Enantioselective synthesis of ammonium cations.

Control of molecular chirality is a fundamental challenge in organic synthesis. Whereas methods to construct carbon stereocentres enantioselectively are well established, routes to synthesize enriched heteroatomic stereocentres have garnered less attention1-5. Of those atoms commonly present in organic molecules, nitrogen is the most difficult to control stereochemically. Although a limited number of resolution processes have been demonstrated6-8, no general methodology exists to enantioselectively prepare a nitrogen stereocentre. Here we show that control of the chirality of ammonium cations is easily achieved through a supramolecular recognition process. By combining enantioselective ammonium recognition mediated by 1,1'-bi-2-naphthol scaffolds with conditions that allow the nitrogen stereocentre to racemize, chiral ammonium cations can be produced in excellent yields and selectivities. Mechanistic investigations demonstrate that, through a combination of solution and solid-phase recognition, a thermodynamically driven adductive crystallization process is responsible for the observed selectivity. Distinct from processes based on dynamic and kinetic resolution, which are under kinetic control, this allows for increased selectivity over time by a self-corrective process. The importance of nitrogen stereocentres can be revealed through a stereoselective supramolecular recognition, which is not possible with naturally occurring pseudoenantiomeric Cinchona alkaloids. With practical access to the enantiomeric forms of ammonium cations, this previously ignored stereocentre is now available to be explored.

LONG-TERM OUTCOMES OF SUTURELESS INTRASCLERAL INTRAOCULAR LENS FIXATION IN CHILDREN AND ADULTS: Single-Surgeon Case Series With and Without Haptic Flanging With Up to 11 Years of Follow-Up.

PURPOSE: Report and compare long-term outcomes and complications of sutureless scleral tunnel (SST) and flanged haptic (FH) scleral-fixated intraocular lens, with spontaneous intraocular lens (IOL) dislocation as primary outcome measure. METHODS: Retrospective single-surgeon case series of 95 SST and 458 FH eyes from 2011 to 2022 (553 total eyes). Demographics, surgical indications, ocular history, visual acuity, and complication rates were collected. RESULTS: Reoperation-requiring spontaneous IOL dislocation rate was significantly different ( P = 0.0167) between FH (3.7%) and SST (10.5%). Mean follow-up was 3.31 ± 0.30 versus 1.58 ± 0.07 years for SST and FH, respectively. There was no significant difference between preoperative (20/305 vs. 20/300) or final postoperative (20/77 vs. 20/62) visual acuity. Other complications included any cystoid macular edema (20.0% vs. 25.3%), elevated intraocular pressure (16.8% vs. 9.6%), IOL tilt requiring reoperation (5.3 vs. 0%), haptic exposure (2.1% vs. 3.3%), and reverse pupillary block (4.2% vs. 1.1%). CONCLUSION: Haptic flanging resulted in fewer eyes meeting the primary end point of IOL dislocation. We reported the longest-to-date follow-up of both nonflanged SST IOL fixation and our FH-modified Yamane technique. Our FH-modified Yamane technique represents a safe, durable, and potentially superior option for scleral-fixated intraocular lens.

Cardiac Rhabdomyomas Presenting with Critical Cardiac Obstruction in Neonates and Infants: Treatment Strategies and Outcome, A Single-Center Experience.

Cardiac rhabdomyomas are the most common benign pediatric heart tumor in infancy, which are commonly associated with tuberous sclerosis complex (TSC). Most rhabdomyomas are asymptomatic and spontaneously regress over time. However, some cases especially in neonates or small infants can present with hemodynamic instability. Surgical resection of the tumor, which has been the gold standard in alleviating obstruction, is not always possible and may be associated with significant morbidity and mortality. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be safe and effective in the treatment of TSC. We present the outcomes of neonates and an infant who received treatment for symptomatic rhabdomyomas at a tertiary cardiology center. Medical records were reviewed to obtain clinical, demographic, and outcome data. Six patients received interventions for symptomatic rhabdomyomas, median age at presentation was 1 day old (range from 1 to 121 days old), and 67% of the patients had a pathogenic mutation in TSC gene. One patient underwent surgical resection of solitary tumor at right ventricular outflow tract (RVOT) successfully. In the four patients with left ventricular outflow tract (LVOT) obstruction, two patients received combined therapy of surgical debulking of LVOT tumor, Stage I palliation procedure, and mTORi and two patients received mTORi therapy. One patient with RVOT obstruction underwent ductal stenting and received synergistic mTORi. Four of the five patients had good response to mTORi demonstrated by the rapid regression of rhabdomyoma size. 83% of patients are still alive at their latest follow-up, at two to eight years of age. One patient died on day 17 post-LVOT tumor resection and Hybrid stage one due to failure of hemostasis, in the background of familial factor VII deficiency. Treatment of symptomatic rhabdomyoma requires individualized treatment strategy based on the underlying pathophysiology, with involvement of multidisciplinary teams. mTORi is effective and safe in inducing rapid regression of rhabdomyomas. A standardized mTORi prescription and monitoring guide will ensure medication safety in neonates and infants with symptomatic cardiac rhabdomyoma. Although the majority of tumors responded to mTORi, some prove to be resistant. Further studies are warranted, ideally involving multiple international centers with a larger number of patients.

Influence of improved antenatal detection on the outcomes of complete atrioventricular block diagnosed in fetal-neonatal life and childhood periods - a single-centre experience in South Wales for 55 years.

OBJECTIVE: This study aimed to analyse the influence of improved antenatal detection on the course, contemporary outcomes, and mortality risk factors of the complete atrioventricular block during fetal-neonatal and childhood periods in South Wales. METHODS: The clinical characteristics and outcomes of complete atrioventricular block in patients without structural heart disease at the University Hospital of Wales from January 1966 to April 2021 were studied. Patients were divided into two groups according to their age at diagnosis: I-fetal-neonatal and II-childhood. Contemporary outcomes during the post-2001 era were compared with historical data preceding fetal service development and hence earlier detection. RESULTS: There were 64 patients: 26 were identified in the fetal-neonatal period and the remaining 38 in the childhood period. Maternal antibodies/systemic lupus erythematosus disease (anti-Ro/Sjögren's-syndrome-related Antigen A and/or anti-La/Sjögren's-syndrome-related Antigen B) were present in 15 (57.7%) of the fetal-neonatal. Fetal/neonatal and early diagnosis increased after 2001 with an incidence of 1:25000 pregnancies. Pacemaker implantation was required in 34 patients, of whom 13 were diagnosed in the fetal-neonatal group. Survival rates in cases identified before 2001 were at 96.3% (26/27), whereas it was 83.8% (31/37) in patients diagnosed after 2001 (P > 0.05). Other mortality risk factors comprised a lower gestational week at birth, maternal antibodies, and an average ventricular heart rate of < 55 bpm. CONCLUSIONS: Fetal diagnosis of complete atrioventricular block is still portends high fetal and neonatal mortality and morbidity despite significantly improved antenatal detection after 2001. Pacemaker intervention is needed earlier in the fetal-neonatal group. Whether routine antenatal medical treatment might alter this outcome calls for further prospective multicentre studies.

Defining the Canadian rural general surgeon.

BACKGROUND: A total of 18%-30% of Canadians live in a rural area and are served by 8% of the country's general surgeons. The demographic characteristics of Canada's population and its geography greatly affect the health outcomes and needs of the population living in rural areas, and rural general surgeons hold a unique role in meeting the surgical needs of these communities. Rural general surgery is a distinct area of practice that is not well understood. We aimed to define the Canadian rural general surgeon to inform rural health human resource planning. METHODS: A scoping review of the literature was undertaken of Ovid, MEDLINE, and Embase using the terms "rural," "general surgery," and "workforce." We limited our review to articles from North America and Australia. RESULTS: The search yielded 425 titles, and 110 articles underwent full-text review. A definition of rural general surgery was not identified in the Canadian literature. Rurality was defined by population cut-offs or combining community size and proximity to larger centres. The literature highlighted the unique challenges and broad scope of rural general surgical practice. CONCLUSION: Rural general surgeons in Canada can be defined as specialists who work in a small community with limited metropolitan influence. They apply core general surgery skills and skills from other specialties to serve the unique needs of their community. Surgical training programs and health systems planning must recognize and support the unique skill set required of rural general surgeons and the critical role they play in the health and sustainability of rural communities.

Resonant Acoustic Rheometry to Measure Coagulation Kinetics in Hemophilia A and Healthy Plasma: A Novel Viscoelastic Method.

Compared with conventional coagulation tests and factor-specific assays, viscoelastic hemostatic assays (VHAs) can provide a more thorough evaluation of clot formation and lysis but have several limitations including clot deformation. In this proof-of-concept study, we test a noncontact technique, termed resonant acoustic rheometry (RAR), for measuring the kinetics of human plasma coagulation. Specifically, RAR utilizes a dual-mode ultrasound technique to induce and detect surface oscillation of blood samples without direct physical contact and measures the resonant frequency of the surface oscillation over time, which is reflective of the viscoelasticity of the sample. Analysis of RAR results of normal plasma allowed defining a set of parameters for quantifying coagulation. RAR detected a flat-line tracing of resonant frequency in hemophilia A plasma that was corrected with the addition of tissue factor. Our RAR results captured the kinetics of plasma coagulation and the newly defined RAR parameters correlated with increasing tissue factor concentration in both healthy and hemophilia A plasma. These findings demonstrate the feasibility of RAR as a novel approach for VHA, providing the foundation for future studies to compare RAR parameters to conventional coagulation tests, factor-specific assays, and VHA parameters.

Flanged Sutureless Intrascleral Fixation of Dislocated Hard 1-Piece Polymethyl Methacrylate Intraocular Lenses.

PURPOSE: To describe the vitreoretinal surgical technique and report the outcomes of our method of sutureless flanged intrascleral haptic fixation of dislocated 1-piece polymethyl methacrylate intraocular lenses with rigid haptics. METHODS: Ciliary sulcus-based scleral tunnels were created by placing valved 27-gauge (g) trocar cannulas limbus parallel with conjunctival displacement. After complete vitrectomy, the rigid haptics were then externalized using 27g forceps. Cautery was then used to form flanges at the haptic tips. The haptics were then pushed back into the mouths of the scleral tunnels. RESULTS: Flanged intrascleral fixation was successfully achieved in eight eyes of seven patients. The average age at the time of surgery was 75 ± 13.7 years, with a mean follow-up of 17.9 ± 16.3 months (range 3-42 months). Intraocular lens dislocation/subluxation was the most common indication for surgery. All patients fully recovered to their potential acuity by their third postoperative visit. The most significant complication was erosion of one haptic in one patient, which was successfully managed without requiring intraocular lens exchange. There were no complications of subsequent dislocation, endophthalmitis, retinal detachment, or uveitis-glaucoma-hyphema syndrome. CONCLUSION: Flanged sutureless intrascleral fixation of dislocated 1-piece polymethyl methacrylate intraocular lenses with rigid haptics can be safely and successfully performed, avoiding the large wound creation accompanying intraocular lens exchange and the disadvantages of suture-based techniques.

Planning Transition of Care for Adolescents Affected by Congenital Heart Disease: The Irish National Pathway.

At some point in their life, adolescent patients with a congenital heart disease (CHD) transition from paediatric services to adult care facilities. The process is not without any risks, as it is often linked with a significantly progressive deterioration in adolescents' health and loss of follow-up. In fact, transition patients often encounter troubles in finding a care giver who is comfortable managing their condition, or in re-establishing trust with the new care provider. Planning the rules of transition is pivotal in preventing these risks. Unfortunately, the American and European guidelines on CHD provide just generic statements about transition. In a recently published worldwide inter-societies consensus document, a hybrid model of transition, which should be adapted for use in high- and low- resource settings, has been suggested. Currently, in literature there are a few models of transition for CHD patients, but they are by far local models and cannot be generalized to other regions or countries. This paper describes the Irish model for transition of care of CHD patients. Due to the peculiarity of the healthcare organization in the Republic of Ireland, which is centralized with one main referral centre for paediatric cardiology (in Dublin, with a few smaller satellite centres all around, according to the "hub and spoke" model) and one centre for adult with CHD (in Dublin), the model can be considered as a national one and the first to be released in the old continent.

The Choice between Plasma-Based Common Coagulation Tests and Cell-Based Viscoelastic Tests in Monitoring Hemostatic Competence: Not an either-or Proposition.

There has been a significant interest in the last decade in the use of viscoelastic tests (VETs) to determine the hemostatic competence of bleeding patients. Previously, common coagulation tests (CCTs) such as the prothrombin time (PT) and partial thromboplastin time (PTT) were used to assist in the guidance of blood component and hemostatic adjunctive therapy for these patients. However, the experience of decades of VET use in liver failure with transplantation, cardiac surgery, and trauma has now spread to obstetrical hemorrhage and congenital and acquired coagulopathies. Since CCTs measure only 5 to 10% of the lifespan of a clot, these assays have been found to be of limited use for acute surgical and medical conditions, whereby rapid results are required. However, there are medical indications for the PT/PTT that cannot be supplanted by VETs. Therefore, the choice of whether to use a CCT or a VET to guide blood component therapy or hemostatic adjunctive therapy may often require consideration of both methodologies. In this review, we provide examples of the relative indications for CCTs and VETs in monitoring hemostatic competence of bleeding patients.

Relative Hypercoagulopathy of the SARS-CoV-2 Beta and Delta Variants when Compared to the Less Severe Omicron Variants Is Related to TEG Parameters, the Extent of Fibrin Amyloid Microclots, and the Severity of Clinical Illness.

Earlier variants of SARS-CoV-2 have been associated with hypercoagulability and an extensive formation of fibrin amyloid microclots, which are considered to contribute to the pathology of the coronavirus 2019 disease (COVID-19). The newer omicron variants appear to be far more transmissible, but less virulent, even when taking immunity acquired from previous infections or vaccination into account. We here show that while the clotting parameters associated with omicron variants are significantly raised over those of healthy, matched controls, they are raised to levels significantly lower than those seen with more severe variants such as beta and delta. We also observed that individuals infected with omicron variants manifested less extensive microclot formation in platelet-poor plasma compared with those harboring the more virulent variants. The measurement of clotting effects between the different variants acts as a kind of "internal control" that demonstrates the relationship between the extent of coagulopathies and the virulence of the variant of interest. This adds to the evidence that microclots may play an important role in reflecting the severity of symptoms observed in COVID-19.

Positron Emission Tomography and Computed Tomography Contributions to Patient Dose and Personnel Exposure to Radiation during PET/CT-Guided Tumor Ablations.

This study sought to quantify the positron emission tomography (PET) and computed tomography (CT) components of patient radiation doses and personnel exposure to radiations during PET/CT-guided tumor ablations and assess the utility of a rolling lead shield for operator protection. Two operators performed 21 PET/CT-guided ablations behind a customized, 25-mm-thick lead shield with midchest-to-midthigh coverage. The mean patient radiation dose per procedure was 3.90 mSv ± 1.13 (11.3%) from PET and 30.51 mSv ± 19.05 (88.7%) from CT. The mean primary and secondary operator exposure outside neck-level thyroid shields was 0.05 and 0.02 mSv per procedure, respectively. The radiation exposure levels behind the rolling lead shield, inside the primary operator's thyroid shield, and on the other personnel were below the measurable threshold cumulatively over 21 procedures. The mean PET exposure level at continuous close proximity to patients was 0.02 mSv per procedure. The PET radiation doses to the patients and personnel were small. Thus, the rolling lead shield provided limited benefit.

Consensus statement on networks for high-quality rural anesthesia, surgery, and obstetric care in Canada.

OBJECTIVE: To describe the essential components of well-resourced and high-functioning multidisciplinary networks that support high-quality anesthesia, surgery, and maternity care for rural Canadians, delivered as close to home as possible. COMPOSITION OF THE COMMITTEE: A volunteer Writers' Group was drawn from the Society of Obstetricians and Gynaecologists of Canada, the Society of Rural Physicians of Canada, the Royal College of Physicians and Surgeons of Canada, the Canadian Association of General Surgeons, the College of Family Physicians of Canada, and the Association of Canadian University Departments of Anesthesia. METHODS: A collaborative effort over the past several years among the professional stakeholders has culminated in this consensus statement on networked care designed to integrate and support a specialist and non-specialist, urban and rural, anesthesia, surgery, and maternity work force into high-functioning networks based on the best available evidence. REPORT: Surgical and maternity triage needs to be embedded within networks to address the tensions between sustainable regional programs and local access to care. Safety and quality must be demonstrated to be equivalent across similar patients and procedures, regardless of network site. Triage of patients across multiple sites is a quality outcome metric requiring continuous iterative scrutiny. Clinical coaching between rural and regional centres can be helpful in building and sustaining high-functioning networks. Maintenance of quality and the provision of continuing professional development in low-volume settings represent a mutual value proposition. CONCLUSION: The trusting relationships that are foundational to successful networks are built through clinical coaching, continuing professional development, and quality improvement. Currently, a collaborative effort in British Columbia is delivering a provincial program-Rural Surgical Obstetrical Networks-built on the principles and supporting evidence described in this consensus statement.

Projected paediatric cervical spine imaging rates with application of NEXUS, Canadian C-Spine and PECARN clinical decision rules in a prospective Australian cohort.

BACKGROUND: Clinical decision rules (CDRs) are commonly used to guide imaging decisions in cervical spine injury (CSI) assessment despite limited evidence for their use in paediatric populations. We set out to determine CSI incidence, imaging rates and the frequency of previously identified CSI risk factors, and thus assess the projected impact on imaging rates if CDRs were strictly applied as a rule in our population. METHODS: A single-centre prospective observational study on all aged under 16 years presenting for assessment of possible CSI to a tertiary paediatric emergency department over a year, commencing September 2015. CDR variables from the National Emergency X-Radiography Utilization Study (NEXUS) rule, Canadian C-Spine rule (CCR) and proposed Paediatric Emergency Care Applied Research Network (PECARN) rule were collected prospectively and applied post hoc. RESULTS: 1010 children were enrolled; 973 had not received prior imaging. Of these, 40.7% received cervical spine imaging; 32.4% X-rays, 13.4% CT scan and 3% MRI. All three CDRs identified the five children (0.5%) with CSI who had not received prior imaging. If CDRs were strictly applied as a rule for imaging, projected imaging rates in our setting would be as follows: NEXUS-44% (95% CI 41% to 47.4%), CCR-at least 48.4% (95% CI 45.3% to 51.7%) and PECARN-68% (95% CI 65.1% to 71.1%). CONCLUSION: CSIs were rare (0.5% of our cohort), however, 40% of children received imaging. CDRs have been designed to guide imaging decisions; if strictly applied as a rule for imaging, the CDRs assessed in this study would increase imaging rates. Projected rates differ considerably depending on the CDR applied. These findings highlight the need for a validated paediatric-specific cervical spine imaging CDR.

Management of a Pediatric Type 3C Open Femoral Fracture Following a High-Velocity Gunshot Wound at an Adult Level II Trauma Center.

ABSTRACT: We present a case of a 10-year-old girl shot in the thigh by a stray bullet who had a favorable outcome when treated with a multidisciplinary approach at the nearest nonpediatric level II trauma center. Point-of-care thromboelastography facilitated effective resuscitation based on her coagulation profile, minimized blood product use, and allowed for damage-control surgery to stabilize and revascularize her complex femur fracture.

Changes in Coagulation following Brain Injury.

Traumatic brain injury (TBI) is a worldwide public health concern due to increasing mortality, affecting around 10 million patients per year. A wide variety of clinical presentations are a function of the magnitude of injury and the anatomical perturbation of the brain parenchyma, supporting structures, and cerebral vasculature, with subsequent alteration of the blood-brain barrier. These disturbances correspond with the evolution of intracerebral hemorrhage and clinical outcomes. The associated hemostatic alterations associated with TBI are caused by the disruption of the delicate balance between bleeding and thrombosis formation, which can exacerbate initial injury. TBI-associated coagulopathy is a function of a cross-talk between coagulation and inflammation, with varying influences on the immunomodulation and regulation of coagulation that occur on platelets and the endothelium of injured TBI patients. In addition to the severity of initial injury, the following factors modulate the hemocoagulative response to TBI: time from the onset of injury to treatment, age, gender, catecholamine secretion, platelet dysfunction, endotheliopathy, premorbid anticoagulation, fibrinolysis, tissue factor, and activated protein C contribution. All these entities are intertwined and influence the pathologic evolution of TBI. These factors have implications for therapeutic options such as the choice of blood components for transfusion and hemostatic agents such as tranexamic acid. Monitoring hemostatic changes of TBI patients requires an understanding of these interactions between immunology and coagulation, which can be discerned by point-of-care viscoelastic testing with specific limitations. This review considers the implications of these interrelated influences on the evaluation of coagulopathy in TBI.

Diagnosis and Treatment of Trauma-Induced Coagulopathy by Viscoelastography.

This article explores the application of viscoelastic tests (VETs) in trauma-induced coagulopathy and trauma resuscitation. We describe the advantages of VETs over conventional coagulation tests in the trauma setting and refer to previous disciplines in which VET use has reduced blood product utilization, guided prohemostatic agents, and improved clinical outcomes such as the mortality of critically bleeding patients. We describe different VETs and provide guidance for blood component therapy and prohemostatic therapy based on specific VET parameters. Because the two most commonly used VET systems, rotational thromboelastometry and thromboelastography, use different activators and have different terminologies, this practical narrative review will directly compare and contrast these two VETs to help the clinician easily interpret either and use the interpretation to determine hemostatic integrity in the bleeding trauma patient. Finally, we anticipate the future of new viscoelastic technologies that can be used in this setting.

Whole Blood for Civilian Urban Trauma Resuscitation: Historical, Present, and Future Considerations.

Whole blood (WB) has been used for more than a century for far-forward combat resuscitation. Following the Iraq/Afghanistan combat, maritime, and austere environment use of WB for the resuscitation of severely hemorrhaging patients, there has been an increasing use of WB for the civilian urban resuscitation environment population. The impetus for this was not just improved outcomes in far-forward hospitals, which had different populations and different needs than the civilian urban population, but also an application of the lessons suggested by recent 1:1:1 plasma:platelets:packed red cells fixed-ratio studies for patients with massive transfusion needs. Mechanistic, logistic, and standardization concerns have been addressed and are evolving as the WB project advances. A small number of studies have been published on WB in the civilian urban trauma population. In addition, European experience with viscoelastic testing and resuscitation with fibrinogen and prothrombin complex concentrate has provided another viewpoint regarding the choice of resuscitation strategies for severely bleeding trauma patients in urban civilian environments. There are randomized controlled trials in process, which are testing the hypothesis that WB may be beneficial for the civilian urban population. Whether WB will improve mortality significantly is now a matter of intense study, and this commentary reviews the history, mechanistic foundations, and logistical aspects for the use of WB in the civilian trauma population.

Viscoelastic testing in benign hematologic disorders: Clinical perspectives and future implications of point-of-care testing to assess hemostatic competence.

Viscoelastic tests (VETs) have been used routinely for liver transplantation, cardiac surgery, and trauma, but only recently have found clinical utility in benign hematologic disorders. Therefore, guidelines for diagnosis and treatment of these disorders based on viscoelastic variables have been adapted from the existing transplant, cardiothoracic surgery, and trauma resuscitation literature. As a result, diagnostic and therapeutic strategies for benign hematologic disorders utilizing VETs are not uniform. Accordingly, even though there has been a recent increase in the utilization of VET for the diagnosis and treatment of such disorders, the literature is still in its early stages. Analysis of point-of-care viscoelastic tracings from benign hematologic disorders has the potential to allow prompt recognition of disease and to guide patient-specific intervention. Here we present a review describing the application of VETs to benign hematologic disorders.

Viscoelastic testing in oncology patients (including for the diagnosis of fibrinolysis): Review of existing evidence, technology comparison, and clinical utility.

The quantification of the coagulopathic state associated with oncologic and hematologic diseases is imperfectly assessed by common coagulation tests such as prothrombin time, activated partial thromboplastin time, fibrinogen levels, and platelet count. These tests provide a static representation of a component of hemostatic integrity, presenting an incomplete picture of coagulation in these patients. Viscoelastic tests (VETs), such as rotational thromboelastometry (ROTEM) and thromboelastography (TEG), as whole blood analyses, provide data related to the cumulative effects of blood components and all stages of the coagulation and fibrinolytic processes. The utility of VETs has been demonstrated since the late 1960s in guiding blood component therapy for patients undergoing liver transplantation. Since then, the scope of viscoelastic testing has expanded to become routinely used for cardiac surgery, obstetrics, and trauma. In the past decade, VETs' expanded usage has been most significant in trauma resuscitation. However, use of VETs for patients with malignancy-associated coagulopathy (MAC) and hematologic malignancies is increasing. For the purposes of this narrative review, we discuss the similarities between trauma-induced coagulopathy (TIC) and MAC. These similarities center on the thrombomodulin-thrombin complex as it switches between the thrombin-activatable fibrinolysis inhibitor coagulation pathway and activating the protein C anticoagulation pathway. This produces a spectrum of coagulopathy and fibrinolytic alterations ranging from shutdown to hyperfibrinolysis that are common to TIC, MAC, and hematologic malignancies. There is expanding literature regarding the utility of TEG and ROTEM to describe the hemostatic integrity of patients with oncologic and hematologic conditions, which we review here.

Bayesian inference on stochastic gene transcription from flow cytometry data.

Motivation: Transcription in single cells is an inherently stochastic process as mRNA levels vary greatly between cells, even for genetically identical cells under the same experimental and environmental conditions. We present a stochastic two-state switch model for the population of mRNA molecules in single cells where genes stochastically alternate between a more active ON state and a less active OFF state. We prove that the stationary solution of such a model can be written as a mixture of a Poisson and a Poisson-beta probability distribution. This finding facilitates inference for single cell expression data, observed at a single time point, from flow cytometry experiments such as FACS or fluorescence in situ hybridization (FISH) as it allows one to sample directly from the equilibrium distribution of the mRNA population. We hence propose a Bayesian inferential methodology using a pseudo-marginal approach and a recent approximation to integrate over unobserved states associated with measurement error. Results: We provide a general inferential framework which can be widely used to study transcription in single cells from the kind of data arising in flow cytometry experiments. The approach allows us to separate between the intrinsic stochasticity of the molecular dynamics and the measurement noise. The methodology is tested in simulation studies and results are obtained for experimental multiple single cell expression data from FISH flow cytometry experiments. Availability and implementation: All analyses were implemented in R. Source code and the experimental data are available at https://github.com/SimoneTiberi/Bayesian-inference-on-stochastic-gene-transcription-from-flow-cytometry-data. Supplementary information: Supplementary data are available at Bioinformatics online.