The war on drugs is a war on us: young people who use drugs and the fight for harm reduction in the Global South.

In the Global South, young people who use drugs (YPWUD) are exposed to multiple interconnected social and health harms, with many low- and middle-income countries enforcing racist, prohibitionist-based drug policies that generate physical and structural violence. While harm reduction coverage for YPWUD is suboptimal globally, in low- and middle-income countries youth-focused harm reduction programs are particularly lacking. Those that do exist are often powerfully shaped by global health funding regimes that restrict progressive approaches and reach. In this commentary we highlight the efforts of young people, activists, allies, and organisations across some Global South settings to enact programs such as those focused on peer-to-peer information sharing and advocacy, overdose monitoring and response, and drug checking. We draw on our experiential knowledge and expertise to identify and discuss key challenges, opportunities, and recommendations for youth harm reduction movements, programs and practices in low- to middle-income countries and beyond, focusing on the need for youth-driven interventions. We conclude this commentary with several calls to action to advance harm reduction for YPWUD within and across Global South settings.

Clinical benefit of AI-assisted lung ultrasound in a resource-limited intensive care unit.

BACKGROUND: Interpreting point-of-care lung ultrasound (LUS) images from intensive care unit (ICU) patients can be challenging, especially in low- and middle- income countries (LMICs) where there is limited training available. Despite recent advances in the use of Artificial Intelligence (AI) to automate many ultrasound imaging analysis tasks, no AI-enabled LUS solutions have been proven to be clinically useful in ICUs, and specifically in LMICs. Therefore, we developed an AI solution that assists LUS practitioners and assessed its usefulness in  a low resource ICU. METHODS: This was a three-phase prospective study. In the first phase, the performance of four different clinical user groups in interpreting LUS clips was assessed. In the second phase, the performance of 57 non-expert clinicians with and without the aid of a bespoke AI tool for LUS interpretation was assessed in retrospective offline clips. In the third phase, we conducted a prospective study in the ICU where 14 clinicians were asked to carry out LUS examinations in 7 patients with and without our AI tool and we interviewed the clinicians regarding the usability of the AI tool. RESULTS: The average accuracy of beginners' LUS interpretation was 68.7% [95% CI 66.8-70.7%] compared to 72.2% [95% CI 70.0-75.6%] in intermediate, and 73.4% [95% CI 62.2-87.8%] in advanced users. Experts had an average accuracy of 95.0% [95% CI 88.2-100.0%], which was significantly better than beginners, intermediate and advanced users (p < 0.001). When supported by our AI tool for interpreting retrospectively acquired clips, the non-expert clinicians improved their performance from an average of 68.9% [95% CI 65.6-73.9%] to 82.9% [95% CI 79.1-86.7%], (p < 0.001). In prospective real-time testing, non-expert clinicians improved their baseline performance from 68.1% [95% CI 57.9-78.2%] to 93.4% [95% CI 89.0-97.8%], (p < 0.001) when using our AI tool. The time-to-interpret clips improved from a median of 12.1 s (IQR 8.5-20.6) to 5.0 s (IQR 3.5-8.8), (p < 0.001) and clinicians' median confidence level improved from 3 out of 4 to 4 out of 4 when using our AI tool. CONCLUSIONS: AI-assisted LUS can help non-expert clinicians in an LMIC ICU improve their performance in interpreting LUS features more accurately, more quickly and more confidently.

A modified Sequential Organ Failure Assessment score for dengue: development, evaluation and proposal for use in clinical trials.

BACKGROUND: Dengue is a neglected tropical disease, for which no therapeutic agents have shown clinical efficacy to date. Clinical trials have used strikingly variable clinical endpoints, which hampers reproducibility and comparability of findings. We investigated a delta modified Sequential Organ Failure Assessment (delta mSOFA) score as a uniform composite clinical endpoint for use in clinical trials investigating therapeutics for moderate and severe dengue. METHODS: We developed a modified SOFA score for dengue, measured and evaluated its performance at baseline and 48 h after enrolment in a prospective observational cohort of 124 adults admitted to a tertiary referral hospital in Vietnam with dengue shock. The modified SOFA score included pulse pressure in the cardiovascular component. Binary logistic regression, cox proportional hazard and linear regression models were used to estimate association between mSOFA, delta mSOFA and clinical outcomes. RESULTS: The analysis included 124 adults with dengue shock. 29 (23.4%) patients required ICU admission for organ support or due to persistent haemodynamic instability: 9/124 (7.3%) required mechanical ventilation, 8/124 (6.5%) required vasopressors, 6/124 (4.8%) required haemofiltration and 5/124 (4.0%) patients died. In univariate analyses, higher baseline and delta (48 h) mSOFA score for dengue were associated with admission to ICU, requirement for organ support and mortality, duration of ICU and hospital admission and IV fluid use. CONCLUSIONS: The baseline and delta mSOFA scores for dengue performed well to discriminate patients with dengue shock by clinical outcomes, including duration of ICU and hospital admission, requirement for organ support and death. We plan to use delta mSOFA as the primary endpoint in an upcoming host-directed therapeutic trial and investigate the performance of this score in other phenotypes of severe dengue in adults and children.

Productivity costs from a dengue episode in Asia: a systematic literature review.

BACKGROUND: Dengue is a mosquito-borne viral infection which has been estimated to cause a global economic burden of US$8.9 billion per year. 40% of this estimate was due to what are known as productivity costs (the costs associated with productivity loss from both paid and unpaid work that results from illness, treatment or premature death). Although productivity costs account for a significant proportion of the estimated economic burden of dengue, the methods used to calculate them are often very variable within health economic studies. The aim of this review was to systematically examine the current estimates of the productivity costs associated with dengue episodes in Asia and to increase awareness surrounding how productivity costs are estimated. METHOD: We searched PubMed and Web of Knowledge without date and language restrictions using terms related to dengue and cost and economics burden. The titles and abstracts of publications related to Asia were screened to identify relevant studies. The reported productivity losses and costs of non-fatal and fatal dengue episodes were then described and compared. Costs were adjusted for inflation to 2017 prices. RESULTS: We reviewed 33 relevant articles, of which 20 studies reported the productivity losses, and 31 studies reported productivity costs. The productivity costs varied between US$6.7-1445.9 and US$3.8-1332 for hospitalized and outpatient non-fatal episodes, respectively. The productivity cost associated with fatal dengue episodes varied between US$12,035-1,453,237. A large degree of this variation was due to the range of different countries being investigated and their corresponding economic status. However, estimates for a given country still showed notable variation. CONCLUSION: We found that the estimated productivity costs associated with dengue episodes in Asia are notable. However, owing to the significant variation in methodology and approaches applied, the reported productivity costs of dengue episodes were often not directly comparable across studies. More consistent and transparent methodology regarding the estimation of productivity costs would help the estimates of the economic burden of dengue be more accurate and comparable across studies.

Motivations, facilitators and barriers to accessing hepatitis C treatment among people who inject drugs in two South African cities.

BACKGROUND: Treatment of hepatitis C (HCV) among people who inject drugs (PWID) is a critical component of efforts to eliminate viral hepatitis. A recent study found high HCV prevalence among PWID in two cities, Pretoria (84%) and Cape Town (44%). Very few (< 5%) HCV-infected individuals attended follow-up appointments. This sub-study explores differences between stated desire for cure and appointment attendance in light of perceived facilitators and barriers to HCV treatment and care access among PWID. METHOD: Two sets of semi-structured interviews were implemented in a group of HCV-infected participants opportunistically sampled and recruited at harm reduction service sites. Initial interviews, conducted before the planned hospital appointment date, asked participants (N = 17, 9 in Pretoria and 8 in Cape Town) about past experiences of healthcare provision, plans to attend their referral appointment and perceived barriers and facilitators to seeking hepatitis treatment. Second interviews (n = 9, 4 in Pretoria, 5 in Cape Town), conducted after the planned referral appointment date, asked about appointment attendance and treatment experience. Trained social scientists with experience with PWID conducted the interviews which were recorded in detailed written notes. Data was thematically analysed in NVivo 11. RESULTS: Despite routine experiences of being stigmatised by the healthcare system in the past, most participants (n = 16, 94%) indicated a desire to attend their appointments. Attendance motivators included the desire to be cured, fear of dying and the wish to assist the research project. Perceived barriers to appointment attendance included fear of again experiencing stigmatisation and concerns about waiting periods and drug withdrawal. Perceived facilitators included the knowledge they would be treated quickly, and with respect and access to opioid substitution therapy. In the end, very few participants (n = 5) went to their appointment. Actual barriers to attendance included lack of finances, lack of urgency and forgetting and fatalism about dying. CONCLUSIONS: South Africa can learn from other countries implementing HCV treatment for PWID. Successful linkage to care will require accessible, sensitive services where waiting time is limited. Psychosocial support prior to initiating referrals that focuses on building and maintaining a sense of self-worth and emphasising that delayed treatment hampers health outcomes is needed.

Fatal Yellow Fever in Travelers to Brazil, 2018.

Yellow fever virus is a mosquito-borne flavivirus that causes yellow fever, an acute infectious disease that occurs in South America and sub-Saharan Africa. Most patients with yellow fever are asymptomatic, but among the 15% who develop severe illness, the case fatality rate is 20%-60%. Effective live-attenuated virus vaccines are available that protect against yellow fever (1). An outbreak of yellow fever began in Brazil in December 2016; since July 2017, cases in both humans and nonhuman primates have been reported from the states of São Paulo, Minas Gerais, and Rio de Janeiro, including cases occurring near large urban centers in these states (2). On January 16, 2018, the World Health Organization updated yellow fever vaccination recommendations for Brazil to include all persons traveling to or living in Espírito Santo, São Paulo, and Rio de Janeiro states, and certain cities in Bahia state, in addition to areas where vaccination had been recommended before the recent outbreak (3). Since January 2018, 10 travel-related cases of yellow fever, including four deaths, have been reported in international travelers returning from Brazil. None of the 10 travelers had received yellow fever vaccination.

Angiostrongylus cantonensis Is an Important Cause of Eosinophilic Meningitis in Southern Vietnam.

We utilized polymerase chain reaction (PCR) to demonstrate that Angiostrongylus cantonensis was responsible for 67.3% of 55 cases of eosinophilic meningitis from a cohort of 1,690 adult patients with CNS infection at a tertiary hospital in southern Vietnam. Longer duration of illness, depressed consciousness, and peripheral blood eosinophilia were associated with PCR positivity.

Serving on a hospital board: A case study.

BACKGROUND: It is important for nurses to serve on hospital boards, largely to give voice to matters of quality and patient safety. PURPOSE: Describe what one nurse was able to accomplish on a statewide board over time as chair of the board's Quality and Patient Safety Committee. METHODS: The experience was analyzed using auto-ethnography and narrative analysis. DISCUSSION: After describing the organization, the paper summarizes the key issues on which the nurse took the lead, measures of success in the role, and learning acquired along the way. CONCLUSION: The "system" orientation of nurses is an asset in getting hospital boards to view themselves as institutional champions of quality.

Robert Wood Johnson Foundation Nurse Faculty Scholars program leadership training.

BACKGROUND: The Robert Wood Johnson Foundation Nurse Faculty Scholars program was created to address the nursing shortage via development of the next generation of national leaders in academic nursing. PURPOSE: The leadership training combined development at the scholar's home institution with in-person didactic and interactive sessions with notable leaders in nursing and other disciplines. METHODS: A curriculum matrix, organized by six domains, was evaluated quantitatively and qualitatively. DISCUSSION: What set this program apart is that it immersed junior faculty in concerted leadership development with regard to all aspects of the faculty role so that teaching interactively, making use of the latest in information technology, giving testimony before a policy-making group, participating in strategic planning, and figuring out how to reduce the budget without jeopardizing quality were all envisioned as part of the faculty role. CONCLUSION: The domains covered by this program could easily be used as the framework to plan other leadership-development programs for the next generation of academic leaders.

Building a mentoring network.

BACKGROUND: Mentoring has long been regarded as one of the key components of research training and faculty development. PURPOSE: The Robert Wood Johnson Foundation Nurse Faculty Scholars program purposely facilitated scholars' development of a mentoring network by providing each individual with three mentors: a school-of-nursing mentor (primary), a university-based non-nurse research mentor (research), and a nationally-recognized nurse leader at another university (national). METHOD: The Mentorship Effectiveness Scale was used to assess the effectiveness of each type of mentor in the first five completed cohorts. DISCUSSION: The ratings of mentorship effectiveness for all three kinds of mentors were generally high. Scholars valued most their mentors' support and advocacy; the biggest weakness in dealing with all mentors was accessibility. CONCLUSION: Even when one mentor proved a poor match, another mentor turned out to be an advocate and helpful, thus reaffirming the benefits of a mentoring network as opposed to only a single mentoring relationship. One lesson learned is the importance of preparing mentors for their role via written materials, in-person or phone orientations, and discussions at the annual meeting.

The impact of the Nurse Faculty Scholars program on schools of nursing.

BACKGROUND: The Robert Wood Johnson Foundation Nurse Faculty Scholars program was conceptualized as not only promoting the growth and development of early-career faculty but as enhancing the research infrastructure of scholars' schools of nursing. PURPOSE: At the completion of the scholars' three years of support, deans/directors were asked to provide feedback regarding the institutional impact of the scholars' participation in the program. METHODS: Phone interviews were conducted on the first five completed cohorts and a six-item questionnaire was developed to obtain some quantitative data. DISCUSSION: The program was viewed as having accelerated the scholars' leadership and scholarship, and their influence within the school/university and regionally/nationally. Deans/directors generally agreed that the scholars' experience helped build the school's research portfolio. CONCLUSION: Looking back on how the participating schools of nursing fared, one can say that the program's institutional expectations were achieved most of the time. The program helped scholars build their own reputations and that in turn had consequences for the school's standing as a whole. A number of components are described that can be replicated singly or in various combinations by schools/universities interested in adopting aspects of this program.

Overview of the Robert Wood Johnson Foundation Nurse Faculty Scholars program.

BACKGROUND: The Robert Wood Johnson Foundation Nurse Faculty Scholars program was created to address the nursing faculty shortage and thereby decrease the nursing shortage. PURPOSE: The purpose of the study was to describe the program development, implementation, and ongoing outcome evaluation. METHODS: Data on scholarly productivity, impact of research, research funding, and leadership positions were compiled, including an h-index (impact of publications) comparison with a comparison group of other interdisciplinary faculty at the same institutions of the 90 current and alumni scholars. DISCUSSION: There is evidence of the achievements of the individual scholars; however, the effect of the synergy of the multiple components of the program is difficult to capture in traditional evaluation strategies. CONCLUSIONS: The sense of possibility and responsibility (to the profession, to improving the health of all Americans, and to one's school of nursing and university) was a significant outcome of the program. Lessons learned from the program are important for the leadership development and retention of nursing faculty.

Resistance at virological failure using boosted protease inhibitors versus nonnucleoside reverse transcriptase inhibitors as first-line antiretroviral therapy--implications for sustained efficacy of ART in resource-limited settings.

BACKGROUND: Increases in the prevalence of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been observed among previously untreated individuals in all areas of sub-Saharan Africa. We aimed to examine whether first-line use of 2 NRTIs plus a boosted protease inhibitor (bPI) could protect against emergence of NRTI resistance mutations, compared to the use of 2 NRTIs plus 1 NNRTI. METHODS: We carried out a weighted meta-analysis of randomized clinical trials comparing bPI- with NNRTI-based first-line antiretroviral therapy regimens using random effects modeling. RESULTS: In intention to treat analyses, there was no difference in the risk of viral failure at week 48 between NNRTI and bPI (P = .19). At week 48, the overall difference between NNRTI- and PI-based regimens in selection of any major NRTI resistance mutation (crude unweighted prevalence 3.3% vs 1.6%) was 1.7% (95% confidence interval [CI], .4-3.0; P = .00927). There was a statistically significant difference in prevalence of K65R when comparing NNRTI (1.3%) with PI (0.67%); absolute weighted difference 1.0% (95% CI, .3-1.7; P = .00447). There was also a significant difference in prevalence of M184V/I between NNRTI and PI (crude unweighted prevalence 3.2% vs 1.4%); difference 1.6% (95% CI 0.1-3.1; P = .0368). CONCLUSIONS: Despite the equivalent efficacy and more favorable resistance implications of PI- versus NNRTI-based first line therapy, widespread use of PI-based first-line therapy is not warranted at this time, due to resource limitations and predicted increased risk of resistance-related failure of NNRTI/NRTI second-line regimens. PI-based first-line therapy could be reconsidered when antiretroviral agents from other classes become available for second-line regimens in resource-limited settings.

Endothelial and inflammatory pathophysiology in dengue shock: New insights from a prospective cohort study in Vietnam.

Dengue shock (DS) is the most severe complication of dengue infection; endothelial hyperpermeability leads to profound plasma leakage, hypovolaemia and extravascular fluid accumulation. At present, the only treatment is supportive with intravenous fluid, but targeted endothelial stabilising therapies and host immune modulators are needed. With the aim of prioritising potential therapeutics, we conducted a prospective observational study of adults (≥16 years) with DS in Vietnam from 2019-2022, comparing the pathophysiology underlying circulatory failure with patients with septic shock (SS), and investigating the association of biomarkers with clinical severity (SOFA score, ICU admission, mortality) and pulmonary vascular leak (daily lung ultrasound for interstitial and pleural fluid). Plasma was collected at enrolment, 48 hours later and hospital discharge. We measured biomarkers of inflammation (IL-6, ferritin), endothelial activation (Ang-1, Ang-2, sTie-2, VCAM-1) and endothelial glycocalyx breakdown (hyaluronan, heparan sulfate, endocan, syndecan-1). We enrolled 135 patients with DS (median age 26, median SOFA score 7, 34 required ICU admission, 5 deaths), together with 37 patients with SS and 25 healthy controls. Within the DS group, IL-6 and ferritin were associated with admission SOFA score (IL-6: ßeta0.70, p<0.001 & ferritin: ßeta0.45, p<0.001), ICU admission (IL-6: OR 2.6, p<0.001 & ferritin: OR 1.55, p<0.001) and mortality (IL-6: OR 4.49, p = 0.005 & ferritin: OR 13.8, p = 0.02); both biomarkers discriminated survivors and non-survivors at 48 hours and all patients who died from DS had pre-mortem ferritin ≥100,000ng/ml. IL-6 most strongly correlated with severity of pulmonary vascular leakage (R = 0.41, p<0.001). Ang-2 correlated with pulmonary vascular leak (R = 0.33, p<0.001) and associated with SOFA score (ß 0.81, p<0.001) and mortality (OR 8.06, p = 0.002). Ang-1 was associated with ICU admission (OR 1.6, p = 0.005) and mortality (OR 3.62, p = 0.006). All 4 glycocalyx biomarkers were positively associated with SOFA score, but only syndecan-1 was associated with ICU admission (OR 2.02, p<0.001) and mortality (OR 6.51, p<0.001). This study highlights the central role of hyperinflammation in determining outcomes from DS; the data suggest that anti-IL-1 and anti-IL-6 immune modulators and Tie2 agonists may be considered as candidates for therapeutic trials in severe dengue.

Kinetics of cardiovascular and inflammatory biomarkers in paediatric dengue shock syndrome.

Glycocalyx disruption and hyperinflammatory responses are implicated in the pathogenesis of dengue-associated vascular leak, however little is known about their association with clinical outcomes of patients with dengue shock syndrome (DSS). We investigated the association of vascular and inflammatory biomarkers with clinical outcomes and their correlations with clinical markers of vascular leakage. We performed a prospective cohort study in Viet Nam. Children ≥5 years of age with a clinical diagnosis of DSS were enrolled into this study. Blood samples were taken daily during ICU stay and 7-10 days after hospital discharge for measurements of plasma levels of Syndecan-1, Hyaluronan, Suppression of tumourigenicity 2 (ST-2), Ferritin, N-terminal pro Brain Natriuretic Peptide (NT-proBNP), and Atrial Natriuretic Peptide (ANP). The primary outcome was recurrent shock. Ninety DSS patients were enrolled. Recurrent shock occurred in 16 patients. All biomarkers, except NT-proBNP, were elevated at presentation with shock. There were no differences between compensated and decompensated DSS patients. Glycocalyx markers were positively correlated with inflammatory biomarkers, haematocrit, percentage haemoconcentration, and negatively correlated with stroke volume index. While Syndecan-1, Hyaluronan, Ferritin, and ST-2 improved with time, ANP continued to be raised at follow-up. Enrolment Syndecan-1 levels were observed to be associated with developing recurrent shock although the association did not reach the statistical significance at the P < 0.01 (OR = 1.82, 95% CI 1.07-3.35, P = 0.038). Cardiovascular and inflammatory biomarkers are elevated in DSS, correlate with clinical vascular leakage parameters and follow different kinetics over time. Syndecan-1 may have potential utility in risk stratifying DSS patients in ICU.

Diagnosing and treating leprosy in a non-endemic setting in a national centre, London, United Kingdom 1995-2018.

BACKGROUND: Leprosy is rare in the United Kingdom (UK), but migration from endemic countries results in new cases being diagnosed each year. We documented the clinical presentation of leprosy in a non-endemic setting. METHODS: Demographic and clinical data on all new cases of leprosy managed in the Leprosy Clinic at the Hospital for Tropical Diseases, London between 1995 and 2018 were analysed. RESULTS: 157 individuals with a median age of 34 (range 13-85) years were included. 67.5% were male. Patients came from 34 different countries and most contracted leprosy before migrating to the UK. Eighty-two (51.6%) acquired the infection in India, Sri Lanka, Bangladesh, Nepal and Pakistan. 30 patients (19.1%) acquired leprosy in Africa, including 11 from Nigeria. Seven patients were born in Europe; three acquired their leprosy infection in Africa, three in South East Asia, and one in Europe. The mean interval between arrival in the UK and symptom onset was 5.87 years (SD 10.33), the longest time to diagnosis was 20 years. Borderline tuberculoid leprosy (n = 71, 42.0%), and lepromatous leprosy (n =, 53 33.1%) were the commonest Ridley Jopling types. Dermatologists were the specialists diagnosing leprosy most often. Individuals were treated with World Health Organization recommended drug regimens (rifampicin, dapsone and clofazimine). CONCLUSION: Leprosy is not a disease of travellers but develops after residence in an leprosy endemic area. The number of individuals from a leprosy endemic country reflect both the leprosy prevalence and the migration rates to the United Kingdom. There are challenges in diagnosing leprosy in non-endemic areas and clinicians need to recognise the symptoms and signs of leprosy.

Direct Medical Costs of Tetanus, Dengue, and Sepsis Patients in an Intensive Care Unit in Vietnam.

Background: Critically ill patients often require complex clinical care by highly trained staff within a specialized intensive care unit (ICU) with advanced equipment. There are currently limited data on the costs of critical care in low-and middle-income countries (LMICs). This study aims to investigate the direct-medical costs of key infectious disease (tetanus, sepsis, and dengue) patients admitted to ICU in a hospital in Ho Chi Minh City (HCMC), Vietnam, and explores how the costs and cost drivers can vary between the different diseases. Methods: We calculated the direct medical costs for patients requiring critical care for tetanus, dengue and sepsis. Costing data (stratified into different cost categories) were extracted from the bills of patients hospitalized to the adult ICU with a dengue, sepsis and tetanus diagnosis that were enrolled in three studies conducted at the Hospital for Tropical Diseases in HCMC from January 2017 to December 2019. The costs were considered from the health sector perspective. The total sample size in this study was 342 patients. Results: ICU care was associated with significant direct medical costs. For patients that did not require mechanical ventilation, the median total ICU cost per patient varied between US$64.40 and US$675 for the different diseases. The costs were higher for patients that required mechanical ventilation, with the median total ICU cost per patient for the different diseases varying between US$2,590 and US$4,250. The main cost drivers varied according to disease and associated severity. Conclusion: This study demonstrates the notable cost of ICU care in Vietnam and in similar LMIC settings. Future studies are needed to further evaluate the costs and economic burden incurred by ICU patients. The data also highlight the importance of evaluating novel critical care interventions that could reduce the costs of ICU care.

Clustering excellence to exert transformative change: the Hartford Geriatric Nursing Initiative (HGNI).

This paper describes how the John A. Hartford Foundation sought to maximize the influence of its various geriatric nursing projects by organizing and managing them collectively as the Hartford Geriatric Nursing Initiative (HGNI). This initiative aimed to develop a shared identity, encouraged cross-pollination of efforts, convened project leaders to address opportunities and problems, launched across-project collaborations, and created tools and resources to support overall efforts. This paper ends with some reflections on the processes implemented to maximize HGNI effectiveness, particularly the importance of forging a common identity in order to encourage expanded solutions. The HGNI can serve as an example of how intersecting interests can fuel new ideas, thus helping others think more strategically about change efforts in the future.

Studying the Endothelial Glycocalyx in vitro: What Is Missing?

All human cells are coated by a surface layer of proteoglycans, glycosaminoglycans (GAGs) and plasma proteins, called the glycocalyx. The glycocalyx transmits shear stress to the cytoskeleton of endothelial cells, maintains a selective permeability barrier, and modulates adhesion of blood leukocytes and platelets. Major components of the glycocalyx, including syndecans, heparan sulfate, and hyaluronan, are shed from the endothelial surface layer during conditions including ischaemia and hypoxia, sepsis, atherosclerosis, diabetes, renal disease, and some viral infections. Studying mechanisms of glycocalyx damage in vivo can be challenging due to the complexity of immuno-inflammatory responses which are inextricably involved. Previously, both static as well as perfused in vitro models have studied the glycocalyx, and have reported either imaging data, assessment of barrier function, or interactions of blood components with the endothelial monolayer. To date, no model has simultaneously incorporated all these features at once, however such a model would arguably enhance the study of vasculopathic processes. This review compiles a series of current in vitro models described in the literature that have targeted the glycocalyx layer, their limitations, and potential opportunities for further developments in this field.