Clinical Associations Research Articles

Clinical association of habitual breakfast skipping with cognitive decline and neurodegeneration among older adults

ObjectiveUnhealthy lifestyles have a considerable impact on the incidence of dementia. Skipping breakfast disturbs energy homeostasis and impairs brain function. In this study, we investigated the association between breakfast skipping and cognitive performance among community-dwelling adults. MethodsWe recruited 859 community-dwelling adults aged ≥60 years from January 1 to December 31, 2021. Participants’ sociodemographic information and breakfast skipping habits were self-reported. Participants were followed up for 36 months and cognitive function was assessed using the Mini-Mental State Examination (MMSE) with an interval of 18 months. Trajectories of cognitive change were compared between individuals with and without breakfast skipping. To reduce the risk of bias owing to unmatched sample sizes between the groups, we conducted 1:1 propensity score matching (PSM) based on age, sex, education level, and ApoE genotype. ResultsAt baseline and 18-month follow-up, no difference was found in MMSE scores between participants with and without breakfast skipping. However, those who habitually skipped breakfast had significantly lower MMSE scores than those who did not at 36-month follow-up. Individuals with habitual breakfast skipping had a steeper rate of cognitive decline than those without habitual breakfast skipping during follow-up. Breakfast skipping was a risk factor for longitudinal cognitive decline, defined as a decrease in MMSE scores of ≥3, adjusted for age, sex, education, body mass index, ApoE ε4 carrier status, hypertension, diabetes, and hyperlipidemia. At the last follow-up, participants who habitually skipped breakfast had significantly higher levels of ptau181 and NfL than those who did not. In the PSM cohort, similar findings were obtained regarding cognitive trajectories and plasma biomarkers. ConclusionBreakfast skipping was linked to an increased risk of long-term cognitive decline and neurodegeneration among older adults. The link between unhealthy dietary habits and cognitive decline may be attributed to a deficiency in neurorestoration resulting from inadequate energy consumption.

The Basis of Cognitive and Behavioral Dysfunction in Amyotrophic Lateral Sclerosis.

To summarize and evaluate evidence pertaining to the clinical, genetic, histopathological, and neuroimaging correlates of cognitive and behavioral dysfunction in amyotrophic lateral sclerosis (ALS). We comprehensively reviewed the literature on cognitive and behavioral manifestations of ALS, narrating findings from both cross-sectional and longitudinal studies. We discussed knowledge gaps in the evidence base and key limitations affecting studies to date, before formulating a framework for future research paradigms aimed at investigating clinicopathological correlates of neuropsychological dysfunction in ALS. Studies have demonstrated clinical associations with cognitive dysfunction in ALS e.g., bulbar-onset of symptoms, pathological associations (extramotor TDP-43 deposition), and imaging associations (frontotemporal involvement). The most common behavioral deficit, apathy, is highly associated with verbal fluency, but longitudinal studies assessing behavioral dysfunction in ALS are comparatively lacking. Longitudinal studies have been helpful in identifying several potential correlates of cognitive and behavioral dysfunction but have frequently been confounded by selection bias and inappropriate testing platforms. This review provides a framework for more robust assessment of clinicopathological associations of neuropsychological abnormalities in ALS in the future, advocating for greater utilization of pre-symptomatic C9orf72 repeat expansion-carrying cohorts.

Veno-Venous Extracorporeal Membrane Oxygenation Support for Severe Primary Graft Dysfunction Is Associated With Reduced Airway Complications After Lung Transplantation.

Early utilization of extracorporeal membrane oxygenation (ECMO) improves the clinical outcomes of patients with severe primary graft dysfunction (PGD3) after lung transplantation. Although there is a survival benefit, the impact of ECMO on airway complications has not been investigated. This study aims to describe the clinical association between posttransplant methods of support and the severity of acute airway anastomosis complications in patients with PGD3 following bilateral lung transplantation. Data from adult bilateral lung transplant patients diagnosed with PGD3 at our institution were retrospectively reviewed. Bronchial anastomosis necrosis (ischemia reperfusion injury [IRI]) that developed within a month after transplantation was graded. The data were compared among the groups of veno-venous ECMO (VV-ECMO) (n = 77), veno-arterial ECMO (VA-ECMO) (n = 14), and mechanical ventilation (MV, n = 33). Higher levels of support (VV/VA-ECMO) were associated with a lower incidence of PGD3, which was highest in recipients on MV only (M2 = 19.54, r = -0.41, p<0.001). In a multivariable competing risk analysis, VV-ECMO was protective against chronic allograft dysfunction (CLAD) relative to the MV group (HR: 0.36 [0.13-0.96], p = 0.042). There was no relationship between posttransplant support and survival. This study suggests posttransplant VV-ECMO support in patients who develop PGD3 may confer a protective advantage over MV alone in the prevention of ischemic reperfusion injury. VV-ECMO was associated with lower IRI grades and lower rates of BOS after transplantation. Future studies investigating the causal mechanisms are warranted.

Clinical XLNet-based End-to-End Knowledge Discovery on Clinical Text Data using Natural Language Processing

Abstract A modern framework for assessing patient histories and conducting clinical research has been developed as the number of clinical narratives evolves. To discover the knowledge from such clinical narratives, clinical entity recognition and relation extraction tasks were performed subsequently in existing approaches, which resulted in error propagation. Therefore, a novel end-to-end clinical knowledge discovery strategy has been proposed in this paper. The clinical XLNet was used as a base model for handling the discrepancy issue. To predict the dependent clinical relation association, the multinomial Naïve Bayes probability function has been incorporated. In order to improve the performance of the proposed strategy, it takes into account entity pairs presented consecutively through the multi-head attention layer. Tests have been conducted using the N2C2 corpus, and the proposed methodology achieves a greater than 20% improvement in accuracy over existing neural network-based and transformer-based methods.

Spinal cord evaluation in multiple sclerosis: clinical and radiological associations, present and future.

Spinal cord disease is important in most people with multiple sclerosis, but assessment remains less emphasized in patient care, basic and clinical research and therapeutic trials. The North American Imaging in Multiple Sclerosis Spinal Cord Interest Group was formed to determine and present the contemporary landscape of multiple sclerosis spinal cord evaluation, further existing and advanced spinal cord imaging techniques, and foster collaborative work. Important themes arose: (i) multiple sclerosis spinal cord lesions (differential diagnosis, association with clinical course); (ii) spinal cord radiological-pathological associations; (iii) 'critical' spinal cord lesions; (iv) multiple sclerosis topographical model; (v) spinal cord atrophy; and (vi) automated and special imaging techniques. Distinguishing multiple sclerosis from other myelopathic aetiology is increasingly refined by imaging and serological studies. Post-mortem spinal cord findings and MRI pathological correlative studies demonstrate MRI's high sensitivity in detecting microstructural demyelination and axonal loss. Spinal leptomeninges include immune inflammatory infiltrates, some in B-cell lymphoid-like structures. 'Critical' demyelinating lesions along spinal cord corticospinal tracts are anatomically consistent with and may be disproportionately associated with motor progression. Multiple sclerosis topographical model implicates the spinal cord as an area where threshold impairment associates with multiple sclerosis disability. Progressive spinal cord atrophy and 'silent' multiple sclerosis progression may be emerging as an important multiple sclerosis prognostic biomarker. Manual atrophy assessment is complicated by rater bias, while automation (e.g. Spinal Cord Toolbox), and artificial intelligence may reduce this. Collaborative research by the North American Imaging in Multiple Sclerosis and similar groups with experts combining distinct strengths is key to advancing assessment and treatment of people with multiple sclerosis spinal cord disease.

Adverse effects of CXCR2 deficiency in mice reared under non-gnotobiotic conditions

The family of pro-inflammatory and pro-angiogenic chemokines including Interleukin-8 (IL-8, aka CXCL8) and its homologues (CXCL1,2,3,5,6, and 7) exhibit promiscuous binding and activation of several G-protein-coupled receptors (i.e., CXCR2, CXCR1, and the atypical chemokine receptor (ACKR1)). A high proportion of their biological activity is attributed to CXCR2 activation, thus many CXCR2 inhibitors are in clinical trials for several chronic diseases. However, CXCR2 inhibition is often only investigated acutely in these trials or in Cxcr2−/− mice grown in gnotobiotic conditions. Since humans do not live in germ-free environments, our first goal is to highlight novel retinal and systemic observations in Cxcr2−/− mice grown in non-gnotobiotic conditions that suggest potential harmful consequences of long-term CXCR2 deficiency or blockade. Beyond confirmation of circulating blood/immune cell-related phenotypes, we report novel findings in Cxcr2−/− mice including: (1) delayed dye transit to the retinal vasculature, (2) alterations in the density and distribution of retinal vessels, astrocytes and microglia, (3) decreased electroretinogram a- and b-wave amplitudes, (4) reduced visual acuity, and (5) increased polymorphonuclear cell accumulation in vascular lumina abutting venular walls in the retina and in vital non-ocular tissues (lung and liver). Furthermore, PheWAS of CXCR2 CXCR1, and ACKR1 gene variants using data from UK Biobank participants suggest clinical associations with both retinal and vascular disease phenotypes. We conclude that chronic CXCR2 deficiency in mice contributes to functional damage to the retina and that the long-term safety of CXCR1/2 inhibitors designed for chronic use in humans should be explored before clinical adoption to safeguard sight and overall vascular health.

Characterization of Telecare Conversations on Lifestyle Management and Their Relation to Health Care Utilization for Patients with Heart Failure: Mixed Methods Study.

Telehealth interventions where providers offer support and coaching to patients with chronic conditions such as heart failure (HF) and type 2 diabetes mellitus (T2DM) are effective in improving health outcomes. However, the understanding of the content and structure of these interactions and how they relate to health care utilization remains incomplete. This study aimed to characterize the content and structure of telecare conversations on lifestyle management for patients with HF and investigate how these conversations relate to health care utilization. We leveraged real-world data from 50 patients with HF enrolled in a postdischarge telehealth program, with the primary intervention comprising a series of telephone calls from nurse telecarers over a 12-month period. For the full cohort, we transcribed 729 English-language calls and annotated conversation topics. For a subcohort (25 patients with both HF and T2DM), we annotated lifestyle management content with fine-grained dialogue acts describing typical conversational structures. For each patient, we identified calls with unusually high ratios of utterances on lifestyle management as lifestyle-focused calls. We further extracted structured data for inpatient admissions from 6 months before to 6 months after the intervention period. First, to understand conversational structures and content of lifestyle-focused calls, we compared the number of utterances, dialogue acts, and symptom attributes in lifestyle-focused calls to those in calls containing but not focused on lifestyle management. Second, to understand the perspectives of nurse telecarers on these calls, we conducted an expert evaluation where 2 nurse telecarers judged levels of concern and follow-up actions for lifestyle-focused and other calls (not focused on lifestyle management content). Finally, we assessed how the number of lifestyle-focused calls relates to the number of admissions, and to the average length of stay per admission. In comparative analyses, lifestyle-focused calls had significantly fewer utterances (P=.01) and more dialogue acts (Padj=.005) than calls containing but not focused on lifestyle management. Lifestyle-focused calls did not contain deeper discussions on clinical symptoms. These findings indicate that lifestyle-focused calls entail short, intense discussions with greater emphasis on understanding patient experience and coaching than on clinical content. In the expert evaluation, nurse telecarers identified 24.2% (29/120) of calls assessed as concerning enough for follow-up. For these 29 calls, nurse telecarers were more attuned to concerns about symptoms and vitals (19/29, 65.5%) than lifestyle management concerns (4/29, 13.8%). The number of lifestyle-focused calls a patient had was modestly (but not significantly) associated with a lower average length of stay for inpatient admissions (Spearman ρ=-0.30; Padj=.06), but not with the number of admissions (Spearman ρ=-0.03; Padj=.84). Our approach and findings offer novel perspectives on the content, structure, and clinical associations of telehealth conversations on lifestyle management for patients with HF. Hence, our study could inform ways to enhance telehealth programs for self-care management in chronic conditions.

Clinical profile of patients undergoing percutaneous stellate ganglion block for electrical storm and association with antiarrhythmic efficacy

Abstract Background Percutaneous stellate ganglion block (PSGB) usage for patients with refractory ventricular arrhythmias (VAs) in form of electrical storm (ES) is in quickly expanding. The clinical profile of patients and the potential association with the antiarrhythmic efficacy of the procedure are mostly unexplored. Purpose To better characterize clinical profile and potential association with antiarrhythmic efficacy of patients undergoing PSGB for ES. Methods Patients undergoing PSGB for ES in our Center from 2/2021 to 2/2024 were enrolled; all the dynamic variables were evaluated in a per procedure analysis. Results 45 patients (93% male, 64 ± 10 years) received a total of 80 PSGB performed with the lateral, ultrasound (US) guided technique; most PSGB consisted of a single bolus anesthetic injection (lidocaine + ropivacaine), 26% in an additional continuous infusion, mostly with ropivacaine. All procedures except for 3 in a single patient who had previously received left cardiac sympathetic denervation, were performed on the left side. Most of the patients (60%) suffered ischemic cardiomyopathy (CMP), including 10 with an acute coronary syndrome; the rest had non-ischemic CMP; 60% had an ICD. The type of VAs was ventricular tachycardia (VTs) only in 86% of the procedures (cycle length 404 ± 143 msec), VT and VF in 10% and VF only in 3 (4%). Most PSGB (81%) were performed in the setting of impending or manifest cardiogenic shock (SCAI classification B or more), including 20% with sepsis. Cardiac US performed before (within 12 hours) each PSGB showed a severely depressed left ventricular (LV) function (mean LVEF 22 ± 10%, mean LV outflow tract velocity time integral 12 ± 4 cm), calculated at a mean heart rate of 81 ± 16 bpm. Mean LVEDV was 252 ± 104 ml, 79% had mitral regurgitation (MR) ≥2+/4+ (including 39% severe MR), 50% had ≥ moderate diastolic dysfunction, 29% had right ventricular dysfunction (mean fractional areal change 33± 7%). Most cases (75%) experienced a complete VAs suppression (sustained or treated) in the 12 hours after PSGB; only 3/80 cases required additional urgent antiarrhythmic strategies (intra-aortic ballon pump in one case, urgent pacing in another one, urgent revascularization in the last one). None of the assessed clinical or echocardiographic characteristics was significantly associated with VT cycle length or the response to PSGB. Only 1 (1%) major complication occurred (respiratory arrest), that was quickly and effectively treated with lipid emulsion. Conclusions PSGB in our Center was mostly performed in the setting of primary impending or manifest cardiogenic shock with severely impaired cardiac function, with an excellent safety profile. None of the assessed clinical or echocardiographic variables were associated with response to PSGB. Our data, despite preliminary and requiring confirmation, suggests always considering PSGB in the urgent/emergent setting independently from patients’ characteristics.

Impact of glucose fluctuation on the paracrine secretome profile of human epicardial adipocyte

Abstract Background Glucose fluctuations (GF) is known to be the significant factor related to poor cardiovascular outcome in the diabetic patients. We investigated the potential impact of GF on paracrine effect of human epicardial adipocyte on cardiomyocyte. Methods Human EAT biopsies obtained during surgery and isolated preadipocyte/adipocytes were used to evaluate the direct impact of GF on the adipocytes. Matured adipocytes were exposed to the media containing normal glucose (100 mg/dl, NG), high glucose (300 mg/dl, HG), or high-low glucose (75-300 mg/dl, GF) for 1 week. Transcriptomic profiling of the cultured matured adipocyte was performed using microarray analysis. The impact of GF on the paracrine effect of adipocyte was evaluated using a co-culture with human iPS-derived atrial cardiomyocytes and the adipocytes. Clinical association study verified the validity of the findings. Results GF for 1 week altered the expression of 595 differentially expressed genes (up-regulated or down-regulated) with an effect size of &amp;gt;50% or `−50% and a significant statistical difference (P &amp;lt; 0.05) in human epicardial adipocytes, while the continuous HG for 1 week altered the expression of only 182 differentially expressed genes. Of the genes affected by GF, top 3 most affected genes included IL1β, IL33, IL8. Regarding the other major pro-inflammatory cytokines, IL1α, CCL2 and IL6 were also significantly increased in the adipocyte treated with GF, however these were not increased in the adipocyte treated with HG. Co-culture of human iPS cell-derived atrial cardiomyocytes and adipocytes treated with NG, HG and GF revealed that GF-treated adipocyte strikingly increased oxidative stress in the cardiomyocyte through the paracrine effect. In the real-world clinical association study, IL1β mRNA expression in human epicardial adipose tissue showed significant positive correlation with the severity of GF during hospitalization and oxidative stress in the left atrial myocardium. Conclusions GF adversely affect the paracrine secretome profile of human epicardial adipocyte. IL1β may be a critical epicardial adipocyte-derived adipokine that is enhanced by GF.

MELD score as predictor of mortality in patients with advanced heart failure: a longitudinal evaluation

Abstract Aims Advanced heart failure (AHF) is characterized by recurrent episodes of hemodynamic instability, frequent hospitalizations leading to a progressive decline in quality of life, and high mortality rates. The objective of this study was to assess the clinical associations of the MELD score and its efficacy in predicting mortality among patients with AHF. Methods 102 patients with AHF were enrolled, all patients included in the study were on top of tolerated medical therapy according to guidelines. The MELD score was measured at baseline, and every 6 months during follow-up. All patients underwent echocardiographic assessment, six-minute walking test, and cardiopulmonary testing with evaluation of VO2 max and VE/VCO2. Results The mean age of the study group was 57.8±11.9 years. There were 26 deaths during a follow-up period of 31.9±15.4 months. The mean NYHA class was 2.8±0.6, ejection fraction was 26.5±6.3%, TAPSE was 17.5±4.1 mm, and NT-pro-BNP was 2746.0±2475.9 pg/mL. The mean VO2 max was 11.7±3.5 ml/kg/min, and the distance covered in the six-minute walk test was 270.1±151.5 meters. Data stratified by mortality showed that deceased patients had higher NYHA class (2.7±0.6 vs. 3.2±0.3; p&amp;lt;0.001), NT-pro-BNP levels (4767.2±2888.1 vs. 1884.0±1669.5 pg/mL; p&amp;lt;0.001), and MELD score (19.3±3.8 vs. 11.9±5.1; p&amp;lt;0.001) compared to those who were alive at follow-up. Multiple regression analysis revealed a positive correlation between MELD score and NT-pro-BNP (Beta = 0.300; p=0.010), and a negative correlation between MELD score and TAPSE (Beta = -0.236; p=0.026). Cox regression analysis identified MELD score as a predictor of mortality (HR = 1.113; 95%CI = 1.011-1.225; p=0.029), independently by the effect of age, NYHA class, NT-pro-BNP, ejection fraction, TAPSE, and VO2 max. Changes in MELD score percentage, considered as a dichotomous variable (≤100% and &amp;gt;100%), were found to be predictors of mortality. Receiver operating characteristic (ROC) curves showed an area under the curve (AUC) of 0.897 for MELD score and mortality. Conclusions The MELD score and its longitudinal changes are effective predictors of mortality in patients with AHF, regardless of age, NYHA class, and NT-pro-BNP.

How different types of cardiomyopathy with hypertrophic phenotype affect left atrial remodeling and function

Abstract Background Left atrial (LA) dysfunction is a common feature in hypertrophic cardiomyopathies. How the underlying etiology and pathophysiology of different cardiomyopathies affects LA remodeling and function remains unexplored. Purpose The aim of our study is to investigate the influence of various cardiomyopathies with hypertrophic phenotype on LA remodeling and function. Methods Patients with left ventricular (LV) hypertrophic phenotype who underwent cardiac magnetic resonance (CMR) were included. A group of patients with a normal CMR was included as a control group. CMR acquisitions used for clinical indication of heart failure diagnosis and etiology were retrospectively analyzed to obtain LA reservoir, conduit, and booster strain, left atrioventricular coupling index (LACI) and LA sphericity. Differences between groups were assessed. To investigate the independent clinical associates of LA reservoir, conduit and booster strain, multivariable linear regression analyses were performed. Results A total of 375 individuals were analyzed including 321 patients diagnosed with LV hypertrophy and 54 patients with a normal CMR. Of the 321 patients with LV hypertrophy, 148 were diagnosed with hypertrophic cardiomyopathy (HCM), 35 with cardiac amyloidosis (CA), 41 with hypertensive cardiomyopathy (HTN) and 97 with severe asymptomatic aortic stenosis (AS). CMR LA characteristic and strain analysis results are summarized in Figure 1. The indexed LA end-systolic volume (iLAVmax), indexed LA end-diastolic volume (iLAVmin) and LA sphericity were larger in patients with CA when compared to other groups (all p&amp;lt;0.05). CA patients displayed more left atrioventricular uncoupling (lower LACI) when compared to individuals with HCM, HTN, AS, and controls (all p&amp;lt;0.001), while no significant differences were observed across other groups. CA patients exhibited lower LA reservoir and booster strains compared to the other groups (all p&amp;lt;0.05), whereas no significant differences were observed across other hypertrophic phenotype diseases. Age, iLAVMax and LACI were independently associated with all the three LA strain components (Figure 2, all p&amp;lt;0.05). Conclusions LA remodeling and function are affected differently across the various etiologies of LV hypertrophy. CA patients exhibit more pronounced atrial involvement, whereas those with HCM, asymptomatic AS, and HTN display similar patterns of atrial dysfunction and remodeling. Additionally, CMR-derived iLAVmax and LACI are independently correlated with LA function.

APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans.

Apolipoprotein L1 gene (APOL1) variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of APOL1 variants with CKD in West Africans, a major group in the Black population. We conducted a case-control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease. We analyzed the association of CKD with APOL1 variants among participants with high-risk genotypes (two APOL1 risk alleles) and those with low-risk genotypes (fewer than two APOL1 risk alleles) by fitting logistic-regression models that controlled for covariates, including clinical site, age, and sex. Among 8355 participants (4712 with CKD stages 2 through 5, 866 with glomerular diseases, and 2777 with no kidney disease), the prevalence of monoallelic APOL1 variants was 43.0% and that of biallelic APOL1 variants was 29.7%. Participants with two APOL1 risk alleles had higher odds of having CKD than those with one risk allele or no risk alleles (adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.11 to 1.40), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.84; 95% CI, 1.30 to 2.61). Participants with one APOL1 risk allele had higher odds of having CKD than those with no risk alleles (adjusted odds ratio, 1.18; 95% CI, 1.04 to 1.33), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.61; 95% CI, 1.04 to 2.48). The inclusion of covariates did not modify the association of monoallelic and biallelic APOL1 variants with CKD or focal segmental glomerulosclerosis. In this study, monoallelic APOL1 variants were associated with 18% higher odds of CKD and 61% higher odds of focal segmental glomerulosclerosis; biallelic APOL1 variants were associated with 25% higher odds of CKD and 84% higher odds of focal segmental glomerulosclerosis. (Funded by the National Human Genome Research Institute and others.).

Regional cerebral blood flow in behavioral variant of FTD: hypoperfusion patterns and clinical associations.

Findings from functional neuroimaging techniques, such as single-photon emission computed tomography (SPECT), may add useful evidence improving Frontotemporal Dementia (FTD) diagnosis. The aim of the present study was to investigate patterns of hypoperfusion in a group of patients diagnosed with the behavioral variant of FTD (bvFTD) and to explore the relationship between brain perfusion and clinical characteristics. Brain perfusion of 23 bvFTD patients was measured with SPECT scintigraphy in lobes and Brodmann areas (BAs) and the NeurogamTM software was used for image analysis. To assess behavioral disturbances and dementia severity, patients' informants completed the Frontotempotal Behavioral Inventory and the Frontotemporal Dementia Rating Scale. Descriptive statistics were used for the detection of pathological hypoperfusion in lobes and selected BAs. Associations among patients' clinical characteristics and perfusion in lobes were explored via non-parametric correlations. Participants presented pathological hypoperfusion in frontal, limbic and temporal lobes. The most prominent deficit was observed in limbic lobes, where all participants showed pathological hypoperfusion. Decreased perfusion was also observed in limbic, frontal and temporal BAs. Perfusion in the left and right frontal lobe was associated with behavioral disturbances and disease severity, which was also correlated with perfusion in right limbic, left and right temporal areas. Patterns of limbic, frontal and temporal hypopefusion were reported in the present study, along with associations between brain perfusion, behavioral disturbance and severity of dementia. Perfusion patterns can help to understand further associated brain biomarkers, contributing to early diagnosis and intervention in bvFTD.

Skeletal muscle size and quality in healthy kidney donors, normal range and clinical associations

The gold standard to estimate muscle mass and quality is computed tomography (CT) scan. Lower mass and density (intramuscular fat infiltration) of skeletal muscles are markers of sarcopenia, associated with increased mortality risk, impaired physical function, and poorer prognosis across various populations and medical conditions. We aimed to describe standard reference values in healthy population, prospective kidney donors, and correlate clinical parameters to muscle mass and density. Included in the cohort 384 consecutive kidney donors. Mean age was 44.6 ± 11.5 (range 18.4–74.2), 46% were female and mean BMI was 25.6 ± 3.8 kg/m2. Our quantified reference values for psoas cross -sectional area (CSA) index at L3 level (males/females respectively) were 6.3 ± 1.8 and 4.8 ± 1.9 cm2 /m2, and density was 46.1 ± 5 and 41 ± 5 HU at that level. Older age (standardized beta coefficient − 0.12, p = 0.04), sex (− 0.32, p < 0.001) and BMI (0.17, p = 0.002) were significantly associated with CSA index of psoas at L3. Density, however, was associated with triglycerides level (− 0.21, p < 0.001), in addition to age (− 0.22, p < 0.0001), sex (− 0.27, p < 0.001) and BMI (− 0.1, p = 0.05). Our study validates the normative values of psoas muscle mass and density in healthy individuals and suggests correlations with clinical parameters. We demonstrate the significance of measuring not only the mass of the muscle, but also its density, as it has a valid association with metabolic parameters, including BMI and lipid level, even in healthy individuals and in the normal range of the tests.

Clinical associations with thyroid disease in ANCA-associated vasculitis.

To evaluate the frequency and the clinical relevance of thyroid disease in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients. A total of 305 AAV patients admitted to the Second Affiliated Hospital of Chongqing Medical University between October 2010 and December 2023 were analyzed. Demographic, clinical, and laboratory data were compared between AAV patients with and without thyroid disease. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with thyroid disease in AAV patients. Among the 305 AAV patients, 52 (17.0%) had concurrent thyroid disease. In univariate analysis, gender, coronary artery disease, renal involvement, anti-Ro/SSA antibodies, anti-Ro52 antibodies, anti-thyroglobulin antibodies (TgAb), and anti-thyroid peroxidase antibodies (TPOAb) exhibited significant differences between AAV patients with and without thyroid disease (P < 0.05). Multivariate analysis revealed that female gender (odds ratio (OR) = 2.423, 95% confidence interval (95% CI) 1.241, 4.729; P = 0.009), concurrent coronary artery disease (OR = 2.998, 95% CI 1.280, 7.019; P = 0.011), and positive anti-Ro/SSA antibodies (OR = 4.697, 95% CI 1.960, 11.257; P = 0.001) were associated with thyroid disease in AAV patients. AAV patients have a higher incidence of thyroid disease. Regular monitoring of thyroid function is advised for AAV patients, particularly for women, those with coronary artery disease, and those who are positive for anti-Ro/SSA antibodies. Key Points • AAV patients have a higher incidence of thyroid disease. • The potential clinical relevance of AAV patients with thyroid disease was explored. • Regular monitoring of thyroid function is advised for AAV patients.

Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

Postnatal Outcomes of Fetal Variants of Unknown Significance in Prenatal Chromosomal Microarray Analysis: A Single-Center Study

Introduction: Chromosomal microarray analysis (CMA) can identify clinically significant microdeletions and microduplications, providing valuable insights into the genetic basis of various disorders. Our study was to evaluate clinical management and prognosis of fetuses with prenatal variants of unknown significance (VOUS) and determine diagnostic approaches for subsequent pregnancies. Methods: This study included 2,953 fetuses undergoing CMA at the Prenatal Diagnostic Center of Changzhou Maternal and Child Health Care Hospital from January 2018 to December 2022, identifying 162 cases with VOUS. Parent-of-origin testing determined the origin of copy number variations. Prenatal genetic counseling was provided, and outcomes were followed for 3–36 months post-birth. Results: All 162 VOUS cases received prenatal genetic counseling. Among these, 123 continued the pregnancy; 22 chose termination, and 17 were lost to follow-up. Of the continuations, 116 delivered at term and 7 preterm. Post-birth follow-up showed 5/123 live-born fetuses developed relevant clinical phenotypes. Parent-of-origin testing in 21 cases identified 18 hereditary and 3 de novo variants. Additionally, five subsequent pregnancies were monitored, with two undergoing amniocentesis and three receiving low-risk noninvasive prenatal testing, all with positive outcomes. Conclusion: VOUS, occurring in approximately 5% of cases, require comprehensive prenatal genetic counseling and show generally favorable outcomes. Despite low association with adverse clinical phenotypes, the importance of postnatal follow-up and regular report updates is emphasized to detect potential clinical associations early.

Subtypes of Childhood Trauma Exposure Associated with Earlier Onset and Delayed Treatment in Rapid Cycling Bipolar Disorder: A CaseControl Study

ABSTRACT Studies on bipolar disorder (BD) have suggested that exposure to childhood trauma (CT) and rapid cycling BD (RC-BD) are associated with earlier onset and overall worse prognosis. The association between CT exposure and RC-BD in patients from low/middle-income countries has not been sufficiently characterized. Therefore, we performed a case–control study of patients with RC-BD (n = 35), patients without RC-BD (n = 35), and healthy controls (HC) (n = 105) in a low/middle-income country, Colombia, to evaluate CT exposure and RC-BD for clinical associations. We reported a significant number of patients with RC-BD exposed to physical abuse and/or sexual abuse compared with patients without RC-BD during the course of illness. In addition, CT exposure and RC-BD were associated with an earlier age of onset and delayed diagnosis and treatment. In the future, recognition of early CT exposure in populations at risk for BD may help tailor precise interventions and thus change the course of illness and worse prognosis.

Latent profile analysis identifies four different clinical schizophrenia profiles through aberrant salience

Understanding the role of aberrant salience (AS) in psychosis is crucial for comprehending schizophrenia spectrum disorders (SSDs). Researchers emphasize the importance of salience attribution in schizophrenia, acknowledging its interaction with environmental stressors and multiple neurotransmitter systems. Childhood trauma and adversities (CTA) play a significant role in SSDs, potentially contributing to prodromal symptoms characterized by AS. While empirical evidence supports the relationship between AS and SSD, the interplay between different AS patterns, CTA, and psychotic symptoms remains unclear. Clinical diagnosis followed DSM-5 criteria, and participants completed assessments including the Aberrant Salience Inventory (ASI), Childhood Trauma Questionnaire – Short form (CTQ-SF), and Positive and Negative Symptom Scale (PANSS). Latent profile analysis (LPA) was employed to identify distinct AS profiles within the sample, with subsequent analyses examining differences in psychopathological variables among these profiles. Among 262 participants, four distinct AS profiles emerged from LPA: low AS, high AS with severe symptoms and CTA, intermediate AS with sexual abuse correlation, and chronic AS with specific childhood trauma associations. Profile distinctions included differences in age, hospitalizations, psychotic symptoms, and CTA. Logistic regression analyses showed significant associations between the four profiles and emotional and sexual abuse, physical neglect and clinical variables. Subtyping individuals with SSD based on AS revealed four distinct profiles, each with unique clinical characteristics and associations with CTA. Future studies should investigate whether these profiles correspond to diverse treatment outcomes. These findings highlight the complexity of schizophrenia presentation and underscore the importance of considering individualized diagnostic and therapeutic approaches.

Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.