Neurochemistry and circuit organization of the lateral spiriform nucleus of birds: A uniquely nonmammalian direct pathway component of the basal ganglia.

We used diverse methods to characterize the role of avian lateral spiriform nucleus (SpL) in basal ganglia motor function. Connectivity analysis showed that SpL receives input from globus pallidus (GP), and the intrapeduncular nucleus (INP) located ventromedial to GP, whose neurons express numerous striatal markers. SpL-projecting GP neurons were large and aspiny, while SpL-projecting INP neurons were medium sized and spiny. Connectivity analysis further showed that SpL receives inputs from subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr), and that the SNr also receives inputs from GP, INP, and STN. Neurochemical analysis showed that SpL neurons express ENK, GAD, and a variety of pallidal neuron markers, and receive GABAergic terminals, some of which also contain DARPP32, consistent with GP pallidal and INP striatal inputs. Connectivity and neurochemical analysis showed that the SpL input to tectum prominently ends on GABAA receptor-enriched tectobulbar neurons. Behavioral studies showed that lesions of SpL impair visuomotor behaviors involving tracking and pecking moving targets. Our results suggest that SpL modulates brainstem-projecting tectobulbar neurons in a manner comparable to the demonstrated influence of GP internus on motor thalamus and of SNr on tectobulbar neurons in mammals. Given published data in amphibians and reptiles, it seems likely the SpL circuit represents a major direct pathway-type circuit by which the basal ganglia exerts its motor influence in nonmammalian tetrapods. The present studies also show that avian striatum is divided into three spatially segregated territories with differing connectivity, a medial striato-nigral territory, a dorsolateral striato-GP territory, and the ventrolateral INP motor territory.

Regulatory Toxicology and Pharmacology New limits proposed for the management of non-mutagenic impurities.

Multiple international guidelines exist that describe both quality and safety considerations for the control of the broad spectrum of impurities inherent to drug substance and product manufacturing processes. However, regarding non-mutagenic impurities (NMI) the most relevant ICH Q3A/B guidelines are not applicable during early phases of drug development leading to confusion about acceptable limits at this stage. Thus, there is need for more flexible approaches that ensure that patient safety remains paramount, while taking into consideration the limited duration of exposure. An EFPIA survey, which collected quantitative data from different types of studies applied to qualify impurities in accordance with ICH Q3A, shows that no toxicities could be attributed to any of the 467 impurities at any tested level in vivo. This data combined with earlier published toxicological datasets encompassing drug substances and intermediates, food related substances and chemicals provide convincing evidence that for NMIs, the application of a generic 5 mg/day limit for an exposure duration <6 months, and a 1 mg/day generic limit for life-long exposure, provides sufficient margins to ensure patient safety. Hence, application of these absolute limits to trigger qualification studies (instead of the relative limits described in Q3A/B), is considered warranted. This approach will prevent conduct of unnecessary dedicated impurity qualification studies and the resulting use of animals.

The effect of hypertension on cerebrovascular carbon dioxide reactivity in atrial fibrillation patients.

Atrial fibrillation (AF) and hypertension (HTN) are both associated with impaired cerebrovascular carbon dioxide reactivity (CVRCO2), an indicator of cerebral vasodilatory reserve. We hypothesised that CVRCO2 would be lower in patients with both AF and HTN (AF + HTN) compared to normotensive AF patients, due to an additive effect of AF and HTN on CVRCO2. Forty AF (68 ± 9 years) and fifty-seven AF + HTN (68 ± 8 years) patients underwent transcranial Doppler ultrasound measurement of middle cerebral artery blood velocity (MCA Vm) during stepped increases and decreases in end-tidal carbon dioxide (PETCO2). A cerebrovascular conductance index (CVCi) was calculated as the ratio of MCA Vm and mean arterial pressure (MAP). CVRCO2 was determined from the linear slope for MCA Vm and MCA CVCi vs PETCO2. Baseline MAP was higher in AF + HTN than AF (107 ± 9 vs. 98 ± 9 mmHg, respectively; p < 0.001), while MCA Vm was not different (AF + HTN:49.6 [44.1-69.0]; AF:51.7 [45.2-63.3] cm.s-1; p = 0.075), and CVCi was lower in AF + HTN (0.46 [0.42-0.57] vs. 0.54 [0.44-0.63] cm.s-1.mmHg-1; p < 0.001). MCA Vm CVRCO2 was not different (AF + HTN: 1.70 [1.47-2.19]; AF 1.74 [1.54-2.52] cm/s/mmHg-2; p = 0.221), while CVCi CVRCO2 was 13% lower in AF + HTN (0.013 ± 0.004 vs 0.015 ± 0.005 cm.s-1.mmHg-1; p = 0.047). Our results demonstrate blunted cerebral vasodilatory reserve (determined as MCA CVCi CVRCO2) in AF + HTN compared to AF alone. This may implicate HTN as a driver of further cerebrovascular dysfunction in AF that may be important for the development of AF-related cerebrovascular events and downstream cognitive decline. We demonstrated reduced cerebrovascular CO2 responsiveness in atrial fibrillation with hypertension (AF+HTN) vs. atrial fibrillation (AF). Furthermore, AF per se (as opposed to normal sinus rhythm) predicts reduced cerebrovascular CO2 responsiveness. Our findings suggest additional cerebrovascular dysfunction in AF+HTN vs. AF.

Ten-year trend analysis of breast cancer, oncoplastic, and reconstructive breast surgery in a single institution (2010-2019), what has not changed?

PURPOSE: There has been a UK national directive to ensure that patients are offered reconstructive surgical options. We aimed to assess any change in oncoplastic practice over a 10-year period. METHODS: The surgical management of 7019 breast cancers was retrospectively assessed at Nightingale Breast Centre, Manchester University UK, from 2010 to 2019. The procedures were categorised into breast conservative surgery (BCS) and mastectomy ± immediate reconstruction. The data were analysed using inclusion and exclusion criteria. RESULTS: The overall rates of BCS and mastectomy were 60.1% and 39.9% respectively. No statistically significant change in the overall rates of BCS or mastectomy was observed over the last decade (p = 0.08). The rate of simple wide local excision (WLE) decreased from 98.7% to 89.3% (p < 0.001), whilst the rate of therapeutic mammoplasty (TM) increased from 1.3% to 8% (p < 0.01). The rate of chest wall perforator flaps (CWPF) changed from zero to account for 2.7% of all BCS by 2019. The overall rate of immediate breast reconstruction (IBR) did not significantly change over the study period, but it consistently remained above the national average of 27%. The rate of implant-based IBR increased from 61.3% to 76.5% (p = 0.012), whilst the rate of Latissimus Dorsi (LD) reconstruction decreased from 26.7% to 5.1% (p < 0.05). Additionally, the rate of nipple-sparing mastectomy significantly increased from 5.2% to 24%. CONCLUSION: No significant changes in the overall rates of BCS was observed, the rates of advanced breast conservation techniques, nipple-sparing mastectomy, and implant-based IBR all have increased, whilst the use of LD reconstruction decreased.

State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis.

Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy homeostasis. Glucagon-like peptide-1 (GLP-1, encoded by Gcg), secreted by a distinct population of neurons located within the nucleus tractus solitarius (NTS), suppresses feeding through projections to multiple brain targets1-3. Although GLP-1 analogs are proven clinically effective in treating type 2 diabetes and obesity4, the mechanisms of GLP-1 action within the brain remain unclear. Here, we investigate the involvement of GLP-1 receptor (GLP-1R) mediated signaling in a descending circuit formed by GLP-1R neurons in the paraventricular hypothalamic nucleus (PVNGLP-1R) that project to dorsal vagal complex (DVC) neurons of the brain stem in mice. PVNGLP- 1R→DVC synapses release glutamate that is augmented by GLP-1 via a presynaptic mechanism. Chemogenetic activation of PVNGLP-1R→DVC neurons suppresses feeding. The PVNGLP-1R→DVC synaptic transmission is dynamically regulated by energy states. In a state of energy deficit, synaptic strength is weaker but is more profoundly augmented by GLP-1R signaling compared to an energy-replete state. In an obese state, the dynamic synaptic strength changes in the PVNGLP-1R→DVC descending circuit are disrupted. Blocking PVNGLP-1R→DVC synaptic release or ablation of GLP-1R in the presynaptic compartment increases food intake and causes obesity, elevated blood glucose, and impaired insulin sensitivity. These findings suggest that the state-dependent synaptic plasticity in this PVNGLP-1R→DVC descending circuit mediated by GLP-1R signaling is an essential regulator of energy homeostasis.

Functional decline in older breast cancer survivors treated with and without chemotherapy and non-cancer controls: results from the Hurria Older PatiEnts (HOPE) prospective study.

PURPOSE: This study aimed to assess whether physical functional decline in older women with early-stage breast cancer is driven by cancer, chemotherapy, or a combination of both. METHODS: We prospectively sampled three groups of women aged ≥ 65: 444 with early-stage breast cancer receiving chemotherapy (BC Chemo), 98 with early-stage breast cancer not receiving chemotherapy (BC Control), and 100 non-cancer controls (NC Control). Physical function was assessed at two timepoints (T1 [baseline] and T2 [3, 4, or 6 months]) using the Physical Functioning Subscale (PF-10) of the RAND 36-item Short Form. The primary endpoint was the change in PF-10 scores from T1 to T2, analyzed continuously and dichotomously (Yes/No, with "yes" indicating a PF-10 decline > 10 points, i.e., a substantial and clinically meaningful difference). RESULTS: Baseline PF-10 scores were similar across all groups. The BC Chemo group experienced a significant decline at T2, with a median change in PF-10 of -5 (interquartile range [IQR], -20, 0), while BC Control and NC Control groups showed a median change of 0 (IQR, -5, 5; p < 0.001). Over 30% of BC Chemo participants had a substantial decline in PF-10 vs. 8% in the BC Control and 5% in the NC Control groups (p < 0.001). CONCLUSION: In this cohort of older adults with early-stage breast cancer, the combination of breast cancer and chemotherapy contributes to accelerated functional decline. Our findings reinforce the need to develop interventions aimed at preserving physical function, particularly during and after chemotherapy. IMPLICATIONS FOR CANCER SURVIVORS: The high prevalence of accelerated functional decline in older women undergoing breast cancer chemotherapy underscores the urgency to develop interventions aimed at preserving physical function and improving health outcomes. CLINICAL TRIAL: NCT01472094, Hurria Older PatiEnts (HOPE) with Breast Cancer Study.

Metformin's role in lowering colorectal cancer risk among individuals with diabetes from the Southern Community Cohort Study.

BACKGROUND: Metformin, utilized to manage hyperglycemia, has been linked to a reduced risk of colorectal cancer (CRC) among individuals with diabetes. However, evidence is lacking for non-Hispanic Black individuals and those with lower socioeconomic status (SES), who face elevated risk for both diabetes and CRC. In this study, we investigated the association between metformin use and incident CRC risk within the Southern Community Cohort Study (SCCS), a racially- and SES-diverse prospective cohort. METHODS: Participants reported their diabetes diagnosis and medications, including metformin, upon enrollment (2002-2009) and during follow-up surveys approximately every five years. Incident cases of CRC were identified through state cancer registries and the National Death Index. Proportional hazards models were employed to explore the relationship between metformin use and CRC risk, adjusted for cancer risk factors. RESULTS: A total of 25,992 participants with diabetes were included in the analysis, among whom 10,095 were taking metformin. Of these participants, 76% identified as non-Hispanic Black, and 60% reported household incomes <$15,000/year. Metformin use was associated with a significantly lower CRC risk (HR [95% CI]: 0.71 [0.55-0.93]), with consistent results for both colon (0.80 [0.59-1.07]) and rectal cancers (0.49 [0.28-0.86]). The protective association appeared to be stronger among non-Hispanic White individuals (0.51 [0.31-0.85]) compared to non-Hispanic Black participants (0.80 [0.59-1.08], p-interaction =.13). Additionally, a protective association was observed among obese individuals (BMI ≥30 kg/m2, 0.59 [0.43-0.82] but not among non-obese participants (0.99 [0.65-1.51], p-interaction =.05) CONCLUSION: Our findings indicate that metformin use is associated with a reduced risk of CRC in individuals with diabetes, including among those from predominantly low SES backgrounds. These results support previous epidemiological findings, and demonstrate that the protective association for metformin in relation to incident CRC likely generalizes to populations with higher underlying risk.

Engagement in Meaningful Activity Mediates the Relationship Between Stressful Life Events and Functional Resilience.

Resilience during stressful life events is a priority for administering the most client-centered care as possible. Occupational therapy practitioners have the unique opportunity to support resilience through promoting meaningful participation. The current study aims to understand the associations between meaningful activity engagement, resilience, and stressful life events. We specifically focused on answering if meaningful participation mediates the relationship between stressful life events and resilience. 492 participants from a non-clinical convenience sample of Amazon's MTurk completed the study. Participants completed an online survey and reported their experiences of stressful life events, resilience, well-being, and meaningful participation. We used SPSS and PROCESS to analyze our data. Stressful event severity and resilience were inversely related. When accounting for the effect of meaningful participation, the relationship became non-significant, indicating evidence of mediation. Implications: Focusing on measuring meaningful participation may be worth studying in further research.

Engagement in Meaningful Activity Mediates the Relationship between Stressful Life Events and Functional ResilienceSupporting recovery both psychologically and physically after a stressful life event is an important aspect of providing client-centered care. By supporting patients' and clients' engagement in meaningful participation, therapists can promote resilient outcomes for all patients and clients. The current study explored the relationship between resilience and meaningful activity participation during stressful life events. The sample was comprised of a convenience sample of 492 participants who were recruited from the online crowdsourcing platform MTurk. The results of the study include that when the stressful life experience was more severe for an individual, they reported lower resilience scores. When meaningful activity participation was accounted for, the relationship between stressful life event severity and resilience became non-existent. The results of the study suggest the importance of using and measuring meaningful activity when supporting recovery after an stressful and adverse life event.

Spatial variability in size and lipid content of the marine copepod Calanus finmarchicus across the Northwest Atlantic continental shelves: implications for North Atlantic right whale prey quality.

Copepod size and energy content are influenced by regional and seasonal variation in temperature and food conditions, with implications for planktivorous consumers such as the endangered North Atlantic right whale (Eubalaena glacialis). Historical data (1990-2020) on Calanus finmarchicus stage CV copepodite prosome length and oil sac metrics were analyzed to determine the extent of variation in individual body size and estimated lipid and energy content in five regions of the Northwest Atlantic continental shelves [Gulf of Maine (GoM), Scotian Shelf (SS), Gulf of St. Lawrence (GSL), St. Lawrence Estuary (SLE) and Newfoundland Shelf]. Large-scale spatial patterns in size and lipid content were related to latitude, indicating that C. finmarchicus CV in the GSL and SLE were historically larger in body size, and had significantly higher lipid content compared with those in the GoM and the SS. The observed patterns of C. finmarchicus CV size and lipid storage capacity suggest that regional variation in whale prey energy content can play a role in the suitability of current and future whale foraging habitats in the Northwest Atlantic, with the larger lipid-rich individuals in the GSL providing a high-quality diet compared with those in southern areas.

Who's doing more and when? Gender, parenting, and housework trajectories.

Drawing on five waves of longitudinal survey data (N = 520, 51% female, 39% with a university degree, 90% White), this study examined trajectories of women's and men's contributions to cooking, kitchen cleaning, grocery shopping, house cleaning, laundry, and overall housework from Age 25 to 50 years and explored time-invariant (traditional gender role attitudes, homemaker mother, mother and father education assessed at Age 18) and time-varying (raising children at Ages 25, 32, 43, and 50 years) predictors of housework trajectories. Growth curve analyses revealed that women contributed more to all housework tasks than men at Age 25, a gender gap maintained to Age 50. Housework increased to Age 32 and stabilized until Age 43 before declining by Age 50 for women's and men's laundry, women's kitchen cleaning, grocery shopping, and overall housework, and men's house cleaning. There was no change in women's and men's trajectory of cooking meals, women's house cleaning, and men's contributions to kitchen cleaning, grocery shopping, and overall housework. Traditional gender role attitudes, having a homemaker mother, and mother's and father's education inconsistently predicted women's and men's trajectories. Raising children, however, was consistently linked with within-person fluctuations in housework. When raising children, women contributed more than average to housework, whereas when men were raising children, they contributed less than normal. The results highlight a gendered pattern of housework evident in the twenties and persisting well into midlife, with parenthood widening the gap. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Photo-induced processes in photosynthesis-from femtoseconds to seconds.

Photosynthesis nourishes nearly all life on Earth. Therefore, a deeper understanding of the processes by which sunlight is converted into stored chemical energy presents an important and continuing challenge for fundamental scientific research. This Special Issue is dedicated to academician Vladimir A. Shuvalov (1943-2022). We are delighted to present 15 manuscripts in the Special Issue, including two review articles and 13 research papers. These papers are contributed by 67 authors from 8 countries, including China (9), Germany (8), Hungary (4), Italy (6), Japan (2), Russia (24), Taiwan (9), and USA (5). This Special Issue provides some of the recent updates on the dynamical aspects of the initial steps of photosynthesis, including excitation energy transfer, electron transport, and dissipation of energy across time domains from femtoseconds to seconds. We hope that the readers will benefit from the work presented in this Special Issue in honor of Prof. Shuvalov in many ways. We hope that the Special Issue will provide a valued resource to stimulate research efforts, initiate potential collaboration, and promote new directions in the photosynthesis community.

Distinguishing Clinical From Statistical Significances in Contemporary Comparative Effectiveness Research.

OBJECTIVE: To determine the prevalence of clinical significance reporting in contemporary comparative effectiveness research (CER). BACKGROUND: In CER, a statistically significant difference between study groups may or may not be clinically significant. Misinterpreting statistically significant results could lead to inappropriate recommendations that increase health care costs and treatment toxicity. METHODS: CER studies from 2022 issues of the Annals of Surgery , Journal of the American Medical Association , Journal of Clinical Oncology , Journal of Surgical Research , and Journal of the American College of Surgeons were systematically reviewed by 2 different investigators. The primary outcome of interest was whether the authors specified what they considered to be a clinically significant difference in the "Methods." RESULTS: Of 307 reviewed studies, 162 were clinical trials and 145 were observational studies. Authors specified what they considered to be a clinically significant difference in 26 studies (8.5%). Clinical significance was defined using clinically validated standards in 25 studies and subjectively in 1 study. Seven studies (2.3%) recommended a change in clinical decision-making, all with primary outcomes achieving statistical significance. Five (71.4%) of these studies did not have clinical significance defined in their methods. In randomized controlled trials with statistically significant results, sample size was inversely correlated with effect size ( r = -0.30, P = 0.038). CONCLUSIONS: In contemporary CER, most authors do not specify what they consider to be a clinically significant difference in study outcome. Most studies recommending a change in clinical decision-making did so based on statistical significance alone, and clinical significance was usually defined with clinically validated standards.

Consideration of Metastasis-Directed Therapy for Patients With Metastatic Colorectal Cancer: Expert Survey and Systematic Review.

BACKGROUND: A survey of medical oncologists (MOs), radiation oncologists (ROs), and surgical oncologists (SOs) who are experts in the management of patients with metastatic colorectal cancer (mCRC) was conducted to identify factors used to consider metastasis-directed therapy (MDT). MATERIALS AND METHODS: An online survey to assess clinical factors when weighing MDT in patients with mCRC was developed based on systematic review of the literature and integrated with clinical vignettes. Supporting evidence from the systematic review was included to aid in answering questions. RESULTS: Among 75 experts on mCRC invited, 47 (response rate 62.7%) chose to participate including 16 MOs, 16 ROs, and 15 SOs. Most experts would not consider MDT in patients with 3 lesions in both the liver and lung regardless of distribution or timing of metastatic disease diagnosis (6 vs. 36 months after definitive treatment). Similarly, for patients with retroperitoneal lymph node and lung and liver involvement, most experts would not offer MDT regardless of timing of metastatic disease diagnosis. In general, SOs were willing to consider MDT in patients with more advanced disease, ROs were more willing to offer treatment regardless of metastatic site location, and MOs were the least likely to consider MDT. CONCLUSIONS: Among experts caring for patients with mCRC, significant variation was noted among MOs, ROs, and SOs in the distribution and volume of metastatic disease for which MDT would be considered. This variability highlights differing opinions on management of these patients and underscores the need for well-designed prospective randomized trials to characterize the risks and potential benefits of MDT.

Cognitive and Cerebrospinal Fluid Alzheimer's Disease-related Biomarker Trajectories in Older Surgical Patients and Matched Nonsurgical Controls.

BACKGROUND: Anesthesia and/or surgery accelerate Alzheimer's disease pathology and cause memory deficits in animal models, yet there is a lack of prospective data comparing cerebrospinal fluid (CSF) Alzheimer's disease-related biomarker and cognitive trajectories in older adults who underwent surgery versus those who have not. Thus, the objective here was to better understand whether anesthesia and/or surgery contribute to cognitive decline or an acceleration of Alzheimer's disease-related pathology in older adults. METHODS: The authors enrolled 140 patients 60 yr or older undergoing major nonneurologic surgery and 51 nonsurgical controls via strata-based matching on age, sex, and years of education. CSF amyloid ß (Aß) 42, tau, and p-tau-181p levels and cognitive function were measured before and after surgery, and at the same time intervals in controls. RESULTS: The groups were well matched on 25 of 31 baseline characteristics. There was no effect of group or interaction of group by time for baseline to 24-hr or 6-week postoperative changes in CSF Aß, tau, or p-tau levels, or tau/Aß or p-tau/Aß ratios (Bonferroni P > 0.05 for all) and no difference between groups in these CSF markers at 1 yr (P > 0.05 for all). Nonsurgical controls did not differ from surgical patients in baseline cognition (mean difference, 0.19 [95% CI, -0.06 to 0.43]; P = 0.132), yet had greater cognitive decline than the surgical patients 1 yr later (ß, -0.31 [95% CI, -0.45 to -0.17]; P < 0.001) even when controlling for baseline differences between groups. However, there was no difference between nonsurgical and surgical groups in 1-yr postoperative cognitive change in models that used imputation or inverse probability weighting for cognitive data to account for loss to follow up. CONCLUSIONS: During a 1-yr time period, as compared to matched nonsurgical controls, the study found no evidence that older patients who underwent anesthesia and noncardiac, nonneurologic surgery had accelerated CSF Alzheimer's disease-related biomarker (tau, p-tau, and Aß) changes or greater cognitive decline.

Polyphosphate kinase deletion increases laboratory productivity in cyanobacteria.

Identification and manipulation of cellular energy regulation mechanisms may be a strategy to increase productivity in photosynthetic organisms. This work tests the hypothesis that polyphosphate synthesis and degradation play a role in energy management by storing or dissipating energy in the form of ATP. A polyphosphate kinase (ppk) knock-out strain unable to synthesize polyphosphate was generated in the cyanobacterium Synechocystis sp. PCC 6803. This mutant strain demonstrated higher ATP levels and faster growth than the wildtype strain in high-carbon conditions and had a growth defect under multiple stress conditions. In a strain that combined ppk deletion with heterologous expression of ethylene-forming enzyme, higher ethylene productivity was observed than in the wildtype background. These results support the role of polyphosphate synthesis and degradation as an energy regulation mechanism and suggest that such mechanisms may be effective targets in biocontainment design.

In persons aged ≥45 y, the mt-sRNA test had 94% sensitivity for colorectal cancer and 46% for advanced adenomas.

SOURCE CITATION: Barnell EK, Wurtzler EM, La Rocca J, et al. Multitarget stool RNA test for colorectal cancer screening. JAMA. 2023;330:1760-1768. 37870871.

Global metabolomics revealed deviations from the metabolic aging clock in colorectal cancer patients.

Background: Markers of aging hold promise in the context of colorectal cancer (CRC) care. Utilizing high-resolution metabolomic profiling, we can unveil distinctive age-related patterns that have the potential to predict early CRC development. Our study aims to unearth a panel of aging markers and delve into the metabolomic alterations associated with aging and CRC. Methods: We assembled a serum cohort comprising 5,649 individuals, consisting of 3,002 healthy volunteers, 715 patients diagnosed with colorectal advanced precancerous lesions (APL), and 1,932 CRC patients, to perform a comprehensive metabolomic analysis. Results: We successfully identified unique age-associated patterns across 42 metabolic pathways. Moreover, we established a metabolic aging clock, comprising 9 key metabolites, using an elastic net regularized regression model that accurately estimates chronological age. Notably, we observed significant chronological disparities among the healthy population, APL patients, and CRC patients. By combining the analysis of circulative carcinoembryonic antigen levels with the categorization of individuals into the "hypo" metabolic aging subgroup, our blood test demonstrates the ability to detect APL and CRC with positive predictive values of 68.4% (64.3%, 72.2%) and 21.4% (17.8%, 25.9%), respectively. Conclusions: This innovative approach utilizing our metabolic aging clock holds significant promise for accurately assessing biological age and enhancing our capacity to detect APL and CRC.

Identification of novel F2-isoprostane metabolites by specific UDP-glucuronosyltransferases.

UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of glucuronic acid with endogenous and exogenous lipophilic small molecules to facilitate their inactivation and excretion from the body. This represents approximately 35 % of all phase II metabolic transformations. Fatty acids and their oxidized eicosanoid derivatives can be metabolized by UGTs. F2-isoprostanes (F2-IsoPs) are eicosanoids formed from the free radical oxidation of arachidonic acid. These molecules are potent vasoconstrictors and are widely used as biomarkers of endogenous oxidative damage. An increasing body of evidence demonstrates the efficacy of measuring the ß-oxidation metabolites of F2-IsoPs rather than the unmetabolized F2-IsoPs to quantify oxidative damage in certain settings. Yet, the metabolism of F2-IsoPs is incompletely understood. This study sought to identify and characterize novel phase II metabolites of 15-F2t-IsoP and 5-epi-5-F2t-IsoP, two abundantly produced F2-IsoPs, in human liver microsomes (HLM). Utilizing liquid chromatography-mass spectrometry, we demonstrated that glucuronide conjugates are the major metabolites of these F2-IsoPs in HLM. Further, we showed that these molecules are metabolized by specific UGT isoforms. 15-F2t-IsoP is metabolized by UGT1A3, 1A9, and 2B7, while 5-epi-5-F2t-IsoP is metabolized by UGT1A7, 1A9, and 2B7. We identified, for the first time, the formation of intact glucuronide F2-IsoPs in human urine and showed that F2-IsoP glucuronidation is reduced in people supplemented with eicosapentaenoic and docosahexaenoic acids for 12 weeks. These studies demonstrate that endogenous F2-IsoP levels can be modified by factors other than redox mechanisms.

Transportation Factors and Postoperative Attendance and Weight Loss Through 24 Months.

PURPOSE: Transportation, access to follow-up care, and association with weight loss are understudied in the bariatric population. The objective of this study was to determine how transportation variables associate with postoperative attendance and weight loss through 24 months. MATERIALS AND METHODS: Seven hundred eighty-seven patients (81.3% female; 59.1% White) who had primary surgery (48.6% gastric bypass) from 2015 to 2019 were included. Sidewalk coverage and number of bus stops from patients' homes, driving distance in miles and minutes from patients' homes to the nearest bus stop and the clinic were measured. Bivariate analyses were conducted with the transportation variables and attendance and %TWL at 2 or 3, 6, 12, and 24 months. One mixed multilevel model was conducted with dependent variable %TWL over 24 months with visits as the between-subjects factor and covariates: race, insurance, surgical procedure, and driving distance to the clinic in minutes, attendance, and %TWL over 24 months; an interaction between distance, attendance, and visits. RESULTS: There were no significant differences between the majority of the transportation variables and postoperative attendance or %TWL. Patients who had perfect attendance had improved %TWL at 12 months [t(534)=-1.92, p=0.056] and 24 months [t(393)=-2.69, p=0.008] compared to those who missed at least one appointment. Patients with perfect attendance and who had shorter driving times (under 20 min) to the clinic had greater weight loss through 24 months [F(10, 1607.50)=2.19, p=0.016)]. CONCLUSIONS: Overall, transportation factors were not associated with attendance and weight loss, with the exception of the interaction between shorter driving minutes to follow-up and perfect attendance.