Citations

AbstractBackgroundCharacterizing stress can inform our understanding of direct and indirect pathways impacting mental and physical health outcomes, including age‐related cognitive decline. Chronic stress has been strongly associated with increased risk for cognitive decline, and hair cortisol concentration (HCC) has emerged as a viable neuroendocrine biomarker for its quantification. Cognitive appraisal of stress (CAS) provides key insight into the cognitive framework for responding to a given stressor. We implemented a multi‐pronged approach to evaluate chronic stress and examined its relation to cognition in older adults.MethodParticipants were 22 cognitively normal individuals (x̄ MMSE = 29.33, 0.92; x̄ age: 67.3 ± 8.8 years old, 17.0 ± 2.9 years of education, 54.5% female, 92.6% Non‐Hispanic White). Participants completed the Stress and Adversity Inventory (STRAIN) assessing lifetime stressor exposure and the Primary and Secondary Cognitive Appraisal Scale (PSCAS). HCC was used as a neuroendocrine biomarker of chronic stress. A brief cognitive battery assessing episodic memory and executive functions (Digit Span, HVLT‐R, Trail Making Test, Letter Fluency) and mood/anxiety measures were completed. To correct for skewness, log‐transformed HCC values were used for Pearson and partial correlation analyses controlling for age and education.ResultLifetime stressor exposure and CAS were not significantly related to cognitive performance (all ps > 0.05). There was a marginally significant association between HCC and executive functions (r = ‐0.41, p = 0.08). Total lifetime stressor count, chronicity, and severity were unrelated to symptoms of depression and anxiety (all ps > 0.05). Although lifetime stressor exposure and mood were not significantly related to HCC, higher HCC was associated with higher perceived control of stress (r = 0.45, p = 0.03).ConclusionHCC may be more sensitive to CAS rather than to objective stressor exposure. This highlights the potential of interventions targeted at improving coping in those with chronic stress. Results are preliminary, and the present study will explore impact of social and structural determinants of health on chronic stressor exposure, appraisal, and cognition.

Abstract Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene–drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene–disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.

AbstractBackgroundThe TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome‐wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD‐TDP). However, the causal variant that drives the association has thus far remained elusive.MethodsWe generated long‐read whole‐genome sequencing data of 256 individuals, primarily from Dutch descent. We characterized SNPs and larger structural variants in the TMEM106B locus using de novo genome assembly.ResultsWe identified an insertion of an AluYb8 retrotransposon in the 3’ UTR of TMEM106B gene, that was in complete linkage with the TMEM106B risk‐SNP. AluYb8 retrotransposons have the propensity to propagate through our genomes by utilising a ‘copy‐paste’ mechanism, and once integrated can disrupt transcription and translation of nearby genes. However, propagation of retrotransposons can be suppressed by methylation of the insert and its surrounding regions. Indeed, we observed that the risk haplotype with the AluYb8 insertion, but not the protective haplotype, accumulated CpG islands over evolutionary time. Notably, we observed similar retrotransposon insertions in the 3’ UTR of TMEM106B orthologs in non‐primate species. This suggests a survival advantage, which may be explained by recent findings that TMEM106B is an entry‐receptor for specific viruses in lung‐tissue, such that SINE‐mediated downregulation of TMEM106B may limit viral infection‐load across species.ConclusionsWe speculate that AluYb8‐mediated downregulation of TMEM106B may be protective at younger ages in lung tissues, but that at advanced ages its downregulation in the brain may contribute to increased risk of neurodegenerative diseases. Furthermore, next to the supression of AluYb8 activation by DNA methylation, it may also be suppressed by TDP‐43, in its role in post‐translational RNA‐processing. This leads us to further speculate that age‐related demethylation and age‐related dysregulation of TDP‐43 may result in a negative feedback loop that ultimately reduces the endolysosomal activity in cells. We argue that such a mechanism would explain why increased age is among the strongest risk factors of neurodegenerative diseases.

AbstractBackgroundAutosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.MethodUtilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.ResultNfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.ConclusionIn presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

Introduction: To analyze the association of patient characteristics on operating room (OR) times for robotic-assisted partial nephrectomies (RAPNs). Methods: In total, 248 consecutive RAPNs were performed by a single surgeon from October 2018 to August 2022. Data were collected on the following patient factors: sex, age, race, weight, body mass index (BMI), diabetes, hypertension (HTN), tumor side, tumor mass, and American Society of Anesthesiologists (ASA) score. Total fixed OR times were evaluated as the sum of in-room time to anesthesia-release time (IRAT), anesthesia-release time to cut time (ARCT), close time to wheels out time (CTWO), and in-room time to cut time (IRAT + ARCT). Total variable OR times were defined as cut time to close time (CTCT). Total operative time was defined as wheels into wheel out (WIWO). Results: Median OR time was 265 minutes (interquartile range [IQR]: 247–298 minutes) for WIWO, 191 minutes (IQR: 170–225 minutes) for CTCT, and 75 minutes (IQR: 68–83 minutes) for total fixed time. There was a significant increase in WIWO with the following patient variables: male sex (18.0 minutes, 95% confidence interval [CI]: 6.3–29.7 minutes), weight (5.6 minutes, 95% CI: 2.8–8.4 minutes), BMI (14.3 minutes, 95% CI: 4.2–24.4 minutes), HTN (15.1 minutes, 95% CI: 3.7–26.5 minutes), pathology tumor size (cm) (6.4 minutes, 95% CI: 2.2–10.6 minutes), and ASA score (13.8 minutes, 95% CI: 3.1–24.4 minutes). Sex, age, BMI, weight, HTN, and pathology tumor size significantly impacted CTCT ( P < 0.05). Total fixed OR time was only affected by ASA score ( P = 0.02). Conclusions: Patient variables significantly affect total OR time and variable OR time. These variables do not impact total fixed OR times, confirming fixed OR time as a viable OR efficiency point.

The estimation of surgical blood loss is routinely performed during and after surgical procedures and has morbidity and mortality implications related to the risk of under- and over-resuscitation. The strategies for estimating surgical blood loss include visual estimation, the gravimetric method, the colorimetric method, formula-based methods, and other techniques (e.g., cell salvage). Currently, visual estimation continues to be the most widely used technique. In addition, unique considerations exist when these techniques are applied to various clinical settings such as massive transfusion, cardiac surgery, and obstetrics. Ultimately, when using estimated surgical blood loss to guide perioperative fluid management and transfusion thresholds, it is also important to mitigate the risks associated with resuscitation by targeting a goal-directed fluid therapy approach by utilizing markers of fluid-responsiveness to optimize stroke volume (cardiac output) and delivery of oxygen.

ABSTRACT Patients with newly diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax + hypomethylating agent (Ven‐HMA) therapy. The primary objective in the current study was to develop genetic risk models that are predictive of survival and are applicable at the time of diagnosis and after establishing treatment response. Among 400 ND‐AML patients treated with Ven‐HMA at the Mayo Clinic, 247 (62%) achieved complete remission with (CR) or without (CRi) count recovery. Multivariable analysis–derived hazard ratios (HR), including 1.8 for European LeukemiaNet (ELN) adverse karyotype, 4.7 for KMT2Ar , 1.7 for TP53 MUT , 2.6 for KRAS MUT , and 2.1 for IDH2 WT were applied to develop an HR‐weighted risk model: low, intermediate, and high; respective median survival censored for allogeneic stem cell transplant (ASCT) (3‐year survival) were “not reached” (67%), 19.1 (33%), and 7.1 months (0%). In patients achieving CR/CRi, adverse karyotype, KMT2Ar , KRAS MUT , IDH2 WT predicted inferior survival, allowing for a complementary response‐stratified risk model. The model was externally validated and was shown to be superior to the ELN 2024 risk model (AIC 179 vs. 195 and AUC 0.77 vs. 0.69). Survival was inferior with failure to achieve CR/CRi or not receiving ASCT; 3‐year survival for high‐risk with or without ASCT was 42% versus 0% ( p < 0.01); intermediate 72% versus 43% ( p = 0.06); and low‐risk 88% versus 78% ( p = 0.53). The Mayo genetic risk models offer pre‐treatment and response‐based prognostic tools for ND‐AML treated with Ven‐HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.