Stratigraphy, age, and provenance of the Eocene Chumstick basin, Washington Cascades; implications for paleogeography, regional tectonics, and development of strike-slip basins: Reply

We welcome the comment by Evans (2022) and the opportunity to further discuss our study of the Chumstick Formation. The correlation of fault-bound nonmarine sedimentary units in central and western Washington has been a topic of interest, and debate, for many years (Frizzell, 1979; Taylor et al., 1988; Gresens et al., 1981; Gresens, 1983; Evans and Johnson, 1989; Evans, 1994; Cheney and Hayman, 2009). However, many questions about the regional correlation of these units were resolved with the publication of a suite of internally consistent high-precision 206Pb/238U zircon dates from volcanic interbeds throughout the early to middle Eocene stratigraphy (Eddy et al., 2016). This data set confirmed the timing of sediment deposition of the different members within the Chumstick Formation. Donaghy et al. (2021) provides a detailed study of the Chumstick Formation, which builds on earlier research by Gresens et al. (1981, 1983), McClincy (1986), and Evans (1994) by incorporating new geochronologic information and additional clast counts, detrital zircon geochronology, and facies mapping. We interpret large parts of the Chumstick Formation to represent a spatially and temporally distinct sedimentary system between the Leavenworth and Entiat fault zones that likely formed as a pull-apart basin. Evans (2022) objects to several of the interpretations presented in Donaghy et al. (2021) regarding the relationship between different members of the Chumstick Formation and surrounding sedimentary units, the timing of strike-slip faulting, and the regional tectonic setting of these rocks. We discuss each of these points in the following sections

Comparison of Commercial and Self-Initiated Weight Loss Programs in People With Prediabetes: A Randomized Control Trial

To determine if a widely available weight-management program (Weight Watchers) could achieve sufficient weight loss in persons with prediabetes compared with a Diabetes Prevention Program-based individual counseling program supported by National Diabetes Education Program materials. METHODS: We conducted an individual, randomized intervention trial in Indianapolis, Indiana, in 2013 to 2014, in 225 persons with prediabetes. We compared the Weight Watchers weight-management program (n = 112) with Your Game Plan to Prevent Type 2 Diabetes, a program developed by the National Diabetes Education Program. Outcomes were weight and metabolic markers measured at baseline, 6 months, and 12 months. RESULTS: Intervention participants lost significantly more weight than controls at 6 months (5.5% vs 0.8%) and 12 months (5.5% vs 0.2%; both P < .001). The intervention group also had significantly greater improvements in hemoglobin A1c and high-density lipoprotein cholesterol level than did controls. CONCLUSIONS: A large weight-management program is effective for achieving lifestyle changes associated with diabetes prevention. Such programs could significantly increase the availability of diabetes prevention programs worldwide making an immediate and significant public health impact

Altered Lysosomal Proteins in Neural-Derived Plasma Exosomes in Preclinical Alzheimer Disease

OBJECTIVE: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. METHODS: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. RESULTS: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p ≤ 0.0003). CONCLUSIONS: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies

Alzheimer\u27s disease alters oligodendrocytic glycolytic and ketolytic gene expression

INTRODUCTION: Sporadic Alzheimer\u27s disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. METHODS: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer\u27s Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. RESULTS: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. DISCUSSION: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism

Current approach to genetic testing and genetic evaluation referrals for adults with congenital heart disease

BackgroundCongenital heart disease (CHD) is the most common congenital anomaly. Up to 33% have an identifiable genetic etiology. Improved medical and surgical management of CHD has translated into longer life expectancy and a rapidly growing population of adults living with CHD. The adult CHD (ACHD) population did not have access during childhood to the genetic technologies available today and therefore have not had a robust genetic evaluation that is currently recommended for infants with CHD. Given this potential benefit; the aims of this study were to determine how ACHD cardiologists offer genetics services to patients and identify the indications that influence decision-making for genetics care.MethodsWe performed a descriptive cross-sectional study of ACHD cardiologists. A study-developed questionnaire was distributed via emailed REDCap link. The recruitment email was sent to 104 potential respondents. The survey was open from 06/2022 to 01/2023.ResultsThirty-five cardiologists participated in the study (response rate of 34%). Most cardiologists identified as white (77%) and male (66%). Cardiologists were more likely to refer patients to genetics (91%) than to order testing themselves (57%). Of the testing ordered, chromosomal testing (55%) was ordered more than gene sequencing (14%). Most cardiologists would refer a patient with a conotruncal lesion (interrupted aortic arch) over other indications for a genetics evaluation. There were more reported barriers to ordering genetic testing (66%) compared to referring to genetics for a genetics evaluation (23%). Cardiologists were more confident recognizing features suggestive of a genetic syndrome than ordering the correct test (p = 0.001). Regarding associations between clinical factors and current practices, more years in practice trended towards less referrals and testing. Evaluating a greater number of patients (p = 0.11) and greater confidence recognizing syndromic features (p = 0.12) and ordering the correct test (p = 0.09) were all associated with ordering more testing.ConclusionTesting for microdeletion syndromes is being offered and completed in the ACHD population, however testing for single-gene disorders associated with CHD is being under-utilized. Developing guidelines for genetic testing in adults with CHD could increase access to genetic services, impact medical management, reduce uncertainty regarding prognosis, and inform recurrence risk estimates

Low Neural Exosomal Levels of Cellular Survival Factors in Alzheimer\u27s Disease

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural-derived exosomes of Alzheimer\u27s disease or frontotemporal dementia patients and matched controls. Exosomal levels of low-density lipoprotein receptor-related protein 6, heat-shock factor-1, and repressor element 1-silencing transcription factor all were significantly lower in Alzheimer\u27s disease patients than controls (P \u3c 0.0001). In frontotemporal dementia, the only significant difference was higher levels of repressor element 1-silencing transcription factor than in controls. Exosomal transcription factors were diminished 2-10 years before clinical diagnosis of Alzheimer\u27s disease. Low exosomal levels of survival proteins may explain decreased neuronal resistance to Alzheimer\u27s disease neurotoxic proteins

Symptom experiences in metastatic breast cancer patients: relationships to activity engagement, value-based living, and psychological inflexibility

OBJECTIVE: This study examined symptom-based subgroups of metastatic breast cancer (MBC) patients and the extent to which they differed across key constructs of acceptance and commitment therapy (ACT). METHODS: Eighty women with MBC completed self-report surveys assessing 10 common symptoms and several ACT variables (ie, activity engagement, psychological inflexibility, value obstruction, and value progress) during a single time point. RESULTS: A cluster analysis yielded 3 patient subgroups: low symptoms, low-moderate symptoms, and moderate-high symptoms. Relative to the subgroup with low symptoms, the other subgroups reported less activity engagement. In addition, compared with patients with low symptoms, the subgroup with moderate-high symptoms reported greater psychological inflexibility (ie, avoidance of unwanted internal experiences) and greater difficulty living consistently with their values. CONCLUSIONS: Women with MBC show heterogeneity in their symptom profiles, and those with higher symptom burden are more likely to disengage from valued activities and avoid unwanted experiences (eg, thoughts, feelings, and bodily sensations). Findings are largely consistent with the ACT model and provide strong justification for testing ACT to address symptom interference in MBC patients

Progressive and biased divergent evolution underpins the origin and diversification of peridinin dinoflagellate plastids

Dinoflagellates are algae of tremendous importance to ecosystems and to public health. The cell biology and genome organization of dinoflagellate species is highly unusual. For example, the plastid genomes of peridinin-containing dinoflagellates encode only a minimal number of genes arranged on small elements termed "minicircles". Previous studies of peridinin plastid genes have found evidence for divergent sequence evolution, including extensive substitutions, novel insertions and deletions, and use of alternative translation initiation codons. Understanding the extent of this divergent evolution has been hampered by the lack of characterized peridinin plastid sequences. We have identified over 300 previously unannotated peridinin plastid mRNAs from published transcriptome projects, vastly increasing the number of sequences available. Using these data, we have produced a well-resolved phylogeny of peridinin plastid lineages, which uncovers several novel relationships within the dinoflagellates. This enables us to define changes to plastid sequences that occurred early in dinoflagellate evolution, and that have contributed to the subsequent diversification of individual dinoflagellate clades. We find that the origin of the peridinin dinoflagellates was specifically accompanied by elevations both in the overall number of substitutions that occurred on plastid sequences, and in the Ka/Ks ratio associated with plastid sequences, consistent with changes in selective pressure. These substitutions, alongside other changes, have accumulated progressively in individual peridinin plastid lineages. Throughout our entire dataset, we identify a persistent bias toward non-synonymous substitutions occurring on sequences encoding photosystem I subunits and stromal regions of peridinin plastid proteins, which may have underpinned the evolution of this unusual organelle.Wellcome Trus

Metastatic breast cancer patients' expectations and priorities for symptom improvement

PURPOSE: Little research has examined cancer patients' expectations, goals, and priorities for symptom improvement. Thus, we examined these outcomes in metastatic breast cancer patients to provide patients' perspectives on clinically meaningful symptom improvement and priorities for symptom management. METHODS: Eighty women with metastatic breast cancer participated in a survey with measures of comorbidity, functional status, engagement in roles and activities, distress, quality of life, and the modified Patient-Centered Outcomes Questionnaire that focused on 10 common symptoms in cancer patients. RESULTS: On average, patients reported low to moderate severity across the 10 symptoms and expected symptom treatment to be successful. Patients indicated that a 49% reduction in fatigue, 48% reduction in thinking problems, and 43% reduction in sleep problems would represent successful symptom treatment. Cluster analysis based on ratings of the importance of symptom improvement yielded three clusters of patients: (1) those who rated thinking problems, sleep problems, and fatigue as highly important, (2) those who rated pain as moderately important, and (3) those who rated all symptoms as highly important. The first patient cluster differed from other subgroups in severity of thinking problems and education. CONCLUSIONS: Metastatic breast cancer patients report differing symptom treatment priorities and criteria for treatment success across symptoms. Considering cancer patients' perspectives on clinically meaningful symptom improvement and priorities for symptom management will ensure that treatment is consistent with their values and goals