P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates.

The transcription cycle of RNA polymerase II (Pol II) is regulated at discrete transition points by cyclin-dependent kinases (CDKs). Positive transcription elongation factor b (P-TEFb), a complex of Cdk9 and cyclin T1, promotes release of paused Pol II into elongation, but the precise mechanisms and targets of Cdk9 action remain largely unknown. Here, by a chemical genetic strategy, we identified ∼ 100 putative substrates of human P-TEFb, which were enriched for proteins implicated in transcription and RNA catabolism. Among the RNA processing factors phosphorylated by Cdk9 was the 5'-to-3' "torpedo" exoribonuclease Xrn2, required in transcription termination by Pol II, which we validated as a bona fide P-TEFb substrate in vivo and in vitro. Phosphorylation by Cdk9 or phosphomimetic substitution of its target residue, Thr439, enhanced enzymatic activity of Xrn2 on synthetic substrates in vitro. Conversely, inhibition or depletion of Cdk9 or mutation of Xrn2-Thr439 to a nonphosphorylatable Ala residue caused phenotypes consistent with inefficient termination in human cells: impaired Xrn2 chromatin localization and increased readthrough transcription of endogenous genes. Therefore, in addition to its role in elongation, P-TEFb regulates termination by promoting chromatin recruitment and activation of a cotranscriptional RNA processing enzyme, Xrn2.

Identification of Presymptomatic and Asymptomatic Cases Using Cohort-Based Testing Approaches at a Large Correctional Facility-Chicago, Illinois, USA, May 2020.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to cause significant morbidity and mortality worldwide. Correctional and detention facilities are at high risk of experiencing outbreaks. We aimed to evaluate cohort-based testing among detained persons exposed to laboratory-confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to identify presymptomatic and asymptomatic cases. METHODS: During 1-19 May 2020, 2 testing strategies were implemented in 12 tiers or housing units of the Cook County Jail, Chicago, Illinois. Detained persons were approached to participate in serial testing (n = 137) and offered tests at 3 time points over 14 days (day 1, days 3-5, and days 13-14). The second group was offered a single test and interview at the end of a 14-day quarantine period (day 14 group) (n = 87). RESULTS: 224 detained persons were approached for participation and, of these, 194 (87%) participated in ≥1 interview and 172 (77%) had ≥1 test. Of the 172 tested, 19 were positive for SARS-CoV-2. In the serial testing group, 17 (89%) new cases were detected, 16 (84%) on day 1, 1 (5%) on days 3-5, and none on days 13-14; in the day 14 group, 2 (11%) cases were identified. More than half (12/19; 63%) of the newly identified cases were presymptomatic or asymptomatic. CONCLUSIONS: Our findings highlight the utility of cohort-based testing promptly after initiating quarantine within a housing tier. Cohort-based testing efforts identified new SARS-CoV-2 asymptomatic and presymptomatic infections that may have been missed by symptom screening alone.

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.

p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.

Despite the high and preferential expression of p38γ MAPK in the myocardium, little is known about its function in the heart. The aim of the current study was to elucidate the physiologic and biochemical roles of p38γ in the heart. Expression and subcellular localization of p38 isoforms was determined in mouse hearts. Comparisons of the cardiac function and structure of wild-type and p38γ knockout (KO) mice at baseline and after abdominal aortic banding demonstrated that KO mice developed less ventricular hypertrophy and that contractile function is better preserved. To identify potential substrates of p38γ, we generated an analog-sensitive mutant to affinity tag endogenous myocardial proteins. Among other proteins, this technique identified calpastatin as a direct p38γ substrate. Moreover, phosphorylation of calpastatin by p38γ impaired its ability to inhibit the protease, calpain. We have identified p38γ as an important determinant of the progression of pathologic cardiac hypertrophy after aortic banding in mice. In addition, we have identified calpastatin, among other substrates, as a novel direct target of p38γ that may contribute to the protection observed in p38γKO mice.-Loonat, A. A., Martin, E. D., Sarafraz-Shekary, N., Tilgner, K., Hertz, N. T., Levin, R., Shokat, K. M., Burlingame, A. L., Arabacilar, P., Uddin, S., Thomas, M., Marber, M. S., Clark, J. E. p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin.

Network Characteristics and Visualization of COVID-19 Outbreak in a Large Detention Facility in the United States - Cook County, Illinois, 2020.

Correctional and detention facilities have been disproportionately affected by coronavirus disease 2019 (COVID-19) because of shared space and movement of staff members and detained persons within facilities (1,2). During March 1-April 30, 2020, at Cook County Jail in Chicago, Illinois, >900 COVID-19 cases were diagnosed across all 10 housing divisions, representing 13 unique buildings.† Movement within the jail was examined through network analyses and visualization, a field that examines elements within a network and the connections between them. This methodology has been used to supplement contact tracing investigations for tuberculosis and to understand how social networks contribute to transmission of sexually transmitted infections (3-5). Movements and connections of 5,884 persons (3,843 [65%] detained persons and 2,041 [35%] staff members) at the jail during March 1-April 30 were analyzed. A total of 472 (12.3%) COVID-19 cases were identified among detained persons and 198 (9.7%) among staff members. Among 103,701 shared-shift connections among staff members, 1.4% occurred between persons with COVID-19, a percentage that is significantly higher than the expected 0.9% by random occurrence alone (p<0.001), suggesting that additional transmission occurred within this group. The observed connections among detained persons with COVID-19 were significantly lower than expected (1.0% versus 1.1%, p<0.001) when considering only the housing units in which initial transmission occurred, suggesting that the systematic isolation of persons with COVID-19 is effective at limiting transmission. A network-informed approach can identify likely points of high transmission, allowing for interventions to reduce transmission targeted at these groups or locations, such as by reducing convening of staff members, closing breakrooms, and cessation of contact sports.

An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases.

Reliable quantitation of protein abundances in defined sets of cellular proteins is critical to numerous biological applications. Traditional immunodetection-based methods are limited by the quality and availability of specific antibodies, especially for site-specific post-translational modifications. Targeted proteomic methods, including the recently developed parallel reaction monitoring (PRM) mass spectrometry, have enabled accurate quantitative measurements of up to a few hundred specific target peptides. However, the degree of practical multiplexing in label-free PRM workflows remains a significant limitation for the technique. Here we present a strategy for significantly increasing multiplexing in label-free PRM that takes advantage of the superior separation characteristics and retention time stability of meter-scale monolithic silica-C18 column-based chromatography. We show the utility of the approach in quantifying kinase abundances downstream of previously developed active kinase enrichment methodology based on multidrug inhibitor beads. We examine kinase activation dynamics in response to three different MAP kinase inhibitors in colorectal carcinoma cells and demonstrate reliable quantitation of over 800 target peptides from over 150 kinases in a single label-free PRM run. The kinase activity profiles obtained from these analyses reveal compensatory activation of TGF-ß family receptors as a response to MAPK blockade. The gains achieved using this label-free PRM multiplexing strategy will benefit a wide array of biological applications.

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen.

TGF-ß activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPase-activating protein (GAP) enzymes, and is exclusive to membrane-localized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

Cholesterol levels in fragile X syndrome.

Fragile X syndrome (FXS) is associated with intellectual disability and behavioral dysfunction, including anxiety, ADHD symptoms, and autistic features. Although individuals with FXS are largely considered healthy and lifespan is not thought to be reduced, very little is known about the long-term medical health of adults with FXS and no systematically collected information is available on standard laboratory measures from metabolic screens. During the course of follow up of a large cohort of patients with FXS we noted that many patients had low cholesterol and high density lipoprotein (HDL) values and thus initiated a systematic chart review of all cholesterol values present in charts from a clinic cohort of over 500 patients with FXS. Total cholesterol (TC), low density lipoprotein (LDL) and HDL were all significantly reduced in males from the FXS cohort relative to age-adjusted population normative data. This finding has relevance for health monitoring in individuals with FXS, for treatments with cholesterol-lowering agents that have been proposed to target the underlying CNS disorder in FXS based on work in animal models, and for potential biomarker development in FXS.

Paediatrician knowledge, attitudes, and counselling patterns on teen driving.

BACKGROUND: Motor vehicle crashes (MVCs) are the leading cause of death among teenagers. Little is known about the content of US paediatrician counselling about teen driving. OBJECTIVE: To examine US paediatrician knowledge, attitudes, and counselling patterns regarding teen driving. METHODS: A random sample questionnaire was mailed to American Academy of Pediatrics members in 2009 (n=1606; response=875 (55%)). Analysis was limited to 596 paediatricians who provide adolescent checkups. Questions addressed counselling and attitudes towards roles in promoting safe driving. Logistic regression assessed the relationship between counselling topics and practice characteristics. RESULTS: Most (89%) respondents provide some counselling about driving. Two topics commonly discussed by paediatricians were seatbelts (87%) and alcohol use (82%). Less frequently discussed were: cell phones (47%), speeding (43%), and dangers of transporting teen passengers (41%). Topics rarely discussed were: night driving (21%), graduated driver licensing laws (13%), safe cars (9%), driver education (9%), fatigue (25%), and parental limit setting (23%). Only 10% ever recommend a parent-teen driver agreement. Paediatricians who had a patient injured or killed in an MVC were more likely to discuss night driving (OR=2.86). Physicians caring for a high proportion of adolescents (OR=1.83) or patients with private insurance (OR=1.85) counsel more about the risks of driving with teen passengers. CONCLUSIONS: Paediatricians in the USA support counselling on teen driving during routine office visits, but omit many important risk factors. Few recommend parent-teen driver agreements. Methods that help clinicians efficiently and effectively counsel families about teen driving should be developed.

Real-World Therapy Management and Outcomes of First-Line Axitinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma in the United States.

Background: Combination axitinib plus pembrolizumab is a standard of care in the first-line treatment of patients with advanced clear cell renal cell carcinoma (RCC). This analysis describes the clinical characteristics, treatment management and outcomes of patients receiving first-line (1L) axitinib plus pembrolizumab in a real-world US setting. Methods: Electronic health record (EHR)-derived data from the Flatiron Health Database, which includes ~280 cancer clinics across 800 sites in the US, were used. Patients had confirmed Stage IV or metastatic RCC and initiated 1L axitinib plus pembrolizumab on or after 1/1/2018 to 3/31/2021. Outcomes were best overall response rate; real-world progression-free survival (rwPFS) and overall survival (OS) at landmark time periods (3, 6, 9, and 12 months). Therapy management (TM) included dose hold, dose change and discontinuation. Data are reported as medians (IQR) unless otherwise noted. Results: 355 patients received 1L axitinib plus pembrolizumab, with median follow-up of 9.7 (0.1-24.3) months. IMDC Risk Score was favorable, intermediate, and poor in 27 (7.6%), 126 (35.5%), and 76 (21.4%) patients, respectively (23.4% intermediate/poor, 12.1% unknown). 270 patients (76.1%) received only 1L axitinib plus pembrolizumab and 85 patients (24.3%) received ≥1 subsequent line of treatment; cabozantinib was the most frequent subsequent line of treatment (47.9%). rwPFS at 3 months and 1 year was 77.2% and 39.3%, respectively. OS ranged from 90.8% at 3 months to 73.5% at 1 year. Best overall response rate was 47.9%. Toxicity was the most common reason for first TM events of dose hold, change and discontinuation at, 58.6%, 58.5%, and 45.8%, respectively. Over 80% of patients with TM were able to continue with 1L axitinib plus pembrolizumab. Conclusions: In a real-world setting, axitinib plus pembrolizumab was effective as a 1L treatment for patients with advanced RCC. Dose holds, changes and discontinuation were driven by treatment-related toxicity. Dose holds may represent an effective TM strategy to toxicity.

In vivo residue-specific histone methylation dynamics.

Methylation of specific histone residues is capable of both gene activation and silencing. Despite vast work on the function of methylation, most studies either present a static snapshot of methylation or fail to assign kinetic information to specific residues. Using liquid chromatography-tandem mass spectrometry on a high-resolution mass spectrometer and heavy methyl-SILAC labeling, we studied site-specific histone lysine and arginine methylation dynamics. The detection of labeled intermediates within a methylation state revealed that mono-, di-, and trimethylated residues generally have progressively slower rates of formation. Furthermore, methylations associated with active genes have faster rates than methylations associated with silent genes. Finally, the presence of both an active and silencing mark on the same peptide results in a slower rate of methylation than the presence of either mark alone. Here we show that quantitative proteomic approaches such as this can determine the dynamics of multiple methylated residues, an understudied portion of histone biology.

Treatment patterns and sequencing in patients with rheumatic diseases: a retrospective claims data analysis.

OBJECTIVES: Long-term real-world management of inflammatory rheumatic diseases remains unclear, especially with the advent of new treatment options. This study characterizes the number of advanced treatments used by patients with selected rheumatic diseases (rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing spondylitis, juvenile idiopathic arthritis) and provides a contemporary portrait of treatment patterns and therapeutic sequencing among patients with RA and PsA. METHOD: Patients were selected from a large US claims database and classified into disease subsamples based on the latest rheumatic diagnosis recorded before/on the day of initiation of the first advanced treatment (index date). The total number of advanced treatments was assessed within the first 5 years following the index date. Treatment patterns and therapeutic sequencing were assessed over the first 2 years. RESULTS: Approximately 20% of patients received ≥2 distinct advanced treatments during the first year following index date - the proportion increased to almost 50% among patients with 5 years of observation. Most patients (RA: 76.8%; PsA: 88.7%) initiated a tumor necrosis factor as the first advanced treatment. Over the first 2 years after the index date, 1/3 of RA and PsA patients switched to another advanced treatment. More than 50% initiated a second treatment with the same mechanism of action (MOA). A small proportion of patients received a biosimilar. CONCLUSION: Despite advent of treatments with different MOA, cycling between treatments with the same MOA was common. Further studies with longer data follow-up would be needed to assess the impact of higher adoption of biosimilars on treatment patterns/sequencing.

Community-engaged research to develop a Chicago violence research agenda and recommendations to support future community engagement.

BACKGROUND: Chicago has a history of gun violence with some neighborhoods, particularly Black and Brown communities, being disproportionately affected and Black male youth experiencing an even more disparate impact. Too often, violence prevention research is developed and carried out with little or no input from the people living in the most affected communities. The objective of the Community-Academic Collaboration to Prevent Violence in Chicago (CACPVC) was to bring together individuals from impacted communities with academic researchers and other community stakeholders to discuss violence and co-create a research agenda that addresses topics of mutual concern, and recommendations for engaging stakeholders including community members and organizations and funders in violence and violence prevention research. METHODS: From 2014 to 2015, community members and organizations from seven defined regions across Chicago were recruited to participate. An organization network gathering was held in each region for researchers, funders, and community organization representatives to discuss violence prevention. Open community forums then took place in each community. Violence data by region was shared followed by facilitated group discussions that were recorded by youth scribes. Notes were thematically coded, grouped, and compiled after which a list of topics was refined by the CACPVC Work Group, allowing for investigator triangulation. A survey was disseminated to community stakeholders to prioritize the topics. RESULTS: Seven network gatherings (127 attendees) and community forums (133 attendees) were held. Topic areas identified during the gatherings and forums included root causes/cycle of violence, racism and bias/structural violence, trajectory of violence, protective factors and nonviolence, geographic pattern change, violence prevention strategies, youth, family factors, community factors, school, police, gangs/street organizations, and media and public perceptions. Recommendations to support community engagement were grouped as role of research in reducing violence, role of community in violence research, relationships and respect, academic-community communication, financial considerations, training, practical considerations, research design, sharing results, communication about and use of data, and recommendations for funders. CONCLUSIONS: The violence research agenda will be used to inform community-engaged violence prevention research. The recommendations for community engagement provide a resource for researchers about topics to consider to meaningfully engage community members in future research.

COVID-19 in Pediatric Patients: Observations from the Initial Phase of the Global Pandemic in Rhode Island.

OBJECTIVE: To describe characteristics of children undergoing SARS-CoV-2 testing during the initial wave of infections in Rhode Island. METHODS: This is a descriptive study of 729 children tested for SARS-CoV-2 at four emergency departments April 9 to May 7, 2020 in Rhode Island. Demographic information and symptoms were cataloged for those tested. RESULTS: 81 (11%) children tested positive for SARS-CoV-2. 94% of positive children were symptomatic. 74% of positive cases had constitutional symptoms and 72% had upper respiratory symptoms. While only 34% of those tested were Hispanic, 68% of the SARS-CoV-2- positive cases occurred in Hispanic children. CONCLUSION: This study details the pediatric population's experience during the first wave of the pandemic in Rhode Island. It could inform testing allocation strategies in healthcare settings. It also highlights vulnerable populations in need of further public health support in our state.

Outbreak of COVID-19 and interventions in a large jail - Cook County, IL, United States, 2020.

BACKGROUND: Correctional and detention facilities are disproportionately affected by COVID-19 due to shared space, contact between staff and detained persons, and movement within facilities. On March 18, 2020, Cook County Jail, one of the United States' largest, identified its first suspected case of COVID-19 in a detained person. METHODS: This analysis includes SARS-CoV-2 cases confirmed by molecular detection among detained persons and Cook County Sheriff's Office staff. We examined occurrence of symptomatic cases in each building and proportions of asymptomatic detained persons testing positive, and timing of interventions including social distancing, mask use, and expanded testing and show outbreak trajectory in the jail compared to case counts in Chicago. RESULTS: During March 1-April 30, 907 symptomatic and asymptomatic cases of SARS-CoV-2 infection were detected among detained persons (n = 628) and staff (n = 279). Among asymptomatic detained persons in quarantine, 23.6% tested positive. Programmatic activity and visitation stopped March 9, cells were converted into single occupancy beginning March 26, and universal masking was implemented for staff (April 2) and detained persons (April 13). Cases at the jail declined while cases in Chicago increased. DISCUSSION/CONCLUSIONS: Aggressive intervention strategies coupled with widespread diagnostic testing of detained and staff populations can limit introduction and mitigate transmission of SARS-CoV-2 infection in correctional and detention facilities.

Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells.

Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.

Phosphoregulation of the oncogenic protein regulator of cytokinesis 1 (PRC1) by the atypical CDK16/CCNY complex.

CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that forms an active complex with cyclin Y (CCNY). Although both proteins have been recently implicated in cancer pathogenesis, it is still unclear how the CDK16/CCNY complex exerts its biological activity. To understand the CDK16/CCNY network, we used complementary proteomic approaches to identify potential substrates of this complex. We identified several candidates implicating the CDK16/CCNY complex in cytoskeletal dynamics, and we focused on the microtubule-associated protein regulator of cytokinesis (PRC1), an essential protein for cell division that organizes antiparallel microtubules and whose deregulation may drive genomic instability in cancer. Using analog-sensitive (AS) CDK16 generated by CRISPR-Cas9 mutagenesis in 293T cells, we found that specific inhibition of CDK16 induces PRC1 dephosphorylation at Thr481 and delocalization to the nucleus during interphase. The observation that CDK16 inhibition and PRC1 downregulation exhibit epistatic effects on cell viability confirms that these proteins can act through a single pathway. In conclusion, we identified PRC1 as the first substrate of the CDK16/CCNY complex and demonstrated that the proliferative function of CDK16 is mediated by PRC1 phosphorylation. As CDK16 is emerging as a critical node in cancer, our study reveals novel potential therapeutic targets.

Refusal of Vitamin K Injection: Survey of the Current Literature and Practical Tips for Pediatricians.

Vitamin K refusal and associated sequelae of vitamin K deficiency bleed (VKDB) in the newborn period is becoming a more common occurrence. We present six recent cases from a 4-month period in 2017 of parent refusal of vitamin K and describe the reasons for refusal and the clinical outcomes of these infants. There have been a number of case reports citing the rising incidence of VKDB and the reasons why parents refuse. However, there is a gap in the literature and clinical practice guidelines describing how a physician should approach a refusal in the hospital and in the office, and the need to report a refusal to child welfare. In addition, we describe a scenario in which the caregivers provide a religious reason for refusal of vitamin K that, to the best of our knowledge, has yet to be cited in the literature. [Pediatr Ann. 2018;47(8):e334-e338.].

Discovery of new substrates of the elongation factor-2 kinase suggests a broader role in the cellular nutrient response.

Elongation Factor-2 Kinase (eEF2K) in an unusual mammalian enzyme that has one known substrate, elongation factor-2. It belongs to a class of kinases, called alpha kinases, that has little sequence identity to the >500 conventional protein kinases, but performs the same reaction and has similar catalytic residues. The phosphorylation of eEF2 blocks translation elongation, which is thought to be critical to regulating cellular energy usage. Here we report a system for discovering new substrates of alpha kinases and identify the first new substrates of eEF2K including AMPK and alpha4, and determine a sequence motif for the kinase that shows a requirement for threonine residues as the target of phosphorylation. These new substrates suggest that eEF2K has a more diverse role in regulating cellular energy usage that involves multiple pathways and regulatory feedback.

The cognitive, emotional, and social sequelae of stroke: psychological and ethical concerns in post-stroke adaptation.

In the clinical domain, ethical analyses involve examination of complex individual responses, psychological processes, and social context. Psychological aspects of stroke adaptation include the risk for depression and anxiety, changes in identity and personality processes, and potential for social isolation. Depression and anxiety are heterogeneous constructs and can affect individuals' emotional functioning and cognitive abilities. Executive function, self-agency, and volition may be affected. Alterations in identity and personality may also result from the interaction of fluctuating emotional, cognitive, and physical abilities as well as from changes in social context and family dynamics. Social isolation, or lack of access to social contact or resources, can be a consequence of difficulties in cognitive and emotional function that influence interpersonal relationships, changes in social roles, communication difficulties, and challenges in transportation and employment. Social stigma and marginalization also contribute to isolation. The authors describe these psychological phenomena in the context of brain damage and recovery and raise ethical concerns including impact on decision-making capacity, pre- and postinjury selves and interests, and the social milieu in which strokes are experienced.