Fast and robust quantification of uncertainty in non-linear diffusion MRI models.

Diffusion MRI (dMRI) allows for non-invasive investigation of brain tissue microstructure. By fitting a model to the dMRI signal, various quantitative measures can be derived from the data, such as fractional anisotropy, neurite density and axonal radii maps. We investigate the Fisher Information Matrix (FIM) and uncertainty propagation as a generally applicable method for quantifying the parameter uncertainties in linear and non-linear diffusion MRI models. In direct comparison with Markov Chain Monte Carlo (MCMC) sampling, the FIM produces similar uncertainty estimates at much lower computational cost. Using acquired and simulated data, we then list several characteristics that influence the parameter variances, including data complexity and signal-to-noise ratio. For practical purposes we investigate a possible use of uncertainty estimates in decreasing intra-group variance in group statistics by uncertainty-weighted group estimates. This has potential use cases for detection and suppression of imaging artifacts.

Periconceptional maternal supplement intake and human embryonic growth, development, and birth outcomes: the Rotterdam Periconception Cohort.

STUDY QUESTION: Is periconceptional multiple-micronutrient supplement (MMS) use including folic acid (FA) compared to FA use only associated with increased embryonic growth, development, and birth weight in a high-risk population? SUMMARY ANSWER: Women with MMS intake show no significant differences in first-trimester morphological embryo development, but increased first-trimester embryonic growth trajectories and fewer neonates born small for gestational age (SGA), less than the 3rd percentile (

Periconceptional maternal and paternal alcohol consumption and embryonic and fetal development: the Rotterdam periconception cohort.

RESEARCH QUESTION: What is the impact of maternal and paternal alcohol consumption in the periconception period on embryonic and fetal development assessed using three-dimensional ultrasound and virtual reality techniques? DESIGN: This prospective observational study was embedded in the Rotterdam periconception cohort (Predict study). Participating women received longitudinal three-dimensional transvaginal ultrasound examinations from week 7 to week 12 of gestation to measure crown-rump length and embryonic volume. Mid-pregnancy fetal size parameters and birth weight were retrieved from medical files. Participants completed a periconception exposure questionnaire and a validated food frequency questionnaire. Linear mixed models were used to analyse the association between parental alcohol consumption, and embryonic and fetal developmental parameters. RESULTS: In total, 1141 female and 987 male participants were included in the analyses. Moderate maternal alcohol consumption in the periconception period resulted in a smaller head circumference (ß = -1.85, SE = 0.84, P = 0.03), abdominal circumference (ß = -2.65, SE = 0.93, P = 0.004), femur length (ß = -0.56, SE = 0.22, P = 0.01) and estimated fetal weight (ß = -9.36, SE = 4.35, P = 0.03) at 20 weeks of gestation. Paternal alcohol consumption showed significant positive associations, mainly with fetal size parameters (abdominal circumference: ß = 0.033, SE = 0.01, P = 0.008; estimated fetal weight: ß = 0.131, SE = 0.06, P = 0.03). CONCLUSIONS: Moderate maternal alcohol consumption is negatively associated with fetal growth parameters. Moreover, alcohol is proven to be a strong teratogen, and its consumption before and during pregnancy should be discouraged in both women and men as it affects several parameters of embryonic and fetal development.

The profiling of microbiota in vaginal swab samples using 16S rRNA gene sequencing and IS-pro analysis.

BACKGROUND: 16S rRNA gene sequencing is currently the most common way of determining the composition of microbiota. This technique has enabled many new discoveries to be made regarding the relevance of microbiota to the health and disease of the host. However, compared to other diagnostic techniques, 16S rRNA gene sequencing is fairly costly and labor intensive, leaving room for other techniques to improve on these aspects. RESULTS: The current study aimed to compare the output of 16S rRNA gene sequencing to the output of the quick IS-pro analysis, using vaginal swab samples from 297 women of reproductive age. 16S rRNA gene sequencing and IS-pro analyses yielded very similar vaginal microbiome profiles, with a median Pearson's R2 of 0.97, indicating a high level of similarity between both techniques. CONCLUSIONS: We conclude that the results of 16S rRNA gene sequencing and IS-pro are highly comparable and that both can be used to accurately determine the vaginal microbiota composition, with the IS-pro analysis having the benefit of rapidity.

Association between COVID-19 lockdown measures and the incidence of iatrogenic versus spontaneous very preterm births in the Netherlands: a retrospective study.

BACKGROUND: The COVID-19 pandemic led to regional or nationwide lockdowns as part of risk mitigation measurements in many countries worldwide. Recent studies suggest an unexpected and unprecedented decrease in preterm births during the initial COVID-19 lockdowns in the first half of 2020. The objective of the current study was to assess the effects of the two months of the initial national COVID-19 lockdown period on the incidence of very and extremely preterm birth in the Netherlands, stratified by either spontaneous or iatrogenic onset of delivery, in both singleton and multiple pregnancies. METHODS: Retrospective cohort study using data from all 10 perinatal centers in the Netherlands on very and extremely preterm births during the initial COVID-19 lockdown from March 15 to May 15, 2020. Incidences of very and extremely preterm birth were calculated using an estimate of the total number of births in the Netherlands in this period. As reference, we used data from the corresponding calendar period in 2015-2018 from the national perinatal registry (Perined). We differentiated between spontaneous versus iatrogenic onset of delivery and between singleton versus multiple pregnancies. RESULTS: The incidence of total preterm birth < 32 weeks in singleton pregnancies was 6.1‰ in the study period in 2020 versus 6.5‰ in the corresponding period in 2015-2018. The decrease in preterm births in singletons was solely due to a significant decrease in iatrogenic preterm births, both < 32 weeks (OR 0.71; 95%CI 0.53 to 0.95) and < 28 weeks (OR 0.53; 95%CI 0.29 to 0.97). For multiple pregnancies, an increase in preterm births < 28 weeks was observed (OR 2.43; 95%CI 1.35 to 4.39). CONCLUSION: This study shows a decrease in iatrogenic preterm births during the initial COVID-19-related lockdown in the Netherlands in singletons. Future studies should focus on the mechanism of action of lockdown measures and reduction of preterm birth and the effects of perinatal outcome.

The vaginal microbiome as a predictor for outcome of in vitro fertilization with or without intracytoplasmic sperm injection: a prospective study.

STUDY QUESTION: Is the presence or absence of certain vaginal bacteria associated with failure or success to become pregnant after an in vitro fertilization (IVF) or IVF with intracytoplasmic sperm injection (IVF-ICSI) treatment? SUMMARY ANSWER: Microbiome profiling with the use of interspace profiling (IS-pro) technique enables stratification of the chance of becoming pregnant prior to the start of an IVF or IVF-ICSI treatment. WHAT IS KNOWN ALREADY: Live-birth rates for an IVF or IVF-ICSI treatment vary between 25 and 35% per cycle and it is difficult to predict who will or will not get pregnant after embryo transfer (ET). Recently, it was suggested that the composition of the vaginal microbiota prior to treatment might predict pregnancy outcome. Analysis of the vaginal microbiome prior to treatment might, therefore, offer an opportunity to improve the success rate of IVF or IVF-ICSI. STUDY DESIGN, SIZE, DURATION: In a prospective cohort study, 303 women (age, 20-42 years) undergoing IVF or IVF-ICSI treatment in the Netherlands were included between June 2015 and March 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study subjects provided a vaginal sample before the start of the IVF or IVF-ICSI procedure. The vaginal microbiota composition was determined using the IS-pro technique. IS-pro is a eubacterial technique based on the detection and categorization of the length of the 16S-23S rRNA gene interspace region. Microbiome profiles were assigned to community state types based on the dominant bacterial species. The predictive accuracy of the microbiome profiles for IVF and IVF-ICSI outcome of fresh ET was evaluated by a combined prediction model based on a small number of bacterial species. From this cohort, a model was built to predict outcome of fertility treatment. This model was externally validated in a cohort of 50 women who were undergoing IVF or IVF-ICSI treatment between March 2018 and May 2018 in the Dutch division of the MVZ VivaNeo Kinderwunschzentrum Düsseldorf, Germany. MAIN RESULTS AND THE ROLE OF CHANCE: In total, the vaginal microbiota of 192 women who underwent a fresh ET could be analysed. Women with a low percentage of Lactobacillus in their vaginal sample were less likely to have a successful embryo implantation. The prediction model identified a subgroup of women (17.7%, n = 34) who had a low chance to become pregnant following fresh ET. This failure was correctly predicted in 32 out of 34 women based on the vaginal microbiota composition, resulting in a predictive accuracy of 94% (sensitivity, 26%; specificity, 97%). Additionally, the degree of dominance of Lactobacillus crispatus was an important factor in predicting pregnancy. Women who had a favourable profile as well as <60% L. crispatus had a high chance of pregnancy: more than half of these women (50 out of 95) became pregnant. In the external validation cohort, none of the women who had a negative prediction (low chance of pregnancy) became pregnant. LIMITATIONS, REASONS FOR CAUTION: Because our study uses a well-defined study population, the results will be limited to the IVF or IVF-ICSI population. Whether these results can be extrapolated to the general population trying to achieve pregnancy without ART cannot be determined from these data. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that vaginal microbiome profiling using the IS-pro technique enables stratification of the chance of becoming pregnant prior to the start of an IVF or IVF-ICSI treatment. Knowledge of their vaginal microbiota may enable couples to make a more balanced decision regarding timing and continuation of their IVF or IVF-ICSI treatment cycles. STUDY FUNDING/COMPETING INTEREST(S): This study was financed by NGI Pre-Seed 2014-2016, RedMedTech Discovery Fund 2014-2017, STW Valorisation grant 1 2014-2015, STW Take-off early phase trajectory 2015-2016 and Eurostars VALBIOME grant (reference number: 8884). The employer of W.J.S.S.C. has in collaboration with ARTPred acquired a MIND subsidy to cover part of the costs of this collaboration project. The following grants are received but not used to finance this study: grants from Innovatie Prestatie Contract, MIT Haalbaarheid, other from Dutch R&D tax credit WBSO, RedMedTech Discovery Fund, (J.D.d.J.). Grants from Ferring (J.S.E.L., K.F., C.B.L. and J.M.J.S.S.), Merck Serono (K.F. and C.B.L.), Dutch Heart Foundation (J.S.E.L.), Metagenics Inc. (J.S.E.L.), GoodLife (K.F.), Guerbet (C.B.L.). R.K. is employed by ARTPred B.V. during her PhD at Erasmus Medical Centre (MC). S.A.M. has a 100% University appointment. I.S.P.H.M.S., S.A.M. and A.E.B. are co-owners of IS-Diagnostics Ltd. J.D.d.J. is co-owner of ARTPred B.V., from which he reports personal fees. P.H.M.S. reports non-financial support from ARTPred B.V. P.H.M.S., J.D.d.J. and A.E.B. have obtained patents `Microbial population analysis' (9506109) and `Microbial population analysis' (20170159108), both licenced to ARTPred B.V. J.D.d.J. and A.E.B. report patent applications `Method and kit for predicting the outcome of an assisted reproductive technology procedure' (392EPP0) and patent `Method and kit for altering the outcome of an assisted reproductive technology procedure' by ARTPred. W.J.S.S.C. received personal consultancy and educational fees from Goodlife Fertility B.V. J.S.E.L. reports personal consultancy fees from ARTPred B.V., Titus Health B.V., Danone, Euroscreen and Roche during the conduct of the study. J.S.E.L. and N.G.M.B. are co-applicants on an Erasmus MC patent (New method and kit for prediction success of in vitro fertilization) licenced to ARTPred B.V. F.J.M.B. reports personal fees from Advisory Board Ferring, Advisory Board Merck Serono, Advisory Board Gedeon Richter and personal fees from Educational activities for Ferring, outside the submitted work. K.F. reports personal fees from Ferring (commercial sponsor) and personal fees from GoodLife (commercial sponsor). C.B.L. received speakers' fee from Ferring. J.M.J.S.S. reports personal fees and other from Merck Serono and personal fees from Ferring, unrelated to the submitted paper. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: ISRCTN83157250. Registered 17 August 2018. Retrospectively registered.

Convolutional neural network-based encoding and decoding of visual object recognition in space and time.

Representations learned by deep convolutional neural networks (CNNs) for object recognition are a widely investigated model of the processing hierarchy in the human visual system. Using functional magnetic resonance imaging, CNN representations of visual stimuli have previously been shown to correspond to processing stages in the ventral and dorsal streams of the visual system. Whether this correspondence between models and brain signals also holds for activity acquired at high temporal resolution has been explored less exhaustively. Here, we addressed this question by combining CNN-based encoding models with magnetoencephalography (MEG). Human participants passively viewed 1,000 images of objects while MEG signals were acquired. We modelled their high temporal resolution source-reconstructed cortical activity with CNNs, and observed a feed-forward sweep across the visual hierarchy between 75 and 200 ms after stimulus onset. This spatiotemporal cascade was captured by the network layer representations, where the increasingly abstract stimulus representation in the hierarchical network model was reflected in different parts of the visual cortex, following the visual ventral stream. We further validated the accuracy of our encoding model by decoding stimulus identity in a left-out validation set of viewed objects, achieving state-of-the-art decoding accuracy.

Paternal age and first trimester placental size and growth: The Rotterdam Periconceptional Cohort.

INTRODUCTION: Despite a noticeable trend of delayed fatherhood, less is known about the impact of paternal age on the paternally programmed placenta. We hypothesize that paternal aging affects seminal quality and as such induces ageing-related epigenetic alterations that influence placental growth. Our main aim is to investigate associations between paternal age and first trimester (vascular) placental growth trajectories. METHODS: Pregnant women were enrolled before 10 weeks of gestation in the Rotterdam Periconceptional Cohort (Predict study). Placental volumes (PV) and utero-placental vascular volumes (uPVV) were measured at 7, 9, and 11 weeks gestation. Associations between paternal age and PV and uPVV were investigated using linear mixed models and the maximum likelihood ratio test to test non-linear relationships. We adjusted for gestational age, fetal sex, parental smoking and maternal age, BMI, education and parity, and stratified for conception mode. RESULTS: From 808 pregnancies we obtained 1313 PV and from 183 pregnancies 345 uPVV measurements. We show no associations between paternal age and PV (p = 0.934) and uPVV (p = 0.489) in our total population or in pregnancies conceived naturally (PV p = 0.166; uPVV p = 0.446) and after IVF/ICSI (PV p = 0.909; uPVV p = 0.749). For example, PV was 0.9% smaller (95% CI -5.7%-7.1%) in fathers aged 40 compared to 30 years old at 9 weeks gestation in the total study population. DISCUSSION: We are not demonstrating a significant impact of paternal age on first trimester placental growth in a tertiary care population. Given the trend of increasing paternal age, our study should be repeated in the general population.

Reported experienced stress during the COVID-19 pandemic and patient preferences for the consultation of periconception blended lifestyle care: a survey among (pre)pregnant women.

PURPOSE: To assess experienced stress on different aspects of life and evaluate patient preferences for the consultation of periconception blended lifestyle care, combining face-to-face counseling with eHealth, during the COVID-19 pandemic among (pre)pregnant women. Using this two-fold aim, we were able to analyze the levels of stress among (pre)pregnant women during the COVID-19 pandemic, and to study whether their preferences for the consultation modality of periconception blended lifestyle care was influenced by the levels of stress. METHODS: A quantitative survey among (pre)pregnant women who received blended periconception lifestyle care between March 2020 and December 2021, from the first until the fourth COVID-19 wave in the Netherlands. The questionnaire used a 5-point Likert scale and measured experienced stress and preferred periconception blended lifestyle care modality. RESULTS: 984 women (response rate: 55.2%) filled out the questionnaire. Experienced stress during the COVID-19 pandemic was relatively low and stable over time. The highest percentage of respondents (31.2%) reported to have experienced stress on fertility and pregnancy. 40.4% (309/764) of the respondents indicated that face-to-face consultations could be replaced by digital consultation. Additionally, the mean experienced stress did not differ between the patients who preferred a video consultation (2.60 ± 1.1), or a telephone consultation (2.57 ± 1.2), either a video or telephone consultation (2.54 ± 1.3), still preferred a face-to-face consultation (2.41 ± 1.4) (p = .83). CONCLUSIONS: Our findings indicate willingness for wide implementation of telemedicine within health care delivery, and reorganizing of periconception blended lifestyle care toward personalized and value-based health care.

The influence of size and comminution of the posterior malleolus fragment on gait in trimalleolar ankle fractures.

BACKGROUND: Ankle fractures involving the posterior malleolus generally lead to worse outcome. However, no studies on gait in trimalleolar ankle fractures have evaluated the influence of size and comminution of the posterior malleolar fragment. METHODS: We expected patients with more severely comminuted posterior malleolus, more severe fracture type and larger posterior fragment to have reduced gait kinematics and poorer patient-reported outcomes. 26 trimalleolar ankle fracture patients were compared with 14 healthy controls and kinematically analyzed using the Oxford Foot Model. Functional outcome was based on 4 patient reported outcome questionnaires. Effects of posterior fragment size, comminution and Haraguchi fracture classification were determined on conventional and 3D CT-scans. FINDINGS: Trimalleolar patients had lower walking speed and reduced range of motion between the hindfoot and tibia in both loading and push-off phases in the sagittal and transverse planes. The range between the hindfoot and tibia in the sagittal plane in the push-off phase correlated significantly with patient reported outcomes. The absolute and relative surface area of the posterior fragment on conventional CT-scans and 3D CT-scans, correlated significantly with range of motion. Patients with a posterior malleolus size >10% of the posterior malleolus had lower flexion-extension between forefoot and hindfoot during loading phase than patients with a size ≤10%. INTERPRETATION: Trimalleolar fractures reduce walking speed and range of motion in the talocrural joint. Reduced range in the talocrural joint is associated with poorer outcomes. Posterior fragment size correlated significantly with range of motion in talocrural and midfoot joints and with patient reported outcomes. LEVEL OF EVIDENCE: Level 3, retrospective study.

Effective psychological therapies to improve lifestyle behaviors in (pre)pregnant women: A systematic review.

Poor lifestyle behaviors impact (pre)pregnant women by affecting pregnancy outcomes and offspring health. This systematic review provides an overview of psychological therapies to support lifestyle behavior changes among (pre)pregnant women. Scientific databases were searched from their inception to 20 December 2020 for studies investigating the effects of psychological therapies on improvements in lifestyle behaviors. Studies were eligible if they included (pre)pregnant women, examined the effects of a psychological therapy on at least one lifestyle behavior and used a control group receiving usual pregnancy care or a non-psychological intervention. Lifestyle behaviors of interest were dietary intake, physical activity, smoking, alcohol consumption, drug use, body weight loss and body weight gain during pregnancy. Pregnancy complications were included as outcome measures. Motivational interviewing (MI) (n = 21), cognitive behavioral therapy (CBT) (n = 8), incentive-based contingency management (IBCM) (n = 9), mindfulness (n = 1) and hypnosis (n = 1) were investigated as lifestyle behavior interventions. The findings revealed that MI was effective in reducing (self-reported) smoking and alcohol consumption and restricting gestational weight gain (GWG). CBT was only studied as an intervention to restrict GWG and the results predominantly confirmed its effectiveness. IBCM showed the strongest effect on reducing smoking and substance use. The studies using hypnosis or mindfulness to reduce smoking or restrict GWG, respectively, showed no associations. The use of psychological therapies to improve lifestyle behaviors among (pre)pregnant women is new and the scientific proof is promising. Before wide implementation is legitimated, more evidence is needed on the consequences of lifestyle change for pregnancy outcomes.

[Glucocorticoid treatment in pregnancy; is caution the mother of wisdom?] / Behandeling met glucocorticoïden in de zwangerschap.

Timely prenatal, maternally administered, corticosteroids improve the outcome of preterm newborns. The general aim should therefore be optimal identification of actual imminent preterm birth to provide protection of all preterm infants that are at risk of a substantial level of post-natal morbidity. Unnecessary use of maternal corticosteroids by inadequate estimate of imminent preterm birth, now seems associated with mental and behavioural problems in the offspring during the life course, which calls for a more restricted use. Opportunities to reduce futile use of maternal corticosteroids in case of preterm birth might be found in better timing of administration, improved selection of women at risk and by potential restraint re-use at later gestational ages. Timing and selection can be further improved by the development of better (non-invasive) predictors to pinpoint those women who actual will deliver within 48 hours. Future prospective studies should provide additional evidence to improve antenatal corticosteroid administration.

Role of coagulation FVIII in septic peritonitis assessed in hemophilic mice.

BACKGROUND: Inhibition of blood coagulation appears to be an important therapeutic strategy to improve the outcome in sepsis. However, the beneficial effect of anticoagulant treatment in sepsis is solely based on experimental data using inhibitors of the extrinsic coagulant pathway. The role of the intrinsic pathway of coagulation in the pathogenesis of sepsis has not been explored yet. OBJECTIVE: In the current study, we contribute to determine the role of factor (F)VIII, the key player of the intrinsic coagulant pathway, on host defense against peritonitis. METHOD: Hemizygous FVIII-deficient mice and their wild-type littermates were challenged with 1 x 10(4) bacteria in a septic peritonitis model. RESULTS: The intraperitoneal injection of Escherichia coli led to growth and dissemination of bacteria and provoked an inflammatory response as evident from elevated cytokine levels, increased cell influx into tissues, liver necrosis, and endothelialitis resulting in mortality. The FVIII-deficient genotype slightly reduced bacterial outgrowth but had no effect on markers of inflammation and/or survival. In addition, FVIII-deficient mice showed profound activation of coagulation, thereby improving the hemophilic phenotype of FVIII-deficient mice. CONCLUSION: FVIII deficiency slightly modifies host defense in septic peritonitis in mice, but does not influence the final outcome of peritonitis. Therefore, we question the importance of the intrinsic coagulant pathway during sepsis.

Tissue factor haploinsufficiency during endotoxin induced coagulation and inflammation in mice.

Intervention studies blocking tissue factor (TF) driven coagulation show beneficial effects on survival in endotoxemia models by reducing cytokine production. It is unknown, however, if moderately reduced TF levels influence endotoxemia. The objective was to investigate whether TF haploinsufficiency reduces endotoxin-induced cytokine production in murine cells or in mice. We analyzed the intrinsic capacity of heterozygous TF deficient (TF+/-) leukocytes to produce cytokines. In addition, we determined the consequences of TF haploinsufficiency on endotoxin-induced inflammation during murine endotoxemia. Endotoxin induced the production of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and keratinocyte-derived chemokine (KC) in both whole blood and macrophages. Heterozygous TF deficiency reduced endotoxin induced IL-6 and KC levels about two-fold, while TNF-alpha levels were indistinguishable between TF+/- and wild-type cells. In vivo, endotoxin induced a biphasic coagulant response and significant increases in cytokine levels. Surprisingly, both the inflammatory and the coagulant responses were indistinguishable between wild-type and TF+/- mice. At baseline tissues of TF+/- mice showed a 50% reduction in TF activity compared to wild type. Upon endotoxin administration, TF activity increased and the difference between TF+/- and wild-type mice disappeared after 4 h. After 12 h the baseline difference in TF activity was re-established. TF deficiency reduces cytokine production in vitro, but an enhanced induction of TF during murine endotoxemia eliminates this effect in vivo.

Development of a three-dimensional CysLT1 (LTD4) antagonist model with an incorporated amino acid residue from the receptor.

This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4) receptor antagonists. Several different structural classes of CysLT1 antagonists were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'-[2-(2-quinolinyl)ethenyl]flavone (1, VUF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT1 antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an acidic function were taken as the matching points. In order to optimize the fitting of acidic moieties of all antagonists, an arginine residue from the receptor was proposed as the interaction site for the acidic moieties. Incorporation of this amino acid residue into the model revealed additional interactions between the guanidine group and the nitrogen atoms of quinoline-containing CysLT1 antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of CysLT1 antagonists. The alignment of Montelukast (MK-476) suggests the presence of an additional pocket in the binding site for CysLT1 antagonists. The derived model should be useful for a better understanding of the molecular recognition of the leukotriene CysLT1 receptor.

Microvascular coagulopathy and disseminated intravascular coagulation.

OBJECTIVE: To review the dual characteristics of disseminated intravascular coagulation (DIC), as both a contributor to multiple organ failure as well as a symptom of severe underlying disease associated with systemic vascular changes. DATA SOURCES: Published literature data and unpublished results from the authors. DATA SUMMARY: Clinical and experimental studies strongly suggest that DIC contributes to multiple organ failure and death in patients with severe systemic disorders such as sepsis. DIC is evoked by systemic cytokine activity, and the inflammatory response aggravates vascular permeability, inflammation, and cell damage in tissues. In addition to intravascular fibrin formation, thrombin and fibrin generation in tissues is also an important aspect of DIC. An example of DIC at the organ level is adult respiratory distress syndrome, where fibrin in the lung is a characteristic feature. Intravascular fibrin formation and occlusion may elicit a hypoxic response with induction of hypoxia related transcription factors. The resulting ischemic preconditioning may offer protective effects to the involved organ(s). CONCLUSIONS: Overall, the beneficial or harmful effects of activated coagulation and fibrin formation for organ pathology and recovery from DIC remain to be explored. This may be a critical element in the assessment of ischemia-reperfusion effects of specific anticoagulant therapy.