Search

Importance: Adolescent and young adult (AYA) patients with advanced cancer often die in hospital settings. Data characterizing the degree to which this pattern of care is concordant with patient goals are sparse., Objective: To evaluate the extent of concordance between the preferred and actual location of death among AYA patients with cancer., Design, Setting, and Participants: This multicenter retrospective cohort study included AYA patients (aged 12-39 years) with cancer who died between January 1, 2003, and December 31, 2019, after receiving care at Dana-Farber Cancer Institute and Kaiser Permanente Northern California or who died between January 1, 2009, and December 31, 2019, after receiving care at Kaiser Permanente Southern California. Data were analyzed from January 12 to July 1, 2024., Exposure: Death due to cancer., Main Outcomes and Measures: Medical record documentation of discussions about preferred location of death, actual location of death, and concordance between preferred and actual location of death., Results: The analytic population included 1929 AYA decedents, of whom 1049 (54.4%) were female; 227 (11.8%), Asian; 157 (8.1%), Black; 514 (26.6%), Hispanic; and 1184 (61.4%), White. Median age at death was 32 (IQR, 25-37) years. A total of 1226 AYA patients (63.6%) had a documented discussion about preferred location of death. Among those with a documented discussion, 594 (48.5%) did not have a documented preference, 402 (32.8%) wanted to die at home, 177 (14.4%) preferred a hospital death, and 48 (3.9%) desired inpatient hospice. Eight hundred and thirty patients (43.0%) died in acute care settings (256 [13.3%] intensive care unit [ICU], 548 [28.4%] hospital [non-ICU], and 26 [1.3%] emergency department), while 643 (33.3%) died at home and 47 (2.4%) in an inpatient hospice. Among the 528 patients with both a documented preferred death location of home, hospital, or inpatient hospice and documented death in one of these locations, the concordance between preferred and actual location of death was 401 (75.9%). One hundred and sixty-four of 172 patients (95.3%) who preferred a hospital death died there; 224 of 317 (70.7%) who preferred a home death died at home, and 13 of 39 (33.3%) who desired to die in inpatient hospice did so., Conclusions and Relevance: Although many AYA patients with cancer died in their preferred location, over one-quarter of those who desired to die at home did not realize this goal. These findings highlight the need for effective solutions to enable goal-concordant care for this population.

Importance: Little is known about the nature of change in goals of care (GOC) over time among adolescents and younger adult (AYA) patients aged 12 to 39 years with cancer near the end of life. Understanding how GOC evolve may guide clinicians in supporting AYA patients in making end-of-life decisions., Objective: To assess frequency, timing, and evolution of documented GOC among AYA patients with cancer in the last 90 days of life., Design, Setting, and Participants: This cross-sectional study included a retrospective review of medical records from the Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California of AYA patients with cancer who were 12 to 39 years of age at death and who died between January 1, 2003, and December 31, 2019. Data were analyzed from July 1, 2023, through April 30, 2024., Exposures: Stage IV cancer or stage I-III cancer with new metastasis or recurrence., Main Outcome and Measures: The primary outcome was documented GOC discussions, categorized by timing before death as initial (>60 days), middle (31-60 days), or late (≤30 days). Goals were classified as palliative, nonpalliative, undecided, or not discussed. Subgroup analysis according to race and ethnicity were also performed., Results: Among 1929 AYA patients with a mean (SD) age at cancer diagnosis of 28 (8) years, 1049 (54.5%) were female; 5 (0.3%) were American Indian or Alaska Native, 227 (11.8%) were Asian, 157 (8.1%) were Black or African American, 14 (0.7%) were Native Hawaiian or Other Pacific Islander, 1184 (61.4%) were White, 11 (0.6%) were of more than 1 race, 38 (2.0%) were categorized as other race, 293 (15.2%) were without documented race, 514 (26.6%) were Hispanic or Latino, 762 (39.5%) were not Hispanic or Latino, and 653 (33.9%) had no documented ethnicity. Few AYA patients had palliative goals documented in the initial period (139 [7.2%]), increasing to 331 (17.2%) in the middle period and 1113 (57.7%) in the late period. In total, 393 patients (20.4%) transitioned from documented nonpalliative goals in the initial or middle periods to palliative goals by the late period. Many patients had no documented GOC discussion until close to death (initial, 1364 [70.7%]; middle, 969 [50.2%]; and late, 322 [16.7%]). Among the 1929 patients, non-White patients were disproportionately represented among those not having documented GOC discussions (Black, 30 of 157 [19.1%]; Asian, 45 of 227 [19.8%]; and other or undocumented race, 80 of 361 [22.2%]) compared with White patients (167 of 1184 [14.1%]) (P < .001) as were Hispanic or Latino patients (116 of 514 [22.6%]) compared with non-Hispanic patients (93 of 762 [12.2%]) (P < .001) and individuals with no ethnicity documented (113 of 653 [17.3%]) (P < .001)., Conclusions and Relevance: In this cross-sectional study of AYA patients who died of cancer, palliative goals were rarely documented before the last month of life, highlighting the need for timely and ongoing GOC discussions.

Background/objective: Multilevel barriers to colonoscopy after a positive fecal blood test for colorectal cancer (CRC) are well-documented. A less-explored barrier to appropriate follow-up is repeat fecal testing after a positive test. We investigated this phenomenon using mixed methods., Design: This sequential mixed methods study included quantitative data from a large cohort of patients 50-89 years from four healthcare systems with a positive fecal test 2010-2018 and qualitative data from interviews with physicians and patients., Main Measures: Logistic regression was used to evaluate whether repeat testing was associated with failure to complete subsequent colonoscopy and to identify factors associated with repeat testing. Interviews were coded and analyzed to explore reasons for repeat testing., Key Results: A total of 316,443 patients had a positive fecal test. Within 1 year, 76.3% received a colonoscopy without repeat fecal testing, 3% repeated testing and then received a colonoscopy, 4.4% repeated testing without colonoscopy, and 16.3% did nothing. Among repeat testers (7.4% of total cohort, N = 23,312), 59% did not receive a colonoscopy within 1 year. In adjusted models, those with an initial positive test followed by a negative second test were significantly less likely to receive colonoscopy than those with two successive positive tests (OR 0.37, 95% CI 0.35-0.40). Older age (65-75 vs. 50-64 years: OR 1.37, 95% CI 1.33-1.41) and higher comorbidity score (≥ 4 vs. 0: OR 1.75, 95% CI 1.67-1.83) were significantly associated with repeat testing compared to those who received colonoscopy without repeat tests. Qualitative interview data revealed reasons underlying repeat testing, including colonoscopy avoidance, bargaining, and disbelief of positive results., Conclusions: Among patients in this cohort, 7.4% repeated fecal testing after an initial positive test. Of those, over half did not go on to receive a colonoscopy within 1 year. Efforts to improve CRC screening must address repeat fecal testing after a positive test as a barrier to completing colonoscopy., Competing Interests: Declarations:. Conflict of Interest:: Dr. Green is a member of the National Colorectal Cancer Round Table Steering Committee, which is supported by the American Cancer Society and the Centers for Disease Control and Prevention. She receives no compensation for this position except for travel to steering committee meetings. Dr. Levin reports research support from Freenome, Inc. All other authors report no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background: Adolescents and young adults frequently receive chemotherapy near death. We know less about the use of targeted agents and immunotherapy or trends over time., Methods: We conducted a retrospective cohort study of 1836 adolescents and young adults with cancer who died between 2009 and 2019 after receiving care at 1 of 3 sites (Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California). We reviewed electronic health data and medical records to examine use of cancer-directed therapy in the last 90 days of life, including chemotherapy, targeted therapy, immunotherapy, and investigational drugs., Results: Over the study period, 35% of adolescents and young adults received chemotherapy in the last 90 days of life; 24% received targeted therapy, 7% immunotherapy, and 5% investigational drugs. Additionally, 56% received at least 1 form of systemic cancer-directed therapy in the last 90 days of life. After adjustment for patient sex, race, ethnicity, age, site of care, diagnosis, and years from diagnosis to death, the proportion of adolescents and young adults receiving targeted therapy (odds ratio [OR] = 1.05 per year of death, 95% confidence interval [CI] = 1.02 to 1.10; P = .006), immunotherapy (OR = 1.27, 95% CI = 1.18 to 1.38; P < .0001), and any cancer-directed therapy (OR = 1.04, 95% CI = 1.01 to 1.08; P = .01) in the last 90 days of life increased over time., Conclusions: More than half of adolescents and young adults receive cancer therapy in the last 90 days of life, and use of novel agents such as targeted therapy and immunotherapy is increasing over time. Although some adolescents and young adults may wish to continue cancer therapy while living with advanced disease, efforts are needed to ensure that use of cancer-directed therapy meets preferences of adolescents and young adults approaching death., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Adolescents, young adults with cancer receive limited psychosocial and spiritual support near death.

Background: DATATOP was a study of early Parkinson's disease (PD) conducted in the 1980 s, before mandatory folic acid fortification in the United States. Our analysis of its baseline serum samples revealed a geometric mean vitamin B12 of 369 pg/mL and homocysteine (tHcy) of 9.5μmol/l. We also found that low B12 predicted greater worsening of ambulatory capacity (AC) and elevated tHcy (>15μmol/L) predicted greater declines in cognitive function., Objective: We sought to measure B12 and tHcy in contemporary trial participants with early PD who had not started dopaminergic treatment and to determine whether these analytes were associated with clinical progression., Methods: We measured B12 and tHcy from baseline and end-of-study blood samples from three recent clinical trials., Results: Baseline geometric mean B12 levels for these studies ranged from 484- 618 pg/ml and for tHcy ranged from 7.4- 10μmol/L. Use of B12-containing supplements ranged from 41- 61%, and those taking supplements had higher B12 and lower tHcy. Those who began levodopa, but were not taking B12-supplements, had greater end-of-study tHcy. There was no association of baseline tHcy > 15μmol/L with annualized change in Montreal Cognitive Assessment and no association of baseline B12 tertiles with change in AC., Conclusions: In these longitudinal trials, B12 levels were higher than for DATATOP, due in large part to increased B12-supplement intake, while tHcy levels were similar. Initiation of levodopa was associated with increases of tHcy in those not taking a B12-containing supplement. These smaller studies did not replicate prior findings of low B12 and elevated tHcy with features of progression, possibly due to higher baseline B12.

Previous reports have provided evidence that insufficient or excessive maternal folic acid (FA) intake during pregnancy can alter neurodevelopment of the offspring by modulating prenatal neurogenesis. Furthermore, our earlier work in a mouse model confirmed long-term structural changes at the cellular level of either deficient or excessive FA supply by comparably reducing dendritic arborization of cortical projection neurons. Here, we report that excessive amounts of FA decrease arborization of deep layer projection neurons, but not upper layer neurons and that reduced complexity of deep layer neurons is not observed when folic acid is replaced by folinic acid, a stable reduced form of folate. In addition, deficiency of B 12 , a vitamin that critically regulates folate metabolism, causes even more marked decreases in neuronal arborization in both deep and upper layer neurons and particularly in combination with FA excess. Furthermore, both FA excess and B 12 deficiency affect synaptic density and morphology. Our findings point to neurodevelopmental risks associated with insufficient amounts of prenatal B 12 , particularly in association with high levels of FA intake, suggesting that the neurodevelopmental program is sensitive to an imbalance in the status of these interacting micronutrients., (© 2023. The Author(s).)

Purpose: Adolescents and young adults (AYAs) with cancer receive high rates of medically intensive measures at the end of life. This study aimed to characterize the prevalence and timing of conversations about goals of care and advance care planning among AYAs at the end of life as one potential influence on care received., Methods: This was a review of electronic health data and medical records for 1,929 AYAs age 12-39 years who died after receiving care at one of three sites between 2003 and 2019, including documented conversations about goals of care and advance care planning, and care received., Results: A majority of AYAs were female (54%) and White (61%); 12% were Asian, 8% Black, and 27% Hispanic. Most patients had documented discussions about prognosis (86%), goals of care (83%), palliative care (79%), hospice (79%), and preferred location of death (64%). When last documented goals of care were evaluated, 69% of patients wanted care focused on palliation; however, 29% of those with palliative goals spent time in the intensive care unit (ICU) in the last month of life, and 32% had multiple emergency room (ER) visits. When goals-of-care discussions happened earlier, >30 days before death, AYAs were less likely to receive chemotherapy in the last 14 days of life ( P = .001), ICU care ( P < .001), ER visits ( P < .001), and hospitalizations in the last month ( P < .001)., Conclusion: High rates of medically intensive measures among AYAs near the end of life do not appear to be the result of a lack of discussions about goals of care and advance care planning. Although some interventions may be used to support palliative goals, earlier discussions have potential to reduce late-life intensive measures.

Background: COVID-19 is an infectious disease caused by a Coronavirus in humans, namely SARS-CoV-2, which has quickly become a global pandemic. The infection is responsible for a severe form of pneumonia, which may lead to lung failure and death. Among the therapeutic strategies, the antiviral agent remdesivir has become one of the most used drugs. The current literature reports a causal correlation between remdesivir administration and the incidence of cardiovascular effects. We aimed to further investigate this relationship, by exploring the association between the use of remdesivir and the onset of bradyarrhythmic disorders., Methods: We reviewed medical records, blood exams and chest imaging of 85 patients with COVID-19 pneumonia (M/F: 57/28, age: 61±12 years) admitted between September 2020 and May 2021 to the Division of Respiratory Diseases in Palermo, Italy., Results: We found a significant correlation between treatment with remdesivir and the occurrence of bradycardia, lasting for at least 3 days, which returned to normal values after the discontinuation of the drug. A significant reduction in heart rate (HR) was observed in the days following remdesivir administration (L. ratio 47.4, P<0.0001) in 24 patients (HR on the first day of observation: 75±14 bpm; at discharge: 72±14 bpm). Cardiac events occurred more frequently in subjects with extensive pulmonary involvement (greater than 50% of the total parenchyma, as assessed by chest CT)., Conclusions: We suggest to carefully monitor the administration of the drug in patients with risk factors for arrhythmic or cardiovascular events.

Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity. Among the identified suppressors, linked to HD-associated processes, we focus on Metal response element binding transcription factor 1 (Mtf1). Forced expression of Mtf1 counteracts cell death and oxidative stress caused by mHTT in mouse ESCs and in human neuronal precursor cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mHTT. In R6/2 mice, Mtf1 ablates motor defects and reduces mHTT aggregates and oxidative stress. Our screening strategy enables a quick in vitro identification of promising suppressor genes and their validation in vivo, and it can be applied to other monogenic diseases., (© 2023. The Author(s).)

Background: We sought to evaluate the trends of HPV vaccination between 03/2019-09/2021 and whether the impact of the COVID pandemic on HPV vaccination varied by race/ethnicity and neighborhood deprivation index (NDI)., Methods: Electronic medical records at Kaiser Permanente Southern California were used to assess monthly volume of HPV vaccine doses administered among children aged 9-12.9yrs, and up-to-date coverage (% vaccinated) by age 13 between 03/2019-09/2021. Modified Poisson models were used to evaluate the interactions between race/ethnicity, NDI and the pandemic periods on HPV vaccine coverage., Results: HPV vaccine doses administered in 2020/2021 have returned to the 2019 level after the initial drop. The average up-to-date coverage in 05/2021-09/2021 (54.8%) remained lower than the pre-pandemic level (58.5%). The associations between race/ethnicity, NDI and HPV vaccine coverage did not vary due to the pandemic., Conclusion: HPV vaccine promotion efforts are needed to address COVID-19 pandemic's lasting impact on HPV vaccination coverage., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chao CR received research funding from Merck for an unrelated project., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Proper cerebral cortical development depends on the tightly orchestrated migration of newly born neurons from the inner ventricular and subventricular zones to the outer cortical plate. Any disturbance in this process during prenatal stages may lead to neuronal migration disorders (NMDs), which can vary in extent from focal to global. Furthermore, NMDs show a substantial comorbidity with other neurodevelopmental disorders, notably autism spectrum disorders (ASDs). Our previous work demonstrated focal neuronal migration defects in mice carrying loss-of-function alleles of the recognized autism risk gene WDFY3. However, the cellular origins of these defects in Wdfy3 mutant mice remain elusive and uncovering it will provide critical insight into WDFY3-dependent disease pathology., Methods: Here, in an effort to untangle the origins of NMDs in Wdfy3 lacZ mice, we employed mosaic analysis with double markers (MADM). MADM technology enabled us to genetically distinctly track and phenotypically analyze mutant and wild-type cells concomitantly in vivo using immunofluorescent techniques., Results: We revealed a cell autonomous requirement of WDFY3 for accurate laminar positioning of cortical projection neurons and elimination of mispositioned cells during early postnatal life. In addition, we identified significant deviations in dendritic arborization, as well as synaptic density and morphology between wild type, heterozygous, and homozygous Wdfy3 mutant neurons in Wdfy3-MADM reporter mice at postnatal stages., Limitations: While Wdfy3 mutant mice have provided valuable insight into prenatal aspects of ASD pathology that remain inaccessible to investigation in humans, like most animal models, they do not a perfectly replicate all aspects of human ASD biology. The lack of human data makes it indeterminate whether morphological deviations described here apply to ASD patients or some of the other neurodevelopmental conditions associated with WDFY3 mutation., Conclusions: Our genetic approach revealed several cell autonomous requirements of WDFY3 in neuronal development that could underlie the pathogenic mechanisms of WDFY3-related neurodevelopmental conditions. The results are also consistent with findings in other ASD animal models and patients and suggest an important role for WDFY3 in regulating neuronal function and interconnectivity in postnatal life., (© 2022. The Author(s).)

Purpose: Clinical trial enrollment is low among adolescents and young adults (AYAs) with cancer and may contribute to inferior survival gains in recent years in this population compared with other age groups. We investigated clinical trial participation among AYA women with cancer, and examined whether patients discussed clinical trial participation with their doctor and reasons for nonparticipation. Methods: Women with a diagnosis of breast cancer, thyroid cancer, melanoma, lymphoma, or gynecologic cancer at ages 15-39 years during 2004-2016 were identified from the North Carolina Central Cancer Registry and the Kaiser Permanente Southern California health system. During 2018-2019, a total of 1264 eligible women completed an online survey (response = 13%), which examined survivorship issues among AYAs. Results: Overall, 5% of participants reported that they had participated in a clinical trial. Most women reported that they had not discussed clinical trial participation with a medical provider (76%) and that they did not know whether a relevant trial was available for their cancer (73%). Among those who knew that a trial was available but did not participate, the most commonly reported reasons for nonparticipation included concerns about side effects of the treatment in the trial and concerns that the treatment had not been sufficiently tested. Conclusion: Only a small proportion of AYA women with cancer in our cohort reported discussing a clinical trial with a provider or knowing whether a relevant trial was available. Our findings point to opportunities to improve patient/provider communication to increase clinical trial enrollment among AYAs with cancer.

Neocortical astrogenesis follows neuronogenesis and precedes oligogenesis. Among key factors dictating its temporal articulation, there are progression rates of pallial stem cells (SCs) towards astroglial lineages as well as activation rates of astrocyte differentiation programs in response to extrinsic gliogenic cues. In this study, we showed that high Foxg1 SC expression antagonizes astrocyte generation, while stimulating SC self-renewal and committing SCs to neuronogenesis. We found that mechanisms underlying this activity are mainly cell autonomous and highly pleiotropic. They include a concerted downregulation of 4 key effectors channeling neural SCs to astroglial fates, as well as defective activation of core molecular machineries implementing astroglial differentiation programs. Next, we found that SC Foxg1 levels specifically decline during the neuronogenic-to-gliogenic transition, pointing to a pivotal Foxg1 role in temporal modulation of astrogenesis. Finally, we showed that Foxg1 inhibits astrogenesis from human neocortical precursors, suggesting that this is an evolutionarily ancient trait., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)