Citations

Abstract INTRODUCTION Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A−) individuals. METHODS We included 290 A−, cognitively unimpaired Mayo Clinic Study of Aging participants. We estimated the association of each baseline plasma biomarker with progression from A− to A+ and with rate of amyloid PET change. RESULTS Interquartile range differences in amyloid beta 42/40, percent phosphorylated tau 217 (%p‐tau217), and Amyloid Probability Score 2 were associated with 1.29 ( P = 0.09), 1.38 ( P < 0.001), and 1.20 ( P = 0.05) increases, respectively, in the hazard of progression from A− to A+ and 0.27 ( P = 0.16), 0.50 ( P = 0.007), and 0.28 ( P = 0.15) Centiloid/year increases, respectively, in annual rate of amyloid PET change. DISCUSSION Plasma %p‐tau217 may be a useful screening tool to enrich for participants with increased likelihood of progressing from normal to abnormal amyloid PET in a primary prevention trial. Highlights Plasma phosphorylated tau 217 was associated with amyloid positron emission tomography progression, negative to positive. The associations were weaker for amyloid beta 42/40 and Amyloid Probability Score 2. Age and apolipoprotein E ε4 carriership were also important predictors. These markers may be useful for enrichment of a primary prevention trial.

AbstractBackgroundColon cancer patients have inferior overall survival than a matched general population (MGP). It is unknown if physical activity is associated with a reduction in this survival disparity.MethodsData were analyzed from two National Cancer Institute–sponsored postoperative treatment trials in stage III colon cancer, Cancer and Leukemia Group B (CALGB) 89803 and 80702, with 2876 patients who self‐reported physical activity. Physical activity was converted to metabolic equivalents (MET‐hours/week). The MGP was derived from the National Center for Health Statistics and matched on age, sex, and year.ResultsIn CALGB 89803, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −17.1% (95% confidence interval [CI], −22.4 to −11.8) and −3.5% (95% CI, −7.7 to 0.3) lower than MGP, respectively. In CALGB 80702, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −10.8% (95% CI, −15.4 to −6.9) and −4.4% (95% CI, −7.6 to −1.6) lower than MGP, respectively. In pooled analyses, among patients who were alive and did not have tumor recurrence by year 3 (n = 1908), those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −3.1% (95% CI, −6.2 to −0.3) lower and 2.9% (95% CI, 1.5–4.2) higher than MGP, respectively.ConclusionsPhysical activity is associated with an attenuation of the survival disparity between patients with stage III colon cancer participating in clinical trials and MGP. Colon cancer survivors who are physically active may achieve survival that approximates the MGP.

Purpose: To report the anatomic and visual outcomes of eyes developing delayed rhegmatogenous retinal detachment (RRD) after macular surgery. Methods: This was a retrospective, multicentric study including eyes undergoing RRD repair at least 3 months after macular surgery for either full-thickness macular hole (FTMH) or epiretinal membrane (ERM). Anatomic and functional assessment, i.e., pre- and postoperative best-corrected visual acuity (BCVA), indications and details of macular and RRD surgery, time interval from macular surgery to RRD, intraocular tamponade, location, extent of RRD, and nature of retinal break, was performed. Results: Sixteen out of 2,906 eyes (0.55%) undergoing macular surgery developed RRD after 8.4 ± 5.8 months (mean ± SD). Intraoperative peripheral retina evaluation showed missed/de novo break (11 eyes; 68.75%), no identifiable break i.e., probable microbreak (two eyes; 12.5%), giant retinal tear (two eyes; 12.5%), and retinoschisis related break (one eye; 6.25%). Anatomical success, i.e., attached retina after one surgery, was seen in 14 eyes (87.5%). BCVA worsened from 0.6 ± 0.3 logMAR (Snellen equivalent 20/80) at baseline to 0.9 ± 0.8 logMAR (20/160) through the last visit (P < 0.001). Conclusion: RRD after macular surgery occurs predominantly via missed/de novo retinal breaks. A significant percentage (50%) of eyes showed worse visual acuity compared with baseline despite successful retinal reattachment.

In 2023, Faith Kipyegon set the female world record for running one mile (4:07.64). Here, we quantitatively explore if improved aerodynamic drafting could allow her to run just 3.19% faster and thus break the 4-minute mile barrier. Drafting involves other athletes (pacers) running in formation around a designated athlete to reduce the aerodynamic drag force acting on the designated runner. Drafting allows the designated athlete to run faster at the same rate of metabolic energy consumption. Our overall approach was to estimate Kipyegon’s metabolic energy consumption during her mile world record performance. Then, we used empirically established relationships between horizontal resistive force, running velocity and metabolic power to estimate how much faster she could run at the same metabolic power if the aerodynamic force was reduced via drafting. Our calculations suggest that Kipyegon could run ~3:59.37 with drafting provided by one pacer in front and one in back who change out with two other pacers at 800 m.

Objective: This post hoc analysis evaluated the efficacy of abaloparatide treatment in a subgroup of postmenopausal women from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE; NCT01343004) study who met high fracture risk criteria (defined in several professional society guidelines). Methods: Women from ACTIVE meeting ≥1 of the following fracture risk criteria were included: fracture within the past 12 months or prevalent vertebral fracture, baseline T score of <−3.0 at any site, very high fracture risk probability by FRAX (ie, 10-yr major osteoporotic fracture >30% or hip fracture >4.5%), or multiple prior fractures at baseline since age ≥45 years. Results: A total of 2,026 participants met ≥1 fracture risk criteria defined in clinical guidelines (abaloparatide, n = 664; placebo, n = 677; teriparatide, n = 685). New vertebral fracture risk was reduced in participants receiving abaloparatide (4 [0.72%]) and teriparatide (6 [0.99%]) versus placebo (28 [4.77%]; both P < 0.0001). Estimated Kaplan-Meier cumulative incidence of nonvertebral fracture was 3.0%, 5.3%, and 3.0% in the abaloparatide, placebo, and teriparatide groups, respectively; 4.0%, 9.0%, 4.3% for clinical fracture; 1.6%, 6.8%, 3.0% for major osteoporotic fractures; and 1.1%, 2.1%, 2.1% for wrist fracture. Abaloparatide was associated with bone mineral density gains from baseline at the lumbar spine, total hip, and femoral neck at all time points (6, 12, and 18 mo; P < 0.0001 for all). Common adverse events reported in participants treated with abaloparatide were hypercalciuria (11.5%), dizziness (11.0%), and arthralgia (8.9%). Conclusions: Abaloparatide reduced fracture incidence and increased bone mineral density in participants at highest fracture risk, consistent with the overall ACTIVE study.

Abstract The dorsomedial striatum (DMS) is primarily recognized for regulating goal-directed reward-seeking behaviors, while the dorsolateral striatum (DLS) is predominantly associated with movement and habitual behaviors. In this study, we sought to investigate two pathways, direct medium spiny neuron (dMSN) and indirect medium spiny neuron (iMSN) in the two dorsal striatal subregions (DMS and DLS) in ethanol-seeking and drinking behaviors. Here, we selectively ablated iMSN DMS→GPe and iMSN DLS→GPe and trained mice to exhibit goal-directed and habitual reward-seeking behaviors using random ratio (RR) and random interval (RI) operant conditioning, respectively. We found that partial ablation of iMSN DLS→GPe exhibited increased resilience to bitter-tasting ethanol solution when subjected to quinine adulterated reward in operant conditioning paradigms, suggesting compulsive-like seeking behavior. Consistently, in a separate cohort of mice, we found that the iMSN DLS→GPe ablated mice show higher preference and consumption of quinine adulterated ethanol solution than control mice in two-bottle choice continuous access drinking, with increasing quinine concentration and exhibit more compulsive-like behavior. On the other hand, ablation of iMSN DMS→GPe resulted in insensitivity to satiety-based reward devaluation in RR-trained mice, consistent with a shift toward habitual behavior but no change in compulsive ethanol-seeking and drinking behavior. Together, our findings demonstrate that DLS iMSN function is essential in inhibiting compulsive-like behavior.

ABSTRACT Engrams are neuronal alterations that encode associations between environmental contexts and subjectively rewarding or aversive experiences within sparsely activated neuronal assemblies that regulate behavioral responses. How positive- or negative-hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate or maladaptive behavior, respectively. It is well-known that animals avoid noxious stimuli and experiences. Little is known, however, how the conditioning of environmental or contextual stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations leading to compulsive maladaptive behavior. Here we have studied engrams that encode the conditioned effects of alcohol-related stimuli associated with the reversal of the dysphoric withdrawal state in alcohol dependent rats and document the recruitment of engrams in the paraventricular nucleus of the thalamus (PVT), the central nucleus of the amygdala (CeA), and the Dorsal Striatum (DS). The findings suggest that the encoding of associations between reversal of negative hedonic states and environmental contexts in these engrams may serve as a neural mechanism for compulsive alcohol seeking and vulnerability to relapse associated with dysregulation of reward to a pathological allostatic level.