Cancer-related fatigue among patients with advanced cancer receiving immune-checkpoint inhibitors: a prospective study.

PURPOSE: The aim of this study was to determine the frequency and factors associated with severity of cancer related fatigue (CRF) as assessed by Functional Assessment of Cancer Illness Therapy-Fatigue (FACIT-F), prior to, and during 12 weeks of immune-checkpoint inhibitors (ICIs). We also explored the effects of ICIs on fatigue dimensions and interference with daily activities (Multidimensional Functional Symptom Inventory, MFSI-SF, Patient-Related Outcome Symptom Measurement Information System Short form Fatigue 7a, PROMIS F-SF), QOL (Functional Assessment of Cancer Therapy-General, FACT-G), and cancer symptoms (Edmonton Symptom Assessment Scale, ESAS). METHODS: In this prospective, longitudinal observational study, patients with a diagnosis of advanced cancer receiving ICIs were evaluated. Patient demographics, FACT-G, FACIT-F, MFSI-SF, PROMIS F-SF, and ESAS were collected prior to, and during 12 weeks of ICIs. RESULTS: A total of 160 of the 212 enrolled patients were analyzed. The median age was 61 years, 60% were female, most common cancer was melanoma (73%), and most common ICI was nivolumab 46%. The frequency of clinically significant fatigue (defined as ≤ 34/52 on FACIT-F score) was 25.6% at baseline, 25.7% at week 8, and 19.5% at week 12. There was significant improvement in FACIT-F (P = 0.016), FACT-G physical well-being (P = 0.041), FACT-G emotional well-being (P = 0.011), ESAS anxiety (P = 0.045), and ESAS psychological distress (P = 0.03) scores from baseline to week 12 of ICIs. Multivariate analysis found significant association between clinically significant CRF and PROMIS F-SF (P < 0.001) and MFSI-SF global scores (P < 0.001). CONCLUSIONS: CRF is frequent prior to the initiation of ICI treatment. Over 12 weeks of ICI treatment, CRF significantly improved. FACT-G physical well-being, FACT-G emotional well-being, ESAS anxiety, and ESAS psychological distress scores improved overtime. Further studies are needed to validate these findings.

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

The urgent need for contingency management among Tribal communities in the United States: Considerations for implementation, policy, and sovereignty.

In two randomized controlled trials, culturally adapted contingency management (i.e., incentives provided for substance-negative urine samples) was associated with reduced alcohol and drug use among geographically diverse American Indian and Alaska Native (AI/AN) adults. In response to interest in contingency management from other Tribal and AI/AN communities, our research team in collaboration with AI/AN behavioral health experts, translated the research into practice with new AI/AN community partners. Tenets of community-based participatory research were applied to develop, pilot, and refine contingency management training and implementation tools, and identify implementation challenges. In partnership with the AI/AN communities, four members of the university team developed tools and identified implementation and policy strategies to increase the successful uptake of contingency management in each location. Through our collaborative work, we identified policy barriers including inadequate federal funding of contingency management incentives and a need for further clarity regarding federal anti-kickback regulations. Adoption of contingency management is feasible and can strengthen Tribal communities' capacity to deliver evidence-based substance use disorder treatments to AI/AN people. Unfortunately, non-evidence-based limits to the use of federal funding for contingency management incentives discriminate against AI/AN communities. We recommend specific federal policy reforms, as well as other practical solutions for Tribal communities interested in contingency management.

Troubled spots: Human impacts constrain the density of an apex predator inside protected areas.

Effective conservation requires understanding the processes that determine population outcomes. Too often, we assume that protected areas conserve wild populations despite evidence that they frequently fail to do so. Without large-scale studies, however, we cannot determine what relationships are the product of localized conditions versus general patterns that inform conservation more broadly. Leopards' (Panthera pardus) basic ecology is well studied but little research has investigated anthropogenic effects on leopard density at broad scales. We investigated the drivers of leopard density among 27 diverse protected areas in northeastern South Africa to understand what conditions facilitate abundant populations. We formulated 10 working hypotheses that considered the relative influence of bottom-up biological factors and top-down anthropogenic factors on leopard density. Using camera-trap survey data, we fit a multi-session spatial capture-recapture model with inhomogenous density for each hypothesis and evaluated support using an information theoretic approach. The four supported hypotheses indicated that leopard density is primarily limited by human impacts, but that habitat suitability and management conditions also matter. The proportion of camera stations that recorded domestic animals, a proxy for the extent of human impacts and protected area effectiveness, was the only predictor variable present in all four supported models. Protected areas are the cornerstone of large felid conservation, but only when the human-wildlife interface is well managed and protected areas shelter wildlife populations from anthropogenic impacts. To ensure the long-term abundance of large carnivore populations, reserve managers should recognize the ineffectiveness of "paper parks" and promote contiguous networks of protected areas that offer leopards and other large mammal populations greater space and reduced human impacts.

Quality Improvement: Assessing Your Clinical Microsystem.

There is a call to action for nurses in all types of practice settings to lead change efforts that impact quality of care. An intervention may focus on an outcome or improvement of an existing process. In both instances, an understanding of organizational culture and readiness for change are needed. Evidence-based tools are available for use by nurses and interprofessional teams to assess the clinical work environment and plan for measurement of change. Learning the use of these tools is a key step in advancing quality improvement. Use of quality improvement techniques can have an immediate impact at the clinical microsystem level.

Exploring digital support for the student transition to university through questionable concepts.

New students face challenges when they make the transition from school to university. Existing digital technologies used during this transition can sometimes increase the stressors associated with change. In order to explore ways forward for technology design in this space, we developed a brochure of questionable concepts. The concepts were grounded in findings of our prior research, yet were also intended to act as provocations to promote discussion in workshops involving 32 first year university students. Our analysis of workshop discussions documents the diverse issues students face around social bonding, their home environment, and their academic performance. Our findings challenge assumptions made in prior work about the ease of transition to university. We demonstrate how questionable concepts can play an important role in prompting 'safe' conversations around stressful life events for adolescents.

Observations of Distortion Product Otoacoustic Emission Components in Adults With Hearing Loss.

OBJECTIVES: Distortion product otoacoustic emissions (DPOAEs) measured in the ear canal are composed of OAEs generated by at least two mechanisms coming from different places in the cochlea. Otoacoustic emission (OAE) models hypothesize that reduction of cochlear gain will differentially impact the components. The purpose of the current experiment was to provide preliminary data about DPOAE components in adults with hearing loss in relation to OAE models and explore whether evaluation of the relative amplitudes of generator and reflection components can enhance identification of hearing loss. DESIGN: DPOAEs were measured from 45 adult ears; 21 had normal hearing (≤15 dB HL) and 24 with mild-to-severe sensorineural hearing loss (>15 dB HL). The higher frequency primary (f2) was swept logarithmically between 1500 and 6000 Hz, and f2/f1 was 1.22. The two equal-level primaries varied from 55 to 75 dB SPL in 5 dB steps. The swept primary procedure permitted the measurement of the amplitude and phase of the DPOAE fine structure and the extraction of the two major components (generator and reflection) by varying the predicted delays of the analysis windows. RESULTS: DPOAE fine structure was reduced or absent in ears with hearing loss. DPOAE generator and reflection components were lower in ears with hearing loss than those with normal hearing, especially for the reflection component. Significant correlations were found between the generator component and hearing threshold but not between reflection levels and hearing threshold. Most ears with normal hearing had both components, but only a small number of ears with hearing loss had both components. CONCLUSIONS: The reflection component is not recordable or low in level in ears with hearing loss, explaining the reduced or absent DPOAE fine structure. DPOAE generator components are also lower in level in ears with hearing loss than in ears without hearing loss. In ears that had both measurable generator and reflection components, the relationship between the two did not depend on the presence or absence of hearing loss. Because reflection components are not measurable in many ears with hearing thresholds >15 dB HL, stimuli that evoke other types of reflection emissions, such as stimulus-frequency or long-latency transient-evoked emissions, should be explored in conjunction with DPOAE generator components.

Increasing temperature seasonality may overwhelm shifts in soil moisture to favor shrub over grass dominance in Colorado Plateau drylands.

Ecosystems in the southwestern U.S. are predicted to experience continued warming and drying trends of the early twenty-first century. Climate change can shift the balance between grass and woody plant abundance in these water-limited systems, which has large implications for biodiversity and ecosystem processes. However, variability in topo-edaphic conditions, notably soil texture and depth, confound efforts to quantify specific climatic controls over grass vs. shrub dominance. Here, we utilized weather records and a mechanistic soil water model to identify the timing and depth at which soil moisture related most strongly to the balance between grass and shrub dominance in the southern Colorado Plateau. Shrubs dominate where there is high soil moisture availability during winter, and where temperature is more seasonally variable, while grasses are favored where moisture is available during summer. Climate change projections indicate consistent increases in mean temperature and seasonal temperature variability for all sites, but predictions for summer and winter soil moisture vary across sites. Together, these changes in temperature and soil moisture are expected to shift the balance towards increasing shrub dominance across the region. These patterns are strongly driven by changes in temperature, which either enhance or overwhelm effects of changes in soil moisture across sites. This approach, which incorporates local, edaphic factors at sites protected from disturbance, improves understanding of climate change impacts on grass vs. shrub abundance and may be useful in other dryland regions with high edaphic and climatic heterogeneity.

Using concept maps and goal-setting to support the development of self-regulated learning in a problem-based learning curriculum.

Problem-based learning (PBL) in medical education focuses on preparing independent learners for continuing, self-directed, professional development beyond the classroom. Skills in self-regulated learning (SRL) are important for success in PBL and ongoing professional practice. However, the development of SRL skills is often left to chance. This study presents the investigated outcomes for students when support for the development of SRL was embedded in a PBL medical curriculum. This investigation involved design, delivery and testing of SRL support, embedded into the first phase of a four-year, graduate-entry MBBS degree. The intervention included concept mapping and goal-setting activities through iterative processes of planning, monitoring and reflecting on learning. A mixed-methods approach was used to collect data from seven students to develop case studies of engagement with, and outcomes from, the SRL support. The findings indicate that students who actively engaged with support for SRL demonstrated increases in cognitive and metacognitive functioning. Students also reported a greater sense of confidence in and control over their approaches to learning in PBL. This study advances understanding about how the development of SRL can be integrated into PBL.

Community perspectives on drug/alcohol use, concerns, needs, and resources in four Washington State Tribal communities.

Community-university teams investigated substance use, abuse, and dependence (SUAD) and related concerns, needs, strengths, and resources in four Washington State Tribal communities. A total of 153 key community members shared their perspectives through 43 semi-structured interviews and 19 semi-structured focus groups. Qualitative data analysis revealed robust themes: prescription medications and alcohol were perceived as most prevalent and concerning; family and peer influences and emotional distress were prominent perceived risk factors; and SUAD intervention resources varied across communities. Findings may guide future research and the development of much needed strength-based, culturally appropriate, and effective SUAD interventions for American Indians, Alaska Natives, and their communities.

Second-generation high-throughput forward genetic screen in mice to isolate subtle behavioral mutants.

Forward genetic screens have been highly successful in revealing roles of genes and pathways in complex biological events. Traditionally these screens have focused on isolating mutants with the greatest phenotypic deviance, with the hopes of discovering genes that are central to the biological event being investigated. Behavioral screens in mice typically use simple activity-based assays as endophenotypes for more complex emotional states of the animal. They generally set the selection threshold for a putative mutant at 3 SDs (z score of 3) from the average behavior of normal animals to minimize false-positive results. Behavioral screens using a high threshold for detection have generally had limited success, with high false-positive rates and subtle phenotypic differences that have made mapping and cloning difficult. In addition, targeted reverse genetic approaches have shown that when genes central to behaviors such as open field behavior, psychostimulant response, and learning and memory tasks are mutated, they produce subtle phenotypes that differ from wild-type animals by 1 to 2 SDs (z scores of 1 to 2). We have conducted a second-generation (G2) dominant N-ethyl-N-nitrosourea (ENU) screen especially designed to detect subtle behavioral mutants for open field activity and psychostimulant response behaviors. We successfully detect mutant lines with only 1 to 2 SD shifts in mean response compared with wild-type control animals and present a robust statistical and methodological framework for conducting such forward genetic screens. Using this methodology we have screened 229 ENU mutant lines and have identified 15 heritable mutant lines. We conclude that for screens in mice that use activity-based endophenotypic measurements for complex behavioral states, this G2 screening approach yields better results.

Telehealth Preferences Among Patients With Advanced Cancer in the Post COVID-19 Vaccine Era.

BACKGROUND: Few studies have examined patient preferences for telehealth in palliative care after the availability of COVID-19 vaccines. We examined patient preferences for video versus in-person visits and factors contributing to preferences in the postvaccine era. METHODS: This is a cross-sectional survey of patients who were seen at our palliative care clinic between April 2021 and March 2022. Patients were surveyed directly their preference for either video or in-person visits for outpatient palliative care (primary outcome). We also surveyed preferences including convenience, cost, wait time, and perceptions of COVID-19 safety regarding their palliative virtual-video visit. We examined clinical factors associated with preferences with multivariate logistic regression. RESULTS: About 200 patients completed the survey. 132 (67%, 95% confidence interval [CI]: 60%, 74%) preferred virtual-video, while 16 (8%) preferred in-person visits during the COVID-19 pandemic. About 120 (61%, 95%CI: 54%, 68%) preferred virtual-video after the pandemic. Patients perceived virtual-video favorably regarding travel and related costs (179 [91%]), convenience (175 [88%]), and wait time (136 [69%]). Multivariable analysis showed concerns for catching COVID-19 from healthcare providers (odds ratio [OR]: 4.20; 95%CI: 1.24-14.25; P = 0.02) and feeling comfortable with computers or mobile devices (OR: 4.59; 95%CI: 1.02, 20.60; P = 0.047) were significantly associated with preferring virtual-video. Patients who were of Hispanic or Latino ethnicity (OR: 0.25; 95%CI: 0.09, 0.71) and had increased dypsnea (OR: 0.74; 95%CI: 0.59, 0.93) were less likely to prefer video over in-person. CONCLUSION: Patients expressed strong preference for video over in-person visits in the outpatient palliative care setting.

Location tracking: views from the older adult population.

BACKGROUND: there has been a rise in the use of social media applications that allow people to see where friends, family and nearby services are located. Yet while uptake has been high for younger people, adoption by older adults is relatively slow, despite the potential health and social benefits. In this paper, we explore the barriers to acceptance of location-based services (LBS) in a community of older adults. OBJECTIVE: to understand attitudes to LBS technologies in older adults. METHODS: eighty-six older adults used LBS for 1-week and completed pre- and post-use questionnaires. Twenty available volunteers from the first study also completed in-depth interviews after their experience using the LBS technology. RESULTS: the pre-use questionnaire identified perceptions of usefulness, individual privacy and visibility as predictive of intentions to use a location-tracking service. Post-use, perceived risk was the only factor to predict intention to use LBS. Interviews with participants revealed that LBS was primarily seen as an assistive technology and that issues of trust and privacy were important. CONCLUSION: the findings from this study suggest older adults struggle to see the benefits of LBS and have a number of privacy concerns likely to inhibit future uptake of location-tracking services and devices.

Effective Interventions for Nursing Student Burnout: A Scoping Review.

BACKGROUND: Burnout in nursing students negatively impacts students' health, decreases academic success, increases attrition, and threatens the quality of patient care. PURPOSE: To identify empiric research evaluating the effectiveness of interventions to prevent nursing student burnout. METHODS: This scoping review examined the PubMed, CINAHL, PsycINFO, and Google Scholar databases to identify original studies evaluating burnout interventions in nursing students. RESULTS: Of the 258 studies identified in the primary search, 208 were screened and 29 were selected for full-text review. Five quantitative reports and 1 qualitative study met the inclusion criteria. Effective interventions included recreational music-making, mindfulness-based and resilience education, integral-caring-holistic-science curriculum, Acceptance and Commitment Training, and progressive muscle relaxation. Statistically significant reductions in burnout were reported in all 5 of the quantitative studies. CONCLUSION: This review demonstrates a need for further research. Burnout interventions should be embedded in the nursing curriculum to yield a more sustainable profession.

Postvaccine Era COVID-19 Pandemic-Related Distress in Palliative Care Patients With Advanced Cancer.

CONTEXT: The COVID-19 pandemic represents a source of distress in patients with advanced cancer; however, few studies have examined the extent of pandemic-related distress in the postvaccine era. OBJECTIVES: We conducted a cross-sectional survey to examine pandemic-related distress among patients seen by palliative care after vaccine availability. METHODS: Patients at our palliative care clinic were surveyed from April 2021 to March 2022 regarding 1) pandemic-related distress level, 2) potential contributors to pandemic-related distress, 3) coping strategies, 4) demographic factors and symptom burden. Univariate and multivariate analyses identified factors associated with pandemic-related distress. RESULTS: A total of 200 patients completed the survey. Of 79 (40%, 95% confidence interval [CI]: 33%, 46%) reported worse pandemic-related distress. Patients who reported greater distress were more likely to report worse social isolation (67 [86%] vs. 52 [43%]), staying home more often (75 [95%] vs. 95 [79%]), more negative experience staying at home (26 [33%] vs. 11 [9%]), worse stress with child-care duties (14 [19%] vs. 4 [3%]), less seeing family/friends (63 [81%] vs. 72 [60%]), and more difficulty traveling to medical appointments (27 [35%] vs. 20 [17%]). Thirty-seven patients (19%) reported more difficulty getting medical appointments. In multivariable analysis, younger age (odds ratio [OR], 0.97; 95% CI, 0.92-0.99; P = 0.01), worse isolation status (OR, 6.87; 95% CI, 2.76-17.12; P < 0.001), and more negative attitude towards staying home (OR, 4.49; 95% CI, 1.6-12.57; P = 0.004) were associated with pandemic-related distress. CONCLUSIONS: Patients with advanced cancer continued to experience pandemic-related distress in the postvaccine era. Our findings highlight potential opportunities to support patients.

DR3 Regulates Intestinal Epithelial Homeostasis and Regeneration After Intestinal Barrier Injury.

BACKGROUND & AIMS: Tumor necrosis factor (TNF) superfamily member tumor necrosis factor-like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor-like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration. METHODS: Clinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), Tl1a-/- and Dr3-/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3ΔIEC) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential. RESULTS: Dr3-/- mice developed more severe colonic inflammation than wild-type mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IECs was increased in Dr3-/- mice, but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occludens-1 were altered, leading to increased homeostatic intestinal permeability. Dr3ΔIEC mice recapitulated the phenotype observed in Dr3-/- mice with increased intestinal permeability and IEC proliferation under homeostatic conditions and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered zonula occludens-1 localization also were observed in Dr3ΔIEC enteroids. CONCLUSIONS: Our findings establish a novel function of DR3 in IEC homeostasis and postinjury regeneration independent of its established role in innate lymphoid cells and T-helper cells.

Substance use, treatment admissions, and recovery trends in diverse Washington State tribal communities.

BACKGROUND: Qualitative and quantitative data and participatory research approaches might be most valid and effective for assessing substance use/abuse and related trends in American Indian and Alaska Native (AIAN) communities. METHOD: Twenty-nine federally recognized AIAN tribes in Washington (WA) State were invited to participate in Health Directors (HD) interviews and State treatment admissions data analyses. Ten Tribal HD (or designees) from across WA participated in 30-60-minute qualitative interviews. State treatment admissions data from 2002 to 2008 were analyzed for those who identified with one of 11 participating AIAN communities to explore admission rates by primary drug compared to non-AIANs. Those who entered treatment and belonged to one of the 11 participating tribes (n = 4851) represented 16% of admissions for those who reported a tribal affiliation. RESULTS: Interviewees reported that prescription drugs, alcohol, and marijuana are primary community concerns, each presenting similar and distinct challenges. Additionally, community health is tied to access to resources, services, and culturally appropriate and effective interventions. Treatment data results were consistent with interviewee-reported substance use/abuse trends, with alcohol as the primary drug for 56% of AIAN adults compared to 46% of non-AIAN, and other opiates as second most common for AIAN adults in 2008 with 15% of admissions. LIMITATIONS: Findings are limited to those tribal communities/community members who agreed to participate. CONCLUSION: Analyses suggest that some diverse AIAN communities in WA State share similar substance use/abuse, treatment, and recovery trends and continuing needs. SCIENTIFIC SIGNIFICANCE: Appropriate and effective research with AIAN communities requires respectful and flexible approaches.