Faster Progression Research Articles

Scoliosis in osteogenesis imperfecta: identifying the genetic and non-genetic factors affecting severity and progression from longitudinal data of 290 patients

BackgroundScoliosis is widely prevalent among osteogenesis imperfecta (OI) patients, and is progressive with age. However, factors affecting scoliosis in OI are not well known.MethodsWe retrospectively retrieved longitudinal radiographic and clinical records of consecutive OI patients seeking treatments at our hospital from 2014 to 2022, graded their pre-operative spinal conditions into four outcome groups, estimated their progression rates, and descriptively and inferentially analyzed the genetic and non-genetic factors that may affect the outcomes and progression rates.ResultsIn all, 290 OI patients met the inclusion criteria, where 221 had genetic records. Of these 221, about 2/3 had mutations in COL1A1 or COL1A2, followed by mutations in WNT1 (9.0%), IFITM5 (9.0%) and other OI risk genes. With an average age of 12.0 years (interquartile range [IQR] 6.9–16.1), 70.7% of the cohort had scoliosis (Cobb angle > 10°), including 106 (36.5%) mild (10°–25°), 40 (13.8%) moderate (25°–50°), and 59 (20.3%) severe (> 50°) scoliosis patients. Patients with either COL1A1 and COL1A2 were strongly biased toward having mild or no scoliosis, whereas patients with mutations in IFITM5, WNT1 and other recessive genes were more evenly distributed among the four outcome grades. Lower-limb discrepancy, bone mineral density (BMD) and age of first drug used were all significantly correlated with severity outcomes. Using multivariate logistic regression, we estimated that each year older adds an odds ratio of 1.13 (95% confidence interval [CI] 1.07–1.2) in progression into advanced stages of scoliosis. We estimated a cohort-wide progression rate of 2.7 degrees per year (95% CI 2.4–3.0). Early-onset patients experienced fast progressions during both infantile and adolescent stages. Twenty-five of the 59 (42.8%) patients with severe scoliosis underwent spinal surgeries, enjoying an average Cobb angle reduction of 33° (IQR 23–40) postoperatively.ConclusionThe severity and progression of scoliosis in osteogenesis imperfecta were affected by genetic factors including genotypes and mutation types, and non-genetic factors including age and BMD. As compared with COL1A1, mutations in COL1A2 were less damaging while those on IFITM5 and other recessive genes conferred damaging effects. Progression rates were the fastest in the adolescent adult age-group.

Clinical Profile of Various Mnd Cases that Presented to a Tertiary Centre over the Past 3 Years

INTRODUCTION: Motor neurone disease (MND) is a disabling and ultimately fatal disease of the motor system, with few effective treatments. Considerable heterogeneity is observed in the clinical motor features of MND, with extra-motor manifestations now also recognized as part of the condition. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. Diagnosis remains clinical. There are no specific laboratory markers which make the diagnosis independent of the clinical pattern but there are a few appropriate investigations to exclude mimics. The clinical syndrome once observed is recognized easily because of a distinctive appearance and course. OBJECTIVES: To demonstrate and compare the etiology, demography & clinical profile of various forms of Motor Neuron Diseases DESIGN: Cross sectional (Observational) study SETTING: Sapthagiri Institute of Medical Sciences & Research Centre METHODS: 30 MND cases diagnosed clinically (as per Awaji Shima modification of the El Escorial Criteria) with few supportive investigations that presented to our centre over the past 3 years were compiled and compared CONCLUSIONS: Mortality rates in MND depends on type of MND and subtypes like Madras Motor Neuron disease, SMA, PLS has the slowest progression and best prognosis of all the subtypes. Secondary MND due to exposure to heavy metals has faster progression and worst prognosis

Identification of Fast Progressors Among Patients With Nonalcoholic Steatohepatitis Using Machine Learning

There is a high unmet need to develop noninvasive tools to identify nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) patients at risk of fast progression to end-stage liver disease (ESLD). This study describes the development of a machine learning (ML) model using data around the first clinical evidence of NAFLD/NASH to identify patients at risk of future fast progression. Adult patients with ESLD (cirrhosis or hepatocellular carcinoma) due to NAFLD/NASH were identified in Optum electronic health records (2007-2018 period). Patients were stratified into fast (0.5 and 3 years) and standard progressor (6-10 years) cohorts based on retrospectively established progression time between ESLD and the earliest observable disease, and characteristics were reported using descriptive statistics. Two ML models predicting fast progression were created, performance was compared, and top predictive features from the final model were compared between cohorts. Among a total of 4013 NAFLD patients with cirrhosis or hepatocellular carcinoma (mean age 58.6 ± 12.5; 65% female), 24% were fast (n= 951) and 25% standard (n= 992) progressors that were used for modeling. The cohorts were comparable for gender, body mass index, type 2 diabetes, and arterial hypertension, but differed significantly for obesity, hyperlipidemia, and age at index. The final model (NASH FASTmap) is a 44 feature light gradient boosting model which performed better (area under the curve [0.77], F1-score [0.74], accuracy [0.71], and precision [0.71]) than eXtreme gradient boosting model to predict fast progression. Future fast progression to ESLD in NAFLD/NASH patients can be predicted from clinical data using ML. Electronic health record implementation of NASH FASTmap could support clinical assessment for risk stratification and potentially improve disease management.

Clinical factors and vascular endothelial growth factor as determinants of disease progression in Indian patients with amyotrophic lateral sclerosis

Objective Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Prognostication remains sub-optimally defined. We aimed to assess clinical determinants of disease progression rates in Indian patients with ALS and to assess the role of vascular endothelial growth factor (VEGF) in disease progression. Methods In this cross-sectional study, consecutive patients with clinically definite/probable ALS according to the revised El Escorial criteria and controls were included. Patients were classified into fast or slow progressors based on disease progression rate (DPR). Serum and CSF VEGF level was assessed for patients and controls. Results Of 142 patients recruited, 93 (65.5%) were male. Mean age at enrollment was 49.37 ± 12.65 years. Mean duration of symptoms was 20.53 ± 20.88 months. Mean DPR was 1.14 ± 0.94. Based on DPR, 81 (57%) patients were slow progressors and 61 (43%) were fast progressors. Univariate analysis demonstrated a statistically significant association of DPR with age at onset, symptom duration, time to spread, wasting of small muscles of the hand, frontal release signs, and neurophysiologic bulbar abnormalities. On multivariate analysis, age at onset and symptom duration had a significant association with disease progression. The CSF VEGF levels of ALS patients (46.18 ± 27.8) were significantly elevated compared to controls (25.95 ± 25.64 pg/ml) (p = 0.001), but not serum VEGF. Conclusion Age at symptom onset and duration of disease had a significant impact on disease progression in Indian patients with ALS. CSF VEGF levels were significantly elevated in ALS compared to controls, indicating the role of CSF VEGF as a potential biomarker.

Mortality in Two Waves of COVID-19: A Comparative Analysis of a Tertiary Care Hospital in India.

Background COVID-19 has spread as two distinct surges of cases in many countries. Several countries have reported differences in disease severity and mortality in the two waves. Objective Compare the in-hospital mortality in the two COVID-19 waves at a tertiary care hospital in India. Methods We conducted a retrospective data collection. Distinct periods of surges in cases and admissions were defined as the first wave spanning from March 2020 to December 2020 and the second wave from April 2021 to June 21, 2021. The primary outcome of this study was to compare mortality rates in terms of total hospital mortality rate (TMR) and case fatality rate (CFR). Results Mortality rates of wave 2 were approximately 10 times that of wave 1 (TMR of 20.3% in wave 2 versus 2.4% in wave 1 and CFR of 1.5% versus 17.7% in wave 1 and 2, respectively). Mortalities in wave 2 had a larger proportion of severe disease at presentation, faster progression of symptoms to death, and more patients without any chronic comorbid condition dying due to the direct effect of COVID-19 acute respiratory distress syndrome (ARDS). Conclusion Our data matches the worldwide reported pooled hospital mortality figures and shows the comparative difference in disease severity between the two waves.

Depression, psychosocial factors, and laboratory routine testing in people living with HIV in Northeastern Mexico: prevalence, correlations, and its associations

Introduction: Depression is up to five times more prevalent in people living with HIV (PLWHIV). There are neurohormonal, virological and psychosocial factors involved and it is associated with antiretroviral treatment non-adherence, decreased life expectancy, faster progression to AIDS and premature death. Studies support that with lower CD4 levels, and the higher viral load (VL), depression increases. Objective: To establish whether there is a correlation and association between the VL and CD4 count with depression and its symptoms in PLWHIV. Method: Under follow-up in the Infectious Disease outpatient clinic a survey of sociodemographic variables, and a Beck's Depression Inventory (BDI) was applied to the study subjects, whose results were analyzed using Rho Spearman (rs) and Chi Squared test (X2) with VL and CD4 levels. Results: 137 individuals were included, from 18-73 years, which 97 (70.8%) were male assigned at birth. The prevalence of depression reported, was 25.5%. A positive correlation was found between VL and BDI score, and a negative correlation between BDI score and CD4. In addition, correlation was found between VL, and depressive symptoms such as guilt, discouragement and self-image perception. These symptoms were strongly associated with death wishes, previous suicide attempts, and treatment non-dherence. Conclusion: VL may have implication in depression and its symptoms in this population, so their control is extremely important to prevent depressive episodes and suicidal behavior and prolong treatment adherence.

SerpinA1 levels in amyotrophic lateral sclerosis patients: An exploratory study.

SerpinA1, a serine protease inhibitor, is involved in the modulation of microglial-mediated inflammation in neurodegenerative diseases. We explored SerpinA1 levels in cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients to understand its potential role in the pathogenesis of the disease. SerpinA1, neurofilament light (NfL) and heavy (NfH) chain, and chitinase-3-like protein-1 (CHI3L1) were determined in CSF and serum of ALS patients (n = 110) and healthy controls (n = 10) (automated next-generation ELISA), and correlated with clinical parameters, after identifying three classes of progressors (fast, intermediate, slow). Biomarker levels were analyzed for diagnostic power and association with progression and survival. SerpinA1serum was significantly decreased in ALS (median: 1032 μg/mL) compared with controls (1343 μg/mL) (p = 0.02). SerpinA1CSF was elevated only in fast progressors (8.6 μg/mL) compared with slow (4.43 μg/mL, p = 0.01) and intermediate (4.42 μg/mL, p = 0.03) progressors. Moreover, SerpinA1CSF correlated with neurofilament and CHI3L1 levels in CSF. Contrarily to SerpinA1CSF , neurofilament and CHI3L1 concentrations in CSF correlated with measures of disease progression in ALS, while SerpinA1serum mildly related with time to generalization (rho = 0.20, p = 0.04). In multivariate analysis, the ratio between serum and CSF SerpinA1 (SerpinA1 ratio) and NfHCSF were independently associated with survival. Higher SerpinA1CSF levels are found in fast progressors, suggesting SerpinA1 is a component of the neuroinflammatory mechanisms acting upon fast-progressing forms of ALS. Both neurofilaments or CHI3L1CSF levels outperformed SerpinA1 at predicting disease progression rate in our cohort, and so the prognostic value of SerpinA1 alone as a measure remains inconclusive.

Nursing workforce competencies and job satisfaction: the role of technology integration, self-efficacy, social support, and prior experience

BackgroundThe nursing profession has significant importance in delivering high-quality healthcare services. Nursing practitioners who have essential competencies and who are satisfied with their job are vital in achieving optimum patient outcomes. Understanding the effects of technology integration on nurse workforce competencies and job satisfaction is crucial due to the fast progress of technology in healthcare settings. Furthermore, many elements, including self-efficacy, social support, and prior experience have been recognized as possible mediators or moderators within this association. The primary objective of this quantitative research was to examine the influence of nursing education and the integration of technology on the competencies and job satisfaction of nursing professionals. Additionally, this study aimed to explore the potential mediating and moderating effects of self-efficacy and social support in this relationship.MethodsThis cross-sectional, quantitative study employed an online survey questionnaire with standardized scales to measure nursing workforce competencies, job satisfaction, self-efficacy, social support, and prior experience. It was completed by 210 registered nurses from various healthcare settings in the Kingdom of Saudi Arabia. Data were analyzed by descriptive statistics, Pearson correlation analysis, multiple regression analysis, and structural equation modeling performed with SPSS 23 and SmartPLS 3.0 software.ResultsThe study’s findings revealed that nursing workforce competencies and job satisfaction were significantly predicted by nursing training and technology integration. The relationship between nursing training and technology integration, as well as nursing workforce competencies and job satisfaction, was partially mediated by self-efficacy and social support. Furthermore, prior experience moderated the relationship between nursing education and technological integration, nursing workforce competencies, and job satisfaction.ConclusionsThe study’s findings suggest that nursing training and technology integration can improve nursing workforce competencies and job satisfaction and that self-efficacy and social support play an important role in mediating this relationship. Furthermore, prior experience can have an impact on the efficacy of nursing training and technology integration programs for developing nursing workforce competencies. The study has several practical implications for nursing education, training, and professional development programs, as well as strategies used by healthcare organizations to improve nursing workforce competencies and job satisfaction. To maximize their impact on nursing workforce competencies and job satisfaction, this study recommends that nursing training and technology integration programs focus on enhancing self-efficacy and social support. Furthermore, the study emphasizes the significance of prior experience when designing and implementing nursing training and technology integration programs.

Kidney disease progression in pediatric and adult posterior urethral valves (PUV) patients.

Posterior urethral valves (PUV) is the most common cause of obstructive uropathy in boys; approximately 15% develop kidney failure by early adulthood. However, rates of kidney function decline are poorly defined in PUV children and adults, as is the impact of potentially modifiable chronic kidney disease (CKD) progression risk factors. We conducted a retrospective review of all PUV patients followed at our institution from 1995 to 2018. Inclusion criteria were estimated glomerular filtration rate (eGFR) > 20ml/min/1.73 m2 after 1year of age, no dialysis or kidney transplant history, and ≥ 2 yearly serum creatinine values after age 1year. eGFRs were calculated using creatinine-based estimating formulas for children (CKID U25) or adults (CKD-EPI). The primary outcome was annualized change in eGFR, assessed with linear mixed effects models. We also examined the association of acute kidney injury (AKI), proteinuria, hypertension (HTN), and recurrent febrile urinary tract infections (UTIs) with eGFR decline. Fifty-two PUV patients met the inclusion criteria. Median (interquartile range) eGFR decline was 2.6 (2.1, 3.1) ml/min/1.73 m2/year. Children (n = 35) and adults (n = 17) demonstrated progressive decline. Proteinuria and recurrent UTIs were significantly associated with faster progression; AKI and HTN were also associated but did not reach significance. PUV patients show progressive loss of kidney function well into adulthood. Proteinuria and recurrent UTIs are associated with faster progression, suggesting potential modifiable risk factors. This is the first study to report annualized eGFR decline rates in PUV patients, which could help inform the design of clinical trials of CKD therapies.

Serum Aldosterone in patients with Chronic Kidney Disease of uncertain etiology in Girandurukotte and Wilgamuwa, Sri Lanka

The Renin Angiotensin Aldosterone System (RAAS) is the main regulator of body fluid and electrolyte balance in the human body. Features of RAAS activation, such as hypertension and fluid retention, are not apparent in some categories of CKD-like tubular interstitial diseases. The beneficial effects of RAAS blockers are controversial if not activated. This study was conducted to identify the features of RAAS activation in CKDu and to evaluate the representativeness of Aldosterone as a marker of activation. A cross-sectional study was conducted on 119 definite CKDu patients at the renal clinics in Girandurukotte and Wilgamuwa, Sri Lanka. The basic biochemical parameters, serum electrolytes, and osmolality were measured by using serum and urine samples of the participants. Statistical analysis was performed in IBM SPSS statistics version 23. Only 4.4% and 6.7% of study subjects had increased serum Aldosterone and serum Angiotensin II. There was a significant positive correlation between serum Aldosterone with serum creatinine (r=0.477, p<0.01) and Angiotensin II (r=0.379, p<0.01). Inversely, it was negatively correlated with eGFR (r=-0.353, p<0.01). Moreover, serum aldosterone had a significant elevation in the late stages (p=0.024) than early stages and was significantly associated with proteinuria (p=0.032). Results showed no indications of activated RAAS in patients with the diagnosis of definite CKDu. A significant number of the population had hypernatremia which is positively correlated with hyperosmolality, indicating dehydration. The possibility of subclinical dehydration that may have an effect with faster progression.

EMG-Based Control of Active Ankle-Foot Prosthesis

Most below-knee prostheses are manufactured in Iraq without considering the fast progress in smart prostheses, which can offer movements in the desired directions according to the type of control system designed for this purpose. The proposed design appears to have the advantages of simplicity, affordability, better load distribution, suitability for subjects with transtibial amputation, and viability in countries with people having low socio-economic status. The designed prosthetics consisted of foot, ball, and socket joints, two stepper motors, a linkage system, and an EMG shield. All these materials were available in the local markets in Iraq. The experimental results showed that the maximum range of motion to move the designed prosthetic in the sagittal and frontal planes reached 70% of the healthy foot range of motion relative to the signals of the gastrocnemius muscle of a healthy leg person. The angles that represented the range of motion achieved in various directions at the ankle joint were Dorsiflexion Angle (35˚), Plantar Flexion Angle (25˚), Inversion Angle (20˚), and Eversion Angle (15˚).

GUILLAIN-BARRÉ SYNDROME

Guillain-Barré Syndrome (GBS) is an infection-preceded autoimmune disease attacking myelin sheath of neurons through molecular mimicry, causing neuron demyelination and conduction disruption. GBS is classified into four subtypes: Acute Inflammatory Demyelinating (AIDP), Acute Motor Axonal Neuropathy (AMAN), Acute Motor Sensory Axonal Neuropathy (AMSAN), and Miller Fisher Syndrome. It affects spinal radix which resulted in polyneuropathy, showing mainly symptoms of ascending paresis of the extremity and areflexia. Cerebrospinal fluid evaluation is essential to distinguish GBS from its vast differential diagnosis, with main finding of albuminocytologic dissociation. GBS needs to be managed as fast as possible with intravenous immunoglobulin administration or fresh frozen plasma exchange due to its fast progression.

Kidney Function and the Use of Vitamin K Antagonists or Direct Oral Anticoagulants in Atrial Fibrillation

Abstract Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a five-fold increase in the risk for ischemic stroke. Therefore, lifelong use of anticoagulants is crucial to reduce the morbidity and mortality burden of AF. The incidence of AF in chronic kidney disease (CKD) is two to three times greater than in the general population, and there is a mutual aggravation of the two conditions as well as the presence of both an increased thromboembolic risk in CKD and an increased bleeding risk in severe CKD. The preservation of kidney function in patients with cardiovascular diseases is important, as the latter is the leading cause of death in patients with eGFR <60 mL/min/1.73 m2. Similarly, kidney dysfunction is a serious limitation to the use of many cardiovascular drugs, including anticoagulants. Evidence is present for the faster progression of kidney disease with vitamin K antagonists, likely due to the vitamin K-related process of vascular calcification. Conversely, direct oral anticoagulants (DOACs) have been shown to reduce the progression of CKD and have a beneficial effect as far as the modulation of inflammation and oxidative stress are concerned in experimental models. Another less-discussed problem is the use of DOACs in advanced CKD.

Raman Spectroscopy of Formamidinium-Based Lead Mixed-Halide Perovskite Bulk Crystals.

In recent years, there has been an impressively fast technological progress in the development of highly efficient lead halide perovskite solar cells. Nonetheless, the stability of perovskite films and associated solar cells remains a source of uncertainty and necessitates sophisticated characterization techniques. Here, we report low- to mid-frequency resonant Raman spectra of formamidinium-based lead mixed-halide perovskites. The assignment of the different Raman lines in the measured spectra is assisted by DFT simulations of the Raman spectra of suitable periodic model systems. An important result of this work is that both experiment and theory point to an increase of the stability of the perovskite structure with increasing chloride doping concentration. In the Raman spectra, this is reflected by the appearance of new lines due to the formation of hydrogen bonds. Thus, higher chloride doping results in less torsional motion and lower asymmetric bending contributing to higher stability. This study yields a solid basis for the interpretation of the Raman spectra of formamidinium-based mixed-halide perovskites, furthering the understanding of the properties of these materials, which is essential for their full exploitation in solar cells.

Proteomics and mathematical modeling of longitudinal CSF differentiates fast versus slow ALS progression.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a complex etiology that lacks biomarkers predicting disease progression. The objective of this study was to use longitudinal cerebrospinal fluid (CSF) samples to identify biomarkers that distinguish fast progression (FP) from slow progression (SP) and assess their temporal response. We utilized mass spectrometry (MS)-based proteomics to identify candidate biomarkers using longitudinal CSF from a discovery cohort of SP and FP ALS patients. Immunoassays were used to quantify and validate levels of the top biomarkers. A state-transition mathematical model was created using the longitudinal MS data that also predicted FP versus SP. We identified a total of 1148 proteins in the CSF of all ALS patients. Pathway analysis determined enrichment of pathways related to complement and coagulation cascades in FPs and synaptogenesis and glucose metabolism in SPs. Longitudinal analysis revealed a panel of 59 candidate markers that could segregate FP and SP ALS. Based on multivariate analysis, we identified three biomarkers (F12, RBP4, and SERPINA4) as top candidates that segregate ALS based on rate of disease progression. These proteins were validated in the discovery and a separate validation cohort. Our state-transition model determined that the overall variance of the proteome over time was predictive of the disease progression rate. We identified pathways and protein biomarkers that distinguish rate of ALS disease progression. A mathematical model of the CSF proteome determined that the change in entropy of the proteome over time was predictive of FP versus SP.

Wheat Genotype Evaluation for Spot Blotch Disease Resistance: Unveiling Resilient Varieties

Spot blotch, caused by Bipolaris sorokiniana (Sacc.) Shoemaker is a major disease of wheat (Triticum aestivum L.), in all the six agro climatic zones of India. Estimation of losses due to this disease vary from location to location, due to diverse environmental conditions. The use of resistant cultivars is the most effective, long-lasting, cost-effective, and environmentally friendly technique for sustainable disease control. The experiment was conducted at Crop Research Centre, Chirodi farm of Sardar Vallabhbhai Patel University of Agriculture and Technology, Meerut (U.P.). Among the tested varieties, disease index and AUDPC values varied significantly for both years’ data viz. 2021-22 and 2022-23. In this experiment 32 wheat varieties were screened against B. sorokiniana under artificial epiphytotic conditions in the field. Each variety were sown in two row of three-meter length with three replications, two line of susceptible check RAJ 4015 was sown at every ten genotypes of interval. Among 32 wheat varieties, two varieties were found to be resistant, eleven varieties were found moderately resistant, fourteen varieties were found moderately susceptible and five varieties were found susceptible, none of the variety was found immune and highly susceptible against spot blotch disease. Area Under Disease Progress Curve (AUDPC) calculated for the thirty- two wheat varieties on the basis of disease index. AUDPC varies from 212.90 to 1143.9 and 198.80 to 1144.90 during the 2021-22 and 2022-23 years’ data. The pooled mean, Area Under Disease Progress Curve varied from 205.85 to 1144.40, showing the fast progress of disease in all genotypes. It was observed that different wheat varieties expressed varied type of disease response against B. sorokiniana.

Echocardiographic Progression of Peak Tricuspid Regurgitant Velocity Among Medicare Beneficiaries

BackgroundPeak tricuspid regurgitant velocity (TRV) on transthoracic echocardiography (TTE) is a commonly obtained parameter and robust predictor of subsequent adverse clinical outcomes. ObjectivesThe purpose of this study was to determine the predictors and clinical significance of TRV progression. MethodsWe retrospectively linked consecutive outpatient TTE reports from our institution to 2005 to 2017 Medicare claims. Individuals with prior tricuspid surgery, endocarditis, tricuspid stenosis, missing TRV values, TTEs performed during inpatient hospitalization, or <2 TTEs were excluded. ResultsA total of 4,572 patients (mean age 67.8 ± 11.9 years, 50.4% female) received 13,273 TTEs over a median follow-up of 7.4 (IQR: 4.5-6.9) years. TRV increased by a mean of 0.23 (95% CI: 0.22 to 0.23 m/s/y, P < 0.001) (range, 0.01-0.80 m/s/y). Older age, depressed left ventricular ejection fraction, diabetes, hypertension, hyperlipidemia, atrial fibrillation, heart failure, and chronic kidney disease were associated with faster progression (all P < 0.05). Accounting for 23 demographic, clinical, and TTE variables, faster TRV progression was associated with a stepwise increased risk of all-cause mortality (TRV progression quartile 4 vs 1; adjusted HR: 2.17; 95% CI: 1.74-2.71; P < 0.001). Those with regression of TRV (n = 384 [8.4%]) had a lower mortality risk (adjusted HR: 0.40; 95% CI: 0.28-0.57; P < 0.001). ConclusionsIn this large, multidecade study of Medicare beneficiaries with serial TTEs performed in the outpatient setting, the mean rate of TRV progression was 0.23 m/s/y. Older age, left heart disease, and adverse metabolic features were associated with faster progression. Faster progression was associated with a graded risk for all-cause mortality.

Altered sleep and neurovascular dysfunction in alpha-synucleinopathies: the perfect storm for glymphatic failure.

Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson's disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-β would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies.

Differences in Factors Associated With Glaucoma Progression With Lower Normal Intraocular Pressure in Superior and Inferior Halves of the Optic Nerve Head.

The purpose of this study was to investigate risk factors for progression in the superior and inferior hemi-visual fields (hemi-VFs) and the corresponding hemi-disc/retinas in eyes with normal tension glaucoma (NTG). A 5-year prospective follow-up of 90 patients with NTG with untreated intraocular pressure (IOP) consistently ≤ 15 mm Hg was conducted. The IOP and Humphrey Perimeter measurements and disc/retina stereo-photographs were taken every 3 and 6 months, respectively. Risk factors for progression in the superior and inferior hemi-VFs and in the superior and inferior hemi-disc/retinas were investigated. The mean total deviation values decreased at -0.50 ± 0.76 and -0.13 ± 0.34 dB/year in the superior and inferior hemi-VFs, respectively (P < 0.001). In the superior hemi-VF, the risk factor for faster progression was greater long-term IOP fluctuation (P = 0.022). In the inferior hemi-VF, the risk factors were disc hemorrhage (DH), greater myopic refraction, body mass index (BMI), and vertical cup-to-disc ratio (v-C/D; P < 0.05). The progression probability was 47.7 ± 6.0 and 17.7 ± 4.7% at 5 years in the superior and inferior hemi-disc/retinas respectively (P < 0.001), and DH was a risk factor for progression in both (P = 0.001). In NTG eyes, greater BMI, myopia, and v-C/D are characteristic risk factors for faster progression in the superior half of the optic nerve head (ONH), whereas long-term IOP fluctuation is the significant risk factor in the inferior half of the ONH, whereas DH is a risk factor in both. Different risk factors were identified in superior and inferior hemifields in NTG eyes.

Urine Peptidome Analysis Identifies Common and Stage-Specific Markers in Early Versus Advanced CKD.

Given the pathophysiological continuum of chronic kidney disease (CKD), different molecular determinants affecting progression may be associated with distinct disease phases; thus, identification of these players are crucial for guiding therapeutic decisions, ideally in a non-invasive, repeatable setting. Analyzing the urinary peptidome has been proven an efficient method for biomarker determination in CKD, among other diseases. In this work, after applying several selection criteria, urine samples from 317 early (stage 2) and advanced (stage 3b-5) CKD patients were analyzed using capillary electrophoresis coupled to mass spectrometry (CE-MS). The entire two groups were initially compared to highlight the respective pathophysiology between initial and late disease phases. Subsequently, slow and fast progressors were compared within each group in an attempt to distinguish phase-specific disease progression molecules. The early vs. late-stage CKD comparison revealed 929 significantly different peptides, most of which were downregulated and 268 with collagen origins. When comparing slow vs. fast progressors in early stage CKD, 42 peptides were significantly altered, 30 of which were collagen peptide fragments. This association suggests the development of structural changes may be reversible at an early stage. The study confirms previous findings, based on its multivariable-matched progression groups derived from a large initial cohort. However, only four peptide fragments differed between slow vs. fast progressors in late-stage CKD, indicating different pathogenic processes occur in fast and slow progressors in different stages of CKD. The defined peptides associated with CKD progression at early stage might potentially constitute a non-invasive approach to improve patient management by guiding (personalized) intervention.