Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment.

Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue). The target tissue chamber can be configured to accommodate a three-dimensional (3D) spheroid-shaped microtissue, or a 2-dimensional (2D) cell monolayer. Culture medium and compounds freely diffuse between the 2 chambers. Human-differentiated HepaRG liver cells are used to form the 3D human liver microtissues, which displayed robust protein expression of liver biomarkers (albumin, asialoglycoprotein receptor, Phase I cytochrome P450 [CYP3A4] enzyme, multidrug resistance-associated protein 2 transporter, and glycogen), and exhibited Phase I/II enzyme activities over the course of 17 days. Histological and ultrastructural analyses confirmed that the HepaRG microtissues presented a differentiated hepatocyte phenotype, including abundant mitochondria, endoplasmic reticulum, and bile canaliculi. Liver microtissue zonation characteristics could be easily modulated by maturation in different media supplements. Furthermore, our proof-of-concept study demonstrated the efficacy of this coculture model in evaluating testosterone-mediated androgen receptor responses in the presence of human liver metabolism. This liver-organ coculture system provides a practical, higher-throughput testing platform for metabolism-dependent bioactivity assessment of drugs/chemicals to better recapitulate the biological effects and potential toxicity of human exposures.

Looking back and moving forward: Addressing health inequities after COVID-19.

We will likely look back on 2020 as a turning point. The pandemic put a spotlight on existing societal issues, accelerated the pace of change in others, and created some new ones too. For example, concerns about inequalities in health by income and race are not new, but they became more apparent to a larger number of people during 2020. The speed and starkness of broadening societal conversation, including beyond the direct effects of COVID-19, create an opportunity and motivation to reassess our understanding of health. Perhaps more importantly, it is an opportunity to reduce inequities in who has access to, who uses, and who benefits from the resources that promote health and well-being. To this end, we offer three questions to guide thinking about health and health inequities after 2020: (1) what do we mean by "health" and "health inequality and inequity"? (2) what are the structures and policies we put in place to support or promote health, and how effective are they? And (3) who has the power to shape structures and policies, and whose interests do those structures and policies serve?

Experiences with sexual orientation and gender identity conversion therapy practices among sexual minority men in Canada, 2019-2020.

BACKGROUND: "Conversion therapy" practices (CTP) are organized and sustained efforts to avoid the adoption of non-heterosexual sexual orientations and/or of gender identities not assigned at birth. Few data are available to inform the contemporary prevalence of CTP. The aim of this study is to quantify the prevalence of CTP among Canadian sexual and gender minority men, including details regarding the setting, age of initiation, and duration of CTP exposure. METHODS: Sexual and gender minority men, including transmen and non-binary individuals, aged ≥ 15, living in Canada were recruited via social media and networking applications and websites, November 2019-February 2020. Participants provided demographic data and detailed information about their experiences with CTP. RESULTS: 21% of respondents (N = 9,214) indicated that they or any person with authority (e.g., parent, caregiver) ever tried to change their sexual orientation or gender identity, and 10% had experienced CTP. CTP experience was highest among non-binary (20%) and transgender respondents (19%), those aged 15-19 years (13%), immigrants (15%), and racial/ethnic minorities (11-22%, with variability by identity). Among the n = 910 participants who experienced CTP, most experienced CTP in religious/faith-based settings (67%) or licensed healthcare provider offices (20%). 72% of those who experienced CTP first attended before the age of 20 years, 24% attended for one year or longer, and 31% attended more than five sessions. INTERPRETATION: CTP remains prevalent in Canada and is most prevalent among younger cohorts, transgender people, immigrants, and racial/ethnic minorities. Legislation, policy, and education are needed that target both religious and healthcare settings.

Perceived Barriers to Mental Health Services Among Canadian Sexual and Gender Minorities with Depression and at Risk of Suicide.

This study examines barriers to mental health services among sexual and gender minorities (SGM) who screened positive for depression and risk of suicide. Data from an online survey of SGM (N = 2778) are analyzed. 37.5% met criteria for depression and 73.6% screened for being at risk of suicide. The most frequently cited barriers to mental health services access were inability to pay (62.3%), insufficient insurance (52.2%), a preference for 'waiting' for the problems to go away (51.5%), discomfort discussing emotions (45.7%), and feeling embarrassed and ashamed about mental health challenges (42.5%). Policy and practices implications of these findings are discussed.

Acute Kidney Injury With Ventricular Assist Device Placement: National Estimates of Trends and Outcomes.

RATIONALE & OBJECTIVE: Ventricular assist devices (VADs) are used for end-stage heart failure not amenable to medical therapy. Acute kidney injury (AKI) in this setting is common due to heart failure decompensation, surgical stress, and other factors. Little is known about national trends in AKI diagnosis and AKI requiring dialysis (AKI-D) and associated outcomes with VAD implantation. We investigated national estimates and trends for diagnosed AKI, AKI-D, and associated patient and resource utilization outcomes in hospitalizations in which implantable VADs were placed. STUDY DESIGN: Cohort study of 20% stratified sample of US hospitalizations. SETTING & PARTICIPANTS: Patients who underwent implantable VAD placement in 2006 to 2015. EXPOSURE: No AKI diagnosis, AKI without dialysis, AKI-D. OUTCOMES: In-hospital mortality, length of stay, estimated hospitalization costs. ANALYTICAL APPROACH: Multivariate logistic and linear regression using survey design methods to account for stratification, clustering, and weighting. RESULTS: An estimated 24,140 implantable VADs were placed, increasing from 853 in 2006 to 3,945 in 2015. AKI was diagnosed in 56.1% of hospitalizations and AKI-D occurred in 6.5%. AKI diagnosis increased from 44.0% in 2006 to 2007 to 61.7% in 2014 to 2015; AKI-D declined from 9.3% in 2006 to 2007 to 5.2% in 2014 to 2015. Mortality declined in all AKI categories but this varied by category: those with AKI-D had the smallest decline. Adjusted hospitalization costs were 19.1% higher in those with diagnosed AKI and 39.6% higher in those with AKI-D, compared to no AKI. LIMITATIONS: Administrative data; timing of AKI with respect to VAD implantation cannot be determined; limited pre-existing chronic kidney disease ascertainment; discharge weights not derived for subpopulation of interest. CONCLUSIONS: A decreasing proportion of patients undergoing VAD implantation experience AKI-D, but mortality among these patients remains high. AKI diagnosis with VAD implantation is increasing, possibly reflecting changes in AKI surveillance, awareness, and coding.

Implantable Ventricular Assist Device Use and Outcomes in People With End-Stage Renal Disease.

BACKGROUND: People with end-stage renal disease (ESRD) are at risk for advanced heart failure, but little is known about use and outcomes of durable mechanical circulatory support in this setting. We examined use and outcomes of implantable ventricular assist devices (VADs) in a national ESRD cohort. METHODS AND RESULTS: We performed a retrospective cohort study of Medicare beneficiaries with ESRD who underwent implantable VAD placement from 2006 to 2014. We examined in-hospital and 1-year mortality, all-cause and cause-specific hospitalizations, and heart/kidney transplantation outcomes. We investigated as predictors demographic factors, time-period of VAD implantation, primary or post-cardiotomy implantation, and duration of ESRD before VAD implantation. We identified 96 people with ESRD who underwent implantable VAD placement. At time of VAD implantation, 74 (77.1%) were receiving hemodialysis, 10 (10.4%) were receiving peritoneal dialysis and 12 (12.5%) had renal transplant. Time from incident ESRD to VAD implantation was median 4.0 (interquartile range 1.1, 8.2) years. Mortality during the implantation hospitalization was 40.6%. Within 1 year of implantation 61.5% of people had died. On multivariable analysis, males had half the mortality risk of females. Lower mortality risk was also seen with VAD implantation in a primary setting, and with more recent year of implantation, but these results did not reach statistical significance. CONCLUSIONS: Medicare beneficiaries with ESRD are undergoing durable VAD implantation, often several years after incident ESRD, although in low numbers. Mortality is high among these patients, highlighting the need for investigations to improve treatment selection and management.

"Location is surprisingly a lot more important than you think": a critical thematic analysis of push and pull factor messaging used on Caribbean offshore medical school websites.

BACKGROUND: Offshore medical schools are for-profit, private enterprises located in the Caribbean that provide undergraduate medical education to students who must leave the region for postgraduate training and also typically to practice. This growing industry attracts many medical students from the US and Canada who wish to return home to practice medicine. After graduation, international medical graduates can encounter challenges obtaining residency placements and can face other barriers related to practice. METHODS: We conducted a qualitative thematic analysis to discern the dominant messages found on offshore medical school websites. Dominant messages included frequent references to push and pull factors intended to encourage potential applicants to consider attending an offshore medical school. We reviewed 38 English-language Caribbean offshore medical school websites in order to extract and record content pertaining to push and pull factors. RESULTS: We found two push and four pull factors present across most offshore medical school websites. Push factors include the: shortages of physicians in the US and Canada that require new medical trainees; and low acceptance rates at medical schools in intended students' home countries. Pull factors include the: financial benefits of attending an offshore medical school; geographic location and environment of training in the Caribbean; training quality and effectiveness; and the potential to practice medicine in one's home country. CONCLUSIONS: This analysis contributes to our understanding of some of the factors behind students' decisions to attend an offshore medical school. Importantly, push and pull factors do not address the barriers faced by offshore medical school graduates in finding postgraduate residency placements and ultimately practicing elsewhere. It is clear from push and pull factors that these medical schools heavily focus messaging and marketing towards students from the US and Canada, which raises questions about who benefits from this offshoring practice.

Who tweets? Deriving the demographic characteristics of age, occupation and social class from twitter user meta-data.

This paper specifies, designs and critically evaluates two tools for the automated identification of demographic data (age, occupation and social class) from the profile descriptions of Twitter users in the United Kingdom (UK). Meta-data data routinely collected through the Collaborative Social Media Observatory (COSMOS: http://www.cosmosproject.net/) relating to UK Twitter users is matched with the occupational lookup tables between job and social class provided by the Office for National Statistics (ONS) using SOC2010. Using expert human validation, the validity and reliability of the automated matching process is critically assessed and a prospective class distribution of UK Twitter users is offered with 2011 Census baseline comparisons. The pattern matching rules for identifying age are explained and enacted following a discussion on how to minimise false positives. The age distribution of Twitter users, as identified using the tool, is presented alongside the age distribution of the UK population from the 2011 Census. The automated occupation detection tool reliably identifies certain occupational groups, such as professionals, for which job titles cannot be confused with hobbies or are used in common parlance within alternative contexts. An alternative explanation on the prevalence of hobbies is that the creative sector is overrepresented on Twitter compared to 2011 Census data. The age detection tool illustrates the youthfulness of Twitter users compared to the general UK population as of the 2011 Census according to proportions, but projections demonstrate that there is still potentially a large number of older platform users. It is possible to detect "signatures" of both occupation and age from Twitter meta-data with varying degrees of accuracy (particularly dependent on occupational groups) but further confirmatory work is needed.

Continuous-flow left ventricular assist device implantation as a bridge to transplantation or destination therapy: racial disparities in outcomes.

BACKGROUND: There is a paucity of data assessing racial disparities in outcomes after left ventricular assist device (LVAD) implantation. This may be due to the relatively low percentage of African American (AA) patients at a given center. Given the high proportion of AAs in our patient population, we sought to evaluate outcomes of LVAD implantation in AAs vs Caucasians. METHODS: We stratified 88 LVAD patients by AA or Caucasian race. Variables were compared using 2-sided t-tests, chi-square tests, Cox proportional hazards models, and log-rank tests to determine whether a difference existed between AAs and Caucasians and whether race was a significant independent predictor of outcome. RESULTS: AAs represented 36.4% (32 of 88) of our LVAD patients. The two groups did not differ significantly in the incidence of hypertension, diabetes, or chronic renal insufficiency, reoperation rates, pre-operative body mass index, left ventricular ejection fraction, central venous pressure, pulmonary capillary wedge pressure, pulmonary artery pressure, or right ventricular function. Compared with Caucasians, AAs were significantly younger (48.6 vs 54.8 years, p = 0.019), and had a significantly higher mean body surface area (p = 0.009) and a higher rate of non-ischemic dilated cardiomyopathy (61% vs 39%, p = 0.008). No significant difference was found in 30-day (p = 0.12), 180-day (p = 0.166), or 360-day (p = 0.18) survival. Analysis by univariate Cox proportional hazard models (hazard ratio [95% confidence interval]) showed race was not an independent predictor of 30-day (4.5 [0.56-35.94], p = 0.157), 180-day (3.9 [0.48-31.95], p = 0.2), or 360-day survival (1.8 [0.6-5.71], p = 0.286). Age and pre-operative renal failure were the only independent predictors of survival at 30 days (1.1 [1.02-1.19], p = 0.019; 4.99 [1.24-20], p = 0.023, respectively), 180 days (1.09 [1-1.18], p = 0.041; 4.14 [0.99-17.39], p = 0.05), and 360 days (1.05 [1-1.1], p = 0.044; 2.52 [0.94-6.75], p = 0.05). Analysis by a multivariate logistic regression model showed age and chronic renal failure were no longer statistically significant for survival at 30, 180, and 360 days. CONCLUSIONS: Although multiple studies have demonstrated that AAs experience worse outcomes after coronary artery bypass grafting, heart transplantation, and valve surgery, we did not find similar results in our LVAD population. More rigorous pre-operative LVAD workup, including an evaluation by a multidisciplinary team, along with more intense post-operative follow-up, may explain improved outcomes in AAs after LVAD implantation compared with other cardiac surgical procedures, although additional analysis is required.

Standard versus bicaval techniques for orthotopic heart transplantation: an analysis of the United Network for Organ Sharing database.

OBJECTIVE: Most studies of anastomotic technique have been underpowered to detect subtle differences in survival. We analyzed the United Network for Organ Sharing database for trends in use and outcomes after either bicaval or traditional (biatrial) anastomoses for heart implantation. METHODS: Review of United Network for Organ Sharing data identified 20,999 recipients of heart transplants from 1997 to 2007. Patients were stratified based on the technique of atrial anastomosis: standard biatrial (atrial group, n = 11,919, 59.3%), bicaval (caval group, n = 7661, 38.1%), or total orthotopic (total group, n = 519, 2.6%). RESULTS: The use of the bicaval anastomosis is increasing, but many transplantations continue to use a biatrial anastomosis (1997, 0.2% vs 97.6%; 2007, 62.0% vs 34.7%; P < .0001). Atrial group patients required permanent pacemaker implantation more often (odds ratio, 2.6; 95% confidence interval, 2.2-3.1). Caval group patients had a significant advantage in 30-day mortality (odds ratio, 0.83; 95% confidence interval, 0.75-0.93), and Cox regression analysis confirmed the decreased long-term survival in the atrial group (hazard ratio, 1.11; 95% confidence interval, 1.04-1.19). CONCLUSIONS: Heart transplantations performed with bicaval anastomoses require postoperative permanent pacemaker implantation at lower frequency and have a small but significant survival advantage compared with biatrial anastomoses. We recommend that except where technical considerations require a biatrial technique, bicaval anastomoses should be performed for heart transplantation.

An overview of measurement method tools available to communities for conducting exposure and cumulative risk assessments.

Community-based programs for assessing and mitigating environmental risks represent a challenge to participants because each brings a different level of understanding of the issues affecting the community. These programs often require the collaboration of several community sectors, such as community leaders, local governments and researchers. Once the primary concerns, community vulnerabilities and assets are identified, participants plan on how to address immediate actions, rank known risks, collect information to support decision making, set priorities and determine an evaluation process to assess the success of the actions taken. The evaluation process allows the community to develop new action plans based on the results obtained from earlier actions. Tracking the success of the community actions may be as simple as a visual/tangible result (e.g., cleaning a park) or as complex as the collection of specific measurements to track the reduction of toxic pollutants or to determine the presence of a specific contaminant. Recognizing that communities may need to perform measurements to meet their goals, this paper provides an overview of the available measurement methods for several chemicals and biologicals in relevant environmental samples to a community setting. The measurement methods are organized into several categories according to their level of complexity, estimated cost and sources. Community project technical advisors are encouraged to examine the objective(s) of the community to be addressed by a measurement collection effort and the level of confidence that needed for the data to make appropriate decisions. The tables provide a starting point for determining which measurement method may be appropriate for specific community needs.

Does robotic technology make minimally invasive cardiac surgery too expensive? A hospital cost analysis of robotic and conventional techniques.

BACKGROUND: While potential benefits of robotic technology include decreased morbidity and improved recovery, some have suggested a prohibitively high cost. This study was undertaken to compare actual hospital costs of robotically assisted cardiac procedures with conventional techniques. METHODS: We conducted a retrospective review of clinical and financial data of 20 patients who underwent atrial septal defect (ASD) closure and 20 patients who underwent mitral valve repair (MVr) using either robotic techniques or a conventional approach with a sternotomy. Total hospital cost (actual resource consumption) was subdivided into operative and postoperative costs. RESULTS: Robotic technology did not significantly increase total hospital cost for ASD closure or MVr (p = 0.518 and p = 0.539). However, when including the initial capital investment for the robot through amortization of institutional costs, total hospital cost was increased by $3,773 for robotic ASD closure and $3,444 for robotic MVr (p = 0.021 and p = 0.004). The major driver of cost for robotic cases (operating room time) decreased over time. CONCLUSIONS: Robotic technology did not significantly increase hospital cost. While the absolute cost for robotic surgery was higher than conventional techniques after taking into account the institutional cost of the robot, the major driver of cost for robotic procedures will likely continue to decrease, as the surgical team becomes increasingly familiar with robotic technology. Furthermore, other benefits, such as improvement in postoperative quality of life and more expeditious return to work may make a robotic approach cost-effective. Thus, it is possible that the benefits of robotic surgery may justify investment in this technology.

Cost-effectiveness of left ventricular assist devices.

Implantable left ventricular assist devices are expensive both in terms of the actual device cost and postoperative care. These devices have been successfully used in numerous life saving indications but their cost and cost efficacy remains unclear. This report reviews these issues focusing on device, in-hospital, and posthospitalization costs.