Is preexisting mental illness associated with lower patient satisfaction for older trauma patients? A cross-sectional descriptive study.

BACKGROUND: The purpose of this study was to examine if satisfaction with care differs among older trauma patients with and without preexisting mental illness (PMI+/PMI-). METHODS: Data from two level I trauma centers were examined from 11/2016 through 12/2017. Trauma patients ≥55 years were included and satisfaction of those who had a diagnosis of mental illness prior to the trauma admission (PMI+) to those without a diagnosis (PMI-) (n = 299; 62 PMI+ and 237 PMI-) were compared. Enrolled patients completed the Family Satisfaction with Advanced Care Cancer Scale Patient Survey (FAMCARE-P13) prior to discharge. Associations between mental illness status and patient baseline characteristics, overall mean satisfaction, and mean satisfaction by question were compared. Generalized linear models adjusted for differences in patient satisfaction by mental illness status. Analyses were stratified by hospital to account for the interaction between hospital and mental illness status. RESULTS: Compared to PMI- patients, PMI+ patients were more likely to be younger, female, have multiple comorbidities, and to report lower overall satisfaction with care. Among PMI+ patients, the most common diagnoses were depression and anxiety. After adjustment, PMI+ was associated with lower patient satisfaction at hospital 1; after examining individual questions lower satisfaction was associated with information provided on procedures and questions surrounding "Physical care." Conversely, PMI+ did not affect satisfaction at hospital 2 after adjustment. CONCLUSIONS: At hospital 1, room for improvement was identified in providing information about prognosis and procedures, symptom management, and continuity of care. Reexamining practices for older PMI+ trauma patients is warranted.

Cell Cycle-Dependent Expression of Adeno-Associated Virus 2 (AAV2) Rep in Coinfections with Herpes Simplex Virus 1 (HSV-1) Gives Rise to a Mosaic of Cells Replicating either AAV2 or HSV-1.

Adeno-associated virus 2 (AAV2) depends on the simultaneous presence of a helper virus such as herpes simplex virus 1 (HSV-1) for productive replication. At the same time, AAV2 efficiently blocks the replication of HSV-1, which would eventually limit its own replication by diminishing the helper virus reservoir. This discrepancy begs the question of how AAV2 and HSV-1 can coexist in a cell population. Here we show that in coinfected cultures, AAV2 DNA replication takes place almost exclusively in S/G2-phase cells, while HSV-1 DNA replication is restricted to G1 phase. Live microscopy revealed that not only wild-type AAV2 (wtAAV2) replication but also reporter gene expression from both single-stranded and double-stranded (self-complementary) recombinant AAV2 vectors preferentially occurs in S/G2-phase cells, suggesting that the preference for S/G2 phase is independent of the nature of the viral genome. Interestingly, however, a substantial proportion of S/G2-phase cells transduced by the double-stranded but not the single-stranded recombinant AAV2 vectors progressed through mitosis in the absence of the helper virus. We conclude that cell cycle-dependent AAV2 rep expression facilitates cell cycle-dependent AAV2 DNA replication and inhibits HSV-1 DNA replication. This may limit competition for cellular and viral helper factors and, hence, creates a biological niche for either virus to replicate.IMPORTANCE Adeno-associated virus 2 (AAV2) differs from most other viruses, as it requires not only a host cell for replication but also a helper virus such as an adenovirus or a herpesvirus. This situation inevitably leads to competition for cellular resources. AAV2 has been shown to efficiently inhibit the replication of helper viruses. Here we present a new facet of the interaction between AAV2 and one of its helper viruses, herpes simplex virus 1 (HSV-1). We observed that AAV2 rep gene expression is cell cycle dependent and gives rise to distinct time-controlled windows for HSV-1 replication. High Rep protein levels in S/G2 phase support AAV2 replication and inhibit HSV-1 replication. Conversely, low Rep protein levels in G1 phase permit HSV-1 replication but are insufficient for AAV2 replication. This allows both viruses to productively replicate in distinct sets of dividing cells.

Adeno-Associated Virus Type 2 Rep68 Can Bind to Consensus Rep-Binding Sites on the Herpes Simplex Virus 1 Genome.

Adeno-associated virus type 2 is known to inhibit replication of herpes simplex virus 1 (HSV-1). This activity has been linked to the helicase- and DNA-binding domains of the Rep68/Rep78 proteins. Here, we show that Rep68 can bind to consensus Rep-binding sites on the HSV-1 genome and that the Rep helicase activity can inhibit replication of any DNA if binding is facilitated. Therefore, we hypothesize that inhibition of HSV-1 replication involves direct binding of Rep68/Rep78 to the HSV-1 genome.

Adeno-associated virus type 2 modulates the host DNA damage response induced by herpes simplex virus 1 during coinfection.

Adeno-associated virus type 2 (AAV2) is a human parvovirus that relies on a helper virus for efficient replication. Herpes simplex virus 1 (HSV-1) supplies helper functions and changes the environment of the cell to promote AAV2 replication. In this study, we examined the accumulation of cellular replication and repair proteins at viral replication compartments (RCs) and the influence of replicating AAV2 on HSV-1-induced DNA damage responses (DDR). We observed that the ATM kinase was activated in cells coinfected with AAV2 and HSV-1. We also found that phosphorylated ATR kinase and its cofactor ATR-interacting protein were recruited into AAV2 RCs, but ATR signaling was not activated. DNA-PKcs, another main kinase in the DDR, was degraded during HSV-1 infection in an ICP0-dependent manner, and this degradation was markedly delayed during AAV2 coinfection. Furthermore, we detected phosphorylation of DNA-PKcs during AAV2 but not HSV-1 replication. The AAV2-mediated delay in DNA-PKcs degradation affected signaling through downstream substrates. Overall, our results demonstrate that coinfection with HSV-1 and AAV2 provokes a cellular DDR which is distinct from that induced by HSV-1 alone.

The ACS-TQIP palliative care guidelines at two level I trauma centres: a prospective study of patient and caregiver satisfaction.

OBJECTIVES: To measure trauma patient and caregiver satisfaction before and after implementation of standardised palliative care (PC) guidelines. METHODS: Prospective pre-post study at two level-I trauma centres. PC satisfaction surveys were administered prior to discharge for consented trauma patients (Family Satisfaction with Advanced Cancer Scale, Patient (FAMCARE-P13) survey)≥55 years, and their caregivers (FAMCARE survey), from 1 November 2016 to 30 November 2018. Standardised PC guidelines were implemented January 2018 and included consultations, prognostication assessments, identification of proxies, review of advanced directives and do not resuscitate orders within 24 hours of admission, while advanced goals of care, formal family meetings and spiritual care support were recommended within 72 hours of admission. Generalised linear models were used to determine whether differences in patient or caregiver satisfaction existed pre versus post implementation. RESULTS: There were 572 patients (299 pre; 273 post) and 595 caregivers (334 pre; 261 post) included. Overall patient satisfaction significantly increased post implementation (82.0 vs 86.0, p=0.001). After adjustment, the implementation of the guidelines was an independent predictor of higher overall patient satisfaction (least squares mean (LSM= (83.8% (95%CI 81.2%-86.5%) vs 80.3% (77.7%-82.9%), p=0.003)). Compared with preimplementation, patient satisfaction was significantly higher post implementation in the following domains: information giving (80.9 vs 85.5, p=0.001), followed by physical care (82.2 vs 86.0, p=0.002), availability of care (83.4 vs 86.8, p=0.007) and psychosocial care (84.7 vs 87.6, p=0.04). No significant differences in caregiver satisfaction were found before or after adjustment (LSMpre: 83.1% (95%CI 80.9%-85.3%) vs. post: 82.4% (80.3%-84.5%), p=0.56)) CONCLUSIONS: Our data suggest that the implementation of PC guidelines significantly improved patient satisfaction following traumatic injury, while maintaining robust caregiver satisfaction.

Inhibition of herpes simplex virus type 1 replication by adeno-associated virus rep proteins depends on their combined DNA-binding and ATPase/helicase activities.

Adeno-associated virus (AAV) has previously been shown to inhibit the replication of its helper virus herpes simplex virus type 1 (HSV-1), and the inhibitory activity has been attributed to the expression of the AAV Rep proteins. In the present study, we assessed the Rep activities required for inhibition of HSV-1 replication using a panel of wild-type and mutant Rep proteins lacking defined domains and activities. We found that the inhibition of HSV-1 replication required Rep DNA-binding and ATPase/helicase activities but not endonuclease activity. The Rep activities required for inhibition of HSV-1 replication precisely coincided with the activities that were responsible for induction of cellular DNA damage and apoptosis, suggesting that these three processes are closely linked. Notably, the presence of Rep induced the hyperphosphorylation of a DNA damage marker, replication protein A (RPA), which has been reported not to be normally hyperphosphorylated during HSV-1 infection and to be sequestered away from HSV-1 replication compartments during infection. Finally, we demonstrate that the execution of apoptosis is not required for inhibition of HSV-1 replication and that the hyperphosphorylation of RPA per se is not inhibitory for HSV-1 replication, suggesting that these two processes are not directly responsible for the inhibition of HSV-1 replication by Rep.

Comparing satisfaction of trauma patients 55 years or older to their caregivers during palliative care: Who faces the burden?

BACKGROUND: Many studies report on the patient-caregiver relationship during palliative care (PC); however, this relationship has yet to be examined following traumatic injury. METHODS: This prospective cohort study included trauma patients (≥55 years) and their primary caregivers admitted at two level I trauma centers for 2 years (November 2016 to November 2018), who received PC and who completed satisfaction surveys before discharge; surveys were analyzed by four domains: information giving, availability of care, physical care, and psychosocial care, and by PC assessments: consultations, prognostications, formal family meetings (FFMs), and advanced goals of care discussions. The primary outcome was the percentage of patients and caregivers who were satisfied (defined as ≥80%) and was analyzed using McNemar's test. Adjusted mixed models identified PC assessments that were associated with satisfaction scores ≥80% for patients and caregivers. RESULTS: Of the 441-patient and 441-caregiver pairs, caregivers were significantly less satisfied than patients during prognostications (information giving, physical care), FFMs (information giving, physical care), and consultations (physical care), while caregivers were significantly more satisfied than patients during advanced goals of care discussions (availability of care, psychosocial care). After adjustment, significant predictors of caregiver satisfaction (≥80%) included longer patient hospital length of stay (>4 days), caring for a male patient (physical care, availability of care), higher caregiver age (≥55 years; availability of care), and higher patient age (≥65 years; psychosocial care). Conversely, all PC assessments decreased odds of satisfaction for caregivers in every domain except physical care. Significant predictors of higher patient satisfaction included FFMs (for every domain) and PC consultations (psychosocial care), and decreased odds included advanced goals of care discussions and prognostication assessments (information giving, psychosocial care). CONCLUSIONS: Palliative care increased satisfaction of patients, especially family meetings and consultations, while assessments were predictive of lower caregiver satisfaction, suggesting that caregivers may be experiencing some of the patient burden. LEVEL OF EVIDENCE: Therapeutic/Care Management, level IV.

A validated method for the simultaneous quantification of cannabidiol, Δ9 -tetrahydrocannabinol, and their metabolites in human plasma and application to plasma samples from an oral cannabidiol open-label trial.

Cannabidiol (CBD) and Δ9 -tetrahydrocannabinol (THC) are the two best known and most extensively studied phytocannabinoids within Cannabis sativa. An increasing number of preclinical studies and clinical trials have been conducted with one or both compounds, often probing their therapeutic effects in conditions such as paediatric epilepsy, anxiety disorders or chronic pain. Accurate monitoring of THC and CBD and their metabolites is essential for tracking treatment adherence and pharmacokinetics. However, fully validated methods for the comprehensive analysis of major Phase I CBD metabolites are yet to be developed due to a historical lack of commercially available reference material. In the present study, we developed, optimised and validated a method for the simultaneous quantification of CBD, THC and their major Phase I metabolites 6-hydroxy-CBD (6-OH-CBD), 7-hydroxy-CBD (7-OH-CBD), 7-carboxy-CBD (7-COOH-CBD), 11-hydroxy-tetrahydrocannabinol (11-OH-THC) and 11-carboxy-tetrahydrocannabinol (11-COOH-THC) as per Food and Drug Administration (FDA) guidelines for bioanalytical method validation. The method is accurate, reproducible, sensitive and can be carried out in high-throughput 96-well formats, ideal for larger scale clinical trials. Deuterated internal standards for each analyte were crucial to account for variable matrix effects between plasma lots. The application of the method to plasma samples, taken from people who had been administered oral CBD as part of an open-label trial of CBD effects in anxiety disorders, demonstrated its immediate utility in ongoing and upcoming clinical trials. The method will prove useful for future studies involving CBD and/or THC and can likely accommodate the inclusion of additional metabolites as analytical reference materials become commercially available.

Regional distribution and behavioral correlates of 5-HT(2A) receptors in Alzheimer's disease with [(18)F]deuteroaltanserin and PET.

Postmortem studies show reductions in brain serotonin 2A (5-HT(2A)) receptors in Alzheimer's disease (AD). Converging evidence also suggests that serotonergic dysregulation may contribute to behavioral symptoms that frequently occur in AD. This study aimed to define regional reductions in 5-HT(2A) binding in AD patients and to examine their behavioral correlates. Nine patients with probable AD and eight elderly controls were studied using a constant infusion paradigm for equilibrium modeling of [(18)F]deuteroaltanserin with positron emission tomography (PET). Region of interest analyses were performed on PET images coregistered to MRI scans. The outcome measures BP(P) (ratio of specific brain uptake to total plasma parent concentration) and BP(ND) (ratio of specific to nondisplaceable uptake) were obtained for pertinent cortical and subcortical regions. AD patients showed a statistically significant decrease in the anterior cingulate in both BP(P) and BP(ND), but in no other region. Within the AD patient sample, no significant correlations were observed between regional 5-HT(2A) binding and behavioral measures, including depressive and psychotic symptoms. These results confirm a reduction in cortical 5-HT(2A) receptors in AD, specifically in the anterior cingulate. However, in a limited AD patient sample, they fail to demonstrate a relationship between regional 5-HT(2A) binding and major behavioral symptoms.

Examining satisfaction of older adult patients and their caregivers following traumatic injury: a cross-sectional study of three level I trauma centres.

OBJECTIVE: To explore satisfaction of care received by older adult patients and their primary caregivers following traumatic injury. DESIGN: Prospective, cross-sectional study using the FAMCARE (Family Satisfaction with Advanced Cancer Care Scale) satisfaction surveys prior to discharge. SETTING: Three level I trauma centres in Colorado from November 2016 to December 2017. PARTICIPANTS: Trauma patients ≥55 years old and their primary caregivers. OUTCOME MEASURES: Overall mean (SD) satisfaction, satisfaction <80% vs ≥80%, and mean satisfaction by survey conceptual structures. RESULTS: Of the 319 patients and 336 caregivers included, the overall mean (SD) patient satisfaction was 81.7% (15.0%) and for caregivers was 83.6% (13.4%). The area with the highest mean for patient and caregiver satisfaction was psychosocial care (85.4% and 86.9%, respectively). Information giving was the lowest for patients (80.4%) and caregivers (80.9%). When individual items were examined, patients were significantly more satisfied with 'availability of nurses to answer questions' (84.5 (15.3) vs 87.4 (14.8), p=0.02) and significantly less satisfied with 'speed with which symptoms were treated' (80.6 (17.9) vs 84.0 (17.0), p=0.03) compared with caregivers. Patients with a history of smoking (least squares mean difference: -0.096 (-0.18 to -0.07), p<0.001) and hospital discharge destination to an outside facility of care (adjusted OR: 1.6 (1.0 to 2.4), p=0.048) were identified as independent predictors of lower overall satisfaction in generalised linear and logistic models, respectively. CONCLUSIONS: Our data suggest that patients' medical history was driving both patient and caregiver satisfaction. Patient characteristics and expectations need to be considered when tailoring healthcare interventions.

Stem cells in the management of heart failure: what have we learned from clinical trials?

Research shows that various types of stem cells (SCs) have the ability to rebuild damaged heart tissue. The TIME and Late TIME human trials shed light on the optimum timing of SC therapy administration after myocardial damage. The FOCUS study failed to show a substantial positive effect of bone marrow-derived mononuclear cells in patients suffering from ischemic heart failure; however, some completed human trials do show promise, with improvement in cardiac function. Recent clinical trials have identified a subset of marrow cells that was able to stimulate endogenous adult cardiac SCs where cardiac SCs administration showed promise in the SCIPIO trial. This review addresses some of the lessons learned from clinical trials with SC therapy in ischemic heart failure.

Multifluorescence live analysis of herpes simplex virus type-1 replication.

The possibility to label specific viral and cellular structures with live cell markers such as autofluorescent proteins has greatly contributed to our understanding of diverse steps of the virus life cycle, as it allows monitoring virus replication in a spatial and temporal fashion. Here, we describe the multi-fluorescent analysis of the multi-compartment herpes simplex virus type-1 by live-cell confocal laser scanning microscopy.

Viral and Cellular Components of AAV2 Replication Compartments.

Adeno-associated virus 2 (AAV2) is a helpervirus-dependent parvovirus with a bi-phasic life cycle comprising latency in absence and lytic replication in presence of a helpervirus, such as adenovirus (Ad) or herpes simplex virus type 1 (HSV-1). Helpervirus-supported AAV2 replication takes place in replication compartments (RCs) in the cell nucleus where virus DNA replication and transcription occur. RCs consist of a defined set of helper virus-, AAV2-, and cellular proteins. Here we compare the profile of cellular proteins recruited into AAV2 RCs or identified in Rep78-associated complexes when either Ad or HSV-1 is the helpervirus, and we discuss the potential roles of some of these proteins in AAV2 and helpervirus infection.

The management of the sibling hematopoietic stem cell donor.

Hematopoietic stem cell transplants are procedures with curative potential for patients with diseased, damaged, or absent stem cells. Because a sibling has the best chance of immunocompatibility with one in need of a transplant, siblings are the most suitable donors of stem cells. However, when siblings are stem cell donors, various ethical issues arise concerning the risks and benefits to the pediatric donor. Because of the critical and potential rapid deterioration of the recipient's condition, the needs of the sibling donor may be overlooked. This potential lack of advocacy for the pediatric sibling donor creates a role for the primary care provider to assess the child's physical and psychological ability to undergo the donation procedure, examine the ethical issues in choosing to use the pediatric sibling as the stem cell donor, prepare the child for the procedure, and follow-up with the sibling donor once the procedure is completed.