Del Nido cardioplegia or potassium induces Nrf2 and protects cardiomyocytes against oxidative stress.

Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We addressed here whether cardioplegia essential for cardiopulmonary bypass surgery activates Nrf2, a transcription factor regulating the expression of antioxidant and detoxification genes. With commonly used cardioplegic solutions, high K+, low K+, Del Nido (DN), histidine-tryptophan-ketoglutarate (HTK), and Celsior (CS), we found that DN caused a significant increase of Nrf2 protein in AC16 human cardiomyocytes. Tracing the ingredients in DN led to the discovery of KCl at the concentration of 20-60 mM capable of significant Nrf2 protein induction. The antioxidant response element (ARE) luciferase reporter assays confirmed Nrf2 activation by DN or KCl. Transcriptomic profiling using RNA-seq revealed that oxidation-reduction as a main gene ontology group affected by KCl. KCl indeed elevated the expression of classical Nrf2 downstream targets, including TXNRD1, AKR1C, AKR1B1, SRXN1, and G6PD. DN or KCl-induced Nrf2 elevation is Ca2+ concentration dependent. We found that KCl decreased Nrf2 protein ubiquitination and extended the half-life of Nrf2 from 17.8 to 25.1 mins. Knocking out Keap1 blocked Nrf2 induction by K+. Nrf2 induction by DN or KCl correlates with the protection against reactive oxygen species generation or loss of viability by H2O2 treatment. Our data support that high K+ concentration in DN cardioplegic solution can induce Nrf2 protein and protect cardiomyocytes against oxidative damage.NEW & NOTEWORTHY Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We report here that Del Nido cardioplegic solution or potassium is an effective inducer of Nrf2 transcription factor, which controls the antioxidant and detoxification response. This indicates that Del Nido solution is not only essential for open heart surgery but also exhibits cardiac protective activity.

Identification of the Aß37/42 peptide ratio in CSF as an improved Aß biomarker for Alzheimer's disease.

INTRODUCTION: Identifying CSF-based biomarkers for the ß-amyloidosis that initiates Alzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. METHODS: We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid ß-protein and identified a novel biomarker, the Aß 37/42 ratio, that outperforms the canonical Aß42/40 ratio as a means to evaluate the γ-secretase activity and brain Aß accumulation. RESULTS: We show that Aß 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD. DISCUSSION: We conclude that the Aß 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aß42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD.

Predictors of Substance Abuse Assessment and Treatment Completion for Parents Involved with Child Welfare: One State's Experience in Matching across Systems.

To date, few studies have examined the effect of interagency collaboration on substance abuse assessment ity of Southern California and treatment completion for parents who are involved in child welfare. The purpose of this paper is to: (1) describe a statewide, interagency collaborative program aimed at providing targeted substance abuse assessment and treatment to parents engaged in the child welfare system; (2) document the specialized assessment and treatment outcomes for parents engaged through this collaborative program; and (3) determine factors related to successful treatment completion for parents involved in the child welfare system. This is a retrospective study of an open cohort of 13,829 individuals admitted to the New Jersey Child Protection Substance Abuse Initiative (CPSAI) program from October 1, 2009, through September 30, 2010. Data were drawn from two unique administrative data sources. Multivariate Cox regression models were used to explore factors related to successfil treatment completion for parents involved in the child welfare system. Trend analysis for the total sample in the CPSAI program revealed that, of the 10,909 individuals who received a CPSAI assessment, 59% were referred to treatment. Of those referred to treatment, 40% enrolled in a treatment program. Once enrolled in a treatment program, 55% completed or were in the process of completing substance abuse treatment. These findings suggest that when adequate screening and treatment is available through a streamlined process, many of the ethnic and gender disparities present among other populations of individuals seeking treatment are minimized. Utilizing inherent child welfare case factors appears to be an important motivating element that aids parents during the assessment and treatment process.

Organizational implementation of evidence-based substance abuse treatment in racial and ethnic minority communities.

We evaluated organizational factors associated with the implementation of contingency management treatment (CMT) and medication-assisted treatment (MAT) in substance abuse treatment (SAT) programs serving racial and ethnic minority communities. Analysis of cross-sectional data collected in 2010-2011 from a random sample of 148 publicly funded SAT programs showed that accepting private insurance was positively associated with CMT and MAT implementation, whereas larger programs were associated with greater implementation of MAT. Supervisorial openness to and expectations about implementing evidence-based practices (EBPs) and attributes for change were strongly associated with CMT, whereas the interactions between openness to EBPs and programs that accept private insurance and that are governed by parent organizations were positively associated with MAT. These external expectations and managerial attitudes supported the implementation of psychosocial and pharmacotherapy treatments in SAT. Implications for improving standards of care in minority communities are discussed.

Arthroscopic assisted brachial plexus catheter placement: an alternative to the percutaneous interscalene approach.

Background: Brachial plexus catheter placement at the interscalene level is beneficial for shoulder analgesia but presents logistical challenges due to the superficial nature of the plexus at this level, increased patient movement in the neck, and therefore higher likelihood for catheter dislodgement. Methods: Patients requiring shoulder arthroscopy and suprascapular nerve decompression were identified. Under arthroscopic guidance, a catheter was placed percutaneously into the scalene medius muscle next to the suprascapular nerve and the upper trunk of the brachial plexus. Patients were followed postoperatively for perioperative analgesic outcomes. Results: Ten patients were identified and consented for intraoperative brachial plexus catheter placement. Patient demographics and surgical details were determined. Postoperative adjunctive pain management and pain scores were variable. Two patients required catheter replacement using ultrasound guidance in the perioperative anesthesia care unit due to poorly controlled pain. There were no incidents of catheter failure due to dislodgement. Discussion: This study presents the first description of arthroscopically-assisted brachial plexus catheter placement. This method may present an alternative to traditional ultrasound guided interscalene catheter placement. Further study is needed to determine if analgesic outcomes, block success, and dislodgement rates are improved with this method.

A case report and anesthetic implications of situs inversus totalis in video-assisted thoracoscopic pulmonary resection.

Introduction and importance: Reports are limited on video-assisted thoracoscopic surgery for lung malignancy of patients with situs inversus totalis (SIT). Patients with SIT have significant anatomic differences with implications that are important for surgery, anesthesia, and nursing to understand in order to provide care for this patient population. Case presentation: A 64-year-old man with SIT and lung adenocarcinoma needed flexible bronchoscopy and wedge resection of a 9×8 mm adenocarcinoma in the right upper lobe and underwent video-assisted thoracoscopic surgery. Clinical discussion: Preoperative planning, including collaboration with the surgical team, allowed safe monitoring, induction of anesthesia, and airway isolation in this patient allowing them to have successful resection of their pulmonary malignancy. Postoperative care was enhanced by detailed communication and understanding of the patient's anatomy and implications of this condition for post anesthesia care unit nursing care. Conclusion: Patients with rare clinical conditions and backgrounds may require surgical and anesthetic intervention. The authors describe important anesthetic considerations of preoperative evaluation, airway management, cardiac monitoring, and vascular access that should be noted and taken into account for patients with SIT. Proper preparation, planning, and communication allow for patients with SIT to safely undergo surgical procedures.

Patterns of Violence Exposure and Substance Use among Child Welfare Involved Youth.

Emerging research suggests an association between exposure to violence, specifically indirect forms, and substance use among youth involved in the child welfare (CW) system. However, this has only been recently and tentatively explored. This study examined the associations among various forms of indirect violence exposure and substance use among subgroups of youth involved in the CW system. The analytic sample consisted of participants (aged 11 years or older) in the baseline year of the second National Survey of Child and Adolescent Well-Being (2008-2012), including youth and their caregivers. Latent class analysis was used to examine associations among distinct forms of indirect violence exposure and substance use and the potential identification of unique at-risk groups. Models for the overall sample suggested two classes of at-risk youth, with the higher-risk class having higher probabilities of alcohol, marijuana, and hard drug use, which coincided with higher probabilities of exposure to arrests, stealing, drug deals, and weapon use. However, stratified models suggested unique results for youth aged 13-14 and 15-17, suggesting that the confluence of these risks appears to differ developmentally. Prevention and intervention services for CW-involved youth should assess and address violence exposure types among youth as a potential opportunity to mitigate substance use and subsequent high-risk behavior.

Elevated ganglioside GM2 activator (GM2A) in human brain tissue reduces neurite integrity and spontaneous neuronal activity.

BACKGROUND: Alzheimer's Disease (AD) affects millions globally, but therapy development is lagging. New experimental systems that monitor neuronal functions in conditions approximating the AD brain may be beneficial for identifying new therapeutic strategies. METHODS: We expose cultured neurons to aqueous-soluble human brain extract from 43 individuals across a spectrum of AD pathology. Multi-electrode arrays (MEAs) and live-cell imaging were used to assess neuronal firing and neurite integrity (NI), respectively, following treatments of rat cortical neurons (MEA) and human iPSC-derived neurons (iN) with human brain extracts. RESULTS: We observe associations between spontaneous activity and Aß42:40 levels, between neurite integrity and oligomeric Aß, and between neurite integrity and tau levels present in the brain extracts. However, these associations with Aß and tau do not fully account for the effects observed. Proteomic profiling of the brain extracts revealed additional candidates correlated with neuronal structure and activity. Neurotoxicity in MEA and NI assays was associated with proteins implicated in lysosomal storage disorders, while neuroprotection was associated with proteins of the WAVE regulatory complex controlling actin cytoskeleton dynamics. Elevated ganglioside GM2 activator (GM2A) associates with reductions in both NI and MEA activity, and cell-derived GM2A alone is sufficient to induce a loss of neurite integrity and a reduction in neuronal firing. CONCLUSIONS: The techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors in the human brain and provide insights into proteins potentially contributing to AD pathogenesis.

Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors.

We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aß and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.

A Swedish national study: Immigrant-country of birth status and child welfare compulsory care among a sample of parents with risky substance use.

BACKGROUND: Sweden has a high percentage of foreign-born residents (18.5 %) and one of the highest overdose death rates in Europe. For immigrant parents with risky substance use (RSU), risk factors associated with immigration status (e.g., economic strain and psychological stress) potentially heightening the risk of involvement with the child welfare system (CWS). Using Swedish registry national data, this study explored the relationship between immigration-country of birth status, psychosocial risk factors, and child compulsory care for parents with RSU. METHODS: Study sample consisted of 5932 parents from 65 Swedish municipalities assessed for psychosocial problems (including alcohol and drug use) using the Addiction Severity Index (2007-2017). Stepwise multinomial logistic regression models examined the relationship between immigration-country of birth status (Swedish born, Nordic-born, and non-Nordic born), psychosocial problems, and compulsory care in the CWS. RESULTS: Compared to Swedish-born parents, parents not born in Sweden, Norway, Denmark or Finland (non-Nordic born parents) had a lower probability of children living in compulsory care (family homes or institutions). However, after accounting for psychosocial problems, immigration status was no longer significantly associated with children's living arrangements. CONCLUSIONS: Study findings indicate that parental immigrant status (even among parents dealing with RSU) in itself is not a risk factor for compulsory care in the CWS. Moreover, parental employment and health problems posed greater risk for children being in compulsory care. Receipt of targeted services for employment and health problems may help to maintain stable child living arrangements for immigrant parents dealing with RSU.

Suicidal because I don't feel connected or vice versa? A longitudinal study of suicidal ideation and connectedness among child welfare youth.

Suicide is a major public health problem among youth involved with the child welfare system. Although social connectedness rests at the core of many prevention approaches, we know little about this relationship over time in this vulnerable population. This study tested the hypotheses that inverse relationships would exist between connectedness in three social domains (i.e., caregiver, peers, and school) and suicidal ideation over time. The current study used baseline and 18-month follow-up data from 995 youth who participated in the National Survey of Child and Adolescent Well-Being (NSCAW II)-a nationally representative study of children and families investigated by a child welfare agency conducted from 2008 to 2011. A cross-lagged path model was used for the analysis. There were significant main effects of suicidal ideation at Time 1 on peer connectedness (ß= -.17, p < .01) and caregiver connectedness (ß= -.12, p < .05) at Time 2, but not on school connectedness (ß= -.05, ns). There was no main effect of any of the connectedness variables at Time 1 on suicidal ideation at Time 2. Screening for suicidal ideation is important for managing immediate risk but our findings suggest that such ideation also foreshadows disconnectedness from their primary caregiver and peers in the future. These findings demonstrate that there is clinical value in engaging child-welfare-involved youth and their social systems about how their suicide-related experiences may affect vital social ties. Therefore, there may be merit to designing and exploring the effects of pilot programming focused on mitigating social distancing that suicide-related experiences engender.

Examining internal and external job resources in child welfare: Protecting against caseworker burnout.

Given intense job demands, it is not surprising that job burnout is a consistent threat to the well-being and retention of the child welfare workforce. Guided by central postulates of the Job Demands and Resources (JD-R) model which suggests that job burnout develops because of experiences of high work demands coupled with low resources in the workplace, we applied a conceptual model of job burnout (client and work related) that accounts for both internal and external resources available to child welfare workers. Findings among child welfare caseworkers from three states (N = 1917) indicate that job demands (stress and time pressure) were positively related to client- and work-related burnout. Additionally, both internal and external resources moderated the relationships between job demands and client- and work-related burnout. Study findings have workforce management implications in the child welfare sector, including the role resources might play in mitigating the negative impact of job demands on burnout in the child welfare workforce.

Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids.

The development of three-dimensional culture methods has allowed for the study of developing cortical morphology in human cells. This provides a new tool to study the neurodevelopmental consequences of disease-associated mutations. Here, we study the effects of isogenic DISC1 mutation in cerebral organoids. DISC1 has been implicated in psychiatric disease based on genetic studies, including its interruption by a balanced translocation that increases the risk of major mental illness. Isogenic wild-type and DISC1-disrupted human-induced pluripotent stem cells were used to generate cerebral organoids, which were then examined for morphology and gene expression. We show that DISC1-mutant cerebral organoids display disorganized structural morphology and impaired proliferation, which is phenocopied by WNT agonism and rescued by WNT antagonism. Furthermore, there are many shared changes in gene expression with DISC1 disruption and WNT agonism, including in neural progenitor and cell fate markers, regulators of neuronal migration, and interneuron markers. These shared gene expression changes suggest mechanisms for the observed morphologic dysregulation with DISC1 disruption and points to new avenues for future studies. The shared changes in three-dimensional cerebral organoid morphology and gene expression with DISC1 interruption and WNT agonism further strengthens the link between DISC1 mutation, abnormalities in WNT signaling, and neuropsychiatric disease.

Interagency collaboration and receipt of substance abuse treatment services for child welfare-involved caregivers.

Caregivers dealing with problematic substance use pose persistent challenges for families involved with the child welfare (CW) system. Research has indicated that receipt of substance use disorder (SUD) services help improve family outcomes. However, there are many challenging stages of intervention in the SUD treatment process, including detection, assessment, referral, entry, and completion. Considerable work is needed to illuminate factors that strengthen the delivery of SUD-related services at various points in the treatment services continuum. Although a growing body of work has focused on individual-level correlates, few studies have examined organizational factors that potentially affect the delivery of SUD-related services. This study sought to further understanding of the relationship between CW organizational factors (interagency collaboration and organizational resources) and delivery of SUD-related services in a nationally representative sample of CW-involved caregivers. In this study sample, engagement in collaboration through a memorandum of understanding (MOU) and co-location supported caregiver receipt of a referral to SUD services. Caregivers were more likely to receive a formal assessment for SUD problems when their CW agencies reported the availability of a standardized SUD assessment tool. Also, having arrangements with SUD agencies so that CW-involved families had priority status to enter treatment was pertinent to caregiver receipt of SUD treatment services. These results provide evidence that engagement in collaboration activities and greater organizational resources can increase an organization's capacity to deliver services to clients.

Interagency collaboration: Strengthening substance abuse resources in child welfare.

Supporting child welfare (CW) workers' ability to accurately assess substance abuse needs and link families to appropriate services is critical given the high prevalence of parental substance use disorders (SUD) among CW-involved cases. Several barriers hinder this process, including CW workers' lack of expertise for identifying SUD needs and scarcity of treatment resources. Drawing from theories and emergent literature on interagency collaboration, this study examined the role of collaboration in increasing the availability of resources for identifying and treating SUDs in CW agencies. Using data from the second cohort of families from the National Survey of Child and Adolescent Well-Being, study findings highlight a lack of SUD resources available to CW workers. On the other hand, the availability of SUD resources was increased when CW agencies had a memorandum of understanding, co-location of staff, and more intense collaboration with drug and alcohol service (DAS) providers. These results provide evidence to support efforts to improve collaboration between CW and DAS providers and showcase specific collaboration strategies to implement in order to improve service delivery.

Service Receipt and Mental Disorders in Child Welfare and Mental Health Systems in Los Angeles County.

OBJECTIVE: Use of administrative data from child welfare (CW) and mental health systems in Los Angeles County provided a unique opportunity to more closely examine mental health needs of children dually served by these systems. This study examined the presence of mental disorders and correlates of receipt of mental health services by diagnostic classification in this population. METHODS: Data were obtained for 3,191 children receiving services from Los Angeles County's Department of Children and Family Services and Department of Mental Health (DMH) between July 2011 and July 2012. Multivariate linear and logistic regression models examined the relationship between sociodemographic and CW-related characteristics and receipt of outpatient services by clinician-diagnosed mental disorder. RESULTS: Of the 3,191 referred children, 68% met criteria for one of the four diagnostic classifications. Mood disorders were the most common diagnosis (30%), followed by anxiety disorders (20%), behavior disorders (9%), and attention-deficit hyperactivity disorder (9%). Children with prior DMH involvement received more services regardless of diagnosis. Older children (ages ≥15) received more services than younger children, whereas younger children were more likely to receive family therapy. Race-ethnicity did not play a significant role in predicting service receipt. CONCLUSIONS: The unique mental health needs of CW-involved children were exemplified by the differences found in the percentages of children with diagnoses of mental disorders between this sample and children in the general population. Because of family and placement disruptions among CW-involved children, it is important that the provision of individual therapy is not overlooked in favor of family therapy.

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aß, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aß plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Aß and the responsiveness of TAU to Aß are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.

Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulation-intrauterine insemination.

OBJECTIVE: To identify baseline characteristics of couples that are likely to predict conception, clinical pregnancy, and live birth after up to four cycles of ovarian stimulation with IUI in couples with unexplained infertility. DESIGN: Secondary analyses of data from a prospective, randomized, multicenter clinical trial investigating pregnancy, live birth, and multiple pregnancy rates after ovarian stimulation-IUI with clomiphene citrate, letrozole, or gonadotropins. SETTING: Outpatient clinical units. PATIENT(S): Nine-hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. INTERVENTION(S): As part of the clinical trial, treatment was randomized equally to one of three arms and continued for up to four cycles or until pregnancy was achieved. MAIN OUTCOME MEASURE(S): Conception, clinical pregnancy, and live-birth rates. RESULT(S): In a multivariable logistic regression analysis, after adjustment for other covariates, age, waist circumference, income level, duration of infertility, and a history of prior pregnancy loss were significantly associated with at least one pregnancy outcome. Other baseline demographic and lifestyle characteristics including smoking, alcohol use, and serum levels of antimüllerian hormone were not significantly associated with pregnancy outcomes. CONCLUSION(S): While age and duration of infertility were significant predictors of all pregnancy outcomes, many other baseline characteristics were not. The identification of level of income as a significant predictor of outcomes independent of race and education may reflect differences in the underlying etiologies of unexplained infertility or could reveal disparities in access to fertility and/or obstetrical care. CLINICAL TRIAL REGISTRATION: NCT01044862.

Examining intensity and types of interagency collaboration between child welfare and drug and alcohol service providers.

The co-occurrence of child maltreatment and caregiver substance use disorders (SUDs) is a pervasive problem, with an estimated two thirds of child welfare (CW) systems cases involving SUDs. Interagency collaboration between CW and drug and alcohol service (DAS) providers shows promise in improving connections to and delivery of SUD services for CW-involved families. However, interagency collaboration between CW and DAS providers continues to be difficult to achieve and little is known about organizational characteristics and contexts that influence collaboration between these two entities. Using data from the second cohort of families from the National Survey of Child and Adolescent Well-Being, this study examined national trends in interagency collaboration between CW and DAS providers and organizational factors that influence the nature and intensity of interagency collaboration. Results indicated that collaboration intensity was greater for CW agencies that reported increased caseloads and those located in more populated counties. However, collaboration intensity decreased for CW agencies located in counties with higher child poverty. Study findings have implications for policy leaders and directors of CW agencies throughout the United States, especially because collaborating with DAS providers may increase CW agencies' organizational capacity and relieve job stress related to high caseloads. Development of strategies that spur engagement in more intense and multiple types of collaboration between CW agencies and DAS providers has the potential to relieve service burden on CW staffs and expedite service delivery to CW-involved families dealing with SUDs.

Connectedness and suicidal ideation among adolescents involved with child welfare: a national survey.

Using data from the National Survey of Child and Adolescent Well-Being, this study examined the relationship between connectedness in major social domains (i.e., caregiver, peers, deviant peers, and school) and suicidal ideation among adolescents (11-17 years old) investigated by child welfare agencies (N=995). Weighted logistic regression models were used to evaluate the relationships between connectedness variables and suicidal ideation, after adjusting for covariates. Youths with a stronger connection to caregivers were much less likely to report suicidal ideation, whereas youths with stronger deviant peer relationships were significantly more likely to report suicidal ideation. Significant associations found between primary caregiver and deviant peer connectedness and suicidal ideation highlight the need for attentive consideration of these relationships when working with this highly vulnerable population. Identifying domain-specific connectedness factors related to suicidal ideation presents an opportunity for the development of targeted early intervention for child welfare-involved youths.