontinuation., Methods: We analyzed the pattern of discontinuation in the UPLIFT-trial., Measurements and Main Results: Premature discontinuation was substantial and greater in the placebo than in the tiotropium group (45 vs. 37%, p < 0.001). Patients discontinuing were characterized by more severe COPD (p < 0.0001), greater number of pack years (p < 0.002), smaller pre-bronchodilator and post-bronchodilator FEV(1) (p < 0.0001 for both), and worse SGRQ scores (p < 0.0001). Rates of decline of FEV(1) and SGRQ were greater in non-completers (p < 0.0001 for both). The latter differences increased over time indicating that the evolution of variables in time was related to trial completion. The risks of exacerbations and hospitalizations were greater in non-completers. In logistic regression analysis BMI, post-bronchodilator FEV(1), male gender and treatment with tiotropium were positively related to trial completion, whereas age, worse SGRQ, female gender, current smoking and assignment to the placebo group were negatively related., Conclusion: Assignment to the control group is related to premature discontinuation. Discontinuation was important and selective in this large trial. Pulmonary function, health-related quality of life and smoking are the most important other variables related to discontinuation. The evolution of variables during the trial is also related to discontinuation. Complete follow-up of discontinued patients may provide better insight into the efficacy of medication in future trials., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The study was conducted to identify predictors of oligoamenorrhea at 12 months in levonorgestrel-releasing intrauterine system (LNG-IUS) users., Design: A 12-month observational study., Setting: Gynecologic outpatient clinic in a large regional hospital in Flanders, Belgium., Population or Sample: A total of 150 women who had made an informed decision to use a LNG-IUS either as a method of contraception or to manage menorrhagia., Methods: All women were premenopausal and first-time users. The variables recorded prior to insertion on Days 1 to 5 of the menstrual cycle were age, parity, body mass index, indication for LNG-IUS use, prior contraceptive use, menstrual bleeding history, length of the uterine cavity, endometrial thickness, number of antral follicles, serum follicle-stimulating hormone, inhibin B and anti-Müllerian hormone. Menstrual bleeding pattern, patient satisfaction or wish to discontinue the method was noted at 3, 6 and 12 months of follow-up visits., Main Outcome Measures: Menstrual bleeding pattern (amenorrhea, oligomenorrhea, menorrhagia) at 12 months was taken as the primary outcome measurement. Patient satisfaction was followed as a secondary outcome., Results: Oligoamenorrhea was associated with a high patient satisfaction. A bleeding period less than 5 days, absence of severe uterine bleeding at baseline, LNG-IUS use for contraception and oligoamenorrhea at 3 months were predictors of a favorable outcome at 12 months in a univariate analysis. The absence of severe bleeding prior to LNG-IUS insertion was the only clinically useful predictor of favorable outcome in the multivariate analysis (odds ratio 0.13, 95% confidence interval 0.02-0.66)., Conclusions: Patient profiling as described is not helpful in counselling women for intentional LNG-IUS use, especially not if it is planned as a method of managing menorrhagia.

A retrospective cohort study was conducted with an intracytoplasmic sperm injection (ICSI) group and a naturally conceived comparison group. A total of 1655 singleton and 1102 twin ICSI births were studied with regard to perinatal outcome. Control subjects (naturally conceived pregnancies) were selected from a regional registry and were matched for maternal age, parity, place of delivery, year of birth and fetal sex. The main outcome measures were duration of pregnancy, birth weight, Apgar score <5 after 5 min, neonatal complications, perinatal death and congenital malformations. Twin births, when compared with singletons, carry a much higher risk of poor perinatal outcome. For both ICSI singletons and ICSI twins, no significant difference was found between ICSI and naturally conceived pregnancies for all investigated parameters. After excluding like-sex twin pairs, ICSI twin pregnancies were at increased risk for perinatal mortality (OR = 2.74, CI = 1.26-5.98), prematurity (OR = 1.38, CI = 1.10-1.75) and low birth weight (OR = 1.34, CI = 1.06-1.69) compared with spontaneously conceived different-sex twin pairs. In conclusion, the perinatal outcome of ICSI singleton and twin pregnancies was very similar to that of spontaneously conceived pregnancies in this large cohort study. After excluding like-sex twin pairs, ICSI twins were at increased risk for prematurity, low birth weight and higher perinatal mortality compared with the natural conception comparison group.

A total of 3974 IVF and 1655 ICSI singleton births and 2901 IVF and 1102 ICSI twin births were evaluated. Pregnancies after both fresh and frozen transfers were included. IVF and ICSI singleton pregnancies were very similar for most obstetric and perinatal variables. The only significant difference was a higher risk for prematurity (< 37 weeks of amenorrhoea) in IVF pregnancies compared with ICSI pregnancies (12.4 versus 9.2%, OR = 1.39, 95% CI = 1.15-1.70). For twin pregnancies, differences were not statistically different except for a higher incidence of stillbirths in the ICSI group (2.08 versus 1.03%, OR = 2.04, 95% CI = 1.14-3.64). Intrauterine growth retardation with or without pregnancy-induced hypertension was observed more often in the ICSI group. Regression analysis of the data with correction for parity and female age showed similar results for twins. For singletons, this analysis showed similar results with the exception of low birth weight babies (< 2500 g), which were also observed more often in IVF pregnancies (9.6 versus 7.9%, OR = 0.79, CI = 0.65-0.98, P = 0.03). This large case-comparative retrospective analysis showed that the obstetric outcome and perinatal health of IVF and ICSI pregnancies is comparable.

Repeated measures are exploited to study reliability in the context of psychiatric health sciences. It is shown how test-retest reliability can be derived using linear mixed models when the scale is continuous or quasi-continuous. The advantage of this approach is that the full modeling power of mixed models can be used. Repeated measures with a different mean structure can be used to usefully study reliability, correction for covariate effects is possible, and a complicated variance-covariance structure between measurements is allowed. In case the variance structure reduces to a random intercept (compound symmetry), classical methods are recovered. With more complex variance structures (e.g., including random slopes of time and/or serial correlation), time-dependent reliability functions are obtained. The methodology is motivated by and applied to data from five double-blind randomized clinical trials comparing the effects of risperidone to conventional antipsychotic agents for the treatment of chronic schizophrenia. Model assumptions are investigated through residual plots and by investigating the effect of influential observations.

Treatment effects are often evaluated by comparing change over time in outcome measures; however, valid analyses of longitudinal data can be problematic, particularly if some data are missing. For decades, the last observation carried forward (LOCF) approach has been a common method of handling missing data. Considerable advances in statistical methodology and our ability to implement those methods have been made in recent years. Thus, it is appropriate to reconsider analytic approaches for longitudinal data. This review examines the following from a clinical perspective: 1) the characteristics of missing data that influence analytic choices; 2) the attributes of common methods of handling missing data; and 3) the use of the data characteristics and the attributes of the various methods, along with empirical evidence, to develop a robust approach for the analysis and interpretation of data from longitudinal clinical trials. We propose that, in many settings, the primary efficacy analysis should use a repeated measures, likelihood-based, mixed-effects modeling approach, with LOCF used as a secondary, composite measure of efficacy, safety, and tolerability. We illustrate how repeated-measures analyses can be used to enhance decision-making, and we review the caveats that remain regarding the use of LOCF as a composite measure., (Copyright 2003 Society of Biological Psychiatry)

The validation of surrogate endpoints has been studied by Prentice, who presented a definition as well as a set of criteria that are equivalent if the surrogate and true endpoints are binary. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs proposed to replace the proportion explained by two quantities: (1). the relative effect, linking the effect of treatment on both endpoints, and (2). the adjusted association, an individual-level measure of agreement between both endpoints. In a multiunit setting, these quantities can be generalized to a trial-level measure of surrogacy and an individual-level measure of surrogacy. In this paper, we argue that such a multiunit approach should be adopted because it overcomes difficulties that necessarily surround validation efforts based on a single trial. These difficulties are highlighted.

Background: Treatment of advanced colorectal cancer has progressed substantially. However, improvements in response rates have not always translated into significant survival benefits. Doubts have therefore been raised about the usefulness of tumour response as a clinical endpoint., Methods: This meta-analysis was done on individual data from 3791 patients enrolled in 25 randomised trials of first-line treatment with standard bolus intravenous fluoropyrimidines versus experimental treatments (fluorouracil plus leucovorin, fluorouracil plus methotrexate, fluorouracil continuous infusion, or hepatic-arterial infusion of floxuridine). Analyses were by intention to treat., Findings: Compared with bolus fluoropyrimidines, experimental fluoropyrimidines led to significantly higher tumour response rates (454 responses among 2031 patients vs 209 among 1760; odds ratio 0.48 [95% CI 0.40-0.57], p<0.0001) and better survival (1808 deaths among 2031 vs 1580 among 1760; hazard ratio 0.90 [0.84-0.97], p=0.003). The survival benefits could be explained by the higher tumour response rates. However, a treatment that lowered the odds of failure to respond by 50% would be expected to decrease the odds of death by only 6%. In addition, less than half of the variability of the survival benefits in the 25 trials could be explained by the variability of the response benefits in these trials., Interpretation: These analyses confirm that an increase in tumour response rate translates into an increase in overall survival for patients with advanced colorectal cancer. However, in the context of individual trials, knowledge that a treatment has benefits on tumour response does not allow accurate prediction of the ultimate benefit on survival.

In the technique of counterimmunoelectrophoresis (CIE) with serum prediffusion (SPD) serum is allowed to diffuse freely into the gel before pouring the antigenic extract in its trough (or wells) and starting the electrophoresis. Both the immunoprecipitations and the interactions with reference sera are strongly intensified by SPD, leading to higher sensitivity and specificity for the detection of anti-SSA/Ro, anti-SSB/La, anti-U1RNP, anti-Sm, anti-Jo1 and even anti-Scl-70 antibodies. We found that the optimal SPD time was 2 h. To evaluate the relevance of SPD for the clinical laboratory, 92 antinuclear antibody (ANA) positive sera were tested on CIE without SPD and with 2 h SPD in identification tests with SSA/Ro, SSB/La, Sm, U1RNP and Jo1 reference sera (rsa). The precipitation lines and their interactions were evaluated by three independent observers. It was observed that SPD considerably improved the efficiency of CIE for antibody identification. The mechanisms underlying the intensification of the precipitation lines by SPD are discussed as are the characteristics of the CIE in comparison with other test systems such as the enzyme linked immunosorbent assay (ELISA) and immunoblot.