Defining the Denominator for Measuring Quality of End-of-Life Care in Children with Cancer: Results of a Nominal Group Technique.

OBJECTIVE: To determine which groups of children with cancer for whom to apply the newly developed quality measures (QMs) for end-of-life (EOL) care. STUDY DESIGN: In a series of nominal groups, panelists answered the question: "Which children, diagnoses, conditions, or prognoses should be included when examining the quality of EOL care for children with cancer?" In each group, individual panelists proposed answers to the question. After collating individual responses, each panelist ranked their 5 top answers and points were assigned (5 pts for the best answer, 4 pts the second best, etc.). A team of pediatric oncology and palliative care clinician-scientists developed and applied a coding structure for responses and associated themes and subthemes for responses. RESULTS: We conducted 5 nominal groups with a total of 44 participants. Most participants identified as female (88%) and non-Hispanic White (86%). Seventy-nine percent were clinicians, mainly in pediatric palliative care, pediatric oncology, or hospice; 40% were researchers and 12% were bereaved parents. Responses fell into 5 themes: (1) poor prognosis cancer; (2) specific treatment scenarios; (3) certain populations; (4) certain symptoms; and (5) specific utilization scenarios. Poor prognosis cancer and specific treatment scenarios received the most points (320 pts [49%] and 147 pts [23%], respectively). CONCLUSIONS: Participants developed a framework to identify which children should be included in EOL QMs for children with cancer. The deliberate identification of the denominator for pediatric QMs serves as a potent tool for enhancing quality, conducting research, and developing clinical programs.

How we approach sharing child-caregiver PRO disagreement.

Researchers use patient-reported outcomes (PRO) to capture the patient experience, and in pediatrics, parent report of symptom and function often accompanies the child's assessment. Children with cancer and their family caregivers frequently evaluate symptom burden and functional status differently. Child-caregiver PRO disagreement often worries pediatric oncology clinicians, who do not know how to best approach sharing it with families. Openly discussing differences in symptom and functional status reporting is a crucial element of supporting families and can improve family harmony throughout the child's illness journey. This paper offers strategies and language for communicating with families about PRO disagreement.

Isolated Grauer's gorilla populations differ in diet and gut microbiome.

The animal gut microbiome has been implicated in a number of key biological processes, ranging from digestion to behaviour, and has also been suggested to facilitate local adaptation. Yet studies in wild animals rarely compare multiple populations that differ ecologically, which is the level at which local adaptation may occur. Further, few studies simultaneously characterize diet and gut microbiome from the same sample, despite their probable interdependence. Here, we investigate the interplay between diet and gut microbiome in three geographically isolated populations of the critically endangered Grauer's gorilla (Gorilla beringei graueri), which we show to be genetically differentiated. We find population- and social group-specific dietary and gut microbial profiles and covariation between diet and gut microbiome, despite the presence of core microbial taxa. There was no detectable effect of age, and only marginal effects of sex and genetic relatedness on the microbiome. Diet differed considerably across populations, with the high-altitude population consuming a lower diversity of plants compared to low-altitude populations, consistent with plant availability constraining dietary choices. The observed pattern of covariation between diet and gut microbiome is probably a result of long-term social and environmental factors. Our study suggests that the gut microbiome is sufficiently plastic to support flexible food selection and hence contribute to local adaptation.

Navigating prognostic communication when children with poor-prognosis cancer experience prolonged disease stability.

BACKGROUND: Most pediatric patients and families want clear prognostic information across the illness course. Yet when children with poor-prognosis cancer experience prolonged disease stability, uncertainty can make communication particularly challenging. In this study, we aimed to (i) assess how frequently oncologists communicate about prognosis when high-risk cancer does not progress, and (ii) describe prognostic communication patterns in the context of disease stability. PATIENTS AND METHODS: In this prospective, longitudinal, mixed-methods study, we audio-recorded serial disease re-evaluation conversations between children with poor-prognosis cancer, their families, and their primary oncologists. For this secondary analysis, we conducted content analysis across serial conversations among 16 patient-parent-oncologist triads for whom the patient's disease remained stable over the 24-month study period. RESULTS: Prognostic communication was absent in >50% of recorded conversations. Overall, it comprised only 4% of dialog time, nearly 90% of which was dialog about prognostic uncertainty; discussion of curability occurred infrequently. Three distinct patterns for prognostic communication emerged: (a) "Don't know" statements, avoiding or deferring prognostication; (b) "Worry" statements, preparing families for possible future disease progression; and (c) relief-caveat statements, celebrating disease stability while balancing positivity with caution. CONCLUSIONS: Oncologists seldom talked about prognosis with high-risk patients during periods of disease stability; yet when they did, they used thoughtful and effective strategies to prepare families for possible future disease progression. Further research is needed to better understand if, how, and when patients and families with stable disease who are high risk for future disease progression prefer to receive information about prognosis.

Oncologist approaches to communicating uncertain disease status in pediatric cancer: a qualitative study.

BACKGROUND: Most patients with cancer and their caregivers desire honest, clear prognostic communication, yet oncologists often disclose prognosis inconsistently. Prognostic communication becomes even more challenging when disease progression is unclear or equivocal. Presently, oncologist approaches for discussing uncertain disease findings are poorly understood. METHODS: In this prospective, longitudinal study, we audio-recorded serial disease reevaluation conversations between children with high-risk cancer, their families, and their primary oncologists over 24 months and conducted content analysis at recorded timepoints when oncologists categorized disease progression as equivocal. RESULTS: Of the 265 medical discussions recorded across the illness course for 33 patient-parent dyads, a total of 40 recorded discussions took place at equivocal timepoints, comprising > 500 min of medical dialogue. Prognosis talk encompassed < 3% of dialogue and was absent in nearly half of equivocal discussions (17/40, 42.5%). Curability statements were identified in only two conversations. Inductive content analysis of dialogue revealed four distinct patterns for communicating equivocal disease status: (1) up-front reassurance, (2) softening the message, (3) describing possible disease progression without interpretation, (4) expressing uncertainty without discussing the bigger picture. CONCLUSION: Oncologists rarely discuss prognosis with children with high-risk cancer and their families at timepoints when disease progression is not definitive. Formal guidance is needed to better support oncologists in navigating uncertainty while sharing honest, person- and family-centered information about prognosis.

Ranging behavior and the potential for territoriality in pair-living titi monkeys (Plecturocebus discolor).

Patterns of ranging behavior and space use are key for evaluating current ideas about the evolution and maintenance of pair-living and sexual monogamy as they provide insights into the dispersion of females, the potential for territoriality, and whether males are limited to defending an area that can support only one female and her offspring. We examined ranging behavior and space use to evaluate the potential for territoriality in five groups of red titi monkeys (Plecturocebus discolor) during a 10-year study in Ecuadorian Amazonia. Mean home range size, calculated using a time-sensitive local convex hull estimation procedure, was 4.0 ± 1.4 ha. Annual home ranges of neighboring groups overlapped, on average, 0%-7%. Mean daily path length was 670 ± 194 m, resulting in defendability indices of 2.2-3.6 across groups. Groups visited, on average, 4 of 12 sections of their home range border area per day, but that was not more often than would be expected by chance, and intergroup encounters were infrequent. We did not find evidence of active monitoring for intruders in border areas, in that groups did not travel either faster or slower when at the border than when in central areas of their range. The absence of overt monitoring might be compensated for by engaging in loud calls, which the study groups did throughout their home ranges; these calls may serve as an advertisement of occupancy and a deterrent to intruding conspecifics. Our finding that red titis have a high potential for territoriality is consistent with several of the main hypotheses proposed to explain pair-living in mammals.

Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation.

Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a-/- Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.

Clinical Competencies for the Care of Hospitalized Patients with Alcohol Use Disorders.

AIMS: The UK government aims to develop alcohol care teams (ACTs) that provide care for alcohol dependence in general hospital settings. Service descriptors have been identified to support the development of ACTs. The aim of this study was to use Delphi panel principles to identify the clinical competencies required to provide these elements of service. METHODS: We formed an expert consensus panel of 24 senior clinical alcohol practitioners, leaders and experts by experience drawn from all regions of England. The study was divided into three distinct phases: (a) a review and synthesis of current literature in this area, (b) a face-to-face meeting of the expert panel and (c) subsequent iterations to refine the competencies until consensus was reached. RESULTS: Our initial search strategy resulted in 555 competency statements being extracted from a range of national clinical professional and occupational standards and other sources. The research team refined these statements to 98 competencies in advance of the expert meeting. The panel identified 14 additional statements and reduced the number of competencies to 78. Subsequent iterations finalized 72 competencies across the 8 service descriptors. CONCLUSIONS: Drawing on the existing published resources and clinical experience, the expert panel has provided consensus on the core clinical competencies required for alcohol care teams in caring for hospitalized patients with alcohol use disorders. Whilst it is acknowledged that the range of current provision is variable, these competencies provide a template for clinical practice and the development of multidisciplinary ACTs.

The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement.

The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient-reported outcome measures in the future.

Ranging behavior and potential for territoriality in equatorial sakis (Pithecia aequatorialis) in Amazonian Ecuador.

OBJECTIVES: Territoriality refers to the consistent defense of an area within the home range (HR) against intrusions of conspecifics. It implies exclusive space use with low degree of overlap among neighboring groups, high site fidelity, specific ranging behavior such as high mobility relative to HR size and frequent visits of territory borders, and monitoring behavior. We examined ranging behavior and use of space to evaluate territoriality in Pithecia aequatorialis in Ecuador. MATERIALS AND METHODS: Between 2005 and 2015, we monitored one main study group continuously and five additional groups for shorter periods (5 months to 2.5 years) at the Tiputini Biodiversity Station, in eastern Ecuador. We scored the location of the study groups at 20 min intervals during, on average, 5 days per month. We estimated saki HRs and core areas (CAs) using the fixed kernel density method (95 and 50%, respectively). RESULTS: The average HR size was 57 ha and the average CA 14 ha. The degree of overlap between HRs of neighboring groups was low (2-9%). For the main study group, the average overlap between annual HRs was 82%. Mean daily path length across groups was 1,151 m; the defensibility index varied between 1.1 and 2.3 (values >1 are suggestive of territoriality), and the fractional monitoring rate varied between 0.06 and 0.15 (values >0.08 are suggestive of territoriality). Groups did not visit their HR borders (100 m inner buffer) more often than would be expected by chance. Travel speed and directness were comparable between the borders and the centers of groups' HRs. DISCUSSION: Our multiyear study suggests that equatorial sakis show low degree of range overlap and high site fidelity and have the potential to be territorial, given their high mobility relative to HR size that allows for frequent border monitoring. Nevertheless, their movement patterns in border areas did not reveal evidence for monitoring behavior.

Delayed Dispersal and Immigration in Equatorial Sakis (Pithecia aequatorialis): Factors in the Transition from Pair- to Group-Living.

Saki monkeys (Pithecia spp.) live in pairs and small groups, sometimes with more than 1 same-sex adult. Previous studies have not been able to distinguish additional, unrelated adults from adult-sized offspring, but both can influence social relationships and mating strategies, albeit in different ways. In this study, we documented the immigration of an adult male equatorial saki (P. aequatorialis) into a group following the departure of the previous resident male. At immigration, the group contained an adult female, her 5-year-old (adult age) and 1.5-year-old daughters, and her 1-month-old infant. We used nearest neighbor, approach, grooming, playing, aggression, and copulation data to describe the social dynamics between the immigrant male and the 2 adult females. In the 12 months following his arrival, the immigrant male tended to be closer to and groom the adult daughter more than the mother, but he mated with both females. Both females interacted more with the immigrant male than with each other, and both females eventually reproduced. These observations provide evidence that in equatorial sakis, adult offspring may delay dispersal and reproduce within their natal group, thus transitioning from groups of reproductive pairs to groups with more than 1 reproductive adult of the same sex.

AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer.

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

A Saki Saga: Dynamic and Disruptive Relationships among Pithecia aequatorialis in Ecuador.

Saki monkeys live in socially monogamous groups and in groups containing more than one same-sex adult. As part of a 10-year study of equatorial sakis (Pithecia aequatorialis) in Ecuador, we documented the immigration of a second adult male into a group containing a resident male-female pair that had associated with one another for seven years and the resident female's two daughters. In the first month after immigration, the resident male spent more time closer to and grooming his putative adult daughter than the resident female, and the two males were seen performing a cooperative territorial display. After two months, the resident male interacted more with the resident female than with his putative adult daughter, while that daughter interacted more with the immigrant male and copulated with him. After three months, the males left the group together and associated with an unfamiliar female, leaving the resident females and a neonate behind. The resident male then paired with a new female, while the immigrant male joined another group, again as a second male. Compared to other socially monogamous primates, sakis appear to have a more variable social system whereby additional males can join established groups and form relationships with putatively unrelated males.

Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.

We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH).

Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.

Longitudinal Impact of a Novel Condolence Expression Curriculum.

Background: Pediatric residents lack training in expressing condolences to bereaved families after a child's death. We previously developed a novel curriculum that improved residents' comfort with expressing condolences, and now we report assessment of the longitudinal impact of this curriculum on residents' practices of condolence expression. Methods: We applied Kern's 6-step approach to develop, implement, and evaluate a condolence expression curriculum. Residents completed surveys before, immediately after, and six months after participating in the educational intervention to assess curricular impact over time. Results: Twenty pediatric residents participated in the curriculum. Residents reported an increase in their practice of expressing condolences following participation in the curriculum, as well as appreciation for the value of the intervention. Conclusion: A condolence expression curriculum has potential to increase residents' practice of condolence expression to bereaved families over time. Future work will focus on the impact of curricular dissemination across pediatric residency programs.

Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

Associations between childhood obesity and upper and lower extremity injuries.

OBJECTIVES: To estimate the overall and age-specific associations between obesity and extremity musculoskeletal injuries and pain in children. METHODS: This cross-sectional study used information from electronic medical records of 913178 patients aged 2-19 years enrolled in an integrated health plan in the period 2007-2009. Children were classified as underweight, normal weight, overweight, or moderately/extremely obese and, using multivariable logistic regression methods, the associations between weight class and diagnosis of upper or lower extremity fractures, sprains, dislocations and pain were calculated. RESULTS: Overweight (OR 1.18, 95% CI 1.15 to 1.20), moderately obese (OR 1.24, 95% CI 1.20 to 1.27) and extremely obese (OR 1.34, 95% CI 1.30 to 1.39) children had statistically significantly higher odds of lower extremity injuries/pain compared to normal weight, adjusted for sex, age, race/ethnicity and insurance status. Age-stratified analyses yielded similar results. No consistent association was observed between body mass index and injuries/pain of the upper extremities. CONCLUSIONS: Greater body mass index is associated with increased odds of lower extremity injuries and pain issues. Because the benefits of physical activity may still outweigh the risk of injury, attention should be paid to injury prevention strategies for these children at greater risk for lower extremity injuries.

Mismatch between Pediatric Oncologists' Private and Parent-Facing Prognostic Communication: Communication Patterns Used to Soften Prognostic Disclosure.

Purpose: Most parents of children with cancer desire honest prognostic communication, yet oncologists often avoid clear prognostic disclosure. This study explored differences between oncologists' private assessments of prognosis and their prognostic communication with patients and parents. Patients and Methods: In this prospective, longitudinal, mixed-methods study, we audio-recorded serial disease reevaluation conversations between children with advancing cancer, parents, and primary oncologists and separately surveyed and interviewed oncologists at disease progression time points. At time points when oncologists privately described curability as ≤10%, content analysis was used to compare prognostic language in recorded dialogue with private responses about prognosis. Results: Of 33 enrolled patient-parent dyads, 17 patients with high-risk cancer under the care of 6 primary oncologists experienced disease progression during the study period. In 95% of oncologist interviews at disease progression time points, oncologists either predicted curability to be ≤10% or incurable. In most interviews (82%), oncologists stated unequivocally that chances of cure were ≤10%, yet did not communicate these low odds during recorded discussions at the same time point. Analysis revealed three distinct communication patterns through which oncologists softened prognostic disclosure to patients and families: (1) space-holding for hope of cure: statements acknowledging difficult prognosis yet leaving room for possibility of cure; (2) vague warning: statements implying that cancer may progress without offering specifics; and (3) data without interpretation: statements describing disease progression findings in detail without explaining what this meant for the patient's future life or survival. Conclusion: Pediatric oncologists often temper their assessment of poor prognosis when speaking with patients and families. Future work should explore serious conversation guides and other clinical interventions aimed at encouraging person-centered prognostic disclosure for patients with advancing cancer and their families.