Linear Mixed-effects Models Research Articles

Characterization of the Biological Variability of the Angiome Biomarkers over Time in Healthy Subjects.

Biomarker analyses are an integral part of cancer research. Despite the intense efforts to identify and characterize biomarkers in cancer patients, little is known regarding the natural variation of biomarkers in healthy populations. Here we conducted a clinical study to evaluate the natural variability of biomarkers over time in healthy participants. The angiome multiplex array, a panel of 25 circulating protein biomarkers, was assessed in 28 healthy participants across 8 timepoints over the span of 60 days. We utilized the intraclass correlation coefficient (ICC) to quantify the reliability of the biomarkers. Adjusted ICC values were calculated under the framework of a linear mixed-effects model, taking into consideration age, sex, body mass index (BMI), fasting status, and sampling factors. ICC was calculated to determine the reliability of each biomarker. HGF was the most stable marker (ICC=0.973), while PDGF-BB was the most variable marker (ICC=0.167). In total, ICC analyses revealed that 22 out of 25 measured biomarkers display good (≥0.4) to excellent (>0.75) ICC values. Three markers (PDGF-BB, TGF-1, PDGF-AA) had ICC values <0.4. Greater age was associated with higher IL-6 (p=0.0114). Higher BMI was associated with higher levels of IL-6 (p=0.0003) and VEGF-R3 (p=0.0045). Of the 25 protein biomarkers measured over this short time period, 22 markers were found to have good or excellent ICC values, providing additional validation for this biomarker assay. This data further supports the validation of the angiome biomarker assay and its application as an integrated biomarker in clinical trial testing.

Intrinsic functional connectivity of right dorsolateral prefrontal cortex and hippocampus subregions relates to emotional and sensory-perceptual properties of intrusive trauma memories.

Trauma-related intrusive memories (TR-IMs), unwanted and vivid, are core symptoms of posttraumatic stress disorder (PTSD). Prior research links voluntary TR-IM suppression to inhibitory control of the right dorsolateral prefrontal cortex (dlPFC) over the hippocampus (HPC). However, the potential relevance of tonic resting-state inhibition has not been examined, nor has the functional differentiation of the anterior and posterior hippocampus (aHPC/HPC). This study examined relationships of TR-IM frequency and properties with resting-state negative coupling between the right dlPFC and right aHPC/pHPC in trauma-exposed individuals with PTSD symptoms. Participants (N=109; 88 female) completed two weeks of ecological momentary assessments capturing TR-IM frequency and properties (intrusiveness, emotional intensity, vividness, visual properties, and reliving). Using 3T resting-state magnetic resonance imaging, participant-specific 4-mm spheres were placed at the right dlPFC voxel most anticorrelated with the right aHPC and pHPC. Quasi-Poisson and linear mixed-effects models assessed relationships of TR-IM frequency and properties with right dlPFC-right aHPC and pHPC anticorrelation. TR-IM emotional intensity was positively associated with right dlPFC-aHPC connectivity, while vividness and visual properties were linked to right dlPFC-pHPC connectivity. No significant associations were found between TR-IM frequency, intrusiveness, or reliving, and anticorrelation with either HPC subregion. This study provides novel insights into the neural correlates of TR-IMs, highlighting the relevance of intrinsic negative coupling between the right dlPFC and aHPC/pHPC to their emotional impact and perceptual properties. Further research on inhibitory mechanisms in this circuit could improve understanding of component processes of intrusive reexperiencing, a severe and treatment-refractory PTSD symptom.

Longitudinal associations of life space mobility and domain-specific cognitive measures in ACTIVE

ABSTRACT We tested the longitudinal associations between life space mobility (LSM) at baseline and cognitive performance in three domains (memory, reasoning, and speed of processing) over time. Our analytic sample includes 2,690 older adults (mean age = 73.0, 75.9% female) participating in the ACTIVE Study. We used multiple linear mixed-effects models to evaluate whether LSM, measured using the Life Space Questionnaire, at baseline was longitudinally associated with scores on eight cognitive tests and three composite scores across 10 years. In unadjusted models, there were significant main effects of baseline LSM on memory and reasoning domains, and one speed of processing test (beta: 0.019 to 0.055, p < 0.05). All effects were non-significant in adjusted models. Over time, baseline LSM was associated with one memory test score in adjusted models. Greater LSM at baseline is associated with marginally higher cognitive performance but does not appear to affect the rate of cognitive change at a clinically significant level.

Retinal oxygen metabolic function in choroideremia and retinitis pigmentosa.

To measure the retinal oxygen metabolic function with retinal oximetry (RO) in patients with choroideremia (CHM) and compare these findings with retinitis pigmentosa (RP) patients and controls. Prospective observational study including 18 eyes of 9 molecularly confirmed CHM patients (9♂; 40.2 ± 21.2years (mean ± SD), 77 eyes from 39 patients with RP (15♀ 24♂; 45.6 ± 14.7years) and 100 eyes from 53 controls (31♀ 22♂; 40.2 ± 13.4years). Main outcome parameters were the mean arterial (A-SO2; %), venular (V-SO2; %) oxygen saturation, and their difference (A-V SO2; %) recorded with the oxygen saturation tool of the Retinal Vessel Analyzer (IMEDOS Systems UG, Germany). Statistical analyses were performed with linear mixed-effects models. Eyes suffering from CHM differed significantly from both RP and control eyes, when the retinal oxygen metabolic parameters were taken into account. While RP showed significantly higher A-SO2 and V-SO2 values when compared to controls, CHM showed opposite findings with significantly lower values when compared to both RP and controls (P < 0.001). The A-V SO2, which represents the retinal oxygen metabolic consumption, showed significantly lower values in CHM compared to controls. The retina in CHM is a relatively hypoxic environment. The decrease in oxygen levels may be due to the profound choroidal degeneration, leading to decreased oxygen flux to the retina. RO measurements may help understand the pathogenesis of CHM and RP. These findings may provide useful details to inform the planning of clinical trials of emerging therapies for CHM. What was known before? Retinal oxygen metabolic function measured with retinal oximetry (RO) shows significant alterations in patients with retinitis pigmentosa. RO function in choroideremia is significantly altered when compared to controls. Furthermore, RO in choroideremia shows opposing findings within different oxygen metabolic parameters to those that were so far known for retinitis pigmentosa. By providing insights into the retinal oxygen metabolic mechanisms, RO can help understand the underlying pathophysiology in choroideremia.

Age differences in the change in cognition after stroke

ObjectiveTo compare changes in cognitive trajectories after stroke between younger (18-64) and older (65+) adults, accounting for pre-stroke cognitive trajectories. Materials and methodsPooled cohort study using individual participant data from 3 US cohorts (1971-2019), the Atherosclerosis Risk In Communities Study (ARIC), Framingham Offspring Study (FOS), and REasons for Geographic And Racial Differences in Stroke Study (REGARDS). Linear mixed effect models evaluated the association between age and the initial change (intercept) and rate of change (slope) in cognition after compared to before stroke. Outcomes were global cognition (primary), memory and executive function. ResultsWe included 1,292 participants with stroke; 197 younger (47.2 % female, 32.5 % Black race) and 1,095 older (50.2 % female, 46.4 % Black race). Median (IQR) age at stroke was 59.7 (56.6-61.7) (younger group) and 75.2 (70.5-80.2) years (older group). Compared to the young, older participants had greater declines in global cognition (-1.69 point [95 % CI, -2.82 to -0.55] greater), memory (-1.05 point [95 % CI, -1.92 to -0.17] greater), and executive function (-3.72 point [95 % CI, -5.23 to -2.21] greater) initially after stroke. Older age was associated with faster declines in global cognition (-0.18 points per year [95 % CI, -0.36 to -0.01] faster) and executive function (-0.16 [95 % CI, -0.26 to -0.06] points per year for every 10 years of higher age), but not memory (-0.006 [95 % CI, -0.15 to 0.14]), after compared to before stroke. ConclusionOlder age was associated with greater post-stroke cognitive declines, accounting for differences in pre-stroke cognitive trajectories between the old and the young.

Balance Assessment on a Modified Posturomed Platform in Healthy Dogs.

Reliable, standardized balance tests for dogs are not available yet. The purpose of this study was to investigate the reliability of static and dynamic posturography in healthy dogs. Healthy dogs (n = 20) were positioned with four paws longitudinally and with the forepaws only transversely on a modified pressure-sensitive balance platform (Posturomed-FDM-JS, Zebris, Isny, Germany). Three static and dynamic posturographic trials were recorded (recording duration: 20 s) and repeated after 7-14 days. Center of pressure (COP) parameters COP-path-length (PL; mm), 95% COP-confidence-ellipse-area (CEA; mm2), and COP-average-velocity (AV; mm/s) were calculated for the first steady-state 5 s intervals of each trial. The reliability of COP parameters was assessed with robust linear mixed effects models with nested random effects of patient and trial. The training effect was analyzed using Cohen's d. For static posturography, PL, CEA, and AV did not differ significantly between time points; CEA had the highest reliability (p = 0.92). For dynamic posturography, AV and PL differed significantly between time points (AV: p ≤ 0.043; PL: p ≤ 0.045). Slight training effects were observed for transverse positioning (Cohen's d: PL 0.65; AV 0.267) and moderate training effects for longitudinal positioning (Cohen's d: PL: 0.772; AV: 0.783). This study showed that static posturography on a modified Posturomed-balance platform was reliable in healthy dogs but indicated training effects during dynamic posturography.

Biological mechanisms of resilience to tau pathology in Alzheimer’s disease

BackgroundIn Alzheimer’s disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience).MethodsWe included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline.ResultsRegarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073–-0.069, pFDR 0.001–0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099–-0.063, pFDR < 0.001–0.046), synaptic (14–3-3ζ/δ; βinteraction = -0.092, pFDR = 0.041), axonal (NfL; βinteraction = -0.079, pFDR < 0.001), and neurotrophic (NGF; βinteraction = 0.091, pFDR < 0.001) biomarkers. In MCI higher NfL levels (βmain = -0.690, pFDR = 0.025) were associated with faster cognitive decline independent of tau-PET signal.ConclusionsBiomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience.

Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded.

Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease-modifying treatments have reported their efficacy and safety, long-term natural history data are lacking for comparison. The aim of this prospective study was to report 4-year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number. The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number. In SMA type II (n = 226), the 4-year mean change was -2.20 points. The largest mean changes were observed in sitters aged 5-14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4-year mean change was -2.75 points. The largest mean changes were in those aged 7-15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4-year changes. Our findings provide natural history reference data for comparison with long-term follow-up of clinical trials or real-world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.

Amygdala Subregion Volumes and Apportionment in Preadolescents - Associations with Age, Sex, and Body Mass Index.

The amygdala, a key limbic structure, plays a critical role in emotional, social, and appetitive behaviors that develop throughout adolescence. Composed of a heterogeneous group of nuclei, questions remain about potential differences in the maturation of its subregions during development. To characterize the associations between developmental variables and amygdala subregion volumes during preadolescence. Cross-sectional Adolescent Brain Cognitive Development SM (ABCD®) Study data was collected from 3,953 9- and 10-year-old children between September 1, 2016, and October 15, 2018. Data analysis was conducted between June 1, 2023, and July 30, 2024. Using the CIT168 Amygdala Atlas , nine amygdala subregion volumes were quantified from high-quality MRI scans. Linear mixed-effects models were used to examine the effects of age, sex, pubertal stage, and body mass index z-score (BMIz) on subregion volumes and their relative apportionment within the amygdala. The study population consisted of 3,953 preadolescents (mean [SD] age, 120 [7.41] months; 1,763 [44.6%] female; 57 [1.4%] Asian, 527 [13.3%] Black, 740 [18.7%] Hispanic, 2,279 [57.7%] white, and 350 [8.9%] from other racial/ethnic groups [identified by parents as American Indian/Native American, Alaska Native, Native Hawaiian, Guamanian, Samoan, other Pacific Islander, or other race]). Distinct associations were observed between age, sex, and BMIz and whole amygdala volume, subregion volumes, and subregion apportionment. Pubertal stage was not related to amygdala subregion volumes. Age was associated with near-global expansion of amygdala subregions during this developmental period. Female sex was linked to smaller volumes in most amygdala subregions, with larger relative apportionment in dorsal amygdala subregions and smaller apportionment in the basolateral ventral paralaminar subregion. Higher BMIz was associated with smaller volumes in large laterobasal subregions, with increased relative apportionment in smaller subregions. This cross-sectional study suggests that age, but not pubertal stage, is associated with near-global expansion of the amygdala at ages 9 and 10, while sex and BMIz are linked to distinct changes in amygdala subregions that explain observed differences in total volumes. These findings provide a foundational context for understanding how developmental variables influence amygdala structure in preadolescents, with implications for understanding future risk for brain disorders.

Assessment of weather-driven travel behavior on a small-scale docked bike-sharing system usage

Bike-sharing systems play a crucial role in encouraging sustainable transportation, and understanding their usage characteristics is essential for enhancing their contribution to urban mobility. This research seeks to investigate how weather conditions impact the utilization of a small-scale docked bike-sharing system. The study employed Generalized Linear Mixed Effects (GLME) models to analyze interactive events, using categorized weather parameters to represent various weather conditions. Several models were developed to comprehensively understand distinct travel behaviors and identify significant weather variables affecting the frequency of bike trips for transportation and leisure purposes. The findings reveal that rain had a significant deterrent effect on leisure cycling, particularly on weekdays. Cold and hot weather conditions exhibited a more pronounced impact on weekday bike trips, while weekend bike trips appeared to be less influenced by weather variables. The fall season was found to be the least favorable for leisure trips, while winter was determined to be the most unfavorable for transportation trips. Furthermore, hot days in the summer season negatively impacted bike usage only on weekdays. These insights have important implications for the development of a more resilient bike-sharing system, particularly in small-scale contexts. They provide valuable recommendations for tailored strategies to mitigate the impact of adverse weather conditions, thereby fostering an increase in usage of bike-sharing systems for both leisure and transportation purposes.

Association between maternal stress and child sleep quality: a nationwide ECHO prospective cohort study.

Childhood sleep quality is associated with physical, cognitive, and behavioral health and predicts later sleep quality; it has many determinants, including developmental exposures. To examine associations between maternal stress during pregnancy and childhood sleep quality and determine whether postnatal stress mediates the association. Data from the Environmental Influences on Child Health Outcomes cohort were used. Perceived Stress Scale (PSS) T-scores were the exposure measure. Outcome measures were preschool Child Behavior Checklist (CBCL) sleep syndrome scale and Patient-Reported Outcomes Measurement Information System Sleep Disturbance Parent Proxy short form 4a (PSD4a) T-scores at ages 4-8 years. Linear mixed-effects regression modeling was performed for each sleep outcome, adjusting for maternal age at delivery and education and child sex, gestational age at birth, and age at outcome ascertainment, with random intercepts for cohorts. Prenatal PSS score was associated with both CBCL (B = 0.09, 95% confidence interval [CI]: 0.06, 0.11; p < 0.01) and PSD4a (B = 0.07, 95% CI: 0.03, 0.12; p < 0.01) scores. Postnatal perceived stress mediated a proportion of the total effect of prenatal stress in both CBCL (66.3%) and PSD4a (95.9%) samples. Both pre- and postnatal maternal perceived stress appear to influence sleep quality during early life. Prenatal stress significantly associates with child sleep problems and disturbances at ages 4-8 years; postnatal maternal stress is a significant mediator of these associations. Research suggests a range of prenatal affective/distress exposures associated with child sleep problems, but the conclusions remain in doubt due to the mixture of exposures and outcomes employed. Ours is the first US-based effort to explore associations between perceived maternal stress during pregnancy and child sleep problems and disturbance in early and middle childhood. Even a small effect of a prevalent issue like psychosocial stress may have important public health implications at the population level.

Sharing Stories Versus Explaining Facts: Comparing African American Children's Microstructure Performance Across Fictional Narrative, Informational, and Procedural Discourse.

Both fictional oral narrative and expository oral discourse skills are critical language competencies that support children's academic success. Few studies, however, have examined African American children's microstructure performance across these genres. To address this gap in the literature, the study compared African American children's microstructure productivity and complexity across three discourse contexts: fictional narratives, informational discourse, and procedural discourse. The study also examined whether there were age-related differences in microstructure performance by discourse type. Participants were 130 typically developing African American children, aged 59-95 months old, enrolled in kindergarten through second grades in a Midwestern U.S. public school district. Wordless children's books were used to elicit fictional narratives, informational, and procedural discourse. Indicators of microstructure performance included measures of productivity (i.e., number of total words and number of different words) and complexity (i.e., mean length of communication unit and complex syntax rate). The effects of genre and age on microstructure performance were assessed using linear mixed-effects regression models. Children produced longer discourse and used a greater diversity of words for their fictional stories compared to their informational or procedural discourse. Grammatical complexity was greater for fictional narratives and procedural discourse than informational discourse. Results showed greater productivity and complexity among older children compared to younger children, particularly for fictional and informational discourse. African American children exhibit variation in their microstructure performance by discourse context and age. Understanding this variation is key to providing African American children with support to maximize their oral language competencies.

Relationship between radiation dose and cerebral microbleed formation in dogs with intracranial tumors.

Cerebral microbleeds (CMBs) are a possible sequela in human brain tumor patients treated with radiation therapy (RT). No such association is reported in dogs. To investigate whether CMBs occur in dogs after radiotherapy, and if there is an association between number and dose, and an increase over time. Thirty-four client-owned dogs irradiated for primary intracranial neoplasia. ≥2 magnetic resonance imaging (MRI) scans including susceptibility-weighted imaging (SWI) were required. Retrospective, observational, single-center study. Cerebral microbleeds identified on 3 T SWI were counted within the entire brain, and within low- (<20 Gy), intermediate- (20-30 Gy), and high- (>30 Gy) dose regions. A generalized linear mixed-effects model was used to analyze the relationship between the CMBs count and the predictor variables (irradiation dose, time after treatment). Median follow-up time was 12.6 months (range, 1.8-37.6 months). Eighty-three MR scans were performed. In 4/15 dogs (27%, 95% CI, 10%-52%) CMBs were present at baseline. ≥1 CMBs after RT were identified in 21/34 dogs (62%, 95% CI, 45%-77%). With each month, the number of CMBs increased by 14% (95% CI, 11%-16%; P < .001). The odds of developing CMBs in the high-dose region are 4.7 times (95% CI, 3.9-5.6; P < .001) greater compared with the low-dose region. RT is 1 possible cause of CMBs formation in dogs. Cerebral microbleeds are most likely to occur in the peritumoral high-dose volume, to be chronic, and to increase in number over time. Their clinical relevance remains unknown.

The Role of Kt/V and Creatinine clearance on Assisting Optimization of Serum Phosphorus Levels among Patients on PD.

Hyperphosphatemia is associated with poor outcome and is still very common in peritoneal dialysis (PD) patients. Since peritoneal phosphate clearance is closer to peritoneal creatinine clearance than urea clearance, we hypothesized that weekly creatinine clearance (CrCl) could be a better marker of serum phosphate in PD. In a retrospective observational study, data from adult PD patients were collected across five institutions in North and South America: LATAM, RRI, Mount Sinai Hospital, Hospital Civil de Guadalajara, and the BRAZPD cohort. All centers analyzed routinely available laboratory data, with exclusions for missing data on serum phosphate, CrCl, or urea Kt/V. A unified statistical protocol was employed across centers. Linear mixed-effect models examined associations between longitudinal serum phosphate levels, CrCl, and Kt/V. Adjustments were made for age, gender, and baseline phosphate binder usage. Mixed-effects meta-analysis determined the pooled effect size of CrCl and Kt/V on serum phosphate trajectories, adjusted for confounders. There were 16,796 incident PD patients analyzed. Age, BMI, gender, PD modality, Kt/V and CrCl as well as serum phosphate varied significantly across the different cohorts, but >70% had residual renal function. For most cohorts, both CrCltotal and urea Kt/V associated negatively with serum phosphorus levels, and log-likelihood ratio tests demonstrate that models including CrCltotal have more predictive information than those including only urea Kt/V for the largest cohorts. Models including CrCltotal increase information predicting longitudinal serum phosphate levels irrespective of baseline urea Kt/V, age, use of phosphorus binder, and gender. CrCl was not more accurate in predicting serum phosphate than urea Kt/V, but its inclusion in multivariable models predicting serum phosphate added accuracy. In conclusion, both creatinine clearance and Kt/V are associated with phosphate levels, and using both biomarkers, instead of just one, may better assist in the optimization of serum phosphate levels.

Psychological distress among healthcare providers during the COVID-19 pandemic: patterns over time

BackgroundCOVID-19 added to healthcare provider (HCP) distress, but patterns of change remain unclear. This study sought to determine if and how emotional distress varied among HCP between March 28, 2021 and December 1, 2023.MethodsThis longitudinal study was embedded within the 42-month prospective COVID-19 Cohort Study that recruited HCP from four Canadian provinces. Information was collected at enrollment, from annual exposure surveys, and vaccination and illness surveys. The 10-item Kessler Psychological Distress Scale (K10) was completed approximately every six months after March 28, 2021. Linear mixed effects models, specifically random intercept models, were generated to determine the impact of time on emotional distress while accounting for demographic and work-related factors.ResultsBetween 2021 and 2023, the mean K10 score fell by 3.1 points, indicating decreased distress, but scores increased during periods of high levels of mitigation strategies against transmission of SARS-CoV-2, during winter months, and if taking antidepression, anti-anxiety or anti-insomnia medications. K10 scores were significantly lower for HCP who were male, older, had more children in their household, experienced prior COVID-19 illness(es), and for non-physician but regulated HCP versus nurses. A sensitivity analysis that included only those who had submitted at least five K10 surveys consisted of the factors in the full model excluding previous COVID-19 illness, occupation, and season, after adjustment. Models were also created for K10 anxiety and depression subscales.ConclusionsK10 scores decreased as the COVID-19 pandemic continued but increased during periods of high mitigation and the winter months. Personal and work-place factors also impacted HCP distress scores. Further research into best practices in distress identification and remediation is warranted to ensure future public health disasters are met with healthcare systems that are able to buffer HCP against short- and long-term mental health issues.

Changes and associations between synovial fluid and magnetic resonance imaging markers of osteoarthritis after high tibial osteotomy

BackgroundMechanobiological mechanisms of osteoarthritis (OA) are unclear. Our objectives were to explore: 1) changes in knee joint physiology using a large panel of synovial fluid biomarkers from before to one year after high tibial osteotomy (HTO) surgery, and 2) the association of changes in the synovial fluid biomarkers with the changes in MRI measures of knee effusion-synovitis and articular cartilage composition.MethodsTwenty-six patients with symptomatic knee OA and varus alignment underwent synovial fluid aspirations and 3 T MRI before and one year after medial opening wedge HTO. Cytokine and growth factor levels in synovial fluid were measured with multiplex assays. Ontology and pathway enrichment was assessed using data protein sets with gene set enrichment analysis (GSEA), and analyzed using linear mixed effects models. MRIs were analyzed for effusion-synovitis and T2 cartilage relaxation time using manual segmentations. Changes in biomarker concentrations were correlated to changes in MRI effusion-synovitis volume and articular cartilage T2 relaxation times.ResultsDecreased enrichment in Toll-like receptor and TNF-α signalling was detected one year after HTO. The leading contributors to this reduction included IL-6, TNF-α and IL-1β, whereas the highest contributors to positive enrichment were EGF, PDGF-BB and FGF-2. Effusion-synovitis volume decreased (mean [95%CI]) one year after HTO (-2811.58 [-5094.40, -528.76mm3]). Effusion-synovitis volume was moderately correlated (r [95% CI]) with decreased MMP-1 (0.44 [0.05; 0.71]), IL-7 (0.41 [0.00; 0.69]) and IL-1β (0.59 [0.25; 0.80]) and increased MIP-1β (0.47 [0.10; 0.73]). Medial tibiofemoral articular cartilage T2 relaxation time decreased (mean [95% CI]) one year after HTO (-0.33 [-2.69; 2.05]ms). Decreased T2 relaxation time was moderately correlated to decreased Flt-3L (0.61 [0.28; 0.81]), IL-10 (0.47 [0.09; 0.73]), IP-10 (0.42; 0.03–0.70) and increased MMP-9 (-0.41 [-0.7; -0.03]) and IL-18 (-0.48 [-0.73; -0.10]).ConclusionsDecreased aberrant knee mechanical loading in patients with OA is associated with decreased biological and imaging measures of inflammation (measured in synovial fluid and on MRI) and increased anabolic processes. These exploratory findings suggest that improvement in knee loading can produce long-term (one year) improvement in joint physiology.

Distinct Cognitive Trajectories According to Amyloid Positivity in Non-Alzheimer Disease Dementias.

The clinical effects of β-amyloid positivity (Aβ+) on copathologies in various dementias remain relatively underexamined. Thus, the present study was conducted to investigate the prevalence and clinical effects of Aβ+ in subcortical vascular cognitive impairment (SVCI) and frontotemporal dementia (FTD). We enrolled SVCI (n = 583), FTD (n = 152), and cognitively unimpaired (CU) participants (n = 1,249) who underwent Aβ PET scans. The odds of having Aβ+ were subsequently compared among the diagnostic groups (CU, SVCI, and FTD) according to age and apolipoprotein E genotype. Additionally, a linear mixed-effects model was used to investigate the effects of Aβ+ on cognitive trajectories in SVCI and FTD. Compared with CU, the SVCI group had a higher prevalence of Aβ+ in the 75 to 90 years age group (adjusted odds ratio, 1.97; 95% confidence interval, 1.36-2.85; P < 0.001), as well as within the apolipoprotein E ε3/ε3 group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.63; P = 0.001), whereas the FTD group showed no difference in Aβ+ prevalence. Aβ+ was associated with a worse cognitive trajectory in SVCI (adjusted β-coefficient = -0.6424; P < 0.001), but not in FTD. These findings contribute to our understanding of Aβ biomarker traits in various dementias in Korea.

Assessing a Couples-Based, Digital HIV Serostatus-Neutral Intervention (Para Ti, Para Mí, Para Nosotros) for Adult Cisgender Sexual Minority Male Couples in Lima, Peru: Protocol for a 6-Month Pilot Randomized Controlled Trial.

HIV disproportionately affects sexual minority men (SMM; eg, gay, bisexual, and other men who have sex with men) in Lima, Peru; epidemiological data estimate that 32% to 39% of new HIV infections occur among adult cisgender SMM within primary partnerships (ie, male couples). Most HIV prevention-care research in Lima, Peru, has focused on SMM as individuals and not couples. To help address this critical gap in prevention care, we developed Para Ti, Para Mí, Para Nosotros (P3): a couples-based, digital HIV serostatus-neutral intervention (DHI) for adult cisgender SMM couples in Lima, Peru. The P3 DHI is designed to facilitate couples with skill-building, communication, decision-making, and working together to form and adhere to a detailed prevention care plan that aligns with their explicit sexual agreement. The P3 DHI is theoretically informed, self-guided, directed, sequential, and fully automated. This pilot randomized controlled trial (RCT) aims to examine the preliminary effects of P3 on couples' formation and adherence to a detailed prevention care plan containing evidence-based strategies that also aligns with their explicit sexual agreement over time. In addition, the feasibility of enrollment and retention and couples' acceptability of P3 will be assessed. The research implements a prospective, 6-month pilot RCT with a 3-month delayed control condition. After baseline, 60 enrolled SMM couples will be randomized to 1 of 2 conditions. Couples randomized to the unmatched, delayed control condition will receive access to the P3 DHI to use during the last 3 months of the trial after the 3-month assessment. Couples randomized to the immediate intervention condition will immediately receive access to the P3 DHI for 6 months. Study assessments will occur at baseline and months 3 and 6. Descriptive, comparative, qualitative, and longitudinal analyses using generalized linear mixed-effect, multilevel, and actor-partner interdependence models will be conducted to address the specific aims. The 6-month pilot RCT is ongoing. Recruitment, enrollment, and data collection began in January 2023 and ended in April 2024. A total of 74 adult cisgender SMM couples met all inclusion criteria, provided consent, and were enrolled in the pilot RCT. Retention was 92% (68/74) at month 6. Data are currently being analyzed to address the 3 specific aims regarding feasibility, acceptability, and preliminary efficacy. Findings from this research will reveal whether couples deemed the P3 DHI to be acceptable. Findings will also highlight the preliminary efficacy of the P3 DHI on couples managing their vulnerability to HIV and other sexually transmitted infections (STIs) over time via alignment of their prevention-care plan and sexual agreement. Trial findings will help shape the future direction of the P3 DHI while addressing the existing gap in prevention and care services for couples in the local context. ClinicalTrials.gov NCT05873855; https://clinicaltrials.gov/study/NCT05873855. DERR1-10.2196/63106.

Gait stability improves following unilateral total ankle arthroplasty.

End-stage ankle arthritis is often treated surgically by total ankle arthroplasty (TAA) due to its potential to improve gait through increased joint range of motion and reduce pain. However, TAA's effect on gait stability is not well understood. This study explores the impact of TAA on gait stability, measured by Margin of Stability (MoS), in 148 patients with end-stage ankle arthritis. Kinematic data were collected pre-operatively, at 1-year post-op, and at 2-years post-op and the MoS was determined at heel strike and midstance for the anteroposterior (MoSAP) and mediolateral (MoSML) directions. A linear mixed effects model including gait speed as a factor was used to assess the effects of limb, session, and their interaction on outcome measures. A significant interaction (p < 0.002) between limb (surgical, nonsurgical) and session (pre-op, 1-year post-op, 2-years post-op) was identified for each MoS variable of interest. Cumulatively, our results suggest that the nonsurgical limb, MoSAP at heel strike and MoSML at midstance improved (increased) as time from surgery increased. These results suggest patients developed a compensatory movement pattern to navigate surgical limb single support. TAA reduces this compensation improving side-to-side symmetry, while not fully restoring symmetry by 2-years post-op. These results indicate that TAA could improve gait stability in patients with end-stage ankle arthritis, but further work is needed to understand the impact of TAA on altering fall risk.

Ansa Cervicalis Stimulation Effects on Upper Airway Patency: A Structure-Based Analysis.

Ansa cervicalis stimulation (ACS) of the infrahyoid muscles has been proposed as a neurostimulation therapy for obstructive sleep apnea (OSA). ACS stabilizes the pharynx by pulling it caudally, but its specific effects on flow limitation caused by palatal, oropharyngeal lateral wall, tongue base, or epiglottis collapse remains unclear. To quantify the effect of ACS on collapsibility of different pharyngeal flow-limiting structures. Participants with OSA underwent bilateral ACS during drug-induced sleep endoscopy. Maximum inspiratory airflow was assessed over a range of positive airway pressures while ACS was applied. The flow-limiting structure for each breath was classified based on manometric and endoscopic findings and a linear mixed-effects model characterized their response to ACS. The influence of patient characteristics was explored with univariate models. Forty-one participants yielded 1761 breaths for analysis. On average, bilateral ACS decreased the observed pharyngeal critical closing (PCRIT) and opening (POPEN) pressures by -3.0 [95% confidence interval: [-3.6, -2.3] and -3.7 [-4.4, -3.0] cmH2O, respectively (p<0.001). During tongue base obstruction, modeled ACS effects for PCRIT and POPEN were -2.0 [-2.7, -1.4] and -3.1 [-3.8, -2.4] cmH2O, respectively (p<0.001). Greater reductions were generally observed for other flow-limiting structures. A lower apnea-hypopnea index was associated with a greater decrease in POPEN (p<0.01). Other patient characteristics, including body mass index, did not influence PCRIT or POPEN (p>0.05). Bilateral ACS decreased collapsibility of all airway flow-limiting structures. ACS generally had greater effects on palatal, oropharyngeal lateral wall, and epiglottic collapse than the tongue base.