Procedure-related risk of miscarriage following chorionic villus sampling and amniocentesis

Objective: The objective of our study was to estimate the procedure-related risks of miscarriage following CVS and amniocentesis in a large unselected screened and to determine whether these risks are consistent with those reported in systematic reviews and meta-analysis. Methods: This was a retrospective cohort study undertaken at a large Fetal Medicine Unit in the United Kingdom during the period of January 2009 to May 2018. We included all singleton pregnancies that booked at our unit before 20 weeks after excluding those with multiple pregnancies, major fetal defects, terminations and lost to follow-up. We estimated the risk of miscarriage in those that had a CVS or amniocentesis as well as those that did not have any invasive procedure, to estimate the procedure-related risk as a risk-difference (95% confidence interval [CI]). Univariate and multivariate regression analysis was used to derive odds ratios (OR) (95%CI) and determine which maternal and pregnancy characteristics provided a significant contribution in prediction of miscarriage and whether CVS or amniocentesis provided a significant independent. Results: During the study period, there were 45,120 singleton pregnancies, including 1,546 that had an invasive procedure. We excluded 1,429 pregnancies (3.2%), due to fetal defects, termination of pregnancy or those with missing outcomes. In pregnancies that underwent CVS, the risk of miscarriage was 1.5% (13/861), compared to 1.2% (476/39,152) in pregnancies that did not have a procedure (p=0.437). In pregnancies that underwent an amniocentesis, the risk of miscarriage was 0.8% (3/375), compared to 1.2% (491/42,463) in those that did not (p=0.520). Univariate and multivariate regression analysis demonstrated that there was no significant prediction to the risk of miscarriage from CVS (p=0.399; p=0.592, respectively) or amniocentesis (p=0.543; p=0.550, respectively). The risk of procedure-related loss attributed to CVS was 0.29% (95%CI: -0.53-1.12) and that following amniocentesis was -0.36% (95%CI: -1.26-0.55), which was not significantly different from those that did not have any procedure. Conclusion: The procedure-related risks of miscarriage following CVS and amniocentesis are considerably lower than currently quoted. The estimates of risks based on our study are 0.29% for CVS and -0.36 for amniocentesis

Prevention of stillbirths: impact of a two-stage screening for vasa previa

Objectives: To examine the feasibility and effectiveness of a two-stage ultrasound screening strategy for detection of vasa previa and estimate the potential impact of screening on prevention of stillbirth. Methods: This was a retrospective examination of data from prospective screening for vasa previa in singleton pregnancies undertaken at the Fetal Medicine Centre at Medway Maritime Hospital, UK between 2012 and 2018. Women booked for prenatal care and delivery in our hospital had routine ultrasound examinations at 11-13 and 20-22 weeks’ gestation. Those with velamentous cord insertion at the inferior part of the placenta at the first-trimester scan and those with low-lying placenta at the second-trimester scan were classified as high-risk for vasa previa and had transvaginal sonography specifically searching for vasa previa at the time of the 20-22 weeks scan. The management and outcome of cases with suspected vasa previa is described. We excluded cases of miscarriage or termination at <24 weeks’ gestation. Results: The study population of 26,830 singleton pregnancies, included 21 (0.08% or 1 in 1,278) with vasa previa. In all cases of vasa previa the diagnosis was made at the 20-22 weeks scan and confirmed by gross and histological examination of the placenta postnatally. At the 11-13 weeks scan the cord insertion was classified as central in 25,071 (93.4%) cases, marginal in 1,680 (6.3%), and velamentous in 79 (0.3%). In 16 (76.2%) of the 21 cases of vasa previa, the cord insertion at the first-trimester scan was classified as velamentous at the inferior part of the placenta, in 2 (9.5%) as marginal and in 3 (14.3%) as central. The 21 cases of vasa previa were managed on an outpatient basis with serial scans for measurement of cervical length and elective cesarean section at 34 weeks’ gestation; all babies were liveborn but there was one neonatal death. In the study population there were 83 stillbirths and postnatal examination showed no evidence of vasa previa in any of the cases. On the assumption that if we had not diagnosed prenatally all 21 cases of vasa previa in our population half of these cases would have resulted in stillbirth, then the potential impact of screening is prevention of 9.6% (10/104) of stillbirths. Conclusion: A two-stage strategy of screening for vasa previa can be incorporated into routine clinical practice and such strategy could potentially reduce the rate of stillbirth

Modelling towards a more holistic medicine: The Virtual Physiological Human (VPH).

The Virtual Physiological Human (VPH) is a European initiative, rooted in the international Physiome initiative, focusing on establishing a methodological and technological framework, enabling the collaborative investigation of the human body as a single complex system. This collective framework will facilitate the sharing of resources and observations formed by different institutions and organizations, and the creation of disparate but integrated computer models of the mechanical, physical and biochemical functions of a living human body. The VPH initiative has laid the foundation for integrating heterogeneous data sources into mechanistic computer models of most anatomical systems

Mapping the use of computational modelling and simulation in clinics: A survey

In silico medicine describes the application of computational modelling and simulation (CM&S) to the study, diagnosis, treatment or prevention of a disease. Tremendous research advances have been achieved to facilitate the use of CM&S in clinical applications. Nevertheless, the uptake of CM&S in clinical practice is not always timely and accurately reflected in the literature. A clear view on the current awareness, actual usage and opinions from the clinicians is needed to identify barriers and opportunities for the future of in silico medicine. The aim of this study was capturing the state of CM&S in clinics by means of a survey toward the clinical community. Responses were collected online using the Virtual Physiological Human institute communication channels, engagement with clinical societies, hospitals and individual contacts, between 2020 and 2021. Statistical analyses were done with R. Participants (n = 163) responded from all over the world. Clinicians were mostly aged between 35 and 64 years-old, with heterogeneous levels of experience and areas of expertise (i.e., 48% cardiology, 13% musculoskeletal, 8% general surgery, 5% paediatrics). The CM&S terms “Personalised medicine” and “Patient-specific modelling” were the most well-known within the respondents. “In silico clinical trials” and “Digital Twin” were the least known. The familiarity with different methods depended on the medical specialty. CM&S was used in clinics mostly to plan interventions. To date, the usage frequency is still scarce. A well-recognized benefit associated to CM&S is the increased trust in planning procedures. Overall, the recorded level of trust for CM&S is high and not proportional to awareness level. The main barriers appear to be access to computing resources, perception that CM&S is slow. Importantly, clinicians see a role for CM&S expertise in their team in the future. This survey offers a snapshot of the current situation of CM&S in clinics. Although the sample size and representativity could be increased, the results provide the community with actionable data to build a responsible strategy for accelerating a positive uptake of in silico medicine. New iterations and follow-up activities will track the evolution of responses over time and contribute to strengthen the engagement with the medical community

Occurrence and Treatment of Bone Atrophic Non-Unions Investigated by an Integrative Approach

Recently developed atrophic non-union models are a good representation of the clinical situation in which many nonunions develop. Based on previous experimental studies with these atrophic non-union models, it was hypothesized that in order to obtain successful fracture healing, blood vessels, growth factors, and (proliferative) precursor cells all need to be present in the callus at the same time. This study uses a combined in vivo-in silico approach to investigate these different aspects (vasculature, growth factors, cell proliferation). The mathematical model, initially developed for the study of normal fracture healing, is able to capture essential aspects of the in vivo atrophic non-union model despite a number of deviations that are mainly due to simplifications in the in silico model. The mathematical model is subsequently used to test possible treatment strategies for atrophic non-unions (i.e. cell transplant at post-osteotomy, week 3). Preliminary in vivo experiments corroborate the numerical predictions. Finally, the mathematical model is applied to explain experimental observations and identify potentially crucial steps in the treatments and can thereby be used to optimize experimental and clinical studies in this area. This study demonstrates the potential of the combined in silico-in vivo approach and its clinical implications for the early treatment of patients with problematic fractures

Advancing osteochondral tissue engineering: bone morphogenetic protein, transforming growth factor, and fibroblast growth factor signaling drive ordered differentiation of periosteal cells resulting in stable cartilage and bone formation in vivo.

Chondrogenic mesenchymal stem cells (MSCs) have not yet been used to address the clinical demands of large osteochondral joint surface defects. In this study, self-assembling tissue intermediates (TIs) derived from human periosteum-derived stem/progenitor cells (hPDCs) were generated and validated for stable cartilage formation in vivo using two different animal models.status: publishe

Graviton emission in Einstein-Hilbert gravity

The five-point amplitude for the scattering of two distinct scalars with the emission of one graviton in the final state is calculated in exact kinematics for Einstein-Hilbert gravity. The result, which satisfies the Steinmann relations, is expressed in Sudakov variables, finding that it corresponds to the sum of two gauge invariant contributions written in terms of a new two scalar - two graviton effective vertex. A similar calculation is carried out in Quantum Chromodynamics (QCD) for the scattering of two distinct quarks with one extra gluon in the final state. The effective vertices which appear in both cases are then evaluated in the multi-Regge limit reproducing the well-known result obtained by Lipatov where the Einstein-Hilbert graviton emission vertex can be written as the product of two QCD gluon emission vertices, up to corrections to preserve the Steinmann relations.Comment: 28 pages, LaTeX, feynmf. v2: typos corrected, reference added. Final version to appear in Journal of High Energy Physic

Possible Contexts of Use for In Silico trials methodologies: a consensus- based review

The term In Silico Trial indicates the use of computer modelling and simulation to evaluate the safety and efficacy of a medical product, whether a drug, a medical device, a diagnostic product or an advanced therapy medicinal product. Predictive models are positioned as new methodologies for the development and the regulatory evaluation of medical products. New methodologies are qualified by regulators such as FDA and EMA through formal processes, where a first step is the definition of the Context of Use (CoU), which is a concise description of how the new methodology is intended to be used in the development and regulatory assessment process. As In Silico Trials are a disruptively innovative class of new methodologies, it is important to have a list of possible CoUs highlighting potential applications for the development of the relative regulatory science. This review paper presents the result of a consensus process that took place in the InSilicoWorld Community of Practice, an online forum for experts in in silico medicine. The experts involved identified 46 descriptions of possible CoUs which were organised into a candidate taxonomy of nine CoU categories. Examples of 31 CoUs were identified in the available literature; the remaining 15 should, for now, be considered speculative

Patterned, organoid-based cartilaginous implants exhibit zone specific functionality forming osteochondral-like tissues in vivo.

Tissue engineered constructs have the potential to respond to the unmet medical need of treating deep osteochondral defects. However, current tissue engineering strategies struggle in the attempt to create patterned constructs with biologically distinct functionality. In this work, a developmentally-inspired modular approach is proposed, whereby distinct cartilaginous organoids are used as living building blocks. First, a hierarchical construct was created, composed of three layers of cartilaginous tissue intermediates derived from human periosteum-derived cells: (i) early (SOX9), (ii) mature (COL2) and (iii) (pre)hypertrophic (IHH, COLX) phenotype. Subcutaneous implantation in nude mice generated a hybrid tissue containing one mineralized and one non-mineralized part. However, the non-mineralized part was represented by a collagen type I positive fibrocartilage-like tissue. To engineer a more stable articular cartilage part, iPSC-derived cartilage microtissues (SOX9, COL2; IHH neg) were generated. Subcutaneous implantation of assembled iPSC-derived cartilage microtissues resulted in a homogenous cartilaginous tissue positive for collagen type II but negative for osteocalcin. Finally, iPSC-derived cartilage microtissues in combination with the pre-hypertrophic cartilage organoids (IHH, COLX) could form dual tissues consisting of i) a cartilaginous safranin O positive and ii) a bony osteocalcin positive region upon subcutaneous implantation, corresponding to the pre-engineered zonal pattern. The assembly of functional building blocks, as presented in this work, opens possibilities for the production of complex tissue engineered implants by embedding zone-specific functionality through the use of pre-programmed living building blocks