What features of drug treatment programs help, or not, with access? a qualitative study of the perspectives of family members and community-based organization staff in Atlantic Canada.

BACKGROUND: Withdrawal management and opioid agonist treatment (OAT) programs help to reduce some of the harms experienced by people who use substances (PWUS). There is literature on how features of drug treatment programs (e.g., policies and practices) are helpful, or not helpful, to PWUS when seeking access to, or in, treatment. There is, however, relatively little literature based on the perspectives of family members/family of choice of PWUS and community-based organization staff within the context of Atlantic Canada. This paper explored the perspectives of these two groups on what was helpful, or not, about drug treatment programs in Atlantic Canada in terms of supporting access to, and retention in, treatment. METHODS: One-on-one qualitative telephone interviews were conducted in 2020 with the two groups. Interviews focused on government-funded withdrawal management and OAT programs. Data were coded using a qualitative data management program (ATLAS.ti) and analyzed inductively for key themes/subthemes using grounded theory techniques. RESULTS: Fifteen family members/family of choice and 16 community-based organization staff members participated (n = 31). Participants spoke about features of drug treatment programs in various places, and noted features that were perceived as helpful (e.g., quick access), as well as not helpful (e.g., wait times, programs located far from where PWUS live). Some participants provided their perceptions of how PWUS felt when seeking or accessing treatment. A number of participants reported taking various actions to help support access to treatment, including providing transportation to programs. A few participants also provided suggestions for change to help support access and retention such as better alignment of mental health and addiction systems. CONCLUSIONS: Participants highlighted several helpful and not helpful features of drug treatment programs in terms of supporting treatment access and retention. Previous studies with PWUS and in other places have reported similar features, some of which (e.g., wait times) have been reported for many years. Changes are needed to reduce barriers to access and retention including the changes recommended by study participants. It is critical that the voices of key groups, (including PWUS) are heard to ensure treatment programs in all places support access and retention.

'Planning for a healthy baby and a healthy pregnancy': A critical analysis of Canadian clinical practice guidelines for the treatment of opioid dependence during pregnancy.

As opioid fatalities rise in North America, the need to improve the supports available to those who are dependent on opioids and pregnant has become more urgent. This paper discusses the social organisation of drug treatment supports for those who are pregnant, using Canadian clinical practice guidelines (CPGs) for methadone maintenance treatment (MMT) as a case study. Pregnant patients are a priority population for MMT, both in Canada and internationally; the regulatory bodies that oversee MMT in Canada are the provincial Colleges of Physician and Surgeons and Health Canada. The paper analyses MMT CPGs published by these agencies, comparing their general recommendations to those specific to pregnant patients. We demonstrate that the guidelines address few treatment considerations for pregnant patients, other than improved birth outcomes and child welfare, despite acknowledging their more complex needs. Drawing on social science studies of gender and drugs, we argue that MMT CPGs therefore perpetuate the intensified surveillance and foetal prioritisation that have long generated barriers to care for opiate-dependent pregnant patients. We also discuss how and why the CPGs ultimately only reinforced these current limitations in the drug treatment sector.

Consumers' and health providers' views and perceptions of partnering to improve health services design, delivery and evaluation: a co-produced qualitative evidence synthesis.

BACKGROUND: Partnering with consumers in the planning, delivery and evaluation of health services is an essential component of person-centred care. There are many ways to partner with consumers to improve health services, including formal group partnerships (such as committees, boards or steering groups). However, consumers' and health providers' views and experiences of formal group partnerships remain unclear. In this qualitative evidence synthesis (QES), we focus specifically on formal group partnerships where health providers and consumers share decision-making about planning, delivering and/or evaluating health services. Formal group partnerships were selected because they are widely used throughout the world to improve person-centred care. For the purposes of this QES, the term 'consumer' refers to a person who is a patient, carer or community member who brings their perspective to health service partnerships. 'Health provider' refers to a person with a health policy, management, administrative or clinical role who participates in formal partnerships in an advisory or representative capacity. This QES was co-produced with a Stakeholder Panel of consumers and health providers. The QES was undertaken concurrently with a Cochrane intervention review entitled Effects of consumers and health providers working in partnership on health services planning, delivery and evaluation. OBJECTIVES: 1. To synthesise the views and experiences of consumers and health providers of formal partnership approaches that aimed to improve planning, delivery or evaluation of health services. 2. To identify best practice principles for formal partnership approaches in health services by understanding consumers' and health providers' views and experiences. SEARCH METHODS: We searched MEDLINE, Embase, PsycINFO and CINAHL for studies published between January 2000 and October 2018. We also searched grey literature sources including websites of relevant research and policy organisations involved in promoting person-centred care. SELECTION CRITERIA: We included qualitative studies that explored consumers' and health providers' perceptions and experiences of partnering in formal group formats to improve the planning, delivery or evaluation of health services. DATA COLLECTION AND ANALYSIS: Following completion of abstract and full-text screening, we used purposive sampling to select a sample of eligible studies that covered a range of pre-defined criteria, including rich data, range of countries and country income level, settings, participants, and types of partnership activities. A Framework Synthesis approach was used to synthesise the findings of the sample. We appraised the quality of each study using the CASP (Critical Appraisal Skill Program) tool. We assessed our confidence in the findings using the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach. The Stakeholder Panel was involved in each stage of the review from development of the protocol to development of the best practice principles. MAIN RESULTS: We found 182 studies that were eligible for inclusion. From this group, we selected 33 studies to include in the final synthesis. These studies came from a wide range of countries including 28 from high-income countries and five from low- or middle-income countries (LMICs). Each of the studies included the experiences and views of consumers and/or health providers of partnering in formal group formats. The results were divided into the following categories. Contextual factors influencing partnerships: government policy, policy implementation processes and funding, as well as the organisational context of the health service, could facilitate or impede partnering (moderate level of confidence). Consumer recruitment: consumer recruitment occurred in different ways and consumers managed the recruitment process in a minority of studies only (high level of confidence). Recruiting a range of consumers who were reflective of the clinic's demographic population was considered desirable, particularly by health providers (high level of confidence). Some health providers perceived that individual consumers' experiences were not generalisable to the broader population whereas consumers perceived it could be problematic to aim to represent a broad range of community views (high level of confidence). Partnership dynamics and processes: positive interpersonal dynamics between health providers and consumers facilitated partnerships (high level of confidence). However, formal meeting formats and lack of clarity about the consumer role could constrain consumers' involvement (high level of confidence). Health providers' professional status, technical knowledge and use of jargon were intimidating for some consumers (high level of confidence) and consumers could feel their experiential knowledge was not valued (moderate level of confidence). Consumers could also become frustrated when health providers dominated the meeting agenda (moderate level of confidence) and when they experienced token involvement, such as a lack of decision-making power (high level of confidence) Perceived impacts on partnership participants: partnering could affect health provider and consumer participants in both positive and negative ways (high level of confidence). Perceived impacts on health service planning, delivery and evaluation: partnering was perceived to improve the person-centredness of health service culture (high level of confidence), improve the built environment of the health service (high level of confidence), improve health service design and delivery e.g. facilitate 'out of hours' services or treatment closer to home (high level of confidence), enhance community ownership of health services, particularly in LMICs (moderate level of confidence), and improve consumer involvement in strategic decision-making, under certain conditions (moderate level of confidence). There was limited evidence suggesting partnering may improve health service evaluation (very low level of confidence). Best practice principles for formal partnering to promote person-centred care were developed from these findings. The principles were developed collaboratively with the Stakeholder Panel and included leadership and health service culture; diversity; equity; mutual respect; shared vision and regular communication; shared agendas and decision-making; influence and sustainability. AUTHORS' CONCLUSIONS: Successful formal group partnerships with consumers require health providers to continually reflect and address power imbalances that may constrain consumers' participation. Such imbalances may be particularly acute in recruitment procedures, meeting structure and content and decision-making processes. Formal group partnerships were perceived to improve the physical environment of health services, the person-centredness of health service culture and health service design and delivery. Implementing the best practice principles may help to address power imbalances, strengthen formal partnering, improve the experiences of consumers and health providers and positively affect partnership outcomes.

The Mental Health of Adult Irregular Migrants to Europe: A Systematic Review.

The aim of this systematic review is to summarise the existing evidence on the mental health outcomes of adult irregular immigrants (IMs) to Europe. Database (MEDLINE, EMBASE, CINAHL, PsychINFO) searches were conducted according to PRISMA. The risk of bias was assessed using the Appraisal tool for Cross-Sectional Studies. The database searches yielded 2982 results. Eight cross-sectional studies from Western Europe were included, with 1201 participants. The prevalence of mental disorders varied between studies: depression from 8 to 86%; anxiety from 3.1 to 81%; and post-traumatic stress disorder (PTSD) from 3.4 to 57.6%. The studies had methodological flaws; in particular a risk of unrepresentative samples. There was methodological heterogeneity, therefore pooling of data, and direct comparisons were not possible. The majority of studies found higher rates of depression, anxiety and PTSD than previous estimates for the general population, and higher rates of depression and anxiety than previous estimates for other migrant groups.

Acceptability and feasibility of an online physical activity program for women over 50: a pilot trial.

Regular physical activity benefits health across the lifespan. Women in middle-age often juggle carer and work responsibilities, are often inactive, and may benefit from tailored support to increase physical activity. Establish the acceptability, feasibility, and impact on physical activity of a scalable program for women 50+ years. This pilot trial randomized participants to immediate program access, or to a wait-list control. [Active Women over 50 Online] program included: (1) study-specific website, (2) 8 emails or 24 SMS motivation-based messages, (3) one telephone health-coaching session. Outcomes, at 3 months, were acceptability (recommend study participation, intervention uptake), feasibility (recruitment, reach, completion), intervention impact (physical activity), intervention impressions. At baseline, 62 participants of mean (SD) age 59 (±7) years took 7459 (±2424) steps/day and most (92%) reported ≥2 medical conditions. At 3 months, acceptability and impact data were available for 52 (84%) and 57 (92%) participants, respectively. Study participation was recommended by 83% of participants. Participants mostly agreed to receive health coaching (81%) and messages (87%: email = 56%, SMS = 44%), opened 82% of emails and accessed the website 4.8 times on average. Respondents reported the intervention supported their physical activity. Intervention participants were more likely to increase steps from baseline by 2000+/day (OR: 6.31, 95% CI: 1.22 to 32.70, p = .028) than controls, and trended toward more light-intensity (p = .075) and moderate-vigorous intensity physical activity (p = .11). The [Active Women over 50 Online] program demonstrated acceptability and feasibility among the target population, and effectiveness in some domains in the short term. Results warrant further testing in a full-scale RCT.

Regular physical activity benefits health at all ages. Women in middle-age years often juggle carer and work responsibilities. We investigated the acceptability, feasibility, and effect of a scalable physical activity program targeting this group. Participants were randomly assigned to immediate access to the [Active Women over 50 Online] program or after a 3-month wait. [Active Women over 50 Online] program included: (1) study-specific website with information, case studies and links to physical activity opportunities, (2) email or SMS motivation-based messages, (3) telephone health-coaching session. We recruited 62 participants, who were on average aged 59 years, active, and had at least two medical conditions. At the 3-month follow-up, 83% of participants would recommend study participation. Participants who received the program immediately agreed to receive health coaching (81%) and messages (87%). They accessed an average of five web sessions each in a 3-month period and reported the program supported their physical activity. These participants were also more likely to take an average of 2000+ daily steps more than at baseline, and increased their physical activity at light, moderate, and vigorous intensities more than those who had not received the program. The high uptake, engagement, positive recommendation, and promising impact on physical activity warrants further program testing in a larger trial.

Increased blood viscosity and red blood cell aggregation in patients with COVID-19.

The aim of this study was to (1) analyze blood viscosity, red blood cell (RBC) deformability, and aggregation in hospitalized patients with Coronavirus disease 19 (COVID-19); (2) test the associations between impaired blood rheology and blood coagulation; and (3) test the associations between impaired blood rheology and several indicators of clinical severity. A total of 172 patients with COVID-19, hospitalized in COVID-unit of the Internal Medicine Department (Lyon, France) participated in this study between January and May 2021. Clinical parameters were collected for each patient. Routine hematological/biochemical parameters, blood viscosity, RBC deformability and aggregation, and RBC senescence markers were measured on the first day of hospitalization. A control group of 38 healthy individuals was constituted to compare the blood rheological and RBC profile. Rotational thromboelastography was performed in 76 patients to study clot formation dynamics. Our study demonstrated that patients with COVID-19 had increased blood viscosity despite lower hematocrit than healthy individuals, as well as increased RBC aggregation. In-vitro experiments demonstrated a strong contribution of plasma fibrinogen in this RBC hyper-aggregation. RBC aggregation correlated positively with clot firmness, negatively with clot formation time, and positively with the length of hospitalization. Patients with oxygen supplementation had higher RBC aggregation and blood viscosity than those without, and patients with pulmonary lesions had higher RBC aggregation and enhanced coagulation than those without. This study is the first to demonstrate blood hyper-viscosity and RBC hyper-aggregation in a large cohort of patients with COVID-19 and describe associations with enhanced coagulation and clinical outcomes.

A Randomised Controlled Trial of Local Infiltration Analgesia Versus Femoral Nerve Block for Postoperative Analgesia Following Total Knee Arthroplasty.

Background Total knee replacement is often associated with significant postoperative pain. Although the use of a femoral nerve block is well-established, local infiltration analgesia has gained popularity in recent years. We compared single-shot local infiltration analgesia with a single-shot femoral nerve block for patients undergoing primary total knee arthroplasty. Methods A total of 194 patients were randomised to receive either local infiltration analgesia (150 ml bupivacaine 0.067% with adrenaline) or a femoral nerve block (20 ml 0.375% levobupivacaine). Both groups received spinal anaesthesia. The primary outcome measure was the total morphine consumption. Secondary outcome measures included: post-operative pain scores, rehabilitation goals, readiness for discharge, and physical, mental, and functional outcomes, including the Oxford Knee Score (OKS). Results A total of 69 patients in the local infiltration analgesia group and 79 patients in the femoral nerve block group were analysed. Median total morphine consumption was significantly greater in the local infiltration analgesia group as compared to the femoral nerve block group (54.67 mg vs 45 mg, respectively, p=0.0388). The post-operative OKS at six weeks was slightly more improved for the femoral nerve block group than for local infiltration analgesia (12.5 vs 9 point median improvements for the femoral nerve block and local infiltration analgesia groups, respectively, p=0.0261). There were no statistically significant differences in other secondary outcome measures. Conclusion A single-shot femoral nerve block significantly reduces the opioid requirement for primary total knee arthroplasty but is otherwise comparable to single-shot local infiltration analgesia.

Active Women over 50 online information and support to promote physical activity behaviour change: study protocol for a pilot trial.

BACKGROUND: Physical activity has many physical and mental health benefits and can delay the development of disability in older age. However, uptake of this health behaviour is sub-optimal in women in their middle and older age. This trial aims to establish the acceptability and feasibility of the Active Women over 50 programme involving online information, telephone health coaching and email or SMS support to promote physical activity behaviour change among women aged 50 years and over. METHODS: Sixty community-dwelling women who are insufficiently active according to national guidelines, will be recruited and randomised to 1) receive the Active Women over 50 programme or 2) a wait-list control. Active Women over 50 is a 3-month physical activity programme guided by behaviour change science, providing access to a website, one telephone-delivered health coaching session from a physiotherapist and 8 email or 24 SMS messages. The primary outcome is the proportion of participants at 3 months post-randomisation who would recommend participation in the programme to another person like themselves. Secondary outcomes are feasibility measures: rates of recruitment, retention, completeness of outcome data and uptake of telephone support; and intervention impact measures: accelerometer-assessed average steps/day, proportion of participants meeting national guidelines on moderate to vigorous physical activity; and questionnaire-assessed quality of life, exercise perceptions, mood, physical functioning and self-reported physical activity. Intervention participants will also complete a follow-up survey to assess impressions of the intervention and adoption of strategies for physical activity participation. Data will be analysed descriptively to guide the design of a larger trial. Between-group differences in secondary outcomes will be used to estimate effect sizes for sample size calculations for a fully powered randomised controlled trial. DISCUSSION: This feasibility pilot trial of an efficient eHealth and health coaching intervention guided by user input and behaviour change theory, will inform future interventions to address low physical activity participation among an under-active group at risk of future disability. TRIAL REGISTRATION: ANZCTR, ACTRN12619000490178, registered 26 March 2019.

Central venous access device-related sheaths: a predictor of infective and thrombotic incidence?

Central vascular access device (CVAD)-related sheaths, sometimes described as 'fibrin sheaths', may result in minor or significant sequelae, from persistent withdrawal occlusion (PWO) to infective sheaths associated with increased morbidity and mortality. The authors studied 179 patients who underwent isotope scans, where isotope was infused via the CVAD. Isotope was found to bind to the sheaths around the catheters of some patients. The amount of uptake was taken to be an extent to which a sheath had developed around the CVAD. The degree of uptake of isotope was categorised into three groups: low uptake, moderate uptake and high uptake. Patients were then followed up from the date the CVAD was inserted to 12 months after the date of the isotope scan, until the device was removed or to the date the patient died, to identify incidence of infection, thrombosis and PWO. PWO incidence in all levels of uptake was around 5-7%. Bloodstream infection (BSI) incidence for low uptake was 7% (9/130), moderate uptake 10% (3/30) and for patients with significant uptake 16% (3/19). Thrombosis for no uptake was less than 1% (1/130), moderate uptake 7% (2/30), and significant uptake had no incidence of thrombosis. Total complications: no uptake 15%, moderate uptake 23% and significant uptake 21%. This single-centre study showed that patients with isotope-highlighted sheaths experienced higher incidence of infective, thrombotic and total complications.

Engaging with motherhood and parenthood: A commentary on the social science drugs literature.

The majority of qualitative social scientific research on the topic of parenthood and substance use focuses on mothers who use illicit drugs and their experiences of social marginalization and stigmatization. This commentary argues that new and important insights might be gained about parenting in the context of substance use by engaging more closely with everyday experiences of mothering and with contemporary theorising around motherhood and parenthood. Drawing on recent sociological studies of family life influenced by late-modern individualism and by new expert attention on the quality of parent-child relationships, the commentary proposes directions for future social research on the identities and experiences of mothers and fathers who use alcohol and other drugs.

Volunteering in a mental health service in Uganda: challenges and rewards.

Fiona Martin is a psychiatry trainee who spent 6 months volunteering in a mental health service in Uganda between her core and higher psychiatry training. In this article, she reflects upon this experience, including the challenges and rewards, and in particular the benefits to training of such an experience.

Enhancing Care Transitions for Older People through Interprofessional Simulation: A Mixed Method Evaluation.

INTRODUCTION: The educational needs of the health and social care workforce for delivering effective integrated care are important. This paper reports on the development, pilot and evaluation of an interprofessional simulation course, which aimed to support integrated care models for care transitions for older people from hospital to home. THEORY AND METHODS: The course development was informed by a literature review and a scoping exercise with the health and social care workforce. The course ran six times and was attended by health and social care professionals from hospital and community (n = 49). The evaluation aimed to elicit staff perceptions of their learning about care transfers of older people and to explore application of learning into practice and perceived outcomes. The study used a sequential mixed method design with questionnaires completed pre (n = 44) and post (n = 47) course and interviews (n = 9) 2-5 months later. RESULTS: Participants evaluated interprofessional simulation as a successful strategy. Post-course, participants identified learning points and at the interviews, similar themes with examples of application in practice were: Understanding individual needs and empathy; Communicating with patients and families; Interprofessional working; Working across settings to achieve effective care transitions. CONCLUSIONS AND DISCUSSION: An interprofessional simulation course successfully brought together health and social care professionals across settings to develop integrated care skills and improve care transitions for older people with complex needs from hospital to home.

'Croque&bouge': A feasible and acceptable programme for obesity prevention in preschoolers at risk and their parents.

OBJECTIVES: To conceptualize and pilot test a programme of three workshops aiming to prevent the development of overweight in susceptible preschool children. METHODS: Three workshops were conducted, targeting both parents and children. The curriculum for parents included discussions on feeding responsibilities, healthy eating, taste development, neophobia and physical activity recommendations. Children participated in various play activities with fruits and vegetables and read stories about hunger and satiety feelings. Recruitment was organized through paediatricians and child-care centres. Evaluation of the programme focused on feasibility, adequacy for children's age, parents' perception of impact and, for children, change of the ability to recognize and willingness to taste fruits and vegetables. RESULTS: A total of 21 children and one of their parents participated in the programme. The programme was found to be feasible and adequate for the targeted community. Parents reported perceiving a positive impact of the intervention; however, this finding was not statistically significant. The major difficulty was identifying and recruiting families and engaging the parents in a discussion about weight. CONCLUSIONS: This short programme aiming to improve parents' ability to offer healthy environment and promote healthy eating behaviour was feasible and acceptable for families with young children. When developing and implementing such programmes, close collaboration with paediatricians and other health providers should be sought in order to identify and reach children at risk of obesity and their family.

Regulation of thrombomodulin expression and release in human aortic endothelial cells by cyclic strain.

BACKGROUND AND OBJECTIVES: Thrombomodulin (TM), an integral membrane glycoprotein expressed on the lumenal surface of vascular endothelial cells, promotes anti-coagulant and anti-inflammatory properties. Release of functional TM from the endothelium surface into plasma has also been reported. Much is still unknown however about how endothelial TM is regulated by physiologic hemodynamic forces (and particularly cyclic strain) intrinsic to endothelial-mediated vascular homeostasis. METHODS: This study employed human aortic endothelial cells (HAECs) to investigate the effects of equibiaxial cyclic strain (7.5%, 60 cycles/min, 24 hrs), and to a lesser extent, laminar shear stress (10 dynes/cm2, 24 hrs), on TM expression and release. Time-, dose- and frequency-dependency studies were performed. RESULTS: Our initial studies demonstrated that cyclic strain strongly downregulated TM expression in a p38- and receptor tyrosine kinase-dependent manner. This was in contrast to the upregulatory effect of shear stress. Moreover, both forces significantly upregulated TM release over a 48 hr period. With continuing focus on the cyclic strain-induced TM release, we noted both dose (0-7.5%) and frequency (0.5-2.0 Hz) dependency, with no attenuation of strain-induced TM release observed following inhibition of MAP kinases (p38, ERK-1/2), receptor tyrosine kinase, or eNOS. The concerted impact of cyclic strain and inflammatory mediators on TM release from HAECs was also investigated. In this respect, both TNFα (100 ng/ml) and ox-LDL (10-50 µg/ml) appeared to potentiate strain-induced TM release. Finally, inhibition of neither MMPs (GM6001) nor rhomboids (3,4-dichloroisocoumarin) had any effect on strain-induced TM release. However, significantly elevated levels (2.1 fold) of TM were observed in isolated microparticle fractions following 7.5% strain for 24 hrs. CONCLUSIONS: A preliminary in vitro investigation into the effects of cyclic strain on TM in HAECs is presented. Physiologic cyclic strain was observed to downregulate TM expression, whilst upregulating in a time-, dose- and frequency-dependent manner the release of TM.

Key challenges in providing services to people who use drugs: The perspectives of people working in emergency departments and shelters in Atlantic Canada.

AIMS: Many people who use drugs (PWUD) have multiple health and social needs, and research suggests that this population is increasingly accessing emergency departments (EDs) and shelters for health care and housing. This qualitative study explored the practices of those working in EDs and shelters when providing services to PWUD, with a particular focus on key challenges in service provision. METHODS: EDs and shelters were conceptualized as 'micro environments' with various components (i.e. social, physical and resource). One-on-one interviews were conducted with 57 individuals working in EDs and shelters in Atlantic Canada. FINDINGS: The social, physical and resource environments within some EDs and shelters are key forces in shaping the challenges facing those providing services. For example, the social environments within these settings are focused on acute health care in the case of EDs, and housing in the case of shelters. These mandates do not encompass the complex needs of many PWUD. Resource issues within the wider community (e.g. limited drug treatment spaces) further contribute to the challenges. CONCLUSIONS: Structural issues, internal and external to EDs and shelters need to be addressed to reduce the challenges facing many who work in these settings when providing services to PWUD.

Educational challenges and requirements for managing leg ulcers in the community.

The significant impact of leg ulcers upon quality of life and disease burden cannot be overemphasised, with the financial and economic impact from an individual, local and national perspective being widely acknowledged. This article attempts to highlight issues relating to education in leg ulcer management while identifying some current and emerging challenges faced in this area by professionals. With regard to education, formal training and perception of professionals, the provision of more specialised and focused training, increased use of patient-related outcome measures and the concept of knowledge brokering have been identified as important aspects in the planning and further development of education. Issues in the domains of community nursing, technology, pain management, nursing diagnosis, availability of research and recurrence were also highlighted.

Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects.

Thrombomodulin (TM) is a 557-amino acid protein with a broad cell and tissue distribution consistent with its wide-ranging physiological roles. When expressed on the lumenal surface of vascular endothelial cells in both large vessels and capillaries, its primary function is to mediate endothelial thromboresistance. The complete integral membrane-bound protein form displays five distinct functional domains, although shorter soluble (functional) variants comprising the extracellular domains have also been reported in fluids such as serum and urine. TM-mediated binding of thrombin is known to enhance the specificity of the latter serine protease toward both protein C and thrombin activatable fibrinolysis inhibitor (TAFI), increasing their proteolytic activation rate by almost three orders of magnitude with concomitant anticoagulant, antifibrinolytic, and anti-inflammatory benefits to the vascular wall. Recent years have seen an abundance of research into the cellular mechanisms governing endothelial TM production, processing, and regulation (including flow-mediated mechanoregulation)--from transcriptional and posttranscriptional (miRNA) regulation of TM gene expression, to posttranslational processing and release of the expressed protein--facilitating greater exploitation of its therapeutic potential. The goal of the present paper is to comprehensively review the endothelial/TM system from these regulatory perspectives and draw some fresh conclusions. This paper will conclude with a timely examination of the current status of TM's growing therapeutic appeal, from novel strategies to improve the clinical efficacy of recombinant TM analogs for resolution of vascular disorders such as disseminated intravascular coagulation (DIC), to an examination of the complex pleiotropic relationship between statin treatment and TM expression.