Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial.

MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG-CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5 mg/m2/day, PO. Dose-limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500 µg Q24h (0.5 mg/m2/day in a 30 kg dog), approximately 70% of dogs had an average steady-state concentration of 10 ng/mL, achieved after approximately 2 weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5 mg/m2/day was the recommended dose for phase II studies.

A protocol to determine the acceptability and feasibility of a pilot intervention emergency department virtual observation unit fall prevention program.

BACKGROUND: As a third of all community dwellers aged 65+ fall each year, falls are common reasons for older adults to present to an Emergency Department (ED). Although EDs should assess patients' multifactorial fall risks to prevent future fall-related injuries, this frequently does not occur. We describe our protocol to determine the feasibility, acceptability, and safety of a pilot ED Virtual Observation Unit (VOU) Falls program. METHODS: To ensure standardized conduct and reporting, the Standard Protocol Items for Intervention Trials (SPIRIT) guidelines will be used. The VOU is a program where patients are sent home from the ED but are part of a virtual observation unit in that they can call on-call ED physicians while they are being treated for conditions such as cellulitis, congestive heart failure, or pneumonia. A paramedic conducts daily visits with the patient and facilitates a telemedicine consult with an ED physician. VOU nursing staff conduct daily assessments of patients via telemedicine. The ED VOU Falls program is one of the VOU pathways and is a multi-component fall prevention program for fall patients who present after an ED visit. The paramedic conducts a home safety evaluation, a Timed Up and Go Test (TUG). During the VOU visit, the ED physician conducts a telemedicine visit, while the paramedic is visiting the home, to review patients' fall-risk-increasing drugs and their TUG test. We will determine feasibility by calculating rates of patient enrollment refusal, and adherence to fall-risk prevention recommendations using information from 3-month follow-up telephone calls, as well as qualitative interviews with the paramedics. We will determine the acceptability of the ED VOU Falls program based on patient and provider surveys using a Likert scale. We will ask VOU nursing staff to report any safety issues encountered while the patient is in the ED VOU Falls program (e.g., tripping hazards). We will use the chi-square test or Fisher's exact test for categorical variables, Student's t-test for continuous variables, and Mann-Whitney for nonparametric data. We will review interview transcripts and generate codes. Codes will then be extracted and organized into concepts to generate an overall theme following grounded theory methods. This is a pilot study; hence, results cannot be extrapolated. However, a definite trial would be the next step in the future to determine if such a program could be implemented as part of fall prevention interventions. DISCUSSION: This study will provide insights into the feasibility and acceptability of a novel ED VOU Falls program with the aim of ultimately decreasing falls. In the future, such a program could be implemented as part of fall prevention interventions.

Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders.

Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on the current suite of ligands used to recruit E3 ligases could limit the potential of their application. To address this, potent ligands for DCAF15 were optimized using cryo-EM supported, structure-based design to improve on micromolar starting points. A potent binder, compound 24, was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts on degrading a number of proteins using DCAF15 recruiting PROTACs, only degradation of BRD4 was observed. Deconvolution of the mechanism of action showed that this degradation was not mediated by DCAF15, thereby highlighting both the challenges faced when trying to expand the toolbox of validated E3 ligase ligands for use in PROTAC degraders and the pitfalls of using BRD4 as a model substrate.

Understanding the impacts of chronic pain on autistic adolescents and effective pain management: a reflexive thematic analysis adolescent-maternal dyadic study.

OBJECTIVE: Sensory elements are core features in chronic pain and autism, yet knowledge of the pain experience in autistic adolescents is limited. Little is known regarding how autistic adolescents experience chronic pain, manage their pain and perceive psychological treatment for their chronic pain. METHODS: Ten autistic adolescents (6 female, 3 male, and 1 self-identified as agender) with chronic pain and their mothers (n = 10) participated in semistructured interviews concerning their perceptions of living with chronic pain. Participants were recruited from U.K. pain management services. According to preference, interviews were conducted individually (n = 10) or dyadically (n = 10 participants across 5 dyads). Data were analyzed using inductive reflexive thematic analysis. RESULTS: Two themes were generated. Theme 1, "overstimulated and striving for control" described how adolescents' experience of heightened sensitivity enhanced adolescents' levels of anxiety and subsequent pain, illustrating a reciprocal relationship between anxiety, pain, and sensory elements. Theme 2, "not everyone fits the mold" captured how autistic adolescents positioned themselves as distinct from others due to the unique nature of being autistic and living with pain. This sense of difference negatively impacted adolescents' ability to engage with and benefit from the standard treatment for chronic pain. CONCLUSIONS: Findings suggest that autistic adolescents living with pain experience pain and face barriers to effective pain treatment. Our results identify the need for educational resources to facilitate clinicians to better understand the experience of autistic adolescents living with pain. In turn, such understanding may improve treatment and outcomes in this population.

Metabolomic and Transcriptomic Correlative Analyses in Germ-Free Mice Link Lacticaseibacillus rhamnosus GG-Associated Metabolites to Host Intestinal Fatty Acid Metabolism and ß-Oxidation.

Intestinal microbiota confers susceptibility to diet-induced obesity, yet many probiotic species that synthesize tryptophan (trp) actually attenuate this effect, although the underlying mechanisms are unclear. We monocolonized germ-free mice with a widely consumed probiotic Lacticaseibacillus rhamnosus GG (LGG) under trp-free or -sufficient dietary conditions. We obtained untargeted metabolomics from the mouse feces and serum using liquid chromatography-mass spectrometry and obtained intestinal transcriptomic profiles via bulk-RNA sequencing. When comparing LGG-monocolonized mice with germ-free mice, we found a synergy between LGG and dietary trp in markedly promoting the transcriptome of fatty acid metabolism and ß-oxidation. Upregulation was specific and was not observed in transcriptomes of trp-fed conventional mice and mice monocolonized with Ruminococcus gnavus. Metabolomics showed that fecal and serum metabolites were also modified by LGG-host-trp interaction. We developed an R-Script-based MEtabolome-TRanscriptome Correlation Analysis algorithm and uncovered LGG- and trp-dependent metabolites that were positively or negatively correlated with fatty acid metabolism and ß-oxidation gene networks. This high-throughput metabolome-transcriptome correlation strategy can be used in similar investigations to reveal potential interactions between specific metabolites and functional or disease-related transcriptomic networks.

Hospital Adaptions to Mitigate the COVID-19 Pandemic Effects on MARQUIS Toolkit Implementation and Sustainability.

OBJECTIVE: To explore the perceived effects of COVID-19 on MARQUIS toolkit implementation and sustainability, challenges faced by hospitals in sustaining medication reconciliation efforts, and the strategies used to mitigate the negative effects of the pandemic. DATA SOURCES AND STUDY SETTINGS: Primary qualitative data were extracted from a Web-based survey. Data were collected from hospitals that participated in MARQUIS2 ( n = 18) and the MARQUIS Collaborative ( n = 5). STUDY DESIGN: A qualitative, cross-sectional study was conducted. DATA COLLECTION/DATA EXTRACTION: Qualitative data were extracted from a Research Electronic Data Capture survey databased and uploaded into an Excel data analysis template. Two coders independently coded the data with a third coder resolving discrepancies. PRINCIPAL FINDINGS: Thirty-one team members participated, including pharmacists ( n = 20; 65%), physicians ( n = 9; 29%), or quality-improvement (QI) specialists ( n = 2; 6%) with expertise in medication reconciliation (MedRec) (14; 45%) or QI (10; 32%). Organizational resources were limited, including funding, staffing, and access to pharmacy students. To support program continuation, hospitals reallocated staff and used new MedRec order sets. Telemedicine, workflow adaptations, leadership support, QI team involvement, and ongoing audits and feedback promoted toolkit sustainability. CONCLUSIONS: COVID-19 affected the capacity of hospitals to sustain the MARQUIS toolkit. However, hospitals adapted various strategies to sustain the toolkit.

Two Satellite Gene Clusters Enhance Ergot Alkaloid Biosynthesis Capacity of Aspergillus leporis.

Ergot alkaloids are fungal specialized metabolites that are important in agriculture and serve as sources of several pharmaceuticals. Aspergillus leporis is a soil saprotroph that possesses two ergot alkaloid biosynthetic gene clusters encoding lysergic acid amide production. We identified two additional, partial biosynthetic gene clusters within the A. leporis genome containing some of the ergot alkaloid synthesis (eas) genes required to make two groups of clavine ergot alkaloids, fumigaclavines and rugulovasines. Clavines possess unique biological properties compared to lysergic acid derivatives. Bioinformatic analyses indicated the fumigaclavine cluster contained functional copies of easA, easG, easD, easM, and easN. Genes resembling easQ and easH, which are required for rugulovasine production, were identified in a separate gene cluster. The pathways encoded by these partial, or satellite, clusters would require intermediates from the previously described lysergic acid amide pathway to synthesize a product. Chemical analyses of A. leporis cultures revealed the presence of fumigaclavine A. However, rugulovasine was only detected in a single sample, prompting a heterologous expression approach to confirm functionality of easQ and easH. An easA knockout strain of Metarhizium brunneum, which accumulates the rugulovasine precursor chanoclavine-I aldehyde, was chosen as expression host. Strains of M. brunneum expressing easQ and easH from A. leporis accumulated rugulovasine as demonstrated through mass spectrometry analysis. These data indicate that A. leporis is exceptional among fungi in having the capacity to synthesize products from three branches of the ergot alkaloid pathway and for utilizing an unusual satellite cluster approach to achieve that outcome. IMPORTANCE Ergot alkaloids are chemicals produced by several species of fungi and are notable for their impacts on agriculture and medicine. The ability to make ergot alkaloids is typically encoded by a clustered set of genes that are physically adjacent on a chromosome. Different ergot alkaloid classes are formed via branching of a complex pathway that begins with a core set of the same five genes. Most ergot alkaloid-producing fungi have a single cluster of genes that is complete, or self-sufficient, and produce ergot alkaloids from one or occasionally two branches from that single cluster. Our data show that Aspergillus leporis is exceptional in having the genetic capacity to make products from three pathway branches. Moreover, it uses a satellite cluster approach, in which gene products of partial clusters rely on supplementation with a chemical intermediate produced via another gene cluster, to diversify its biosynthetic potential without duplicating all the steps.

Ergot Alkaloids Contribute to the Pathogenic Potential of the Fungus Aspergillus leporis.

Opportunistically pathogenic fungi have varying potential to cause disease in animals. Factors contributing to their virulence include specialized metabolites, which in some cases evolved in contexts unrelated to pathogenesis. Specialized metabolites that increase fungal virulence in the model insect Galleria mellonella include the ergot alkaloids fumigaclavine C in Aspergillus fumigatus (syn. Neosartorya fumigata) and lysergic acid α-hydroxyethylamide (LAH) in the entomopathogen Metarhizium brunneum. Three species of Aspergillus recently found to accumulate high concentrations of LAH were investigated for their pathogenic potential in G. mellonella. Aspergillus leporis was most virulent, A. hancockii was intermediate, and A. homomorphus had very little pathogenic potential. Aspergillus leporis and A. hancockii emerged from and sporulated on dead insects, thus completing their asexual life cycles. Inoculation by injection resulted in more lethal infections than did topical inoculation, indicating that A. leporis and A. hancockii were preadapted for insect pathogenesis but lacked an effective means to breach the insect's cuticle. All three species accumulated LAH in infected insects, with A. leporis accumulating the most. Concentrations of LAH in A. leporis were similar to those observed in the entomopathogen M. brunneum. LAH was eliminated from A. leporis through a CRISPR/Cas9-based gene knockout, and the resulting strain had reduced virulence to G. mellonella. The data indicate that A. leporis and A. hancockii have considerable pathogenic potential and that LAH increases the virulence of A. leporis. IMPORTANCE Certain environmental fungi infect animals occasionally or conditionally, whereas others do not. Factors that affect the virulence of these opportunistically pathogenic fungi may have originally evolved to fill some other role for the fungus in its primary environmental niche. Among the factors that may improve the virulence of opportunistic fungi are specialized metabolites--chemicals that are not essential for basic life functions but provide producers with an advantage in particular environments or under specific conditions. Ergot alkaloids are a large family of fungal specialized metabolites that contaminate crops in agriculture and serve as the foundations of numerous pharmaceuticals. Our results show that two ergot alkaloid-producing fungi that were not previously known to be opportunistic pathogens can infect a model insect and that, in at least one of the species, an ergot alkaloid increases the virulence of the fungus.

Caregivers' experience with Tele-Savvy Caregiver Program post-hospitalization.

Despite the frequent hospitalizations and readmissions of persons living with dementia (PLWD), no telehealth transitional care interventions focus on PLWDs' unpaid caregivers. Tele-Savvy Caregiver Program is a 43-day evidence-based online psychoeducational intervention for PLWDs' caregivers. The aim of this formative evaluation was to explore caregivers' acceptability of and experience with their participation in Tele-Savvy after their PLWDs' hospital discharge. Additionally, we gathered caregivers' feedback on the recommended features of a transitional care intervention, suitable for caregivers' schedule and needs post-discharge. Fifteen caregivers completed the interviews. Data were analyzed via conventional content analysis. Four categories were identified: (1) Tele-Savvy improved participants' understanding of dementia and caregiving; (2) hospitalization started a "new level of normal"; (3) PLWDs' health concerns; and (4) transitional care intervention development. Participation in Tele-Savvy was acceptable for most caregivers. Participants' feedback provides content and structural guidance for the development of a new transitional care intervention for PLWDs' caregivers.

Pediatrician Explanations of Pediatric Pain in Clinical Settings: A Delicate Craft.

Explaining chronic pain to children and families can be challenging, particularly in the absence of an obvious physiologically identifiable cause for the child's pain. In addition to medical intervention, children and families may expect clinicians to provide clarity around the cause of pain. Such explanations are often provided by clinicians who have not received formal pain training. This qualitative study sought to explore the following question: What do pediatricians consider to be important when providing pain explanations to children and their parents? Using semistructured interview methods, 16 UK pediatricians were interviewed regarding their perceptions of explaining chronic pain to children and families in clinical settings. Data were analyzed using inductive reflexive thematic analysis. Analyses generated 3 themes: 1) timing of the explanation, 2) casting a wider net, and 3) tailoring of the narrative. Study findings demonstrated the need for pediatricians to skilfully interpret where children and families are in their pain journey and deliver an appropriate and adaptable explanation relating to individual needs. Analyses identified the importance of providing a pain explanation that could be repeated and understood by others outside the consultation room, to enable children and families to accept the explanation. PERSPECTIVE: Study findings identify the importance of language in addition to familial and broader factors that may influence the provision and adoption of chronic pain explanations provided by pediatricians to children and families. Improving pain explanation provision may influence treatment engagement for children and their parents, subsequently impacting pain related outcomes.

Patient and caregiver experiences with a telemedicine intensive care unit recovery clinic.

BACKGROUND: Intensive Care Unit Recovery Clinics (ICU-RCs) were founded to address post-intensive care syndrome among ICU survivors. Telemedicine ICU-RCs may facilitate access for more ICU survivors, however, patient and caregiver experiences with telemedicine ICU-RCs have not been explored qualitatively. OBJECTIVE: To explore patient and informal caregiver experiences with a telemedicine ICU-RC. METHODS: Our qualitative exploratory cross-sectional study was guided by qualitative description methodology. Telemedicine ICU-RC visits were conducted at 3- and 12-weeks post-discharge following critical illness. Patients, and caregivers when available, met with an ICU pharmacist, ICU physician, and a neuropsychologist via Zoom. Thereafter, we conducted qualitative (1:1) telephone interviews with 14 patients and 12 caregivers recruited purposefully. Data were analyzed using conventional content analysis. RESULTS: Five themes were identified: (1) general impressions of the intervention; (2) intervention organization and delivery; (3) intervention substance; (4) caregiver participation; and (5) ways to improve the intervention. Participants found the telemedicine delivery acceptable, convenient, time-saving, and conducive to thorough discussions. Participants appreciated the information, reassurance, and validation. Attention to mental health during the visits was strongly endorsed. Caregiver involvement depended on patient self-management and technical ability. Suggestions included scheduling a 1-week post-discharge visit, more follow-up visits, and individualizing content for in-depth discussions, including mental health evaluation. CONCLUSIONS: The study results enhance the understanding of patient and caregiver experiences with a telemedicine ICU-RC. Participants' narratives helped to formulate recommendations to improve telemedicine ICU-RC delivery and content. Acceptability of this intervention indicates the potential for wider implementation of telemedicine ICU-RCs to reach more ICU survivors.

Multidisciplinary ICU Recovery Clinic Visits: A Qualitative Analysis of Patient-Provider Dialogues.

BACKGROUND: Research confirms the heterogeneous nature of patient challenges during recovery from the ICU and supports the need for modifying care experiences, but few data are available to guide clinicians seeking to support patients' individual recovery trajectories. RESEARCH QUESTION: What is the content of patient-provider dialogues in a telemedicine multidisciplinary ICU recovery clinic (ICU-RC)? STUDY DESIGN AND METHODS: We conducted a qualitative descriptive study in a telemedicine multidisciplinary ICU-RC at a tertiary academic medical center in the southeastern United States. The sample included 19 patients and 13 caregivers (≥ 18 years of age) attending a telemedicine ICU-RC visit after critical illness resulting from septic shock or ARDS. Patients and caregivers met with an ICU pharmacist, ICU physician, and a psychologist via a secure web-conferencing platform for 33 ICU-RC visits within 12 weeks of hospital discharge. Telemedicine ICU-RC visits were audio-recorded and transcribed verbatim for analysis. A coding system was developed using iterative inductive and deductive approaches. RESULTS: Two themes were identified from the patient-provider dialogue: (1) problem identification and (2) problem-solving strategies. We identified five subthemes that capture the types of problems identified: health status, mental health and cognition, medication management, health-care access and navigation, and quality of life. Problem-solving subthemes included facilitating care coordination and transitions, providing education, and giving constructive feedback and guidance. INTERPRETATION: Patients surviving a critical illness experience a complexity of problems that may be addressed best by a multidisciplinary ICU-RC. Through analysis of our telemedicine ICU-RC dialogues, we were able to identify problems and solutions to address challenges during a critical transitional phase of ICU recovery. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03926533; URL: www. CLINICALTRIALS: gov.

Factors Influencing Engagement with in-Person Intensive Care Unit Recovery Clinic Services.

Background: Intensive Care Unit recovery clinics (ICU-RC), are multidisciplinary outpatient clinics designed to identify and treat post-intensive care syndrome impairments unique to each survivor of critical illness. Engagement is limited, thus we aimed to describe patient- and hospitalization-related sociodemographic factors associated with scheduling and attending in-person ICU-RC visits. Design: Consecutive case series of prospectively collected ICU-RC referral data. Setting: Data was collected over a 9-year period (2012-2020) for patients referred to an ICU-RC from ICUs at an academic medical center in the southeast United States. Participants: 251 adults admitted to a medical, surgical, burn, or trauma ICU referred to the ICU-RC and eligible to be scheduled for a visit. Main Outcome and Measures: The main study outcome was scheduling and completing an ICU-RC visit. Independent variables included patient demographics, ICU visit characteristics (eg, diagnosis, ventilator days), severity of illness, discharge disposition, ICU-RC referral criteria (eg, shock, delirium), and clinic scheduling administrative data (eg, referral date, clinic visit date). Results: Of 251 ICU-RC referrals eligible for a visit, 128 were scheduled, and 91 completed a visit. In univariate models older age, unspecified shock, and distance from the clinic location were associated with decreased in-person ICU-RC engagement. In a multivariable logistic regression using the same predictors and interactions, older age, unspecified shock, and home-to-clinic distance remained as factors decreasing the likelihood of ICU-RC engagement. There was a decreasing likelihood of scheduling and attending an ICU-RC visit for every additional mile of distance the patient lived from the ICU-RC. Male sex was a strong predictor of completing an ICU-RC visit. Conclusions: Older ICU survivors and those who live farther from the clinic site are less likely to engage in an in-person ICU-RC. Innovation and telemedicine strategies are needed to improve access to ICU recovery care for these populations.

The sands of time: Adolescents' temporal perceptions of peer relationships and autonomy in the context of living with chronic pain.

The incidence of chronic and recurrent pain increases in adolescence. Prevalence of adolescent chronic pain is estimated to be 11%-44%, with approximately 5% adolescents experiencing moderate-to-severe chronic pain. Adolescents with chronic pain also report unwanted changes in emotional, social, and developmental functioning. Very little is known about how adolescents with chronic pain make sense of their development, the role of pain in that development, and how such developmental trajectories progress over time. A multi-methods qualitative study was designed to explore how adolescents make sense of their experience of chronic pain in the context of development. Nine adolescents (8 girls) aged 12-22 years old (Mean = 15.7, SD = 2.8) were recruited from a UK national pain service. Adolescents completed an interview on entering the service, and a follow-up interview 12 months later. They also completed monthly diaries in this 12-month period. Data comprised 18 interviews and 60 diary entries, which were analyzed using inductive reflexive thematic analysis. Analyses generated one overarching theme entitled "tug of war: push and pull," demonstrating developmental tension related to pain, and the cumulative impact these had over time. This overarching theme comprised two subthemes which capture these tensions across the developmental domains of peer relationships and autonomy. The first subtheme, "the shifting sands of peer relationships," explores the ever-changing closeness between self and peers. The second subtheme referred to "restricted choices" and how pain limited the participants' autonomy but that this, over time could push development forward. These results extend previous cross-sectional research on the developmental consequences of chronic pain, showing the dynamic fluctuations and alterations to developmental trajectories over time.

Patients' and Caregivers' Perceptions of Intensive Care Unit Hospitalization and Recovery.

BACKGROUND: Telehealth-based intensive care unit recovery clinics (ICU-RCs) can increase access to post-ICU recovery care for patients and their families. It is crucial to understand patients' and caregivers' experience of illness and recovery to build patient- and family-centered ICU-RCs. OBJECTIVE: To explore patients' and caregivers' perceptions of ICU hospitalization and recovery. METHODS: Individual semistructured telephone interviews were conducted with 14 patients and 12 caregivers who participated in a telehealth ICU-RC. This study was guided by qualitative description methodology. Conventional content analysis was used to analyze the data. RESULTS: Patients described their ICU hospitalization as scary, traumatic, and lonely. Participants' feedback on hospitalization ranged from praise to criticism. Patients wanted more realistic and detailed prognostication about post-ICU recovery and more physical therapy after discharge. Patients strongly valued the mental health component of ICU-RC visits, which contrasted with the scant attention paid to mental health in other postdischarge health care settings. Their knowledge about post-ICU recovery and connectedness to a primary care provider varied. CONCLUSIONS: Examining patients' and caregivers' perceptions of ICU hospitalization and recovery highlights ICU-RC components that can be strengthened to support patient- and family-centered recovery. The ICU-RC staff should invite patients to share feedback about their ICU stay; give a timely, realistic prognosis for recovery; offer mental health consultations; provide physical therapy; and partner with patients and their caregivers to develop and deliver post-ICU care.

Affordable Housing Specialists' Perceptions of Advance Care Planning Among Low-Income Older Adult Residents: A Qualitative Study.

This preliminary qualitative study aimed to explore affordable housing specialists' perceptions of challenges and patterns of advance care planning behaviors among low-income older residents in affordable housing. Advance care planning rates among such residents are disproportionally lower than higher-income older adults. Individual telephone interviews were conducted with affordable housing specialists in a major urban area in the Southeastern United States (N = 5). Using thematic content analysis, 2 independent coders synthesized the 2 coding sets into a single codebook that was iteratively and individually reapplied to the transcripts. The Ecological Model of Active Living, a model that embeds individual behavior within a physical and social environment, was used to categorize prominent codes to visualize relationships among codes and create a cohesive, ecological picture of planning behavior in this population. Four themes emerged from the data and were plotted in an adapted ecological model. Residents' ongoing struggles despite obtaining housing prevent self-initiation and maintenance of advance care planning. Housing specialists possess the expertise and empathy to guide change efforts and provide advance care planning, but aid is required to ensure adequate resources to prevent role conflict and burnout. Recommendations for interprofessional collaboration, practice, policy, and research are discussed.

Perspectives on Aging and End of Life Among Lower Socioeconomic Status (SES) Older Adults.

Objective: To explore the experiences of aging that influence perceptions of and receptivity to planning for aging and EOL among lower SES older adults. Methods: Supported by a frailty-focused communication educational aid, semi-structured interviews were conducted with 20 older adults residing in income-assisted housing. Follow-up interviews were conducted 2 weeks later. Descriptive content analysis was performed. Results: Participants mean age was 62.4, and 75% were African American. Six categories emerged to create a narrative of lower SES older adults' experiences, including (1) readiness to plan for aging and EOL, (2) interaction with the healthcare system, (3) daily life with insufficient resources, (4) the role of religiosity, (5) relationships with others, and (6) motivation and health status. Discussion: Life course vulnerabilities and struggles of lower SES older adults preclude opportunities to proactively plan for aging and EOL. Holistic interventions and innovative approaches are needed to address aging across the life course.

The prevalence of nurse burnout and its association with telomere length pre and during the COVID-19 pandemic.

BACKGROUND: Burnout is a work-related stress syndrome characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment. Nurse burnout is related to nurses' deteriorating mental health and poorer patient care quality and thus, is a significant concern in healthcare. The Coronavirus Disease 2019 (COVID-19) pandemic has swept the world and distressed the healthcare systems. Because of the body's stress mechanism, it is vital to examine the current prevalence of nurse burnout and understand it at a biological level, using an epigenetic biomarker, telomere length. PURPOSE: To determine the prevalence of burnout among nurses in the Peri-Operative and Labor & Delivery settings pre and during the COVID-19 pandemic and to examine the effects of burnout on absolute telomere length. METHODS: This is a cross-sectional study assessing the prevalence of nurses' burnout and the relationships between nurses' burnout and telomere length. Due to the COVID-19 pandemic, we had to stop the study during the mid of data collection. Even though the study was not designed to capture changes before and during the pandemic, we analyzed two groups' data before and during the pandemic. The study took place in a US hospital. Nurses in the hospital's Operating Room, Post-Anesthesia Care Unit, and Labor & Delivery Unit participated in the study. Maslach Burnout Inventory survey and nurses' demographics were administered online. Telomere length was measured via finger-prick blood. RESULTS: 146 nurses participated in the study, with 120 participants' blood samples collected. The high-level burnout rate was 70.5%. Correlation analysis did not reveal a direct correlation between nurse burnout and telomere length. However, in a multiple regression analysis, the final model contained the burnout subscale of emotional exhaustion, years as an RN, and work unit's nursing care quality. There was a low degree of departure from normality of the mean absolute telomere length in the pre-pandemic group and a substantial degree of departure in the during-pandemic group. CONCLUSIONS: Nurse burnout is a prevalent phenomenon in healthcare, and this study indicates that nurses currently experience high levels of burnout. Nurses' cellular biomarker, telomere length, is shorter in the group of nurses during the COVID-19 pandemic than before. Appropriate measures should be implemented to decrease nurses' burnout symptoms and improve nurses' psychological and physical health. Nurses, especially those younger than 60, report higher burnout symptoms, particularly emotional exhaustion. This study indicates the need for intervention to promote nurses' health during the pandemic and beyond. If not appropriately managed, nurse burnout may continue to be a significant issue facing the healthcare system.

Independent Evolution of a Lysergic Acid Amide in Aspergillus Species.

Ergot alkaloids derived from lysergic acid have impacted humanity as contaminants of crops and as the bases of pharmaceuticals prescribed to treat dementia, migraines, and other disorders. Several plant-associated fungi in the Clavicipitaceae produce lysergic acid derivatives, but many of these fungi are difficult to culture and manipulate. Some Aspergillus species, which may be more ideal experimental and industrial organisms, contain an alternate branch of the ergot alkaloid pathway, but none were known to produce lysergic acid derivatives. We mined the genomes of Aspergillus species for ergot alkaloid synthesis (eas) gene clusters and discovered that three species, A. leporis, A. homomorphus, and A. hancockii, had eas clusters indicative of the capacity to produce a lysergic acid amide. In culture, A. leporis, A. homomorphus, and A. hancockii produced lysergic acid amides, predominantly lysergic acid α-hydroxyethylamide (LAH). Aspergillus leporis and A. homomorphus produced high concentrations of LAH and secreted most of their ergot alkaloid yield into the culture medium. Phylogenetic analyses indicated that genes encoding enzymes leading to the synthesis of lysergic acid were orthologous to those of the lysergic acid amide-producing Clavicipitaceae; however, genes to incorporate lysergic acid into an amide derivative evolved from different ancestral genes in the Aspergillus species. Our data demonstrate that fungi outside the Clavicipitaceae produce lysergic acid amides and indicate that the capacity to produce lysergic acid evolved once, but the ability to insert it into LAH evolved independently in Aspergillus species and the Clavicipitaceae. The LAH-producing Aspergillus species may be useful for the study and production of these pharmaceutically important compounds. IMPORTANCE Lysergic acid derivatives are specialized metabolites with historical, agricultural, and medical significance and were known heretofore only from fungi in one family, the Clavicipitaceae. Our data show that several Aspergillus species, representing a different family of fungi, also produce lysergic acid derivatives and that the ability to put lysergic acid into its amide forms evolved independently in the two lineages of fungi. From microbiological and pharmaceutical perspectives, the Aspergillus species may represent better experimental and industrial organisms than the currently employed lysergic acid producers of the plant-associated Clavicipitaceae. The observation that both lineages independently evolved the derivative lysergic acid α-hydroxyethylamide (LAH), among many possible lysergic acid amides, suggests selection for this metabolite.

Delirium-related distress in the ICU: A qualitative meta-synthesis of patient and family perspectives and experiences.

BACKGROUND: Better understanding of patient and family member experiences of delirium and related distress during critical care is required to inform the development of targeted nonpharmacologic interventions. OBJECTIVE: To examine and synthesize qualitative data on patient and family member delirium experiences and relieving factors in the Intensive Care Unit (ICU). DESIGN: We conducted a systematic review and qualitative meta-synthesis. Eligible studies contained adult patient or family quotes about delirium during critical care, published in English in a peer-reviewed journal since 1980. Data sources included PubMed, Embase, CINAHL, PsycINFO, Web of Science, Cochrane and Clinicaltrials.gov. METHODS: Systematic searches yielded 3238 identified articles, of which 14 reporting 13 studies were included. Two reviewers independently extracted data into a Microsoft Excel spreadsheet. Qualitative meta-synthesis was performed through line-by-line coding of relevant quotes, organization of codes into descriptive themes, and development of analytical themes. Five patients/family members with experience of ICU delirium contributed to the thematic analysis. RESULTS: Qualitative meta-synthesis resulted in four major themes and two sub-themes. Key new patient and family-centric insights regarding delirium-related distress in the ICU included articulation of the distinct emotions experienced during and after delirium (for patients, predominantly fear, anger and shame); its 'whole-person' nature; and the value that patients and family members placed on clinicians' compassion, communication, and connectedness. CONCLUSIONS: Distinct difficult emotions and other forms of distress are experienced by patients and families during ICU delirium, during which patients and families highly value human kindness and empathy. Future studies should further explore and address the many facets of delirium-related distress during critical care using these insights and include patient-reported measures of the predominant difficult emotions.