Efficacy of Gastric Electrical Stimulation in Alleviating Symptoms of Refractory Post-Surgical Gastroparesis: A Retrospective Analysis from Two Centers.

BACKGROUND: Post-surgical gastroparesis, resulting from surgical interventions on the stomach or vagal nerve injury, poses significant clinical challenges with patients presenting symptoms like nausea, vomiting, and abdominal pain. While gastric electrical stimulation (GES) offers potential relief, its efficacy in refractory post-surgical gastroparesis requires further examination. OBJECTIVE: This study evaluated the clinical response to GES in patients with refractory post-surgical gastroparesis. METHODS: A retrospective study was conducted across two study sites, involving 185 patients with drug-refractory post-surgical gastroparesis who underwent both temporary and permanent GES placements. Patients were categorized based on their surgical history: Bariatric surgery, Nissen Fundoplication, and others. The impact of GES was evaluated using FDA-compliant Patient Reported Outcomes scores and other relevant clinical metrics at baseline, after temporary GES placement, and 6 months after permanent GES placement. All three groups were also analyzed by the symptom improvement group vs the non-improved group at baseline and 6 months after GES placement. RESULTS: Post-GES implantation, all patient groups significantly improved upper gastrointestinal symptoms. The bariatric surgery group and Nissen fundoplication group specifically identified anorexia as the most severe symptom post-GES after temporary GES placement among three groups (2.5 [0.4, 3.5] and 1.5 [0.0, 2.5], respectively. Nissen fundoplication patients had the highest score of anorexia among the three groups six months post-GES (3.0 [2.0, 3.5], p=0.018). Despite these improvements, GES did not enhance gastric emptying test results. Symptomatic improvements were notably significant in patients who initially reported higher symptom severity than those who did not. CONCLUSION: GES shows promise in alleviating symptoms of refractory post-surgical gastroparesis, particularly in those with severe initial symptoms. However, its impact on gastric emptying remains inconclusive. Further research is needed to establish GES as a standard treatment for post-surgical gastroparesis.

Autonomic and Enteric Profiling May Help Predict Response to Diverse Obesity Therapies.

PURPOSE: Changes in autonomic (ANS) and enteric nervous systems (ENS) may be involved in pathogenesis of obesity. We hypothesized that baseline autonomic and enteric parameters may predict outcomes of diverse obesity therapies. MATERIAL AND METHODS: We studied ANS and ENS physiology in 37 patients (8 male, 29 female, age 45 years, weight 129.7 kg) at 4 centers in patients undergoing medical (9: low-calorie diet) versus invasive (22: 16 sleeve, 6 bypass) and semi-invasive (6: 2 band, 2 high energy stimulation, 2 aspiration) weight loss therapies. Weight loss was reported as percent weight loss from baseline to latest values at 1 year and in some up to 5 years; classified as < or > /= 20% for each group. ANS testing included sympathetic adrenergic function by measuring reflex vasoconstriction and postural adjustment ratio. ENS was measured non-invasively using cutaneous low-resolution electrogastrogram. RESULTS: Percent weight loss was greater with the invasive (28.5%) than semi-invasive (9.1%) or non-invasive low-calorie diet (4.4%) (p < .001). Percent weight loss at 1 year (and up to 5 years) corresponded to the adrenergic measure of postural adjustment ratio (r = .42, p = .012), total pulse amplitude at rest (r = .56, p < .001), and electrogastrogram standing-to-rest difference (r = .33, p = .056). CONCLUSION: Baseline autonomic and enteric function measures correspond to percentage with loss in this pilot study using diverse weight loss methods. Autonomic and enteric profiling has potential clinical use for evaluation and treatment of obesity but needed larger controlled trials.

Clinical and Adverse Outcomes Associated With Concomitant Use of CYP2D6-Metabolized Opioids With Antidepressants in Older Nursing Home Residents : A Target Trial Emulation Study.

BACKGROUND: Limited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home (NH) residents. OBJECTIVE: To investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs). DESIGN: Retrospective cohort study using a target trial emulation framework. SETTING: 100% Medicare NH sample linked to Minimum Data Set (MDS) from 2010 to 2021. PARTICIPANTS: Long-term residents aged 65 years and older receiving CYP2D6-metabolized opioids with a disease indication for antidepressant use. INTERVENTION: Initiating CYP2D6-inhibiting versus CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for 1 day or more. MEASUREMENTS: Clinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments and were analyzed using modified Poisson regression models. The ORAE outcomes included counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose and were analyzed with negative binomial or Poisson regression models. All models were adjusted for baseline covariates via inverse probability of treatment weighting. RESULTS: Among 29 435 identified residents, use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.13 [95% CI, 1.09 to 1.17]) and higher adjusted incidence rate ratios of pain-related hospitalization (1.37 [CI, 1.19 to 1.59]), pain-related ED visit (1.49 [CI, 1.24 to 1.80]), and OUD (1.93 [CI, 1.37 to 2.73]), with no difference in physical function, depression, and opioid overdose. LIMITATION: Findings are generalizable to NH populations only. CONCLUSION: Use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with worsening pain and increased risk for most assessed ORAEs among older NH residents. PRIMARY FUNDING SOURCE: National Institute on Aging.

Frameless image-guided linear accelerator (LINAC) stereotactic radiosurgery for medically refractory trigeminal neuralgia: Clinical outcomes in 116 patients.

Background: Frameless image-guided radiosurgery (IGRS) is an effective and non-invasive method of treating patients who are unresponsive to medical management for trigeminal neuralgia (TN). This study evaluated the use of frameless IGRS to treat patients with medically refractory TN. Methods: We performed a retrospective review of records of 116 patients diagnosed with TN who underwent frameless IGRS using a linear accelerator (LINAC) over 10 years (March 2012-February 2023). All patients had failed medical management for TN. Facial pain was graded using the Barrow Neurological Institute (BNI) scoring system. Each patient received a BNI score before frameless IGRS and following treatment. Failure was defined as a BNI score IV-V at the last follow-up and/or undergoing a salvage procedure following IGRS. Results: All patients had a BNI score of either IV or V before the frameless IGRS. The mean follow-up duration for all 116 patients following IGRS was 44.1 months. Most patients (81 [69.8%]) had not undergone surgery (microvascular decompression [MVD] or rhizotomy) or stereotactic radiosurgery (SRS) for TN before frameless IGRS. A total of 41 (35.3%) patients underwent a salvage procedure (MVD, rhizotomy, or an additional IGRS) following frameless IGRS. The mean duration between the initial frameless IGRS and salvage procedure was 20.1 months. At the last follow-up, a total of 110 (94.8%) patients had a BNI score of I-III. No complications were reported after the frameless IGRS. The BNI score at the last follow-up was lower compared to the initial BNI for patients regardless of prior intervention (P < 0.001). Patients who failed IGRS had a higher BNI score at the last follow-up compared to those who did not fail IGRS (2.8 vs. 2.5, P = 0.05). Patients with pain relief had a shorter follow-up compared to those with pain refractory to SRS (38.0 vs. 55.1, P = 0.005). Conclusion: In this large cohort of patients with medically refractory TN, frameless IGRS resulted in durable pain control in the majority of patients without any toxicity.

Comparative analysis of circulating metabolomic profiles identifies shared metabolic alterations across distinct multistressor military training exercises.

Military training provides insight into metabolic responses under unique physiological demands that can be comprehensively characterized by global metabolomic profiling to identify potential strategies for improving performance. This study identified shared changes in metabolomic profiles across three distinct military training exercises, varying in magnitude and type of stress. Blood samples collected before and after three real or simulated military training exercises were analyzed using the same untargeted metabolomic profiling platform. Exercises included a 2-wk survival training course (ST, n = 36), a 4-day cross-country ski march arctic training (AT, n = 24), and a 28-day controlled diet- and exercise-induced energy deficit (CED, n = 26). Log2-fold changes of greater than ±1 in 191, 121, and 64 metabolites were identified in the ST, AT, and CED datasets, respectively. Most metabolite changes were within the lipid (57-63%) and amino acid metabolism (18-19%) pathways and changes in 87 were shared across studies. The largest and most consistent increases in shared metabolites were found in the acylcarnitine, fatty acid, ketone, and glutathione metabolism pathways, whereas the largest decreases were in the diacylglycerol and urea cycle metabolism pathways. Multiple shared metabolites were consistently correlated with biomarkers of inflammation, tissue damage, and anabolic hormones across studies. These three studies of real and simulated military training revealed overlapping alterations in metabolomic profiles despite differences in environment and the stressors involved. Consistent changes in metabolites related to lipid metabolism, ketogenesis, and oxidative stress suggest a potential common metabolomic signature associated with inflammation, tissue damage, and suppression of anabolic signaling that may characterize the unique physiological demands of military training.NEW & NOTEWORTHY The extent to which metabolomic responses are shared across diverse military training environments is unknown. Global metabolomic profiling across three distinct military training exercises identified shared metabolic responses with the largest changes observed for metabolites related to fatty acids, acylcarnitines, ketone metabolism, and oxidative stress. These changes also correlated with alterations in markers of tissue damage, inflammation, and anabolic signaling and comprise a potential common metabolomic signature underlying the unique physiological demands of military training.

Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Difference in Cyclic Versus Non-cyclic Symptom Patterns in Patients with the Symptoms of Gastroparesis Undergoing Bioelectric Therapy.

INTRODUCTION: Patients with gastroparesis (Gp) have symptoms with or without a cyclic pattern. This retrospective study evaluates differences in cyclic vs. non-cyclic symptoms of Gp by analyzing mucosal electrogastrogram (mEG), familial dysautonomias, and response to gastric stimulation. METHODS: 37 patients with drug refractory Gp, 7 male and 30 female, with a mean age of 41.4 years, were studied. 18 had diabetes mellitus, 25 had cyclic (Cyc), and 12 had a non-cyclic (NoCyc) pattern of symptoms. Patients underwent temporary mucosal gastric stimulator (tGES) placement, which was done as a trial before permanent stimulator (GES) placement. Electrogastrogram (EGG) by mucosal (mEG) measures, including frequency, amplitude, and frequency-amplitude ratio (FAR), were pre- and post-tGES. Patients' history of personal and familial dysautonomias, quality of life, and symptom scores were recorded. Baseline vs. follow-ups were compared by paired t tests and McNemar's tests. T tests contrasted symptom scores, gastric emptying tests (GET), and mEG measures, while chi-squared tests deciphered comorbidity differences between two groups and univariate and multivariate analyses. RESULTS: There were significantly more patients with diabetes in the Cyc group vs. the NoCyc group. Using a 1 point in symptom outcome, 18 patients did not improve and 19 did improve with tGES. Using univariable analysis, with the cyclic pattern as a predictor, patients exhibiting a cyclic pattern had an odds ratio of 0.22 (95% CI 0.05-0.81, p = 0.054) for achieving an improvement of at least one unit in vomiting at follow-up from baseline. The mucosal electrogastrogram frequency to amplitude ratio (FAR) for the "not Improved" group was 19.6 [3.5, 33.6], whereas, for the "Improved" group, it was 54.3 [25.6, 72.5] with a p-value of 0.049. For multivariate logistic regression, accounting for sex and age squared, patients exhibiting a cyclic pattern had an adjusted odds ratio (OR) of 0.16 (95% CI 0.03-0.81, p = 0.027) for achieving an improvement of at least one unit in vomiting at follow-up from baseline. The two groups had no significant differences in the personal or inherited history of investigated familial patterns. CONCLUSION: This study shows differences in Gp patients with Cyc vs. NoCyc symptoms in several areas. Larger studies are needed to elicit further differences between the two groups about cycles of symptoms, EGG, findings, familial patterns, and response to mucosal GES.

Short- and long-term safety of discontinuing chronic opioid therapy among older adults with Alzheimer's disease and related dementia.

BACKGROUND: Limited evidence exists on the short- and long-term safety of discontinuing versus continuing chronic opioid therapy (COT) among patients with Alzheimer's disease and related dementias (ADRD). METHODS: This cohort study was conducted among 162,677 older residents with ADRD and receipt of COT using a 100% Medicare nursing home sample. Discontinuation of COT was defined as no opioid refills for ≥90 days. Primary outcomes were rates of pain-related hospitalisation, pain-related emergency department visit, injury, opioid use disorder (OUD) and opioid overdose (OD) measured by diagnosis codes at quarterly intervals during 1- and 2-year follow-ups. Poisson regression models were fit using generalised estimating equations with inverse probability of treatment weights to model quarterly outcome rates between residents who discontinued versus continued COT. RESULTS: The study sample consisted of 218,040 resident episodes with COT; of these episodes, 180,916 residents (83%) continued COT, whereas 37,124 residents (17%) subsequently discontinued COT. Discontinuing (vs. continuing) COT was associated with higher rates of all outcomes in the first quarter, but these associations attenuated over time. The adjusted rates of injury, OUD and OD were 0, 69 and 60% lower at the 1-year follow-up and 11, 81 and 79% lower at the 2-year follow-up, respectively, for residents who discontinued versus continued COT, with no difference in the adjusted rates of pain-related hospitalisations or emergency department visits. CONCLUSIONS: The rates of adverse outcomes were higher in the first quarter but lower or non-differential at 1-year and 2-year follow-ups between COT discontinuers versus continuers among older residents with ADRD.

A Bayesian nonparametric approach for multiple mediators with applications in mental health studies.

Mediation analysis with contemporaneously observed multiple mediators is a significant area of causal inference. Recent approaches for multiple mediators are often based on parametric models and thus may suffer from model misspecification. Also, much of the existing literature either only allow estimation of the joint mediation effect or estimate the joint mediation effect just as the sum of individual mediator effects, ignoring the interaction among the mediators. In this article, we propose a novel Bayesian nonparametric method that overcomes the two aforementioned drawbacks. We model the joint distribution of the observed data (outcome, mediators, treatment, and confounders) flexibly using an enriched Dirichlet process mixture with three levels. We use standardization (g-computation) to compute all possible mediation effects, including pairwise and all other possible interaction among the mediators. We thoroughly explore our method via simulations and apply our method to a mental health data from Wisconsin Longitudinal Study, where we estimate how the effect of births from unintended pregnancies on later life mental depression (CES-D) among the mothers is mediated through lack of self-acceptance and autonomy, employment instability, lack of social participation, and increased family stress. Our method identified significant individual mediators, along with some significant pairwise effects.

Impact of Reirradiation Utilizing Fractionated Stereotactic Radiotherapy for Recurrent Glioblastoma.

BACKGROUND: Patients with recurrent glioblastoma (GBM) have limited treatment options. This study determined whether patients with recurrent GBM treated with initial radiation/temozolomide (TMZ) and reirradiation using fractionated stereotactic radiotherapy (FSRT) had improved outcomes. MATERIALS AND METHODS: We identified 95 patients with recurrent GBM, 50 of whom underwent FSRT at recurrence and 45 who had systemic treatment only (control). The median total FSRT dose at the time of GBM recurrence was 30 Gy in five fractions of the gadolinium-enhanced tumor only. RESULTS: With a median follow-up of 18 months, the progression-free survival (PFS) and overall survival (OS) following initial GBM diagnosis were longer in the reirradiation group compared to the control group (13.5 vs. 7.5 months [p=0.001] and 24.6 vs. 12.6 months [p<0.001], respectively). For patients who underwent reirradiation, the median time interval between the end of the initial radiation and reirradiation was 15.2 months. The median OS after GBM recurrence was longer in the reirradiation group versus the control group (9.9 vs. 3.5 months [p<0.001]), with a one-year OS survival rate of 22%. The hazard ratio for death of patients in the reirradiation group was 0.31 [0.19-0.50]. The reirradiation group had a higher percentage of patients who received bevacizumab (BEV, 62.0% vs. 28.9%, p=0.002) and a lower percentage of patients whose TMZ was discontinued due to toxicity (8.0% vs. 28.9%, p=0.017) compared to the control group. CONCLUSIONS: Reirradiation utilizing FSRT was associated with improved PFS and OS after GBM recurrence compared to the control group who did not receive additional irradiation.

Pain intensity, physical function, and depressive symptoms associated with discontinuing long-term opioid therapy in older adults with Alzheimer's disease and related dementias.

INTRODUCTION: Limited evidence exists on the associations of discontinuing versus continuing long-term opioid therapy (LTOT) with pain intensity, physical function, and depression among patients with Alzheimer's disease and related dementias (ADRD). METHODS: A cohort study among 138,059 older residents with mild-to-moderate ADRD and receipt of LTOT was conducted using a 100% Medicare nursing home sample. Discontinuation of LTOT was defined as no opioid refills for ≥ 60 days. Outcomes were worsening pain, physical function, and depression from baseline to quarterly assessments during 1- and 2-year follow-ups. RESULTS: The adjusted odds of worsening pain and depressive symptoms were 29% and 5% lower at the 1-year follow-up and 35% and 9% lower at the 2-year follow-up for residents who discontinued versus continued LTOT, with no difference in physical function. DISCUSSION: Discontinuing LTOT was associated with lower short- and long-term worsening pain and depressive symptoms than continuing LTOT among older residents with ADRD. HIGHLIGHTS: Discontinuing long-term opioid therapy (LTOT) was associated with lower short- and long-term worsening pain. Discontinuing LTOT was related to lower short- and long-term worsening depression. Discontinuing LTOT was not associated with short- and long-term physical function.

Clinical importance of changes in magnetic resonance biomarkers for Duchenne muscular dystrophy.

OBJECTIVE: Magnetic resonance (MR) measures of muscle quality are highly sensitive to disease progression and predictive of meaningful functional milestones in Duchenne muscular dystrophy (DMD). This investigation aimed to establish the reproducibility, responsiveness to disease progression, and minimum clinically important difference (MCID) for multiple MR biomarkers at different disease stages in DMD using a large natural history dataset. METHODS: Longitudinal MR imaging and spectroscopy outcomes and ambulatory function were measured in 180 individuals with DMD at three sites, including repeated measurements on two separate days (within 1 week) in 111 participants. These data were used to calculate day-to-day reproducibility, responsiveness (standardized response mean, SRM), minimum detectable change, and MCID. A survey of experts was also performed. RESULTS: MR spectroscopy fat fraction (FF), as well as MR imaging transverse relaxation time (MRI-T2 ), measures performed in multiple leg muscles, and had high reproducibility (Pearson's R > 0.95). Responsiveness to disease progression varied by disease stage across muscles. The average FF from upper and lower leg muscles was highly responsive (SRM > 0.9) in both ambulatory and nonambulatory individuals. MCID estimated from the distribution of scores, by anchoring to function, and via expert opinion was between 0.01 and 0.05 for FF and between 0.8 and 3.7 ms for MRI-T2 . INTERPRETATION: MR measures of FF and MRI T2 are reliable and highly responsive to disease progression. The MCID for MR measures is less than or equal to the typical annualized change. These results confirm the suitability of these measures for use in DMD and potentially other muscular dystrophies.

Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's disease.

Microglial endolysosomal (dys)function is strongly implicated in neurodegenerative disease. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer's disease (AD) models and human AD brain, and that the emergence of this state is emphasised in females. Cst7 (encoding cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7-/- mice with the AppNL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD. Surprisingly, we found that Cst7 plays a sexually dimorphic role regulating microglia in this model. In females, Cst7-/-AppNL-G-F microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (Aß) burden in vivo and were more phagocytic in vitro. However, in males, Cst7-/-AppNL-G-F microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aß burden. Overall, our study reveals functional roles for one of the most commonly upregulated genes in microglia across disease models, and the sex-specific profiles of Cst7-/--altered microglial disease phenotypes. More broadly, the findings raise important implications for AD including crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.

Joint modeling in presence of informative censoring on the retrospective time scale with application to palliative care research.

Joint modeling of longitudinal data such as quality of life data and survival data is important for palliative care researchers to draw efficient inferences because it can account for the associations between those two types of data. Modeling quality of life on a retrospective from death time scale is useful for investigators to interpret the analysis results of palliative care studies which have relatively short life expectancies. However, informative censoring remains a complex challenge for modeling quality of life on the retrospective time scale although it has been addressed for joint models on the prospective time scale. To fill this gap, we develop a novel joint modeling approach that can address the challenge by allowing informative censoring events to be dependent on patients' quality of life and survival through a random effect. There are two sub-models in our approach: a linear mixed effect model for the longitudinal quality of life and a competing-risk model for the death time and dropout time that share the same random effect as the longitudinal model. Our approach can provide unbiased estimates for parameters of interest by appropriately modeling the informative censoring time. Model performance is assessed with a simulation study and compared with existing approaches. A real-world study is presented to illustrate the application of the new approach.

Interspecies interactions determine growth dynamics of biopolymer-degrading populations in microbial communities.

Microbial communities perform essential ecosystem functions such as the remineralization of organic carbon that exists as biopolymers. The first step in mineralization is performed by biopolymer degraders, which harbor enzymes that can break down polymers into constituent oligo- or monomeric forms. The released nutrients not only allow degraders to grow, but also promote growth of cells that either consume the degradation products, i.e., exploiters, or consume metabolites released by the degraders or exploiters, i.e., scavengers. It is currently not clear how such remineralizing communities assemble at the microscale-how interactions between the different guilds influence their growth and spatial distribution, and hence the development and dynamics of the community. Here, we address this knowledge gap by studying marine microbial communities that grow on the abundant marine biopolymer alginate. We used batch growth assays and microfluidics coupled to time-lapse microscopy to quantitatively investigate growth and spatial distribution of single cells. We found that the presence of exploiters or scavengers alters the spatial distribution of degrader cells. In general, exploiters and scavengers-which we collectively refer to as cross-feeder cells-slowed down the growth of degrader cells. In addition, coexistence with cross-feeders altered the production of the extracellular enzymes that break down polymers by degrader cells. Our findings reveal that ecological interactions by nondegrading community members have a profound impact on the functions of microbial communities that remineralize carbon biopolymers in nature.

Joint modeling the frequency and duration of accelerometer-measured physical activity from a lifestyle intervention trial.

Physical activity (PA) guidelines recommend that PA be accumulated in bouts of 10 minutes or more in duration. Recently, researchers have sought to better understand how participants in PA interventions increase their activity. Participants can increase their daily PA by increasing the number of PA bouts per day while keeping the duration of the bouts constant; they can keep the number of bouts constant but increase the duration of each bout; or participants can increase both the number of bouts and their duration. We propose a novel joint modeling framework for modeling PA bouts and their duration over time. Our joint model is comprised of two sub-models: a mixed-effects Poisson hurdle sub-model for the number of bouts per day and a mixed-effects location scale gamma regression sub-model to characterize the duration of the bouts and their variance. The model allows us to estimate how daily PA bouts and their duration vary together over the course of an intervention and by treatment condition and is specifically designed to capture the unique distributional features of bouted PA as measured by accelerometer: frequent measurements, zero-inflated bouts, and skewed bout durations. We apply our methods to the Make Better Choices study, a longitudinal lifestyle intervention trial to increase PA. We perform a simulation study to evaluate how well our model is able to estimate relationships between outcomes.

Multivariate modeling of magnetic resonance biomarkers and clinical outcome measures for Duchenne muscular dystrophy clinical trials.

Although regulatory agencies encourage inclusion of imaging biomarkers in clinical trials for Duchenne muscular dystrophy (DMD), industry receives minimal guidance on how to use these biomarkers most beneficially in trials. This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease-drug-trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6-minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual-level data collected for 10 years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed-effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation-based diagnostics and fivefold cross-validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers.

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8.

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-ß plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.

Creating connections: developing an online space for cross-regional mentorship and network building in the dementia research field.

Background: Effective development and retention of talented early-career researchers (ECRs) is essential to the continued success of biomedical science research fields. To this end, formal mentorship programmes (where researchers are paired with one or more mentors beyond their direct manager) have proven to be successful in providing support and expanding career development opportunities. However, many programmes are limited to pools of mentors and mentees within one institute or geographical area, highlighting that cross-regional connections may be a missed opportunity in many mentorship schemes. Methods: Here, we aimed to address this limitation through our pilot cross-regional mentorship scheme, creating reciprocal mentor-mentee pairings between two pre-established networks of Alzheimer's Research UK (ARUK) Network-associated researchers. We carefully created 21 mentor-mentee pairings between the Scotland and University College London (UCL) networks in 2021, with surveys conducted to assess mentor/mentee satisfaction with the programme. Results: Participants reported very high satisfaction with the nature of the pairings and the mentors' contribution to the career development of mentees; a majority also reported that the mentorship scheme increased their connections outside of their home network. Our assessment of this pilot programme is that it supports the utility of cross-regional mentorship schemes for ECR development. At the same time, we highlight the limitations of our programme and recommend areas for improvement in future programmes, including greater consideration of support for minoritized groups and the need for additional training for mentors. Conclusions: In conclusion, our pilot scheme generated successful and novel mentor-mentee pairings across pre-existing networks; both of which reported high satisfaction with pairings, ECR career and personal development, and the formation of new cross-network connections. This pilot may serve as a model for other networks of biomedical researchers, where existing networks within medical research charities can act as a scaffold to build new cross-regional career development opportunities for researchers.