Spanish Translation and Cultural Adaptation of the Intensive Care Unit Delirium Playbook.

Background: A lack of high-quality provider education hinders the delivery of standard-of-care delirium detection and prevention practices in the intensive care unit (ICU). To fill this gap, we developed and validated an e-learning ICU Delirium Playbook consisting of eight videos and a 44-question knowledge assessment quiz. Given the increasing Spanish-speaking population worldwide, we translated and cross-culturally adapted the playbook from English into Spanish. Objective: To translate and culturally adapt the ICU Delirium Playbook into Spanish, the second most common native language worldwide. Methods: The translation and cross-cultural adaptation process included double forward and back translations and harmonization by a 14-person interdisciplinary team of ICU nurses and physicians, delirium experts, methodologists, medical interpreters, and bilingual professionals representing many Spanish-speaking global regions. After a preeducation quiz, a nurse focus group completed the playbook videos and posteducation quiz, followed by a semistructured interview. Results: The ICU Delirium Playbook: Spanish Version maintained conceptual equivalence to the English version. Focus group participants posted mean (standard deviation) pre- and post-playbook scores of 63% (10%) and 78% (12%), with a 15% (11%) pre-post improvement (P = 0.01). Participants reported improved perceived competency in performing the Confusion Assessment Method for the ICU and provided positive feedback regarding the playbook. Conclusion: After translation and cultural adaptation, the ICU Delirium Playbook: Spanish Version yielded significant knowledge assessment improvements and positive feedback. The Spanish playbook is now available for public dissemination.

Tocilizumab is associated with reduced delirium and coma in critically ill patients with COVID-19.

Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab [7 days (IQR: 3-9 days)] vs control [3 days (IQR: 1-8 days)]; p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives ( ß ^ = 0.671, p = 0.010). There were no significant differences in mortality ( ß ^ = - 0.204, p = 0.561), ventilator duration ( ß ^ = 0.016, p = 0.956), and ICU or hospital length of stay ( ß ^ = - 0.134, p = 0.603; ß ^ = 0.003, p = 0.991, respectively). Tocilizumab use was associated with significantly increased number of days without delirium/coma. Confirmation of these findings in randomized prospective studies may inform a novel paradigm of pharmacological amelioration of delirium/coma during critical illness.

Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.

Systemic inflammation and delirium during critical illness.

PURPOSE: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness. METHODS: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1ß), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives. RESULTS: Among 991 participants with a median age (interquartile range, IQR) of 62 [53-72] years and enrollment SOFA of 9 [7-11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4-2.3]), IL-8 (1.3 [1.1-1.5]), IL-10 (1.5 [1.2-1.8]), TNF-α (1.2 [1.0-1.4]), and TNFR1 (1.3 [1.1-1.6]) and lower concentrations of protein C (0.7 [0.6-0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1-1.7]), IFN-γ (1.3 [1.1-1.5]), IL-6 (2.3 [1.8-3.0]), IL-8 (1.8 [1.4-2.3]), and IL-10 (1.5 [1.2-2.0]) and lower concentrations of protein C (0.6 [0.5-0.8]) were associated with coma the following day. IL-1ß, IL-12, and MMP-9 were not associated with mental status. CONCLUSION: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness.

One-Year Recovery Among Survivors of Prolonged Severe COVID-19: A National Multicenter Cohort.

OBJECTIVES: Understanding the long-term effects of severe COVID-19 illness on survivors is essential for effective pandemic recovery planning. Therefore, we investigated impairments among hospitalized adults discharged to long-term acute care hospitals (LTACHs) for prolonged severe COVID-19 illness who survived 1 year. DESIGN: The Recovery After Transfer to an LTACH for COVID-19 (RAFT COVID) study was a national, multicenter, prospective longitudinal cohort study. SETTING AND PATIENTS: We included hospitalized English-speaking adults transferred to one of nine LTACHs in the United States between March 2020 and February 2021 and completed a survey. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Validated instruments for impairments and free response questions about recovering. Among 282 potentially eligible participants who provided permission to be contacted, 156 (55.3%) participated (median age, 65; 38.5% female; 61.3% in good prior health; median length of stay of 57 d; 77% mechanically ventilated for a median of 26 d; 42% had a tracheostomy). Approximately two-thirds (64%) had a persistent impairment, including physical (57%), respiratory (49%; 19% on supplemental oxygen), psychiatric (24%), and cognitive impairments (15%). Nearly half (47%) had two or more impairment types. Participants also experienced persistent debility from hospital-acquired complications, including mononeuropathies and pressure ulcers. Participants described protracted recovery, attributing improvements to exercise/rehabilitation, support, and time. While considered life-altering with 78.7% not returning to their usual health, participants expressed gratitude for recovering; 99% returned home and 60% of previously employed individuals returned to work. CONCLUSIONS: Nearly two-thirds of survivors of among the most prolonged severe COVID-19 illness had persistent impairments at 1 year that resembled post-intensive care syndrome after critical illness plus debility from hospital-acquired complications.

Improving management of ARDS: uniting acute management and long-term recovery.

Acute Respiratory Distress Syndrome (ARDS) is an important global health issue with high in-hospital mortality. Importantly, the impact of ARDS extends beyond the acute phase, with increased mortality and disability for months to years after hospitalization. These findings underscore the importance of extended follow-up to assess and address the Post-Intensive Care Syndrome (PICS), characterized by persistent impairments in physical, cognitive, and/or mental health status that impair quality of life over the long-term. Persistent muscle weakness is a common physical problem for ARDS survivors, affecting mobility and activities of daily living. Critical illness and related interventions, including prolonged bed rest and overuse of sedatives and neuromuscular blocking agents during mechanical ventilation, are important risk factors for ICU-acquired weakness. Deep sedation also increases the risk of delirium in the ICU, and long-term cognitive impairment. Corticosteroids also may be used during management of ARDS, particularly in the setting of COVID-19. Corticosteroids can be associated with myopathy and muscle weakness, as well as prolonged delirium that increases the risk of long-term cognitive impairment. The optimal duration and dosage of corticosteroids remain uncertain, and there's limited long-term data on their effects on muscle weakness and cognition in ARDS survivors. In addition to physical and cognitive issues, mental health challenges, such as depression, anxiety, and post-traumatic stress disorder, are common in ARDS survivors. Strategies to address these complications emphasize the need for consistent implementation of the evidence-based ABCDEF bundle, which includes daily management of analgesia in concert with early cessation of sedatives, avoidance of benzodiazepines, daily delirium monitoring and management, early mobilization, and incorporation of family at the bedside. In conclusion, ARDS is a complex global health challenge with consequences extending beyond the acute phase. Understanding the links between critical care management and long-term consequences is vital for developing effective therapeutic strategies and improving the quality of life for ARDS survivors.

Intensive care unit interventions to promote sleep and circadian biology in reducing incident delirium: a scoping review.

RATIONALE/OBJECTIVES: Despite plausible pathophysiological mechanisms, research is needed to confirm the relationship between sleep, circadian rhythm and delirium in patients admitted to the intensive care unit (ICU). The objective of this review is to summarise existing studies promoting, in whole or in part, the normalisation of sleep and circadian biology and their impact on the incidence, prevalence, duration and/or severity of delirium in ICU. METHODS: A sensitive search of electronic databases and conference proceedings was completed in March 2023. Inclusion criteria were English-language studies of any design that evaluated in-ICU non-pharmacological, pharmacological or mixed intervention strategies for promoting sleep or circadian biology and their association with delirium, as assessed at least daily. Data were extracted and independently verified. RESULTS: Of 7886 citations, we included 50 articles. Commonly evaluated interventions include care bundles (n=20), regulation or administration of light therapy (n=5), eye masks and/or earplugs (n=5), one nursing care-focused intervention and pharmacological intervention (eg, melatonin and ramelteon; n=19). The association between these interventions and incident delirium or severity of delirium was mixed. As multiple interventions were incorporated in included studies of care bundles and given that there was variable reporting of compliance with individual elements, identifying which components might have an impact on delirium is challenging. CONCLUSIONS: This scoping review summarises the existing literature as it relates to ICU sleep and circadian disruption (SCD) and delirium in ICU. Further studies are needed to better understand the role of ICU SCD promotion interventions in delirium mitigation.

The spectrum of psychological disorders in family members of patients suffering from delirium associated with critical illness: a prospective, observational study.

During intensive care unit admission, relatives of critically ill patients can experience emotional distress. The authors hypothesized that families of patients who are diagnosed with intensive care unit (ICU) delirium experience more profound depression and anxiety disorders related to stress than do families of patients without delirium. We performed a prospective observational single-center study including families of adult patients (age above 18 years) hospitalized in a 17-bed ICU of a university hospital for at least 48 h who completed research questionnaires at day 2 after admission and day 30 after initial evaluation using dedicated questionnaires (HADS, CECS, IES, PTSD-C). A total of 98 family members of patients hospitalized in the ICU were included in the final analysis (50 family members whose relatives were CAM-ICU positive (DEL+), and 48 family members of patients without delirium (DEL-)). No statistically significant differences in demographics and psychosocial data were found between the groups. In the follow-up 30 days after the first conversation with a family member, the mean PTSD score for the relatives of patients with delirium was 11.02 (Me = 13.0; SD = 5.74), and the mean score for nondelirious patients' family members was 6.42 (Me = 5.5; SD = 5.50; p < 0.001). A statistically significant increase in IES scores for family members of patients with delirium was observed for total PTSD (p = 0.001), IES-intrusion (p < 0.001), and IES-hyperarousal (p = 0.002). The prevalence of anxiety symptoms, depression, and posttraumatic stress disorder (PTSD) was higher in families of patients diagnosed with ICU delirium within 48 h of admission to the ICU. No factors increasing the depth of these disorders in family members of patients with ICU delirium were identified. Taking appropriate actions and thus providing families with appropriate support will contribute to the understanding of unfavorable emotional states, including anxiety, stress, depression, anger, agitation, or avoidance.

Oxygen-Saturation Targets and Cognitive and Functional Outcomes in Mechanically Ventilated Adults.

Rationale: Among mechanically ventilated critically ill adults, the PILOT (Pragmatic Investigation of Optimal Oxygen Targets) trial demonstrated no difference in ventilator-free days among lower, intermediate, and higher oxygen-saturation targets. The effects on long-term cognition and related outcomes are unknown.Objectives: To compare the effects of lower (90% [range, 88-92%]), intermediate (94% [range, 92-96%]), and higher (98% [range, 96-100%]) oxygen-saturation targets on long-term outcomes.Methods: Twelve months after enrollment in the PILOT trial, blinded neuropsychological raters conducted assessments of cognition, disability, employment status, and quality of life. The primary outcome was global cognition as measured using the Telephone Montreal Cognitive Assessment. In a subset of patients, an expanded neuropsychological battery measured executive function, attention, immediate and delayed memory, verbal fluency, and abstraction.Measurements and Main Results: A total of 501 patients completed follow-up, including 142 in the lower, 186 in the intermediate, and 173 in the higher oxygen target groups. Median (interquartile range) peripheral oxygen saturation values in the lower, intermediate, and higher target groups were 94% (91-96%), 95% (93-97%), and 97% (95-99%), respectively. Telephone Montreal Cognitive Assessment score did not differ between lower and intermediate (adjusted odds ratio [OR], 1.36 [95% confidence interval (CI), 0.92-2.00]), intermediate and higher (adjusted OR, 0.90 [95% CI, 0.62-1.29]), or higher and lower (adjusted OR, 1.22 [95% CI, 0.83-1.79]) target groups. There was also no difference in individual cognitive domains, disability, employment, or quality of life.Conclusions: Among mechanically ventilated critically ill adults who completed follow-up at 12 months, oxygen-saturation targets were not associated with cognition or related outcomes.

Data-derived subtypes of delirium during critical illness.

BACKGROUND: To understand delirium heterogeneity, prior work relied on psychomotor symptoms or risk factors to identify subtypes. Data-driven approaches have used machine learning to identify biologically plausible, treatment-responsive subtypes of other acute illnesses but have not been used to examine delirium. METHODS: We conducted a secondary analysis of a large, multicenter prospective cohort study involving adults in medical or surgical ICUs with respiratory failure or shock who experienced delirium per the Confusion Assessment Method for the ICU. We used data collected before delirium diagnosis in an unsupervised latent class model to identify delirium subtypes and then compared demographics, clinical characteristics, and outcomes between subtypes in the final model. FINDINGS: The 731 patients who developed delirium during critical illness had a median age of 63 [IQR, 54-72] years, a median Sequential Organ Failure Assessment score of 8.0 [6.0-11.0] and 613 [83.4%] were mechanically ventilated at delirium identification. A four-class model best fit the data with 50% of patients in subtype (ST) 1, 18% in subtype 2, 17% in subtype 3, and 14% in subtype 4. Subtype 2-which had more shock and kidney impairment-had the highest mortality (33% [ST2] vs. 17% [ST1], 25% [ST3], and 17% [ST4], p = 0.003). Subtype 4-which received more benzodiazepines and opioids-had the longest duration of delirium (6 days [ST4] vs. 3 [ST1], 4 [ST2], and 3 days [ST3], p < 0.001) and coma (4 days [ST4] vs. 2 [ST1], 1 [ST2], and 2 days [ST3], p < 0.001). Each of the four data-derived delirium subtypes was observed within previously identified psychomotor and risk factor-based delirium subtypes. Clinically significant cognitive impairment affected all subtypes at follow-up, but its severity did not differ by subtype (3-month, p = 0.26; 12-month, p = 0.80). INTERPRETATION: The four data-derived delirium subtypes identified in this study should now be validated in independent cohorts, examined for differential treatment effects in trials, and inform mechanistic work evaluating treatment targets. FUNDING: National Institutes of Health (T32HL007820, R01AG027472).

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. Objective: To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. Design, Setting, and Participants: An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Interventions: Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Main Outcomes and Measures: Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. Results: A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. Conclusions and Relevance: The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. Trial Registration: ClinicalTrials.gov Identifier: NCT01211522.

In-hospital catatonia, delirium, and coma and mortality: Results from the delirium and catatonia prospective cohort investigation.

BACKGROUND: Catatonia, a form of acute brain dysfunction typically linked with severe affective and psychotic disorders, occurs in critical illness with delirium and coma. Delirium and coma are associated with mortality, though catatonia's relationship with mortality is unclear. We aim to describe whether catatonia, delirium, and coma are associated with mortality. METHODS: We enrolled a convenience cohort of critically ill adults (N = 378) at an academic medical center. We assessed catatonia, delirium, and coma using the Bush-Francis Catatonia Rating Scale, the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale, respectively. We tested the associations between previous day brain dysfunction state occurrence with in-hospital and one-year mortality using multivariable time-dependent risk models. Additionally, we tested the association between brain dysfunction duration and one-year mortality. RESULTS: Catatonia was not associated with death on the day after diagnosis during hospitalization, and neither previous catatonia occurrence nor duration was associated with one-year mortality. Delirium was not associated with death on any day following diagnosis during hospitalization, and neither previous delirium occurrence nor duration was associated with one-year mortality. The occurrence of coma was associated with death on any day after diagnosis during hospitalization (HR 2.30,CI 1.19-4.44,p = 0.014), as well as through one year following hospital discharge (HR 1.68,CI 1.09-2.59,p = 0.02). CONCLUSIONS: Coma, but neither catatonia nor delirium, was associated with future day in-hospital and one-year mortality. More research is needed to understand catatonia's clinical impact. Delirium results differ from existing literature likely due to cohort demographics and size. Coma results highlight the prognostic significance of suppressed arousal while critically ill.

Holistic care in healthy aging: Caring for the wholly and holy human.

Health care should address the holistic gap between health outcomes, spirituality, religion, and humanistic care to optimize patient care. Treating the whole person encompasses both physical and metaphysical elements. Patients want health care professionals to recognize their spiritual and religious preferences, because these matter in their approach to illness, coping, and long-term outcomes.

Correlation of the Critical Care Pain Observation Tool and Numeric Rating Scale in Intensive Care Unit Patients.

PURPOSE: We sought to determine the correlation between the Numeric Rating Scale (NRS) and Critical-Care Pain Observation Tool (CPOT) to determine whether clinical factors modified the relationship between NRS and CPOT assessments. MATERIALS AND METHODS: We included nonventilated adults admitted to the MICU or SICU who could self-report pain and had at least 3 paired NRS and CPOT assessments. We performed Spearman correlation to assess overall correlation and performed proportional odds logistic regression to evaluate whether the relationship between NRS and CPOT assessments was modified by clinical factors. RESULTS: Nursing staff performed NRS and CPOT assessments every 4 h in 1302 patients, leading to 61,142 matched assessments. We found that the NRS and CPOT have a Spearman correlation coefficient of 0.56 and an intraclass correlation coefficient of 0.32 in intensive care unit patients. Factors that modified the relationship between the NRS and CPOT included the presence of delirium (P < .001) and lower mean daily Richmond Agitation Sedation Scale (<0.001). CONCLUSIONS: The correlation coefficient between the NRS and the CPOT was found to be 0.56. The presence of delirium, decreased level of arousal, modified the relationship between the NRS and CPOT. Self-reported and behavioral pain assessments cannot be used interchangeably in critically ill adults.

Designer Fat Cells: Adipogenic Differentiation of CRISPR-Cas9 Genome-Engineered Induced Pluripotent Stem Cells.

Adipose tissue is an active endocrine organ that can signal bidirectionally to many tissues and organ systems in the body. With obesity, adipose tissue is a source of low-level inflammation that contributes to various co-morbidities and damage to downstream effector tissues. The ability to synthesize genetically engineered adipose tissue could have critical applications in studying adipokine signaling and the use of adipose tissue for novel therapeutic strategies. This study aimed to develop a method for non-viral adipogenic differentiation of genome-edited murine induced pluripotent stem cells (iPSCs) and to test the ability of such cells to engraft in mice in vivo . Designer adipocytes were created from iPSCs, which can be readily genetically engineered using CRISPR-Cas9 to knock out or insert individual genes of interest. As a model system for adipocyte-based drug delivery, an existing iPSC cell line that transcribes interleukin 1 receptor antagonist under the endogenous macrophage chemoattractant protein-1 promoter was tested for adipogenic capabilities under these same differentiation conditions. To understand the role of various adipocyte subtypes and their impact on health and disease, an efficient method was devised for inducing browning and whitening of IPSC-derived adipocytes in culture. Finally, to study the downstream effects of designer adipocytes in vivo , we transplanted the designer adipocytes into fat-free lipodystrophic mice as a model system for studying adipose signaling in different models of disease or repair. This novel translational tissue engineering and regenerative medicine platform provides an innovative approach to studying the role of adipose interorgan communication in various conditions.