Slow Progression Group Research Articles

Neuroinflammation and glycosylation-related cerebrospinal fluid proteins for predicting functional decline in amyotrophic lateral sclerosis: a proteomic study.

The rate of disease progression varies widely among patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly anticipated to improve clinical trial design. We aimed to explore the cerebrospinal fluid (CSF) for prognostic biomarkers to predict future functional decline in patients with ALS. We collected CSF samples from 64 patients with ALS and 25 disease controls. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. Factors with significant changes between slow and fast progression groups were investigated via receiver operating characteristic curve analyses. Moreover, the correlation of the CSF factors with progression rate was evaluated by multiple regression analyses. In total, 26 proteins changed significantly (p < 0.05 and q < 0.10), with levels varying within a large dynamic range (fold change of >1.5 or < 0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: glycoprotein non-metastatic melanoma protein B (GPNMB; area under the curve [AUC], 0.88), glial fibrillary acidic protein (AUC, 0.81), glypican-1 (GPC1; AUC, 0.79), alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (AUC, 0.74), and chitinase-3-like protein 2 (CHI3L2; AUC, 0.73). Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate. This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.

Urine complement proteins are associated with kidney disease progression of type 2 diabetes in Korean and American cohorts.

Mechanisms of progression of diabetic kidney disease (DKD) are not completely understood. This study uses untargeted and targeted mass spectrometry-based proteomics in two independent cohorts on two continents to decipher the mechanisms of DKD in patients with type 2 diabetes. We conducted untargeted mass spectrometry on urine samples collected at the time of kidney biopsy from Korean patients with type 2 diabetes and biopsy-proven diabetic nephropathy at Seoul National University Hospital (SNUH-DN cohort; n = 64). These findings were validated using targeted mass spectrometry in urine samples from a Chronic Renal Insufficiency Cohort subgroup with type 2 diabetes and DKD (CRIC-T2D; n = 282). Urinary biomarkers/pathways associated with kidney disease progression (doubling of serum creatinine, ≥50% decrease in estimated glomerular filtration rates, or the development of end-stage kidney disease) were identified. SNUH-DN patients had an estimated glomerular filtration rate (eGFR) of 55 mL/min/1.73 m 2 (interquartile range [IQR], 44-75) and random urine protein-to-creatinine ratio of 3.1 g/g (IQR, 1.7-7.0). Urine proteins clustered into two groups, with cluster 2 having a 4.6-fold greater hazard (95% confidence interval [CI], 1.9-11.5) of disease progression than cluster 1 in multivariable-adjusted, time-to-event analyses. Proteins in cluster 2 mapped to 10 pathways, four of the top five of which were complement or complement-related. A high complement score, constructed from urine complement protein abundance, was strongly correlated to 4 of 5 histopathologic DN features and was associated with a 2.4-fold greater hazard (95% CI, 1.0-5.4) of disease progression than a low complement score. Targeted mass spectrometry of the CRIC-T2D participants, who had an eGFR of 42 mL/min/1.73 m 2 (IQR, 37-49) and 24-hr urine protein of 0.48 g (IQR, 0.10-1.87), showed that the complement score similarly segregated them into rapid and slow DKD progression groups. In both cohorts, the complement score had a linear association with disease progression. Urinary proteomic profiling confirms the association between the complement pathway and rapid DKD progression in two independent cohorts. These results suggest a need to further investigate complement pathway inhibition as a novel treatment for DKD.

#2610 Low skeletal muscle mass and low skeletal muscle quality are associated with thoracic aorta calcification in dialysis patients

Abstract Background and Aims Cardiovascular disease (CVD) is the leading cause of mortality in dialysis patients. Thoracic aorta calcification (TAC) is a common cardiovascular complication in dialysis patients and is independently associated with CVD. Sarcopenia, particularly low skeletal muscle mass, has been found to be associated with increased cardiovascular risk in dialysis patients. This study aims to explore the relationship between skeletal muscle quality and skeletal muscle mass at the first lumbar vertebra (L1) level determined by opportunistic CT scans (chest CT) and TAC, with the goal of providing valuable opportunities for identifying and intervening in high-risk CVD patients. Method We included 2514 patients for cross-sectional analysis, who underwent dialysis in four centers in China from 2020 to 2023 and all had chest CT scans including the L1 level. Additionally, we conducted a follow-up study on TAC in patients who initiated dialysis between 2014 and 2019 as part of the earlier research, including 215 patients who had undergone at least two chest CT scans for cohort analysis. At the L1 level, we assessed skeletal muscle quality [by skeletal muscle density (SMD), HU] and skeletal muscle mass [by skeletal muscle index (SMI), cm2/m2] in dialysis patients. Measurements of thoracic aorta calcification scores (TACS) and calcification scores for three segments of the thoracic aorta, including ascending aorta calcification score (ATACS), aortic arch calcification score (AoACS), and descending thoracic aorta calcification score (DTACS), were obtained in dialysis patients. Patients were divided based on their annual calcification score growth rate: those with a rate greater than or equal to the average annual increase were classified into the rapid progression group, while those with a rate less than the average were classified into the slow progression group (including those with no progression). Multivariable linear regression models were employed to assess the relationships between SMI and SMD with TACS. Multivariable logistic regression models were used to evaluate the associations of SMl and SMD with the risk of rapid progression of TACS. Results The mean (SD) age of participants was 56 (15) years, with 58.2% being male. The prevalence of TAC was 82.2%, while the prevalence of ascending thoracic aorta calcification (ATAC), aortic arch calcification (AoAC), and descending thoracic aorta calcification (DTAC) was 21.4%, 75.3%, and 68.8%, respectively. Over an average follow-up period of 3.22 years, the progression rate of TAC was 85.6%. Comparing the highest quartile of SMD to the lowest quartile, a significant inverse association was observed with TAC (beta −1.19, 95% CI −1.55— −0.83; P &amp;lt; 0.001). Similarly, comparing the highest quartile of SMI to the lowest quartile, a significant inverse association was found with TAC (beta −0.59, 95% CI −0.92— −0.26; P = 0.001). SMI and SMD, as continuous variables, were both significantly negatively correlated with TAC. Higher SMD was associated with a reduced risk of rapid progression of TAC; after full adjustment, for every 1 SD increase in SMD, the risk of TAC rapid progression decreased by 46% (aOR 0.54, 95% CI 0.32—0.91; P = 0.021). SMI showed no significant association with the rapid progression of TAC. The associations of SMI and SMD with AoAC and DTAC were consistent with their associations with TAC, except for ATAC. The ROC curve analysis indicated that incorporating SMD into the model enhanced the discriminative ability for stratifying the risk of rapid progression of thoracic aorta calcification. Conclusion After adjusting for cardiovascular risk factors and inflammatory markers, higher skeletal muscle quality and higher skeletal muscle mass were significantly associated with lower TAC. Improving skeletal muscle quality in initial dialysis patients may reduce the risk of rapid TAC progression.

Analysis of risk factors related to the progression rate of hemifacial spasm.

Although there have been many researches on the etiology and risk factors with the onset of hemifacial spasm, researches on the risk factors related to progression rate are limited. This study aims to analyze the risk factors related to the progression rate of hemifacial spasm. The study enrolled 142 patients who underwent microvascular decompression for hemifacial spasm. Based on the duration and severity of symptoms, patients were classified into rapid progression group and slow progression group. To analyze risk factors, univariate and multivariate logistic regression analyses were conducted. Of 142 patients with hemifacial spasm, 90(63.3%) were classified as rapid progression group, 52(36.7%) were classified as slow progression group. In the univariate analysis, there were significant statistical differences between the two groups in terms of age of onset (P = 0.021), facial nerve angle (P < 0.01), hypertension (P = 0.01), presence of APOE ε4 expression (P < 0.01) and different degrees of brainstem compression in the Root Entry Zone (P < 0.01). In the multivariable analyses, there were significant statistical differences between the two groups in terms of age of symptom onset (P < 0.01 OR = 6.591), APOE ε4 (P < 0.01 OR = 5.691), brainstem compression (P = 0.006 OR = 5.620), and facial nerve angle (P < 0.01 OR = 5.758). Furthermore, we found no significant correlation between the severity of facial spasms and the progression rate of the disease (t = 2.47, P = 0.12>0.05). According to our study, patients with facial nerve angle ≤ 96.5°, severer compression of the brainstem by offending vessels, an onset age > 45 years and positive expression of APOE ε4, may experience faster progression of hemifacial spasm.

A retrospective analysis of optimal timing of thoracic radiotherapy for driver gene-negative metastatic non-small cell lung cancer.

The optimal timing of thoracic radiotherapy (TRT) in driver-gene-negative metastatic non-small cell lung cancer (mNSCLC) patients was retrospectively investigated based on survival and safety profile. The efficacy and safety data of driver-gene-negative mNSCLC patients treated with TRT during maintenance after first-line therapy was collected. Patients whose primary tumor and metastatic lesions remained no progression during maintenance and then received TRT were categorized as the NP (no progression) group, while patients who experienced slow progression during maintenance without reaching progressive disease and then received TRT were categorized as the SP (slow progression) group. The efficacy and adverse events of TRT were analyzed. In total, 149 driver-gene-negative mNSCLC patients treated with TRT during maintenance were enrolled into the study, with 119 in the NP group and 30 in the SP group. After a median follow-up of 30.83 (range: 26.62-35.04) months, the median progression-free survival (PFS) in the NP group was 11.13 versus 9.53 months in the SP group (HR 0.599, p = 0.017). The median overall survival (OS) in the NP group was 32.27 versus 25.57 months in the SP group (HR 0.637, p = 0.088). The median PFS after radiotherapy (rPFS) was 6.33 versus 3.90 months (HR 0.288, p < 0.001). The adverse events were tolerable and manageable in both groups without significant difference (p > 0.05). The addition of TRT during the pre-emptive no progression phase was associated with a significantly longer PFS than during the delayed slow progression phase and had an acceptable safety profile. Our results might support the earlier initiation of TRT after induction therapy for some patients with driver-gene-negative mNSCLC.

Sleep Quality is Associated with Axial Length Elongation in Myopic Children Receiving Orthokeratology: A Retrospective Study.

To identify potential demographic and lifestyle factors associated with progression of myopia with orthokeratology (ortho-k) treatment via follow-up of axial length (AL). In this retrospective observational study, demographics, ocular parameters, near-work distance, outdoor activities, and sleep quality were analyzed in 134 children with myopia aged 8~15 years using ortho-k and a follow-up for one year. Compared with the slow progression group, the participants in the fast progression group were younger in age (10.55 ±1.70 years vs 9.90 ±1.18 years, P = 0.009), demonstrated higher spherical equivalent (SE) value (-2.52 ±0.63 diopters (D) vs -3.05 ±0.89 D, P < 0.001), shorter near-work distance (P = 0.010), and poorer sleep quality (Pittsburgh sleep quality index [PSQI], 4.79 ±1.29 vs 3.81 ±1.38, P < 0.001) in the one-year follow-up. Furthermore, multivariate linear regression analyses showed that baseline age (B =-0.020, P = 0.020), SE (B = 0.0517, P < 0.001), and total PSQI (B=0.026, P = 0.001) were associated with axial elongation. Advanced logistic regression analyses demonstrated that shorter average near-work distance (P = 0.034), higher SE value (P = 0.023), and poorer sleep quality (P = 0.003) were associated with fast axial elongation. Sleep quality is one of the key factors associated with axial elongation in children with myopia after using ortho-k for one year. Further studies are required to confirm this observation and expand its practical applications.

UPSIT subitems may predict motor progression in Parkinson's disease.

The relationship between hyposmia and motor progression is controversial in Parkinson's disease (PD). The aim of this study was to investigate whether preserved identification of Chinese-validated University of Pennsylvania Smell Identification Test (UPSIT) odors could predict PD motor progression. PD patients with two consecutive clinical visits while taking medication were recruited. Based on mean changes in Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3 score and levodopa equivalent daily dosage, the participants were categorized into rapid progression, medium progression, and slow progression groups. Odors associated with the risk of PD motor progression were identified by calculating the odds ratios of UPSIT item identification between the rapid and slow progression groups. Receiver operating characteristic curve analysis of these odors was conducted to determine an optimal threshold for rapid motor progression. A total of 117 PD patients were screened for group classification. Preserved identification of neutral/pleasant odors including banana, peach, magnolia, and baby powder was significantly correlated with rapid motor progression. The risk of rapid progression increased with more detected risk odors. Detection of ≥1.5 risk odors could differentiate rapid progression from slow progression with a sensitivity of 85.7%, specificity of 45.8%, and area under the receiver operating characteristic curve of 0.687. Preserved identification of neutral/pleasant odors may help to predict PD motor progression, and detection of ≥1.5 UPSIT motor progression risk odors could improve the predictive power. In PD patients with a similar level of motor disability during initial screening, preserved pleasant/neutral odor identification may imply relatively better cortical odor discriminative function, which may suggest the body-first (caudo-rostral) subtype with faster disease progression.

Prevention of fetal brain injury in category II tracings.

With category II fetal heart rate tracings, the preferred timing of interventions to prevent fetal hypoxic brain damage while limiting operative interventions remains unclear. We aimed to estimate fetal extracellular base deficit (BDecf ) during labor with category II tracings to quantify the timing of potential interventions to prevent severe fetal metabolic acidemia. A longitudinal study was conducted using the database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy, including infants with severe cerebral palsy born at ≥34 weeks' gestation between 2009 and 2014. Cases included those presumed to have an intrapartum onset of hypoxic-ischemic insult based on the fetal heart rate pattern evolution from reassuring to an abnormal pattern during delivery, in association with category II tracings marked by recurrent decelerations and an umbilical arterial BDecf ≥ 12 mEq/L. BDecf changes during labor were estimated based on stages of labor and the frequency/severity of fetal heart rate decelerations using the algorithm of Ross and Gala. The times from the onset of recurrent decelerations to BDecf 8 and 12 mEq/L (Decels-to-BD8, Decels-to-BD12) and to delivery were determined. Cases were divided into two groups (rapid and slow progression) based upon the rate of progression of acidosis from onset of decelerations to BDecf 12 mEq/L, determined by a finite-mixture model. The median Decels-to-BD8 (28 vs. 144 min, p < 0.01) and Decels-to-BD12 (46 vs. 177 min, p < 0.01) times were significantly shorter in the rapid vs slow progression. In rapid progression cases, physicians' decisions to deliver the fetus occurred at ~BDecf 8 mEq/L, whereas the "decisions" did not occur until BDecf reached 12 mEq/L in slow progression cases. Fetal BDecf reached 12 mEq/L within 1 h of recurrent fetal heart rate decelerations in the rapid progression group and within 3 h in the slow progression group. These findings suggest that cases with category II tracings marked by recurrent decelerations (i.e., slow progression) may benefit from operative intervention if persisting for longer than 2 h. In contrast, cases with sudden bradycardia (i.e., rapid progression) represent a challenge to prevent severe acidosis and hypoxic brain injury due to the limited time opportunity for emergent delivery.

Reclassification of moderate aortic stenosis based on data-driven phenotyping of hemodynamic progression

The management and follow-up of moderate aortic stenosis (AS) lacks consensus as the progression patterns are not well understood. This study aimed to identify the hemodynamic progression of AS, and associated risk factors and outcomes. We included patients with moderate AS with at least three transthoracic echocardiography (TTE) studies performed between 2010 and 2021. Latent class trajectory modeling was used to classify AS groups with distinctive hemodynamic trajectories, which were determined by serial systolic mean pressure gradient (MPG) measurements. Outcomes were defined as all-cause mortality and aortic valve replacement (AVR). A total of 686 patients with 3093 TTE studies were included in the analysis. Latent class model identified two distinct AS trajectory groups based on their MPG: a slow progression group (44.6%) and a rapid progression group (55.4%). Initial MPG was significantly higher in the rapid progression group (28.2 ± 5.6 mmHg vs. 22.9 ± 2.8 mmHg, P < 0.001). The prevalence of atrial fibrillation was higher in the slow progression group; there was no significant between-group difference in the prevalence of other comorbidities. The rapid progression group had a significantly higher AVR rate (HR 3.4 [2.4–4.8], P < 0.001); there was no between-group difference in mortality (HR 0.7 [0.5–1.0]; P = 0.079). Leveraging longitudinal echocardiographic data, we identified two distinct groups of patients with moderate AS: slow and rapid progression. A higher initial MPG (≥ 24 mmHg) was associated with more rapid progression of AS and higher rates of AVR, thus indicating the predictive value of MPG in management of the disease.

Discovery of novel CSF biomarkers to predict progression in dementia using machine learning

Providing an accurate prognosis for individual dementia patients remains a challenge since they greatly differ in rates of cognitive decline. In this study, we used machine learning techniques with the aim to identify cerebrospinal fluid (CSF) biomarkers that predict the rate of cognitive decline within dementia patients. First, longitudinal mini-mental state examination scores (MMSE) of 210 dementia patients were used to create fast and slow progression groups. Second, we trained random forest classifiers on CSF proteomic profiles and obtained a well-performing prediction model for the progression group (ROC–AUC = 0.82). As a third step, Shapley values and Gini feature importance measures were used to interpret the model performance and identify top biomarker candidates for predicting the rate of cognitive decline. Finally, we explored the potential for each of the 20 top candidates in internal sensitivity analyses. TNFRSF4 and TGF upbeta -1 emerged as the top markers, being lower in fast-progressing patients compared to slow-progressing patients. Proteins of which a low concentration was associated with fast progression were enriched for cell signalling and immune response pathways. None of our top markers stood out as strong individual predictors of subsequent cognitive decline. This could be explained by small effect sizes per protein and biological heterogeneity among dementia patients. Taken together, this study presents a novel progression biomarker identification framework and protein leads for personalised prediction of cognitive decline in dementia.

Divergent cognitive trajectories in early stage Huntington's disease: A 3-year longitudinal study.

Cognitive impairment is a central feature of Huntington's disease (HD), but it is unclear to what extent more aggressive cognitive phenotypes exist in HD among individuals with the same genetic load and equivalence in other clinical and sociodemographic variables. We included Enroll-HD study participants in early and early-mid stages of HD at baseline and with three consecutive yearly follow-ups for whom several clinical and sociodemographic as well as cognitive measures were recorded. We excluded participants with low and large CAG repeat length (CAG < 39 & > 55), with juvenile or late onset HD, and with dementia at baseline. We explored the existence of different groups according to the profile of cognitive progression using a two-step k-means cluster analysis model based on the combination of different cognitive outcomes. We identified a slow cognitive progression group of 293 participants and an aggressive progression group (F-CogHD) of 235 for which there were no differences at the baseline visit in any of the measures explored, with the exception of a slightly higher motor score in the F-CogHD group. This group showed a more pronounced annual loss of functionality and a more marked motor and psychiatric deterioration. The rate of progression of cognitive deterioration in HD is strongly variable even between patients sharing, among other variables, equivalent CAG repeat length, age, and disease duration. We can recognize at least two phenotypes that differ in terms of rate of progression. Our findings open new avenues to study additional mechanisms contributing to HD heterogeneity.

Associations of Renal Function Trajectories and Long-Term Cardiovascular Risks Among a Population Without Chronic Kidney Disease.

Background The longitudinal trajectories of renal function have been associated with cardiovascular events in patients with chronic kidney disease (CKD). However, the change pattern of renal function in those without CKD has not yet been reported. We aim to explore patterns of renal function change in a non-CKD population and its associated risks with cardiovascular outcomes. Methods and Results The present study analyzed data from 4 prospective cohorts and was restricted to participants without baseline CKD. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, chronic heart failure, stroke, and cardiovascular deaths. We used a group-based trajectory model to identify latent groups and analyzed the associated risk with Cox regression models. The complete dates of this study were June 1, 2020, through January 1, 2021. The final sample comprised 23 760 participants (mean age, 58.63 [9.12] years, 10 618 men, and 17 799 White participants). During 20.56 years follow-up, 8328 (35.05%) first major adverse cardiovascular events happened. Four trajectories in estimated glomerular renal function and 3 patterns of CKD progression were identified. Compared with subjects assigned to class I trajectory (high to mildly decreased group), the adjusted hazard ratios of major adverse cardiovascular events for class II (normal to mildly decreased group), class III (normal to moderately decreased group), and class IV (mildly to severely decreased group) were 1.11 (95% CI, 1.01-1.23), 1.27 (95% CI, 1.14-1.40), and 1.56 (95% CI, 1.38-1.77), respectively. Likewise, participants assigned to the slow and rapid progression groups had elevated HRs for major adverse cardiovascular events (1.75 [95% CI, 1.39-2.21] and 2.19 [95% CI, 1.68-2.86], respectively) when compared with the stable group. Findings were generally consistent in stratification analysis, but significant interaction effects by age and smoking status were detected. Conclusions In this study, we identified unique trajectory groups for renal function. These findings may signal an underlying high-risk population and inspire future studies on individualized risk management.

Facet Articular Irregularity Is the Most Relevant Risk Factor for Rapidly Progressive Degenerative Cervical Myelopathy.

Facet articular irregularity is associated with rapidly progressive degenerative cervical myelopathy (DCM). However, its significance compared with other known risk factors remains unknown. Therefore, this retrospective study aimed to clarify the potential impact of facet articular irregularity as a risk factor for rapid DCM progression. This study included 141 consecutive patients with DCM who underwent surgical treatment at our institution. Clinical variables and radiological findings related to DCM progression were collected. Imaging findings were analyzed at the segmental level of myelopathy in each case. The patients were divided into 2 groups based on the presence or absence of rapid DCM progression, and independent risk factors were determined using logistic regression analyses. Overall, 131 patients with a mean age of 63.9 ± 12.6 years were analyzed; 27 patients (20.6%) were classified into the rapid DCM progression group. The mean age was significantly higher in the rapid progression group than in the slow progression group (72.4 ± 9.6 vs. 61.7 ± 12.4, p < 0.001). According to univariate analysis, facet articular irregularity, dynamic segmental translation (≥ 1.6 mm), upper cervical spine involvement above C4-5, history of cerebrovascular events, preceding minor trauma, local lordotic angle (≥ 4.5°), diabetes, hypertension, ligamentum flavum hypertrophy, and age were independent risk factors. Additionally, multivariate analysis showed that facet articular irregularity was the highest risk factor for rapid DCM progression (p = 0.001). Facet articular irregularity is the most clinically significant finding among the known risk factors in patients with rapid DCM progression.

Early-Life Slow Enteral Feeding Progression Pattern Is Associated with Longitudinal Head-Size Growth Faltering and Neurodevelopmental Impairment Outcomes in Extremely Preterm Infants

To determine whether feeding progression patterns in the first eight postnatal weeks, depicted by clustering analysis of daily enteral feeding volume, are associated with longitudinal head-circumference (HC) growth and neurodevelopmental outcomes in extremely preterm (EP) infants. 200 infants who were admitted at gestational ages 23-27 weeks between 2011 and 2018; survived to discharge; and underwent longitudinal HC growth measurements at birth, term-equivalent age (TEA), corrected age (CA) 6-month, 12-month, and 24-month; and neurodevelopmental assessment using the Bayley Scales of Infant Development at CA 24 months were included for analysis. kmlShape analysis identified two distinct enteral feeding progression patterns: fast progression in 131 (66%) infants and slow progression in 69 (34%) infants. Compared to the fast progression group, the slow progression group showed significantly lower daily enteral volumes after day 13, was older in postnatal age reaching full feeding, had a higher rate of Delta z scores of HC (zHC) < -1 (p < 0.001) between birth and TEA, and displayed lower longitudinal zHC from TEA to CA 24 months. The slow progression group also showed higher rates of microcephaly [42% vs. 16%, p < 0.001; adjusted odd ratio (aOR): 3.269, p = 0.001] and neurodevelopmental impairment (NDI) (38% vs. 19%, p = 0.007; aOR: 2.095, p = 0.035) at CA 24 months. For NDI, the model including feeding progression patterns showed a lower Akaike information criterion score and a better goodness of fit than the model that did not include feeding patterns. Characterizing feeding progression pattern may help identify EP infants at high-risk of head-size growth faltering and NDI at early childhood.

Identification of distinct subgroups in moderately severe rheumatic mitral stenosis using data-driven phenotyping of longitudinal hemodynamic progression

Abstract Background Rheumatic mitral stenosis (MS) is a significant cause of valvular heart disease. Pulmonary artery systolic pressure (PASP) reflects the hemodynamic consequences of MS and is used to determine treatment strategies. However, PASP progression and expected outcomes in patients with moderately severe MS remain unclear. Purpose We aimed to examine the impact of progression rate of PASP in moderately severe MS. Methods A cohort of 866 consecutive patients with moderately severe rheumatic MS (1.0 cm2. Results Data-driven phenotyping identified two distinct trajectories based on PASP progression: a rapid progression group (N=38, 8.7%) and a slow progression group (N=398, 91.3%). Patients in the rapid progression group were older and had more comorbidities than patients in the slow progression group, including diabetes, and atrial fibrillation (all P&amp;lt;0.05). The initial mean diastolic pressure gradient and PASP were higher in the rapid progression group than in the slow progression group (6.2±2.4 mmHg vs. 5.1±2.0 mmHg, P=0.001, and 42.3±13.3 mmHg vs. 33.0±9.2 mmHg, P&amp;lt;0.001, respectively). During a mean follow-up of 7.0±3.0 years, the event-free survival rate was significantly lower in the rapid progression group than in the slow progression group (log-rank P&amp;lt;0.001). Rapid PASP progression was a significant risk factor for composite outcomes even after adjusting for comorbidities (hazard ratio: 3.08, 95% confidence interval (CI): 1.68–5.64, P&amp;lt;0.001). Multivariate regression analysis revealed that PASP&amp;gt;40 mmHg was independently associated with the probability of rapid progression group allocation (odds ratio: 4.95, 95% CI: 2.08–11.99, P&amp;lt;0.001). Conclusions Two groups with distinct patterns of PASP progression were identified. Rapid PASP progression was associated with a significantly higher risk of the composite outcomes. The main independent echocardiographic predictor for rapid progression group allocation was initial PASP&amp;gt;40 mmHg. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): This study was supported by a Severance Hospital Research fund for Clinical excellence (SHRC) (C-2020-0041) and a faculty research grant of Yonsei University College of Medicine (6-2020-0156).

Identification of Distinct Subgroups in Moderately Severe Rheumatic Mitral Stenosis Using Data-Driven Phenotyping of Longitudinal Hemodynamic Progression.

BackgroundRheumatic mitral stenosis is a significant cause of valvular heart disease. Pulmonary arterial systolic pressure (PASP) reflects the hemodynamic consequences of mitral stenosis and is used to determine treatment strategies. However, PASP progression and expected outcomes based on PASP changes in patients with moderately severe mitral stenosis remain unclear.Methods and ResultsA total of 436 patients with moderately severe rheumatic mitral stenosis (valve area 1.0–1.5 cm2) were enrolled. Composite outcomes included all‐cause mortality and hospitalization for heart failure. Data‐driven phenotyping identified 2 distinct trajectory groups based on PASP progression: rapid (8.7%) and slow (91.3%). Patients in the rapid progression group were older and had more diabetes and atrial fibrillation than those in the slow progression group (all P<0.05). The initial mean diastolic pressure gradient and PASP were higher in the rapid progression group than in the slow progression group (6.2±2.4 mm Hg versus 5.1±2.0 mm Hg [P=0.001] and 42.3±13.3 mm Hg versus 33.0±9.2 mm Hg [P<0.001], respectively). The rapid progression group had a poorer event‐free survival rate than the slow progression group (log‐rank P<0.001). Rapid PASP progression was a significant risk factor for composite outcomes even after adjusting for comorbidities (hazard ratio, 3.08 [95% CI, 1.68–5.64]; P<0.001). Multivariate regression analysis revealed that PASP >40 mm Hg was independently associated with allocation to the rapid progression group (odds ratio, 4.95 [95% CI, 2.08–11.99]; P<0.001).ConclusionsRapid PASP progression was associated with a higher risk of the composite outcomes. The main independent predictor for rapid progression group allocation was initial PASP >40 mm Hg.

Different sensorimotor mechanism in fast and slow progression amyotrophic lateral sclerosis.

The huge heterogeneity of the disease progression rate may cause inconsistent findings between local activity and functional connectivity of the primary sensorimotor area (PSMA) in amyotrophic lateral sclerosis (ALS). For illustration of this hypothesis, resting‐state fMRI (RS‐fMRI) data were collected and analyzed on 38 “definite” or “probable” ALS patients (19 fast and 19 slow, cut off median = 0.41) and 37 matched healthy controls. Amplitude of low frequency fluctuations (ALFFs) and functional connectivity strength (FCS) were analyzed within the PSMA. There was a decreased ALFF (p FDR <.05) and FCS (p = .022) in all ALS patients. The two metrics shared about 50% of variance (R = .7) and both showed significant positive correlation with ALS Functional Rating Scale‐Revised (ALSFRS‐R) in the fast (p values <.034) but not in the slow progression groups. Interestingly, when regressing out the ALFF, the PSMA network FCS, especially the inter‐hemisphere FCS, showed negative correlation with the ALSFRS‐R score in the slow (R = −.54, p = .026) but not the fast progression group. In summary, the current results suggest that RS‐fMRI local activity and network functional connectivity accounts for the severity differently in the slow and fast progression ALS patients.

Effect of serum potassium level on renal function progression in stage Ⅲ-Ⅴ chronic kidney disease patients without dialysis

Objective: To investigate the effect of serum potassium level and hyperkalemia on the renal function decline in chronic kidney disease (CKD) patients. Methods: The clinical data at baseline and follow-up in stage Ⅲ-Ⅴ CKD patients without dialysis who were followed up for more than one year in Tianjin First Central Hospital from May 2015 to June 2019 and Teikyo University School of Medicine from January 2008 to July 2013 were retrospectively collected. All patients were divided into stable group (337 cases), slow progression group (337 cases) and rapid progression group (338 cases) according to the tertile of estimated glomerular filtration rate (eGFR) slope (the annual average percentage of eGFR decline). Multivariate logistic regression analysis models were used to evaluate the correlations of baseline serum potassium or time-averaged serum potassium level with CKD rapid progression. Results: Three hundred and forty-three cases from Tianjin First Central Hospital and 669 cases from Teikyo University School of Medicine were included in the study, and 635 cases (62.7%) were male. The average age was (61±14) years old and the average eGFR decline slope was 4.0%/year. The levels of baseline serum potassium and time-averaged serum potassium of patients in the slow progression group [(4.47±0.52) and (4.51±0.43) mmo/L] and rapid progression group [(4.62±0.62) and (4.76±0.48) mmo/L] were higher than those in the stable group [(4.37±0.49) and (4.38±0.37) mmo/L] (both P<0.05). Meanwhile, 24.6% (83/338) of the patients in the rapid progression group had hyperkalemia at baseline (serum potassium ≥5.0 mmol/L) and 34.9% (118/338) of the patients had time-averaged serum potassium ≥5.0 mmol/L, which were higher than those in the stable group [10.7% (36/337) and 6.5% (22/337)] (both P<0.001). Multivariate logistic regression analysis showed that compared with the stable group, baseline serum potassium (OR=1.843, 95%CI: 1.051-3.234) and time-averaged serum potassium (OR=2.495, 95%CI: 1.040-5.987) were correlated with the rapid progression of CKD. Time-averaged serum potassium ≥5.0 mmol/L was the independent influencing factor for rapid progression of CKD. Conclusions: During the follow-up period, the average level of serum potassium in stage Ⅲ-Ⅴ CKD patients should be controlled under 5.0 mmol/L, which may reduce the risk of rapid decline of renal function.

Prediction of the progression of femoral head collapse in ARCO stage 2-3A osteonecrosis based on the initial bone resorption lesion.

To predict the progression of femoral head collapse in Association Research Circulation Osseous (ARCO) Stage 2-3A osteonecrosis based on the initial bone resorption lesion. A retrospective analysis of the location, attenuation, and maximum area in coronal position (MAC) of the initial bone resorption lesion in ARCO Stage 2 and 3A was conducted in 85 cases of osteonecrosis of the femoral head (ONFH). The cases were divided into rapid and slow progression groups according to whether femoral head collapse at follow-up was greater than 2 mm. The characteristics of the bone resorption lesion between the two groups were compared by analysis of variance. Receiver operating characteristic curve was used to analyze the MAC, regions of A2, and C1 of bone resorption lesion in predicting collapse progression. The MAC of initial bone resorption lesion in rapid progression group (117.8 ± 72.1 mm2) was significantly larger than slow (53.1 ± 39.5 mm2) (p < 0.001). Regions of A2 and C1 involved were significantly higher in rapid than slow progression group. The area under the receiver operating characteristic curve of MAC, regions of A2 and C1 of bone resorption lesion to predict collapse progression were 0.81, 0.72 and 0.62 respectively. A threshold MAC of 49 mm2 had sensitivity of 86.1% and specificity of 61.9% to predict collapse progression. The MAC of initial bone resorption lesion in ARCO Stage 2-3A ONFH can predict the progression of femoral head collapse. If it is greater than 49 mm2 and located in regions of A2 and C1, the possibility of rapid progression is high, active monitoring and intervention should be recommended. This study is the first to find that the maximum area in coronal position of initial bone resorption lesion in ARCO Stage 2 or 3A can predict progression of the femoral head collapse with a threshold of 49 mm2. If the maximum area is larger than 49 mm2 and located in the anterolateral or lateral column of the femoral head, the possibility of rapid collapse progression is high, therefore, monitoring should be strengthened and active intervention should be considered.

Exosomal TAR DNA-binding protein-43 and neurofilaments in plasma of amyotrophic lateral sclerosis patients: A longitudinal follow-up study

ObjectiveAmyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease with characteristic of progressive general muscle weakness and atrophy. ALS is still lack of efficient treatment and laboratory biomarkers. In this study, we longitudinally examined ALS patients' peripheral blood to search potential biomarkers.18 ALS patients aged between 20 and 65 years were recruited in a clinical trial and longitudinal plasma samples were obtained and analyzed at baseline, 1, 3, 6 and 12 months follow up. Neurofilament light chain (NFL), phosphorylated neurofilament heavy chain (pNFH) by ELISA and exosomal TAR DNA-binding protein-43 (TDP-43) ratio were measured by flow cytometry assay in isolated exosomes ResultsExosomal TDP-43 ratio significantly changed in 3-month (increased 60.8 ± 18.9%, p = 0.0005) and 6-month (increased 60.2 ± 32.6%, p = 0.0291) follow-up and close to significance at 12-month follow-up (increased 12.8 ± 10.8%, p = 0.0524). When subclassifying patients into rapid and slow progression groups, NFL but not pNFH is significantly higher in the rapid progression group at baseline (22.74 ± 1.66 pg/mL vs. 43.96 ± 12.87 pg/mL, p = 0.0136) and at 3-month follow-up (28.40 ± 3.39 pg/mL vs. 40.33 ± 5.44 pg/mL, p = 0.0356). ConclusionIn this study, we found exosomal TDP-43 ratio was increasing along with follow-up at 3 and 6 months and NFL levels in plasma was associated with rapid progression in ALS patients. In addition to NFL, exosomal TDP-43 ratio might be a potential candidate of biomarkers for ALS long-term follow-up studies.