Barriers to Pediatric Palliative Care: Trainee and Faculty Perspectives Across Two Academic Centers.

Objective: Barriers to palliative care for children with serious illness include system constraints and vastly different training and attitudes toward palliative care. This study aimed to explore trainee and faculty physician perceptions of barriers to palliative care across two pediatric centers to (1) examine differences between trainees and faculty and (2) compare these data with previous studies. Methods: A mixed-methods study was conducted in fall 2021 among pediatric trainees and faculty physicians at three pediatric hospitals in two pediatric centers in the western United States. Surveys were distributed through hospital listservs and analyzed descriptively and through inductive thematic analysis. Results: There were a total of 268 participants: 50 trainees and 218 faculty physicians. Of the trainees, 46% (23) were fellows and 54% (27) were pediatric residents. Trainees and faculty reported the same four most common barriers, which were consistent with previous studies: family not ready to acknowledge an incurable condition (64% trainees and 45% faculty); family preference for more life-sustaining therapies than staff (52% and 39%); uncertain prognosis (48% and 38%); and parent discomfort with possibility of hastening death (44% and 30%). Other barriers commonly reported included time constraints, staff shortages, and conflict among family about treatment goals. Language barriers and cultural differences were also cited. Conclusions: This study examining palliative care across two pediatric centers suggests that providers' perceptions of family preferences and understanding of illness persist as barriers to the delivery of pediatric palliative care services. Future research should examine family-centered and culturally mindful interventions to better elucidate family perspectives on their child's illness to align care.

Prenatal counseling and parental decision-making following a fetal diagnosis of trisomy 13 or 18.

OBJECTIVES: To evaluate parental decisions following a prenatal diagnosis of trisomy 13 (T13) or trisomy 18 (T18), prenatal counseling received, and pregnancy outcomes. STUDY DESIGN: Single-center, retrospective cohort study of families with a prenatal diagnosis of T13 or T18 from 2000 to 2016. RESULTS: Out of 152 pregnancies, 55% were terminated. Twenty percent chose induction with palliative care, 20% chose expectant management, 2% chose full interventions, and 3% were lost to follow-up. Counseling was based on initial parental goals, but most women were given options besides termination. Women who chose expectant management had a live birth in 50% of the cases. Women who chose neonatal interventions had a live birth in 100% of the cases, but there were no long-term survivors. CONCLUSIONS: The majority of women who continue their pregnancy after a fetal diagnosis of T13 or T18 desire expectant management with palliative care. A live birth can be expected at least half of the time.

A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants.

Microglia are emerging as a key cell type in neurodegenerative diseases, yet human microglia are challenging to study in vitro. We developed an in vitro cell model system composed of human monocyte-derived microglia-like (MDMi) cells that recapitulated key aspects of microglia phenotype and function. We then used this model system to perform an expression quantitative trait locus (eQTL) study examining 94 genes from loci associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We found six loci (CD33, PILRB, NUP160, LRRK2, RGS1, and METTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In the PILRB and LRRK2 loci, the cis-eQTL was found in the MDMi cells but not in human peripheral blood monocytes, suggesting that differentiation of monocytes into microglia-like cells led to the acquisition of a cellular state that could reveal the functional consequences of certain genetic variants. We further validated the effect of risk haplotypes at the protein level for PILRB and CD33, and we confirmed that the CD33 risk haplotype altered phagocytosis by the MDMi cells. We propose that increased LRRK2 gene expression by MDMi cells could be a functional outcome of rs76904798, a single-nucleotide polymorphism in the LRKK2 locus that is associated with Parkinson's disease.

Trans-pQTL study identifies immune crosstalk between Parkinson and Alzheimer loci.

OBJECTIVE: Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes. METHODS: We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study. Linear regression was used to identify associations between 24 PD risk variants and protein expression. The 2 cohorts were meta-analyzed in a discovery analysis, and the 4 most strongly suggestive results were validated in an independent cohort of 50 PGP participants. RESULTS: We discovered and validated an association between the PD risk allele rs12456492(G) in the RIT2 locus and increased CD33 expression (p joint = 3.50 × 10(-5)) and found strongly suggestive evidence that rs11060180(A) in the CCDC62/HIP1R locus decreased PTK2B expression (p joint = 1.12 × 10(-4)). Furthermore, in older individuals, increased CD33 expression on peripheral monocytes was associated with a greater burden of parkinsonism (p = 0.047), particularly bradykinesia (p = 6.64 × 10(-3)). CONCLUSIONS: We find that the rs12456492 PD risk variant affects expression of AD-associated protein CD33 in peripheral monocytes, which suggests that genetic factors for these 2 diseases may converge to influence overlapping innate immune-mediated mechanisms that contribute to neurodegeneration. Furthermore, the effect of the rs12456492(G) PD risk allele on increased CD33 suggests that the inhibition of certain myeloid functions may contribute to PD susceptibility, as is the case for AD.

Genes and Environment in Multiple Sclerosis project: A platform to investigate multiple sclerosis risk.

The Genes and Environment in Multiple Sclerosis project establishes a platform to investigate the events leading to multiple sclerosis (MS) in at-risk individuals. It has recruited 2,632 first-degree relatives from across the USA. Using an integrated genetic and environmental risk score, we identified subjects with twice the MS risk when compared to the average family member, and we report an initial incidence rate in these subjects that is 30 times greater than that of sporadic MS. We discuss the feasibility of large-scale studies of asymptomatic at-risk subjects that leverage modern tools of subject recruitment to execute collaborative projects.

CD33 modulates TREM2: convergence of Alzheimer loci.

We used a protein quantitative trait analysis in monocytes from 226 individuals to evaluate cross-talk between Alzheimer loci. The NME8 locus influenced PTK2B and the CD33 risk allele led to greater TREM2 expression. There was also a decreased TREM1/TREM2 ratio with a TREM1 risk allele, decreased TREM2 expression with CD33 suppression and elevated cortical TREM2 mRNA expression with amyloid pathology.

A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology.

OBJECTIVE: Genome-wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD. METHODS: Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes. RESULTS: We provide evidence that an intronic variant, rs6910730(G) , in TREM1, is associated with an increased burden of neuritic plaques (p = 3.7 × 10(-4) ), diffuse plaques (p = 4.1 × 10(-3) ), and Aß density (p = 2.6 × 10(-3) ) as well as an increased rate of cognitive decline (p = 5.3 × 10(-3) ). A variant upstream of TREM2, rs7759295(C) , is independently associated with an increased tau tangle density (p = 4.9 × 10(-4) ), an increased burden of neurofibrillary tangles (p = 9.1 × 10(-3) ), and an increased rate of cognitive decline (p = 2.3 × 10(-3) ). Finally, a cytometric analysis shows that the TREM1 rs6910730(G) allele is associated with decreased TREM1 expression on the surface of myeloid cells (p = 1.7 × 10(-3) ). INTERPRETATION: We provide evidence that 2 common variants within the TREM locus are associated with pathological features of AD and aging-related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function.