A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics

Impact of primary breast cancer therapy on energetic capacity and body composition

PURPOSE: This observational study was designed to measure baseline energy parameters and body composition in early-stage breast cancer patients, and to follow changes during and after various modalities of treatment. This will provide information to aid in the development of individualized physical activity intervention strategies. METHODS: Patients with newly diagnosed stage 0-III breast cancer were enrolled into three cohorts: A (local therapy alone), B (endocrine therapy), or C (chemotherapy with or without endocrine therapy). At baseline, 6 months, and 12 months, subjects underwent a stationary bicycle protocol to assess power generation and DEXA to assess body composition. RESULTS: Eighty-three patients enrolled. Patients had low and variable levels of power generation at baseline (mean power per kilogram lean mass 1.55 W/kg, SD 0.88). Power normalized to lean body mass (W/kg) decreased significantly, and similarly, by 6 months in cohorts B (1.42-1.04 W/kg, p = 0.008) and C (1.53-1.18 W/kg, p < 0.001). In all cohorts, there was no recovery of power generation by 12 months. Cohort C lost lean body mass (- 1.5 kg, p = 0.007), while cohort B maintained lean body mass (- 0.2 kg, p = 0.68), despite a similar trajectory in loss of power. Seven patients developed sarcopenia during the study period, including four patients who did not receive any chemotherapy (cohort B). CONCLUSIONS: The stationary bike protocol was feasible, easy, and acceptable to patients as a way to measure energetic capacity in a clinical setting. Early-stage breast cancer patients had low and variable levels of power generation, which worsened following primary therapy and did not show evidence of 'spontaneous recovery' by 12 months. Effective physical activity interventions will need to be personalized, accounting for both baseline ability and the effect of treatment

Impact of Optimized Breastfeeding on the Costs of Necrotizing Enterocolitis in Extremely Low Birthweight Infants

To estimate risk of NEC for ELBW infants as a function of preterm formula and maternal milk (MM) intake and calculate the impact of suboptimal feeding on NEC incidence and costs

A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics

Medication Adherence and Cardiometabolic Control Indicators Among American Indian Adults Receiving Tribal Health Services: Protocol for a Longitudinal Electronic Health Records Study

BackgroundAmerican Indian adults have the highest prevalence of type 2 diabetes (T2D) in any racial or ethnic group and experience high rates of comorbidities. Uncontrolled cardiometabolic risk factors—insulin resistance, resulting in impaired glucose tolerance, dyslipidemia, and hypertension—increase the risk of mortality. Mortality is significantly reduced by glucose- and lipid-lowering and antihypertensive medication adherence. Medication adherence is low among American Indian adults living in non–Indian Health Service health care settings. Virtually nothing is known about the nature and extent of medication adherence among reservation-dwelling American Indian adults who primarily receive their medications without cost from Indian Health Service or tribal facilities. Electronic health records (EHRs) offer a rich but underused data source regarding medication adherence and its potential to predict cardiometabolic control indicators (C-MCIs). With the support of the Choctaw Nation of Oklahoma (CNO), we address this oversight by using EHR data generated by this large, state-of-the-art tribal health care system to investigate C-MCIs. ObjectiveOur specific aims are to determine, using 2018 EHR data, the bivariate relationships between medication adherence and C-MCIs, demographics, and comorbidities and each C-MCI and demographics and comorbidities; develop machine learning models for predicting future C-MCIs from the previous year’s medication adherence, demographics, comorbidities, and common laboratory tests; and identify facilitators of and barriers to medication adherence within the context of social determinants of health (SDOH), EHR-derived medication adherence, and C-MCIs. MethodsDrawing on the tribe’s EHR (2018-2021) data for CNO patients with T2D, we will characterize the relationships among medication adherence (to glucose- and lipid-lowering and antihypertensive drugs) and C-MCIs (hemoglobin A1c ≤7%, low-density lipoprotein cholesterol <100 mg/dL, and systolic blood pressure <130 mm Hg); patient demographics (eg, age, sex, SDOH, and residence location); and comorbidities (eg, BMI ≥30, cardiovascular disease, and chronic kidney disease). We will also characterize the association of each C-MCI with demographics and comorbidities. Prescription and pharmacy refill data will be used to calculate the proportion of days covered with medications, a typical measure of medication adherence. Using machine learning techniques, we will develop prediction models for future (2019-2021) C-MCIs based on medication adherence, patient demographics, comorbidities, and common laboratory tests (eg, lipid panel) from the previous year. Finally, key informant interviews (N=90) will explore facilitators of and barriers to medication adherence within the context of local SDOH. ResultsFunding was obtained in early 2022. The University of Florida and CNO approved the institutional review board protocols and executed the data use agreements. Data extraction is in process. We expect to obtain results from aims 1 and 2 in 2024. ConclusionsOur findings will yield insights into improving medication adherence and C-MCIs among American Indian adults, consistent with CNO’s State of the Nation’s Health Report 2017 goal of reducing T2D and its complications. International Registered Report Identifier (IRRID)PRR1-10.2196/3919

An Individualized Approach to Remediating Skill Decay: Framework and Applications

Physicians predominantly use self-monitoring to assess and maintain skill proficiency, and to determine when refresher training is required. However, strikingly low correlations exist between physician self-assessments and observer-expert ratings. In addition, in many military and civilian positions, training and education schedules are often standardized and rigid, potentially leading to wasted resources on training that is not needed for those that remain proficient at needed skills. In order to optimize training, there is a critical need for adaptive learning systems that can objectively measure, and preemptively or timely refresh knowledge and support skill maintenance. This paper outlines challenges associated with objectively quantifying skill decay within the medical domain. Requirements for a skill decay framework are summarized based on identified challenges, and a preliminary Skill- DETECT (Degradation Evaluation Toolkit for Eliminating Competency-loss Trends) framework is presented. This Skill-DETECT framework uses objective data to tailor an education and training program to a user’s specific needs. The current application of the Skill-DETECT framework is developed within a medical environment, and utilizes electronic medical records generated by a physician, as well as real-time cognitive assessment data to suggest recommendations on individualized, optimized retraining regimens to reduce the likelihood of skill decay

Decreased motor coordination deficits in <i>Cln6^nclf</i> mice.

<p><b>(A)</b> Rotarod testing was performed on postnatal day 14, 28, 90, and 270 old WT and <i>Cln6^nclf</i> mice. Data are plotted as average latency to fall from the rotating rod during a 240 second trial period (3 trials per mouse per time point). <i>Cln6^nclf</i> mice had a significant reduction in their ability to remain on the rod as it accelerated, starting at P90 and continuing at P270. <b>(B–C)</b> At six months of age, no difference was noted in additional motor performance measures including the time required to descend in a pole climb test <b>(B)</b> or the mean distance traveled (in meters) over a 15-min test period in an open field activity test <b>(C)</b>. [Mean +/− SEM, <i>n</i> = 6–9 mice per group (**<i>p</i>≤0.01, ***<i>p</i>≤0.0001)].</p

Retinal degeneration and vision loss in the <i>Cln6^nclf</i> mouse.

<p>Cell loss and structural degenerative changes occur in the retina of <i>Cln6^nclf</i> mice. (<b>A</b>) Comparison of gross morphological changes over time in retina of <i>Cln6^nclf</i> mice and their respective age-matched WT controls was done to determine mechanism of degeneration. (<b>B</b>) Micrographs (4X) show a section of one retinal hemisphere. (<b>C</b>) At P0 all layers are present and of equal thickness. By 3 months of age the <i>Cln6^nclf</i> retina has begun to narrow and shows a distinct loss of the rods and cones while the overall cytoarchitecture remains intact. By 9 months the rods and cones are nearly absent and the outer plexiform layer is virtually nonexistent with the merging of a much thinned outer and inner nuclear layers. Additionally, there is a distinct narrowing of the inner plexiform layer. [RC-Rode/Cone layer; ONL-Outer nuclear layer; OPL-Outer plexiform later; INL-Inner nuclear layer; IPL-Inner plexiform layer; GCL-Ganglion cell layer]. (D) At 8 months of age, <i>Cln6^nclf</i> mice displayed a significant reduction in visual acuity in a visual cliff assay. Mutant mice were unable to distinguish between a “safe” region of the visual cliff box versus the “unsafe” cliffed portion, spending equal time between the two regions. [Mean (in seconds) +/- SEM, <i>n</i> = 6–9 mice per group (**<i>p</i>≤0.01)].</p

A reduction in brain mass and cortical volume seen in the adult <i>Cln6^nclf</i> mouse.

<p>Brain mass was assessed in the <i>Cln6^nclf</i>, as a decrease in brain mass is often seen in vLINCL patients. (<b>A</b>) Brain mass was reduced beginning at 5 months when compared to age matched controls. (<b>B</b>) Hippocampal and cerebral cortex volume were further assessed revealing a decrease in cortical volume at 9 months in the <i>Cln6^nclf</i> mouse. (<b>C</b>) No difference in mean body weight is seen between adult WT and <i>Cln6^nclf</i> mice up to 12 months of age. [Mean +/− SEM, <i>n</i> = 3 (**<i>p</i>≤0.01, ***<i>p</i>≤0.0001) for brain mass (A) and cortical volume measurements; <i>n</i> = 7–12 for body weight measurements]].</p