Asymptomatic Participants Research Articles

A Pilot Study of a Finger Kinematic Parameter-Based Tool for Evaluating Degenerative Cervical Myelopathy.

This is a cross-sectional study. To evaluate the effectiveness of a novel finger Kinematic Parameter-Based Tool in the grip and release (G&R) test for assessing degenerative cervical myelopathy (DCM). The development and progression of DCM symptoms are gradual and obscure. Although previous studies have objectively evaluated hand movements specific to myelopathy using the G&R test, virtual reality, or wearable sensors, these methods have limitations, such as limited discrimination or inconvenience for simple screening. Consequently, there is a need to develop effective screening methods. Totally, 297 asymptomatic volunteers and 258 DCM patients were enrolled. This system comprises a wearable acceleration/gyro sensor. The acceleration/gyro sensor was placed on the little finger of the participants to perform 40 cycles of full-range G&R as quickly as possible. The collected data were then transformed into kinematic parameters using sensor-based software and R studio software (version: RStudio 2022.07.2+576, Boston, USA). Gender, age, and body mass index (BMI) subgroups (classified as BMI<18.5-below normal weight; 18.5≤BMI<25-normal weight group; BMI≥25-overweight group) were matched as predictor variables, and 201 pairs were matched. Nonparametric analysis using the Mann-Whitney U test was used for diagnosing the differences between the two groups, and Kruskal-Wallis's test followed by the Mann-Whitney U test was used for analyzing the differences among three different age groups (<40, 41-60, and >60 yr group). The cut-off value of 10s G&R cycles and a combined parameter were determined using receiver operating characteristics curve analysis, area under the curve, and Youden index. The authors found that little finger kinematic parameters were significantly lower in DCM patients than in asymptomatic participants. The optimal diagnostic indicator appeared to be the average of the top 10 linear accelerations with an area under the curve of 0.923. The Finger Kinematic Test System is an objective, practical, and quantitative utility that appears to have the capacity to diagnose and evaluate the severity of DCM. 3.

Prevalence of degenerative vertebral disc changes in elite female Crossfit athletes – a cross-sectional study

BackgroundCrossfit athletes consistently recruit or transfer high levels of repetitive forces through the spine, and MRI has documented a higher rate of intervertebral disc degeneration in athletes compared with matched controls. The aim of this study was to evaluate early degenerative spinal disc changes in elite female CrossFit athletes quantified by 3.0 Tesla magnetic resonance imaging (MRI) matched with female none-athletes.MethodsIn a cross-sectional single-center study 19 asymptomatic adult participants, nine German female elite Crossfit athletes and ten female participants underwent spinal MRI (3.0T). Demographic data, spinal clinical examination results and sport-specific performance parameters were collected prior to the MRI. The primary outcome was the prevalence of degenerative spinal disc changes. The secondary outcome was the grade of degeneration using Pfirrmann grading.ResultsA total of 437 discs underwent spinal MRI (3.0T). The prevalence of early degenerative disc disease was not increased. Pfirrmann degenerative grade did not show significant differences among groups.ConclusionAsymptomatic female elite Crossfit athletes do not show an increased prevalence of degenerative disc disease. Compared to a sex-matched control group, high training volume in Crossfit does not correlate to a higher incidence of degenerative disc changes in young females.

Nasopharyngeal Viral Load Is the Major Driver of Incident Antibody Immune Response to SARS-CoV-2 Infection.

Virologic determinants of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were defined in a post hoc analysis of prospectively studied vaccine- and infection-naïve individuals at high risk for coronavirus disease 2019 (COVID-19). This phase 3 COVID-19 prevention trial (NCT04452318) with casirivimab and imdevimab was conducted in July 2020-February 2021, before widespread vaccine availability. Placebo-treated participants who were uninfected (SARS-CoV-2 quantitative reverse transcription polymerase chain reaction [RT-qPCR] negative) and seronegative were assessed weekly for 28 days (efficacy assessment period [EAP]) for COVID-19 symptoms and SARS-CoV-2 infection by RT-qPCR of nasopharyngeal swab samples and for serostatus by antinucleocapsid immunoglobulin (Ig) G. Regression-based modeling, including causal mediation analysis, estimated the effects of viral load on seroconversion. Of 157/1069 (14.7%) uninfected and seronegative (for antispike IgG, antispike IgA, and antinucleocapsid IgG) participants who became infected during the EAP, 105 (65%) seroconverted. The mean (SD) maximum viral load of seroconverters was 7.23 (1.68) log10 copies/mL vs 4.8 (2.2) log10 copies/mL in those who remained seronegative; viral loads of ∼6.0 log10 copies/mL better predicted seroconversion. The mean of the maximum viral load was 7.11 log10 copies/mL in symptomatic participants vs 5.58 log10 copies/mL in asymptomatic participants. The mean duration of detectable viral load was longer in seroconverted vs seronegative participants: 3.24 vs 1.63 weeks. Maximum SARS-CoV-2 viral load is a major driver of seroconversion and symptomatic COVID-19, with high viral loads (∼6.0 log10 copies/mL) better predicting seroconversion. Serology underestimates infection rates, incidence, and prevalence of SARS-CoV-2 infection.

Plasma tau phosphorylation at T217 predicts amyloid deposition in dominantly inherited and late onset Alzheimer disease participants without clinical symptoms

AbstractBackgroundProgressive amyloid plaque accumulation in the brain precedes the emergence of clinical symptoms in Alzheimer disease (AD). This asymptomatic phase, referred to as preclinical AD, induces significant modification of tau phosphorylation in the cerebrospinal fluid (CSF). CSF tau phosphorylation occupancy at Threonine 217 (T217) becomes abnormal more than 20 years before cognitive decline in dominantly inherited AD (DIAD). CSF hyperphosphorylation at T217 also associates with amyloid pathology in late‐onset AD (LOAD) individuals with preclinical AD. In this study, we examined the performance of plasma T217 phosphorylation to detect amyloid plaques deposition measured by amyloid‐PET in asymptomatic participants with DIAD or late‐onset AD (LOAD).MethodWe measured plasma T217 phosphorylation using tau immunoprecipitation and high‐resolution mass spectrometry. Phosphorylation abundance at T217 was expressed as p‐tau217 ratio defined using the level of T217 phosphorylated tau peptide normalized to total tau level. The DIAD cohort included 355 samples from 176 CDR0 and 51 CDR&gt;0 participants in the DIAN Observational study with 62% mutation carriers, all collected in relation to the estimated years to symptom onset (EYO). The LOAD cohort included 321 cross‐sectional samples from BioFINDER‐2 study. Amyloid positivity was determined using cross sectional amyloid‐PET scan available for each participant.ResultWe observed abnormal plasma p‐tau217 ratio in DIAD mutation carriers more than 15 years before EYO (Figure 1). Plasma p‐tau217 ratio accurately predicted amyloid PET positivity for individuals across multiple preclinical stages (Table 1, AUC respectively 0.89 and 0.98 for EYO brackets ‐20 to ‐10 and ‐10 to 0). The plasma test had similar performance in distinguishing amyloid status in the DIAD and the LOAD cohorts (AUC respectively 0.96 and 0.97, Table 1). In LOAD, plasma p‐tau217 ratio identified amyloid positivity independently of the cognitive status (AUC respectively 0.96 and 0.97 for asymptomatic and symptomatic).ConclusionOur results support the use of plasma p‐tau217 ratio to screen cognitively normal populations at risk of developing AD dementia. This blood‐based biomarker can support the recruitment of asymptomatic participants for prevention trials and help identifying patients who might benefit from early care using future AD drugs more than a decade before the detection of cognitive symptoms.

Naturalistic Assessment of Reaction Time Variability in Older Adults at Risk for Alzheimer’s Disease

AbstractBackgroundBreakdowns in attentional control may underscore cognitive changes seen in the earliest stages of Alzheimer’s disease (AD). One way to measure these changes is to assess variability in cognitive performance. Variability in cognition may be most evident when repeatedly sampled over hours or days and in different environmental contexts or at different times of day. We analyzed data from an ongoing smartphone‐based study of cognition in AD which utilizes extremely brief cognitive tests taken remotely over several days in natural environments.MethodOlder adults (N = 319, aged 75 +/‐ 5 years) completed repeated cognitive testing on the Ambulatory Research in Cognition (ARC) platform and had CSF or PET amyloid biomarkers and APOE genotype available. RTSD was assessed in a brief processing speed task by taking the SD of correct RTs. All models adjusted for baseline age, education, and gender.ResultAveraging across sessions, symptomatic participants (indicated by Clinical Dementia Rating® (CDR®) &gt; 0) showed more variability than asymptomatic (CDR 0) participants (p = 0.009). APOE ε4 carriers showed more variability than non‐carriers, although this was not significant (p = 0.067). More fine‐grained models considered RTSD within each session (e.g. from trial‐to‐trial) using mixed effects models. Symptomatic participants exhibited greater trial‐to‐trial RTSD compared to asymptomatic participants (p = 0.001). APOE ε4 carriers also exhibited greater trial‐to‐trial RTSD compared to non‐carriers (p = 0.004). When limiting the sample to asymptomatic participants to determine if there were changes in the preclinical stage of AD, there remained a strong APOE ε4 effect, with carriers exhibiting greater trial‐to‐trial RTSD than non‐carriers (p = 0.005). Interestingly, amyloid was not significant in any models.ConclusionOlder adults at risk for AD show increased RTSD even in brief assessments. These subtle fluctuations in attention were most evident in APOE e4 carriers at very short time intervals, and less so when averaged across trials and sessions. Overall, these findings suggest that fluctuations in attention in preclinical AD are most evident from moment to moment, highlighting the need for fine‐grained and repeated assessment of attentional control.

Remote assessment of functional impairment in Alzheimer’s disease: results of the RADAR‐AD study

AbstractBackgroundRemote monitoring technologies (RMTs), such as smartphone apps and smartwatches, are changing the way functional and cognitive performance are measured in Alzheimer’s disease (AD). Due to their sensitivity, objectivity, and the option of long‐term and continuous measurement, RMTs have the potential to detect a subtle decline in the earliest stages of AD. Here, we present the results of the European RADAR‐AD project (Remote Assessment of Disease and Relapse – Alzheimer’s disease), which aims to test feasibility, acceptability and validity of RMT measures across all stages of AD, from cognitively normal to mild dementia.MethodFour study groups (amyloid negative healthy controls, and amyloid positive preclinical AD, prodromal AD, mild‐to‐moderate AD) were included in this cross‐sectional study (N = 175). During 8 weeks, participants wore two activity trackers (Fitbit and Axivity) measuring physical activity, heart rate and sleep continuously, and used two interactive smartphone apps (Mezurio and Altoida’s research algorithm: DNS‐MCI) measuring cognition daily/weekly. At baseline, participants underwent extensive neuropsychological, physical examinations, and did two sensor‐based tests (banking app and walk test). Features were extracted for all RMTs (Figure 1) and compared across groups using ANCOVA, with adjustment for relevant confounders. This study is part of an ongoing investigation into high‐end multimodal analyses for real‐world functional performance of continuous RMT data streams.ResultCompliance was high, but decreased with cognitive impairment (feasibility). User experience did not differ between groups but was lower for smartwatches compared to interactive smartphone apps (Table 1) (acceptability). Various individual sensors discriminated symptomatic AD participants from asymptomatic participants (p&lt;0.05), for example the two active apps, but did not discriminate preclinical AD from healthy controls (Table 1) (validity).ConclusionThe RADAR‐AD study provides unique insights in the feasibility, acceptability, and validity of remote monitoring of functional abilities in AD and their potential to differentiate between syndromic stages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999) and their associated partners. www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

Multiomics Blood Test for Increasing Asymptomatic AD Patients Proportion in Preventive Clinical Trials

AbstractBackgroundWith the first positive phase III trials for anti‐amyloid approaches in MCI participants, the drug evaluation during the asymptomatic Alzheimer’s disease (AD) stage is now more relevant than ever. Currently, cognitively unimpaired participants are included in preventive trials based on risk factors such as amyloid positivity. The lifetime risks for an individual without cognitive impairment does not exceed 30% for a 65‐year‐old with amyloidosis alone (Brookmeyer et al., 2018). Based on this risk factor, most participants included will never develop AD and therefore will not respond to anti‐AD therapies. There is a need to develop new biomarkers with high specificity predicting which individuals in the cognitively unimpaired population will exhibit AD symptoms and which will not to conduct effective preventive clinical trials.MethodTargeted mass spectrometry assays were developed for 81 blood biomarkers (45 proteins and 36 metabolites) pre‐identified in AAV‐AD rats (Audrain et al. 2018). 287 participants were collected in plasma at baseline and followed clinically from 1 to 18 years. Participants’ diagnosis (AD, or Healthy Controls) was established at the last clinical visit based on reference diagnosis standard. 73.9% of participants had available amyloid status, 42.9% were determined as amyloid positive. Predictive machine learning models for asymptomatic AD participants (n = 48, followed for an average of 6.1 years) among individuals without cognitive decline (HC, n = 239, followed for an average of 4.6 years) was developed. The training dataset (70%) aimed to select the biomarkers subset, train the algorithm, and define the cut‐off. External test dataset (30%) aimed to validate in blind the locked predictive model.ResultWith 20 blood biomarkers and 2 covariates (age and gender), the model predicted asymptomatic AD (n = 16) from HC participants (n = 72) with 81.9% specificity and 56.3% sensitivity during external validation (AUROC = 69.1%, p = 0.02). When current amyloid tests (CSF or PET) and this predictive ML model were applied in series, and participants positive for both were predicted as asymptomatic AD, 90.9% specificity and 54.5% sensitivity were achieved.ConclusionMultiomics blood peripheral biomarkers predict asymptomatic AD patients among cognitively unimpaired individuals with high specificity. This could constitute an additional tool for the inclusion of participants in preventive clinical trials.

Relationship between loss of awareness of cognitive decline and tau pathology in the Alzheimer’s disease spectrum: modulatory role of resting‐state functional connectivity

AbstractBackgroundPatients with Alzheimer’s disease (AD) often demonstrate anosognosia, which is reduced awareness of cognitive decline. Anosognosia has been associated with tau accumulation (d'Oleire Uquillas et al., 2020) and impaired resting‐state functional connectivity (FC) in self‐referential networks (Vannini et al., 2017, Valera‐Bermejo et al., 2022). The explicit links between AD pathological deposits and large‐scale functional networks associated with anosognosia have yet to be elucidated. Here, we sought to examine whether FC plays a modulatory role in the effect of tau on awareness in participants across the AD spectrum.MethodWe included 58 participants from two observational cohorts—44 asymptomatic (Clinical Dementia Rating (CDR) global score = 0) and 14 symptomatic (CDR≥0.5) individuals (Table1). Awareness was measured as the participant‐study partner discrepancy on the Cognitive Function Index. Flortaucipir‐PET was used to quantify tau accumulation, and segregation analysis was applied to resting‐state fMRI data to asses within‐network connectivity. For both modalities, the mean value in each of the Yeo 7 networks was used. First, a linear regression model was performed to assess the association between awareness and group (i.e., symptomatic/asymptomatic). Linear regression models were also used to assess the relationship between awareness and tau in the 7 networks, separately. Finally, we examined the effect of the FC×tau interaction on awareness. All models were adjusted for age, sex, and education.ResultHolding age, sex, and education constant, mean awareness was 0.18 lower in symptomatic (vs. asymptomatic) participants (p&lt;0.01). Lower awareness was associated with a higher tau burden in all 7 networks (Table2). Interaction effects between tau and FC were observed. Specifically, reduced awareness was associated with high tau burden when the salience network was less functionally connected (Figure1A; β = ‐0.23, p = 0.02) and when the dorsal attention network was more functionally connected (Figure1B; β = 0.70, p = 0.03). For all other networks, the relationship between awareness and tau was not modified by the FC of the same network (Table2).ConclusionThese findings provide new insights into the neuropathological correlates of anosognosia in AD. It suggests that anosognosia is not only due to local pathology in single brain areas but also to altered connectivity between them, especially within self‐referential networks.

Characterization of initial symptoms of prodromal familial Frontotemporal Lobar Degeneration: Data from the ALLFTD Consortium

AbstractBackgroundThe ALLFTD Consortium aims to characterize preclinical and prodromal stage of familial Frontotemporal Lobar Degeneration (f‐FTLD) to prepare for clinical trials in FTLD.MethodWe prospectively followed 320 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD with a mutation in MAPT (n = 106), GRN (n = 74), or C9orf72 (n = 140), and describe the ratings on the eight domains of CDR® plus NACC FTLD (FTLD‐CDR) in those who phenoconverted to Mild Behavioral and/or Cognitive Impairment (MBCI). MBCI was diagnosed by the proposed research criteria for MBCI‐FTD (Barker MS, et al. Brain 2022). Participants who were diagnosed as MBCI but returned to asymptomatic at the following visit were excluded from the FTLD‐CDR assessment. ANOVA was used to compare continuous variables, and chi‐square test was used to compare categorical variables across the groups.ResultThirty‐six participants (15 MAPT, 9 GRN, 12 C9orf72) developed MBCI during follow‐up visits, 13 participants (5 MAPT, 3 GRN, 5 C9orf72) were diagnosed as MBCI but were characterized as asymptomatic at the following visit, and 271 participants stayed asymptomatic. Percentage of male in MBCI participants was 50% (MAPT 60%, GRN 33%, C9orf72 50%, p = 0.45). Age at phenoconversion to MBCI was 53.6±13.0 years old, the youngest in MAPT and the oldest in GRN participants (MAPT 44.3±8.3, GRN 63.1±11.3, C9orf72 56.4±10.8, p&lt;0.001). Abnormal rating on each of the eight CDR® plus NACC FTLD domains at the initial visit of MBCI phenoconversion were observed in: “Memory” 36% (MAPT 33%, GRN 33%, C9orf72 44%, p = 0.95); “Orientation” 8% (MAPT 7%, GRN 8%, C9orf72 11%, p = 0.93); “Judgment/Problem Solving” 44% (MAPT 47%, GRN 50%, C9orf72 33%, p = 0.73); “Community Affairs” 22% (MAPT 27%, GRN 17%, C9orf72 22%, p = 0.82); “Home/Hobbies” 25% (MAPT 40%, GRN 8%, C9orf72 22%, p = 0.16); “Personal Care” 0%; “Behavior/Comportment/Personality” 44% (MAPT 60%, GRN 42%, C9orf72 22%, p = 0.19); “Language” 31% (MAPT 13%, GRN 50%, C9orf72 33%, p = 0.12).ConclusionThe three most common FTLD‐CDR domains initially disturbed in the prodromal stage of fFTLD were “Behavior/Comportment/Personality”, “Judgment/Problem Solving”, and “Memory”, while “Orientation” was intact in the majority of the individuals. Memory impairment without disorientation was seen in one‐third of the prodromal fFTLD participants.

Do key measurement parameters derived from specific cervical vertebral segments differ between lordotic and non-lordotic cervical spine alignments? A study of asymptomatic young adults

BackgroundMeasurement parameters derived from specific cervical vertebral segments (e.g., C2 slope) can provide clinicians with important information on cervical sagittal balance and guide pre- and post-surgical decision-making processes. It is unclear however, what constitutes typical values for these types of measurements in an asymptomatic population of young adults, whether values change depending upon the classification of the cervical spine's global alignment, and if any non-lordotic cervical subtypes display values that are comparable to those reported for pre-surgery patients. MethodsNeutral lateral cervical radiographs of 150 asymptomatic participants (18–30 years) were taken. Global cervical alignment was classified as lordotic or one of four non-lordotic subtypes using a multi-method subtyping protocol. Four key measurement parameters - the anterior translation of the head measure (ATHM), C0–C2 angle, C2 slope, and C7 slope – were derived from specific cervical segments. Independent samples t-tests were used to compare lordotic and non-lordotic groups. ResultsThere was considerable variation in the four key measurement parameters amongst this asymptomatic population of young adults. Thirty-four percent of the sample were classified as lordotic and 66% were classified as non-lordotic. There was a significant difference (p ≤ 0.0125) between lordotic and non-lordotic groups for the C0–C2 angle, C2 slope and C7 slope. There was no difference between groups for the ATHM (p ≥ 0.0125). Within the non-lordotic group, the global-kyphotic (GK) subtype had the largest mean C2 slope, largest mean C0–C2 angle, and smallest mean C7 slope. ConclusionsLong term prospective investigations are required to determine whether possible biomarkers (alignment parameters/radiological measurements) for spinal degenerative changes can be identified so that early interventions can be put in place to try and reduce the impact of neck pain on society.

Insulin-like growth factor binding protein-2 in at-risk adults and autopsy-confirmed Alzheimer brains.

Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.

Speckle-Tracking Analysis of the Right and Left Heart after Peak Exercise in Healthy Subjects with Type 1 Diabetes: An Explorative Analysis of the AppEx Trial.

In eight healthy participants with Type 1 diabetes (T1D) exercise-related dynamic cardiac remodeling was analyzed by performing two-dimensional echocardiography, including deformation analysis of the left-ventricular (LV) global longitudinal strain (LV-GLS), and the deformation pattern of the left atrium (LA) and right ventricle (RV) at rest and post-peak performance on a bicycle. The feasibility echocardiographic speckle-tracking analysis was performed on eight asymptomatic participants with T1D (n = 8, male n = 5, age: 23-65 years). The obtained echocardiographic data were compared for various echocardiographic parameters at rest and post exercise. Across our participating T1D individuals no structural echocardiographic abnormalities of concern could be revealed. All participating T1D subjects showed preserved contractile reserve of the LV and no significant diastolic dysfunction. Significant differences were found for the phasic LA contractile strain pattern at rest and post exercise (p < 0.001), whereby the dynamic RV (p = 0.5839 and p = 0.7419) and LV strain pattern (p = 0.5952) did not reveal significant differences in comparison to resting conditions. This descriptive secondary outcome analysis describes preserved contractile reserve of the LV and elucidates dynamic modification of the phasic LA contractile deformation pattern in asymptomatic T1D individuals after exhaustive exercise on a bicycle.

Comparison of the Odontoid and Orbital-Coronal Vertical Axis Lines in Evaluating Coronal Alignment and Outcomes in Adult Spinal Deformity Surgery.

Asymptomatic Multi-Ethnic Alignment Normative Study (MEANS) cohort: cross-sectional, multicenter. Symptomatic cohort: retrospective, multisurgeon, single-center. To assess the association of odontoid-coronal vertical axis (OD-CVA) and orbital-coronal vertical axis (ORB-CVA) with radiographic parameters, patient-reported outcomes, and clinical outcomes. Previous literature studied the OD-CVA in an asymptomatic cohort and ORB-CVA in a symptomatic cohort, demonstrating their correlations with radiographic parameters and ORB-CVA with outcomes. A total of 468 asymptomatic adult participants were prospectively enrolled in the MEANS cohort. 174 symptomatic patients with adult spinal deformity with ≥6 fused levels and 2-year follow-ups were retrospectively enrolled in the symptomatic cohort. The association between OD-CVA and ORB-CVA, and radiographic parameters, perioperative variables, PROs, and outcomes were analyzed. Pearson correlation was used to assess correlation and logistic regression odds of outcomes. In the MEANS cohort, the ORB-CVA correlated with C7-CVA ( r = 0.58) and OD-CVA ( r = 0.74). In the symptomatic cohort, preoperative ORB-CVA correlated better with leg length discrepancy; r = 0.17, P = 0.029), whereas preoperative OD-CVA correlated better with C7-CVA ( r = 0.90, P < 0.001). Postoperative ORB-CVA correlated with postoperative C7-CVA ( r = 0.66, P < 0.001), and postoperative OD-CVA correlated strongly with postoperative C7-CVA ( r = 0.81, P < 0.001). Both preoperative OD-CVA ( r = 0.199) and ORB-CVA ( r = 0.208) correlated with the preoperative Oswestry Disability Index. ORB-CVA correlated better than OD-CVA in the preoperative Scoliosis Research Society-22r pain category but worse in total and other subcategories. Preoperative ORB-CVA was associated with increased odds of intraoperative complication (odds ratio = 1.28, 1.01-1.22), like OD-CVA (odds ratio = 1.30, 1.12-1.53). Neither preoperative ORB-CVA nor OD-CVA was associated with reoperations and readmissions after multivariate analysis. Preoperative OD-ORB mismatch >1.5 cm was not associated with increased odds of intraoperative and postoperative complications, reoperations, or readmissions. ORB-CVA and OD-CVA correlated with radiographic parameters, patient-reported outcomes, and intraoperative complications. ORB-CVA and OD-CVA can be used interchangeably as cranial coronal parameters in adult spinal deformity surgery.

Motor Imagery and Pain Processing in Patients With Entrapment Neuropathies: A Cross-sectional Study.

(1) To assess the ability to generate both kinesthetic and visual motor imagery in participants with carpal tunnel syndrome (CTS), compared with asymptomatic participants. (2) To assess the influence of psychophysiological and functional variables in the motor imagery process. Twenty patients with unilateral CTS and 18 pain-free individuals were recruited. An observational case-control study with a nonprobability sample was conducted to assess visual and kinesthetic movement imagery ability and psychophysiological variables in patients with CTS compared with asymptomatic participants in a control group. The trial was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement. CTS patients have more difficulties in generating visual motor images compared with asymptomatic individuals ( t =-2.099; P <0.05; d=0.70). They need more time to complete the mental tasks (visual t =-2.424; P <0.05 and kinesthetic t =-2.200; P <0.05). A negative correlation was found between the ability to imagine and functional deficits ( r =-0.569; P =0.021) for the kinesthetic subscale and temporal summation ( r =-0.515; P <0.5). A positive correlation was found between pain pressure threshold homolateral (homolateral) and time to generate the visual mental images ( r =0.537; P <0.05). CTS patients have greater difficulty generating motor images than asymptomatic individuals. Patients also spend more time during mental tasks. CTS patients present a relationship between temporal summation and the capacity to generate kinesthetic images. In addition, the CST patients presented a correlation between chronometry mental tasking and mechanical hyperalgesia.

Molecular Mechanism Biomarkers Predict Diagnosis in Schizophrenia and Schizoaffective Psychosis, with Implications for Treatment.

Diagnostic uncertainty and relapse rates in schizophrenia and schizoaffective disorder are relatively high, indicating the potential involvement of other pathological mechanisms that could serve as diagnostic indicators to be targeted for adjunctive treatment. This study aimed to seek objective evidence of methylenetetrahydrofolate reductase MTHFR C677T genotype-related bio markers in blood and urine. Vitamin and mineral cofactors related to methylation and indolamine-catecholamine metabolism were investigated. Biomarker status for 67 symptomatically well-defined cases and 67 asymptomatic control participants was determined using receiver operating characteristics, Spearman's correlation, and logistic regression. The 5.2%-prevalent MTHFR 677 TT genotype demonstrated a 100% sensitive and specific case-predictive biomarkers of increased riboflavin (vitamin B2) excretion. This was accompanied by low plasma zinc and indicators of a shift from low methylation to high methylation state. The 48.5% prevalent MTHFR 677 CC genotype model demonstrated a low-methylation phenotype with 93% sensitivity and 92% specificity and a negative predictive value of 100%. This model related to lower vitamin cofactors, high histamine, and HPLC urine indicators of lower vitamin B2 and restricted indole-catecholamine metabolism. The 46.3%-prevalent CT genotype achieved high predictive strength for a mixed methylation phenotype. Determination of MTHFR C677T genotype dependent functional biomarker phenotypes can advance diagnostic certainty and inform therapeutic intervention.

Evidence of Ongoing Cerebral Microstructural Reorganization in Children With Persisting Symptoms Following Mild Traumatic Brain Injury: A NODDI DTI Analysis.

Approximately 300-550 children per 100,000 sustain a mild traumatic brain injury (mTBI) each year, of whom ∼25-30% have long-term cognitive problems. Following mTBI, free water (FW) accumulation occurs in white matter (WM) tracts. Diffusion tensor imaging (DTI) can be used to investigate structural integrity following mTBI. Compared with conventional DTI, neurite orientation dispersion and density imaging (NODDI) orientation dispersion index (ODI) and fraction of isolated free water (FISO) metrics may allow a more advanced insight into microstructural damage following pediatric mTBI. In this longitudinal study, we used NODDI to explore whole-brain and tract-specific differences in ODI and FISO in children with persistent symptoms after mTBI (n = 80) and in children displaying clinical recovery (n = 32) at 1 and 2-3 months post-mTBI compared with healthy controls (HCs) (n = 21). Two-way repeated measures analysis of variance (ANOVA) and voxelwise two-sample t tests were conducted to compare whole-brain and tract-specific diffusion across groups. All results were corrected at positive false discovery rate (pFDR) <0.05. We also examined the association between NODDI metrics and clinical outcomes, using logistical regression to investigate the value of NODDI metrics in predicting future recovery from mTBI. Whole-brain ODI was significantly increased in symptomatic participants compared with HCs at both 1 and 2 months post-injury, where the uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF) were particularly implicated. Using region of interest (ROI) analysis in significant WM, bilateral IFOF and UF voxels, symptomatic participants had the highest ODI in all ROIs. ODI was lower in asymptomatic participants, and HCs had the lowest ODI in all ROIs. No changes in FISO were found across groups or over time. WM ODI was moderately correlated with a higher youth-reported post-concussion symptom inventory (PCSI) score. With 87% predictive power, ODI (1 month post-injury) and clinical predictors (age, sex, PCSI score, attention scores) were a more sensitive predictor of recovery at 2-3 months post-injury than fractional anisotropy (FA) and clinical predictors, or clinical predictors alone. FISO could not predict recovery at 2-3 months post-injury. Therefore, we found that ODI was significantly increased in symptomatic children following mTBI compared with HCs at 1 month post-injury, and progressively decreased over time alongside clinical recovery. We found no significant differences in FISO between groups or over time. WM ODI at 1 month was a more sensitive predictor of clinical recovery at 2-3 months post-injury than FA, FISO, or clinical measures alone. Our results show evidence of ongoing microstructural reorganization or neuroinflammation between 1 and 2-3 months post-injury, further supporting delayed return to play in children who remain symptomatic. We recommend future research examining the clinical utility of NODDI following mTBI to predict recovery or persistence of post-concussion symptoms and thereby inform management of mTBI.

The Intra-Rater Reliability of Ultrasonography for the Measurement of Lumbar Multifidus and Erector Spinae Thickness in Different Positions in People with and without Active Extension-Related Non-Specific Low Back Pain.

The paraspinal muscles, including multifidus (MF) and erector spinae (ES) play key roles in the stability and movement of the lumbar spine. This study aimed to determine the intra-rater reliability of the ES and MF muscle thickness measures of the rehabilitative ultrasound imaging (RUSI) in people with active extension pattern (AEP) non-specific chronic low back pain and controls. Fifteen females with AEP and 19 controls participated in this test-retest intra-rater reliability study, including two different testing sessions performed in four to seven days apart. The primary (raw) and derived (normalized) measures of the L4 MF and ES muscles`thickness were examined in three different positions (prone, sitting, and standing) on both days. A two-way mixed average of intra-class correlation coefficient (ICC3, K) with confidence interval (CI = 95%) was used to determine the relative reliability. The standard error of measurement (SEM) and minimal detectable change (MDC) values at a CI of 95% were computed to examine the absolute reliability. The ICC values for the primary thickness of the L4 ES and MF muscles were from 0.85 to 0.91, except for MF muscle thickness in standing (ICC = 0.67) and sitting (ICC = 0.66) positions . The ICC values for derived data were lower in both groups. The SEM and MDC values were small enough to confirm the absolute reliability of the primary data. This study supports the use of RUSI for examining the primary measures of the L4 MF and ES muscles in asymptomatic and AEP participants, but it should be used cautiously for assessing the derived measures.

The Efficacy of Medical Check-up Programs in Screening Healthy, Asymptomatic Individuals: A Cross-Sectional Study

Aim: Healthy asymptomatic individuals can be screened for various diseases using medical check-up programs. On the other hand, the prevalence of diabetes mellitus (DM) and prediabetes (PD), which are common metabolic disorders, are increasing worldwide. In this context, this study aims to determine the prevalence of DM and PD among the asymptomatic participants of a medical check-up program.&#x0D; Material and Methods: The population of this cross-sectional study consisted of 440 healthy, asymptomatic volunteers aged 40 years or older who attended a medical check-up program conducted between January and August 2021. Patients with confirmed morbidities or regular medication use and pregnant women were excluded from the study. All study participants underwent physical examination, laboratory test, and sonographic assessment. The study participants were grouped according to their glycemic states, i.e., DM, PD, and normoglycemia (NG). The study's primary outcomes were the prevalence of DM and PD. &#x0D; Results: The prevalence of DM and PD among the study participants was 12.5% (n=55) and 58.9% (n=259), respectively. The number of males was significantly higher in Group DM than in Groups PD and NG (p=0.014). Additionally, Group DM was significantly older than Groups PD and NG (p0.05 for all cases).&#x0D; Conclusion: The prevalence of DM and PD in presumed healthy asymptomatic participants was 12.5% and 58.9%, respectively, indicating unusually high prevalence in this population. In conclusion, the results of this study demonstrate that it is imperative that presumed healthy individuals are screened within the scope of medical check-up programs and followed closely afterward.

Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects.

The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality. A neural network was developed to count PVCs from ECGs recorded during exercise (6 minutes) and recovery (1 minute) in 48 315 asymptomatic participants from UK Biobank. Associations were estimated using multivariable Cox proportional hazard models. Explorative studies were conducted in subgroups with cardiovascular magnetic resonance imaging data (n=6290) and NT-proBNP (N-terminal Pro-B-type natriuretic peptide) levels (n=4607) to examine whether PVC burden was associated with subclinical cardiomyopathy. Mean age was 56.8±8.2 years; 51.1% of the participants were female; and median follow-up was 12.6 years. Low PVC counts during exercise and recovery were both associated with MI/HF/LTVA risk, independently of clinical factors: adjusted hazard ratio (HR), 1.2 (1-5 exercise PVCs, P<0.001) and HR, 1.3 (1-5 recovery PVCs, P<0.001). Risks were higher with increasing PVC count: HR, 1.8 (>20 exercise PVCs, P<0.001) and HR, 1.6 (>5 recovery PVCs, P<0.001). A similar trend was observed for all-cause mortality, although associations were only significant for high PVC burdens: HRs, 1.6 (>20 exercise PVCs, P<0.001) and 1.5 (>5 recovery PVCs, P<0.001). Complex PVC rhythms were associated with higher risk compared with PVC count alone. PVCs were also associated with incident HF, LTVA, and cardiovascular mortality, but not MI. In the explorative studies, high PVC burden was associated with larger left ventricular volumes, lower ejection fraction, and higher levels of NT-proBNP compared with participants without PVCs. In this cohort of middle-aged and older adults, PVC count during submaximal exercise and recovery were both associated with MI/HF/LTVA, all-cause mortality, HF, LTVAs, and cardiovascular mortality, independent of clinical and exercise test factors, indicating an incremental increase in risk as PVC count rises. Complex PVC rhythms were associated with higher risk compared with PVC count alone. Underlying mechanisms may include the presence of subclinical cardiomyopathy.

A noninvasive multianalytical approach establishment for risk assessment and gastric cancer screening.

Effective screening and early detection are critical to improve the prognosis of gastric cancer (GC). Our study aims to explore noninvasive multianalytical biomarkers and construct integrative models for preliminary risk assessment and GC detection. Whole genomewide methylation marker discovery was conducted with CpG tandems target amplification (CTTA) in cfDNA from large asymptomatic screening participants in a high-risk area of GC. The methylation and mutation candidates were validated simultaneously using one plasma from patients at various gastric lesion stages by multiplex profiling with Mutation Capsule Plus (MCP). Helicobacter pylori specific antibodies were detected with a recomLine assay. Integrated models were constructed and validated by the combination of multianalytical biomarkers. A total of 146 and 120 novel methylation markers were found in CpG islands and promoter regions across the genome with CTTA. The methylation markers together with the candidate mutations were validated with MCP and used to establish a 133-methylation-marker panel for risk assessment of suspicious precancerous lesions and GC cases and a 49-methylation-marker panel as well as a 144-amplicon-mutation panel for GC detection. An integrated model comprising both methylation and specific antibody panels performed better for risk assessment than a traditional model (AUC, 0.83 and 0.63, P < .001). A second model for GC detection integrating methylation and mutation panels also outperformed the traditional model (AUC, 0.82 and 0.68, P = .005). Our study established methylation, mutation and H. pylori-specific antibody panels and constructed two integrated models for risk assessment and GC screening. Our findings provide new insights for a more precise GC screening strategy in the future.