Chronic Impairment Research Articles

Association of physical activity intensity with cardiovascular disease and mortality in high-income, middle-income and low-income countries: the PURE study

Abstract Background The WHO recommends adults get 150-300 minutes of moderate physical activity (MPA) and/or 75-150 minutes of vigorous physical activity (VPA) per week. Few studies have investigated the independent benefits of PA intensity. Those that have, have found VPA to be protective, while others found excessive VPA to be harmful. These studies have primarily been conducted in high-income countries using recreational PA as the exposure of interest. Purpose To evaluate the effects of activity intensity (walking, MPA and VPA) with all-cause mortality, and cardiovascular disease (CVD) in countries at different economic levels. Methods Participants (35-70 years) were recruited from 21 countries at various stages of economic development. Within each country, urban and rural areas in and around selected cities and towns were identified to reflect the geographical diversity. Physical activity (total, walking, MPA, VPA, as well as recreational vs. non-recreational PA) was assessed using the International Physical Activity Questionnaire. Primary outcomes were mortality plus major CVD (CVD mortality, myocardial infarction, stroke, or heart failure), either as a composite or separately. After excluding those with baseline CVD, cancer and HIV, a total of 136,766 participants who had complete data were analyzed. Models were adjusted for age, sex, urban or rural residency, country income level, education, household wealth index, smoking, baseline chronic diseases, physical impairments and center as a random effect. All models were mutually adjusted for PA intensity. Results During the median follow-up of 11.5 (8.6-12.4) years, there were 9846 deaths and 7900 major cardiovascular events. The mean min/wk for walking, MPA and VPA were 339±539, 640±825 and 103±390, respectively. Increasing walking time had a U-shaped relationship with the composite outcome, such that walking between 300-1200 min/wk had the lowest risk, whereas walking at this amount and ≥1200 min/wk was associated with the lowest risk for mortality (p<0.001 for trend). Both MPA and VPA were linearly associated with the composite outcome and mortality even at levels below the recommended guidelines and up to ≥1800 min/wk (p<0.001 for trend). At each PA category, the hazard ratio for VPA was lower than MPA, such that at ≥1800 min/wk it was 0.64 (0.50,0.81) and 0.70 (0.57,0.85), for VPA and MPA, respectively, for the composite outcome. When VPA was stratified into either recreational or non-recreational VPA, recreational VPA displayed a U-shape relationship, whereas increasing non-recreational VPA continued to confer reduced risk even ≥3000 min/wk (Figure). Conclusion For both MPA and VPA, the benefits began at very low levels of PA and continued to increase with increasing PA. At each amount of PA, the lowest risk was in those participating in VPA. We did not observe any harmful effects of VPA, even at extremely high levels. However, at higher recreational VPA, the benefits began to diminish.

Abstract 15439: Association of Vigorous Physical Activity With Cardiovascular Disease and Mortality in 136,766 Adults From High-Income, Middle-Income and Low-Income Countries: The Prospective Urban Rural Epidemiological (PURE) Study

Background: It’s recommended adults get 150-300 minutes of moderate physical activity (MPA) and/or 75-150 minutes of vigorous physical activity (VPA) per week. Some studies have found high VPA to be protective and others found it to be harmful. These studies have been conducted in high-income countries using recreational VPA as the exposure of interest. Purpose: To evaluate the effects of VPA with all-cause mortality, and cardiovascular disease (CVD) in countries at different economic levels. Methods: Participants aged 35-70 years were recruited from 21 countries at various stages of economic development. Physical activity (total, walking, MPA, VPA, as well as recreational vs. non-recreational PA) was assessed using the International Physical Activity Questionnaire. Primary clinical outcomes were the composite of mortality plus major CVD (CVD mortality, myocardial infarction, stroke, or heart failure) and mortality. A total of 136,766 participants without baseline CVD, cancer, and HIV were analyzed. Models were adjusted for age, sex, urban/rural residency, country income level, education, household wealth index, smoking, baseline chronic diseases, physical impairments, MPA, walking and centre as a random effect. Results: During the median follow-up of 11.5 (8.6-12.4) years, there were 9846 deaths and 7900 major CVD events. The median min/wk (IQR) for total PA, walking, MPA and VPA were 690 (250-1530), 40 (0-420), 330 (75-860), 0 (0-0). The mean VPA was 103±390 min/wk. Compared to no VPA, 150-299 minutes per week of VPA was associated with reduced risk for the composite outcome and mortality, HR = 0.82 (0.73,0.92) and 0.74 (0.64,0.86), respectively. When VPA was stratified into either recreational or non-recreational VPA, recreational VPA displayed a U-shape relationship, such that higher levels were associated with less benefit. Increasing non-recreational VPA continued to confer reduced risk even above 3000 min/wk. At any amount of moderate PA, higher VPA was associated with reduced risk for the composite outcome and mortality. Conclusion: Higher levels of VPA were associated with reduced risk for mortality and major CVD events up to more than 40 times the minimum recommended amount. At no point did VPA confer an increased risk.

Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.

Cellular senescence is closely linked to endothelial dysfunction, a key factor in age-related vascular diseases. Senescent endothelial cells exhibit a proinflammatory phenotype known as SASP, leading to chronic inflammation (inflammaging) and vascular impairments. Albeit in a state of permanent growth arrest, senescent cells paradoxically display a high metabolic activity. The relationship between metabolism and inflammation is complex and varies across cell types and senescence inductions. While some cell types shift towards glycolysis during senescence, others favor oxidative phosphorylation (OXPHOS). Despite the high availability of oxygen, quiescent endothelial cells (ECs) tend to rely on glycolysis for their bioenergetic needs. However, there are limited data on the metabolic behavior of senescent ECs. Here, we characterized the metabolic profiles of young and senescent human umbilical vein endothelial cells (HUVECs) to establish a possible link between the metabolic status and the proinflammatory phenotype of senescent ECs. Senescent ECs internalize a smaller amount of glucose, have a lower glycolytic rate, and produce/release less lactate than younger cells. On the other hand, an increased fatty acid oxidation activity was observed in senescent HUVECs, together with a greater intracellular content of ATP. Interestingly, blockade of glycolysis with 2-deoxy-D-glucose in young cells resulted in enhanced production of proinflammatory cytokines, while the inhibition of carnitine palmitoyltransferase 1 (CPT1), a key rate-limiting enzyme of fatty acid oxidation, ameliorated the SASP in senescent ECs. In summary, metabolic changes in senescent ECs are complex, and this research seeks to uncover potential strategies for modulating these metabolic pathways to influence the SASP.

Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

Single-cell transcriptomics of human traumatic brain injury reveals activation of endogenous retroviruses in oligodendroglia

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked invitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.

A Review of the Potential of Nuclear Factor [Erythroid-Derived 2]-like 2 Activation in Autoimmune Diseases.

An autoimmune disease is the consequence of the immune system attacking healthy cells, tissues, and organs by mistake instead of protecting them. Inflammation and oxidative stress (OS) are well-recognized processes occurring in association with acute or chronic impairment of cell homeostasis. The transcription factor Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is of major importance as the defense instrument against OS and alters anti-inflammatory activities related to different pathological states. Researchers have described Nrf2 as a significant regulator of innate immunity. Growing indications suggest that the Nrf2 signaling pathway is deregulated in numerous diseases, including autoimmune disorders. The advantageous outcome of the pharmacological activation of Nrf2 is an essential part of Nrf2-based chemoprevention and intervention in other chronic illnesses, such as neurodegeneration, cardiovascular disease, autoimmune diseases, and chronic kidney and liver disease. Nevertheless, a growing number of investigations have indicated that Nrf2 is already elevated in specific cancer and disease steps, suggesting that the pharmacological agents developed to mitigate the potentially destructive or transformative results associated with the protracted activation of Nrf2 should also be evaluated. The activators of Nrf2 have revealed an improvement in the progress of OS-associated diseases, resulting in immunoregulatory and anti-inflammatory activities; by contrast, the depletion of Nrf2 worsens disease progression. These data strengthen the growing attention to the biological properties of Nrf2 and its possible healing power on diseases. The evidence supporting a correlation between Nrf2 signaling and the most common autoimmune diseases is reviewed here. We focus on the aspects related to the possible effect of Nrf2 activation in ameliorating pathologic conditions based on the role of this regulator of antioxidant genes in the control of inflammation and OS, which are processes related to the progression of autoimmune diseases. Finally, the possibility of Nrf2 activation as a new drug development strategy to target pathogenesis is proposed.

The environmental enrichment ameliorates chronic cerebral hypoperfusion-induced cognitive impairment by activating autophagy signaling pathway and improving synaptic function in hippocampus

BackgroundChronic cerebral hypoperfusion (CCH) is a frequently observed underlying pathology of both Alzheimer's disease (AD) and vascular dementia (VD), which is a common consequence of cerebral blood flow (CBF) dysregulation. Synaptic damage has been proven as a crucial causative factor for CCH-related cognitive impairment. This study aimed to investigate the neuroprotective impact of environmental enrichment (EE) intervention on CCH-induced synaptic destruction and the consequent cognitive impairment. Furthermore, the underlying mechanism of this neuroprotective effect was explored to provide new insights into therapeutic interventions for individuals suffering from AD or VD. MethodsIn this experiment, all rats were initially acclimatized to a standard environment (SE) for a period of one week. On the seventh day, rats underwent either bilateral common carotid artery occlusion (2VO) surgery or sham surgery (Sham) before being subjected to a four-week procedure of exposure to an EE, except for the control group. During the EE or SE procedure, intraperitoneal injection of chloroquine (CQ) into rats was performed once daily for four weeks. Following this, cognitive function was assessed using the Morris water maze (MWM) test. The synapse ultrastructure was subsequently observed using transmission electron microscopy. Expression levels of autophagy-related proteins (LC3, LAMP1, and P62) and synapse-related proteins (Synapsin I and PSD-95) were detected through Western blotting. Finally, immunofluorescence was used to examine the expression levels of Synapsin I and PSD-95 and the colocalization of LAMP-1 and LC3 in the hippocampus. ResultsAfter undergoing 2VO, rats exposed to SE exhibited cognitive impairment, autophagic dysfunction, and synapse damage. The synapse damage was evidenced by ultrastructural damage and degradation of synapse-related proteins. However, these effects were significantly mitigated by exposure to an EE intervention. Moreover, the intervention led to an improvement in autophagic dysfunction. ConclusionThe study found that EE had a positive impact on CCH-induced synaptic damage. Specifically, EE was found to increase synaptic plasticity-associated proteins and postsynaptic density thickness, while decreasing synaptic space. This multifaceted effect resulted in an amelioration of CCH-induced cognitive impairment. It was shown that this beneficial outcome was mediated via the activation of the autophagy-lysosomal pathway. Overall, the findings suggest that EE may have a therapeutic potential for cognitive impairments associated with CCH through autophagy-mediated synaptic improvement.

The elderly health profile and health services access during 2020-2021: results from Passi d’Argento

Abstract Background The COVID-19 pandemic has affected the community in multiple health, economic, social and cultural aspects and the impact was stronger among the over-65s. PASSI d'Argento (PdA) surveillance system monitors the effects on physical activity, partecipation in social life and healthcare renunciation due to fear of Covid contagion or services interruption. Methods Since 2016, PdA has been continuously collecting information on health, behavioural risk factors, quality of life and the care and assistance needs of eldely people. Data is collected through an anonymous and standardised questionnaire. Physical activity is assessed with the Physical Activity Scale for Elderly, an internationally validated instrument that considers all types of activities commonly performed by elderly. High PASE values correspond to high levels of physical activity. Results The percentage of physically active elderly decreased significantly during the pandemic, from 39% (CI95% 38.3-39.8) in 2016-2019 to 35% (CI95% 33.7-36.4) in 2020-2021. The decline is greater among people with economic difficulties (44.4% to 37.5), women (from 36.7% to 33.5%), among those with chronic deseases (from 37% to 31%) or sensory impairment (from 31.3% to 27.5%). Participation in social life declines significantly from 23.1% (95% CI 22.5.1-23.8) in the pre-covid period to 142 (95% CI 13.2-15.1) in 2020-2021. The pandemic develops in a context where inequalities in prevention and care already exist; 32% of elderly declared difficulties in accessing health services in 2016-2019. During pandemic period 28% of the over-65s gave up at least one medical or diagnostic examination with a risk of delayed in diagnosis and treatment. Conclusions PdA shows the importance of monitoring the strong impact of emergency on several aspects of elderly population to riorganize the local health system organization, implement targeted interventions and improve the health services’ offers to reduce inequalities. Key messages • Riorganize the local health system is crucial to improve targeted interventions and reduce inequalities in care and prevention for elderly population. • Early diagnosis and adequate therapy are crucial in old age.

GDF11 mediates H2S to prevent chronic stress-induced cognitive impairment by reducing hippocampal NLRP3/caspase-1-dependent pyroptosis

BackgroundWe previously revealed that hydrogen sulfide (H2S) attenuates chronic stress-induced cognitive impairment, but the underlying mechanism needs to be further clarified. Growth differentiation factor 11 (GDF11) plays an important regulatory role in cognitive function and that hippocampal NLRP3/caspase-1-mediated pyroptosis contributes to the pathogenesis of cognitive impairment. Hence, this research aimed to explore whether promoting GDF11 levels and suppressing hippocampal NLRP3/caspase-1-mediated pyroptosis mediate H2S to alleviate chronic stress-induced cognitive impairment. MethodsSprague–Dawley rats were subjected to unpredictable chronic mild stress lasting four weeks to establish an animal model of chronic stress-induced cognitive impairment. Behavioral performance was assessed by the Y-maze test and the novel object recognition test. The expression levels of proteins were analyzed by Western blot analysis. The levels of IL-1β and IL-18 in the hippocampus were measured by ELISA. ResultsNaHS upregulated the expression of GDF11 in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed rats. Silencing GDF11 blocked NaHS-improved cognitive impairment in CUMS-exposed rats, according to the Y-maze test and the novel object recognition test. Furthermore, NaHS mitigated NLRP3/caspase-1-mediated pyroptosis in the hippocampus of CUMS-exposed rats and this effect was reversed by silencing GDF11. Moreover, overexpression of GDF11 alleviated CUMS-induced cognitive impairment and NLRP3/caspase-1-mediated hippocampal pyroptosis. ConclusionsGDF11 mediates H2S to attenuate chronic stress-induced cognitive impairment via inhibiting hippocampal NLRP3/caspase-1-mediated pyroptosis.

Association Between Poor Sleep and Myocardial Infarction in Patients with Psoriasis: Findings from a Cross-Sectional Study with the National Psoriasis Foundation.

Poor sleep quality occurs in patients with psoriasis at rates nearly twice that of the general population. Chronic sleep impairment is an independent risk factor for the development of cardiovascular disease. Here, we examine the association between sleep quantity and history of myocardial infarction in patients with psoriasis. This observational, cross-sectional study utilized data from the 2020 National Psoriasis Foundation Annual Survey. Effect estimates were obtained using a multivariate logistic regression model, which controlled for prespecified covariates. Based on data from 1405 individuals with psoriasis, our analysis demonstrated a significant association between sleep quantity and history of myocardial infarction: odds ratio (OR) 0.67 [95% confidence interval (CI) 0.49-0.92], p = 0.012. The association was not significantlyinfluencedby psoriasis severity(OR 1.01, [95% CI 0.99-1.03], p = 0.38), comorbid psoriatic arthritis(OR 1.06, [95% CI 0.48-2.38], p = 0.88), sleep apnea, or other traditional risk factors for myocardial infarction. Our analyses indicate an association between sleep quantity and history of myocardial infarction in patients with psoriasis. For each hour increase in average nightly sleep, patients with psoriasis have a 33% decrease in the odds of having a history of myocardial infarction. The chief limitation of this study is its cross-sectional design limiting ascertainment of causality.

Remission of severe forms of long COVID following monoclonal antibody (MCA) infusions: A report of signal index cases and call for targeted research

ObjectiveLong COVID has afflicted tens of millions globally leaving many previously-healthy persons severely and indefinitely debilitated. The objective here was to report cases of complete, rapid remission of severe forms of long COVID following certain monoclonal antibody (MCA) infusions and review the corresponding pathophysiological implications. DesignCase histories of the first three index events (among others) are presented. Unaware of others with similar remissions, each subject independently completed personal narratives and standardized surveys regarding demographics/occupation, past history, and the presence and respective severity grading of 33 signs/symptoms associated with long COVID, comparing the presence/severity of those symptoms during the pre-COVID, long-COVID, post-vaccination, and post-MCA phases. SettingPatient interviews, e-mails and telephone conversations. SubjectsThree previously healthy, middle-aged, highly-functioning persons, two women and one man (ages 60, 43, and 63 years respectively) who, post-acute COVID-19 infection, developed chronic, unrelenting fatigue and cognitive impairment along with other severe, disabling symptoms. Each then independently reported incidental and unanticipated complete remissions within days of MCA treatment. InterventionsThe casirivimab/imdevimab cocktail. Measurements and main resultsIrrespective of sex, age, medical history, vaccination status, or illness duration (18, 8 and 5 months, respectively), each subject experienced the same complete remission of their persistent disabling disease within a week of MCA infusion. Each rapidly returned to normal health and previous lifestyles/occupations with normalized exercise tolerance, still sustained to date over two years later. ConclusionsThese index cases provide compelling clinical signals that MCA infusions may be capable of treating long COVID in certain cases, including those with severe debilitation. While the complete and sustained remissions observed here may only apply to long COVID resulting from pre-Delta variants and the specific MCA infused, the striking rapid and complete remissions observed in these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions and long COVID from other variants. Key points•Question: Considering that long COVID-19 has been devastating for many millions worldwide, what is the proposed pathophysiology and are there any effective treatments?•Findings: Previously-healthy middle-aged persons who had developed persistent debilitating post-acute SARS-CoV-2 sequelae, each experienced complete remission of their symptoms within days of receiving a specific monoclonal antibody infusion despite relative differences in sex, age, medical history, vaccination status, and long COVID duration.•Meaning: Certain monoclonal antibody infusions may be capable of reversing severe long COVID. Beyond providing an effective potential treatment for long COVID, these findings have mechanistic implications for treating other post-viral chronic conditions, including future long COVID variants.

Comparing the association between heavy metals and cognitive status and depression in miners and non-miners: A study from southeast of Iran

Heavy metal toxicity is a major public health crisis worldwide, especially in mining environments. The association between chronic heavy metals exposure and cognitive impairment has not been studied broadly in adults and mining fields. This study aimed to compare the association between arsenic (As), lead (Pb), and copper (Cu) concentration in blood and cognitive status and depression in copper miners and non-miners. Participants were selected from the Rafsanjan cohort study (RCS) as non-miners and miners from Sarcheshmeh Copper Complex. For evaluation of cognitive performance and creativity, comprehensive neurological tests were performed as follows: Mini-Mental Status Examination (MMSE), Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Psychomotor Vigilance Task (PVT), creativity tests including remote association task (RAT) and alternative uses task (AUT). Beck Depression Inventory-II was used to evaluate depression. Standard laboratory tests were also performed. Atomic absorption spectrophotometry was used to estimate the blood's concentration of As, Pb and Cu. We observed a significant difference between arsenic, lead, copper, and depression scores (all P < 0.001) in the two groups (miners and non-miners). Miners had a better performance in cognitive fields except in MMSE and PVT tests. Linear regression analyses showed that the lead had a negative association with the PVT test and depression score. The results suggest that the development of depression, cognitive impairments, and other health problems is possible in chronic heavy metal exposure, especially lead (Pb). Confirmation of our claim requires further study in the coming years.

Role of MRI to Determine Impact on Contralateral ACL/Meniscal Damage Secondary to Unilateral Traumatic Knee Injury in Adults

Background: Knee injuries are one of the most common sports injuries and may cause chronic functional impairment. During a study in emergency department approximately 50% of injuries are caused by sports activities, with majority of the cases comprising of knee soft tissue injuries. The most common modality to diagnose musculoskeletal injury is magnetic resonance imaging nowadays. Knee injuries are one of the most frequently overlooked injuries and cause long term functional impairment. MRI provides the most effective and comprehensive imaging assessment of the knee joint and adjacent structures. Objective: To determine the significance of Magnetic resonance imaging (MRI) of contralateral uninjured knee in suspected meniscal/ACL injury of traumatic patients. Study Design: Prospective study. Settings: Radiology Department of Jinnah Postgraduate Medical Center (JPMC), Karachi Pakistan. Duration: January 2018 to December 2021. Methods: Patients aged 18 years or older who presented with a unilateral traumatic knee injury requiring medical evaluation and treatment and who underwent MRI evaluations for both the injured knee (ipsilateral) and the contralateral knee (opposite side) as part of their medical assessment were included. After taking informed consent, all patients underwent magnetic resonance imaging (MRI) examinations of both their affected (ipsilateral) and non-affected (contralateral) knee joints. These MRI findings were subjected to rigorous statistical analysis, which included comparisons between the affected and non-affected knees. Self-made proforma was used for the data collection. Results: According to our inclusion criteria, we identified 45 patients to participate in the study. Amongst these 82% of the patients were male and 17% were females, ratio between the male and female is 4.6:1. Mean age of the participants was found to be 38.64±14.4 years. Upon analysis, 62.2% of the patients had meniscal injury associated with ACL/PCL damage. While MRI findings were compared with contralateral normal side and found meniscal injury in 17(37.8%) cases, followed ACL/PCL injury 7(15.6%) and ACL/PCL injury associated meniscal injury ± effusion 7(15.6%) was (p = 0.004). Conclusion: MRI has proven to be a valuable imaging modality for identifying ligament tears and meniscal injuries of the knee joint in patients suspected of having meniscal/ACL injuries due to trauma. It not only assists in diagnosis but also provides valuable insights into the complexity of knee trauma.

Apathy Symptoms, Physical and Cognitive Function, Health-Related Quality of Life, and Mortality in Older Patients With CKD: A Longitudinal Observational Study

Apathy reflects diminished motivation, goal-directed behavior, and emotions, as well as less engagement in social interactions. Apathy overlaps with depression and is associated with cognitive decline. In the older individuals with chronic kidney disease (CKD), both depression and cognitive impairments are common, but apathy symptoms have been underreported. We investigated the occurrence of apathy symptoms and their associations with physical and cognitive functioning, health-related quality of life (HRQoL), and mortality in older patients with CKD. Prospective observational cohort study. 180 outpatients aged≥65 years with estimated glomerular filtration rate≤20mL/min/1.73m2 from 5 Dutch nephrology centers. Apathy symptoms at baseline were considered present when a Geriatric Depression Scale's 3-item apathy subscale score was≥2 points. Physical and cognitive functioning, HRQoL (assessed in annual geriatric assessments), and 4-year mortality. Linear regression for cross-sectional associations, linear regression models for longitudinal associations, and Cox regression models for mortality over 4 years of observation. Apathy symptoms were present in 64 patients (36%; 67% men; median age 75.5 years), of whom 32 (50%) had no depressive symptoms. At baseline, the presence of apathy symptoms was associated with significantly more frailty, more functional dependence, less physical capacity, lower visuoconstructive performance, worse delayed recall, and lower HRQoL scores. The presence of apathy symptoms at baseline was also associated with a higher mortality risk (hazard ratio, 2.3 [95% CI, 1.3-4.2], P=0.005 adjusted for age, sex, and high education level), but not with changes in physical and cognitive functioning or HRQoL during the follow-up period. Risk of selection bias and residual confounding. Apathy symptoms were highly prevalent and associated with concurrent lower physical and cognitive status, lower HRQoL, and increased mortality. These findings highlight apathy as a potentially important clinical phenotype in older CKD patients. We observed that older kidney patients often present apathy symptoms, such as less motivation, fewer goal-directed behaviors, fewer emotions, and less social engagement. Prior research has not extensively described apathy in kidney disease. We investigated the link between apathy symptoms and poor outcomes. We measured physical functioning, cognitive functioning, and quality of life. We learned that one-third of our older kidney patients showed symptoms of apathy, only half of whom had symptoms of depression. Patients with apathy symptoms showed lower quality of life and lower physical and cognitive performance. They also had a higher risk of death. These findings highlight the need for awareness of apathy symptoms in older kidney patients.

Algorithm for the classification of phases and stages of sleep in patients with chronic disorders of consciousness based on logical artificial intelligence

BACKGROUND: The analysis of sleep patterns in patients with chronic disorders of consciousness is attracting increasing attention in terms of diagnosis, prognosis, and treatment of severe brain damage. The study describes a software package based on an artificial intelligence (AI) expert system designed to classify the phases and stages of sleep, taking into account the characteristics of impaired cortical rhythm in such patients.&#x0D; AIM: To develop a specialized AI-based software package focused on patients with chronic impairment of consciousness for automatic classification of sleep phases and stages, with an emphasis on identifying sleep spindles and non-rapid eye movement (REM) and REM sleep phases.&#x0D; MATERIALS AND METHODS: To ensure the correct operation of the software package, receiver operating characteristic (ROC) curves were analyzed considering the binary classification of slow sleep, REM sleep, and wakefulness.&#x0D; RESULTS: The average sensitivity and specificity of the algorithm were 87.9 and 70.1, respectively. The average area under the ROC curve was 0.790. The algorithm for determining the REM phase demonstrates low specificity with high sensitivity, and its graph was similar to that of wakefulness, as well as the irregularity of the presence of REMs in the REM sleep phase in patients with CNS and the frequent presence of nystagmus in the waking state. Information about the presence of nystagmus, entered at the start of the program, allowed us to slightly increase the efficiency of the algorithm; however, this aspect probably needs further improvement.&#x0D; CONCLUSION: A software package that takes into account the features of electroencephalography of patients with chronic disorders of consciousness and analyzes sleep and wakefulness automatically is not only useful as a diagnostic tool for neurologists and somnologists but also contributes to a wider dissemination of this technique in clinical practice.

Effects of a Standardized DBT-A Program on Identity Development in Adolescents.

Identity diffusion plays a central role in the onset of borderline personality disorders. Dialectical Behavioral Therapy for Adolescents (DBT-A) is a treatment program for adolescents with emotional instability and dysregulation. The interest of this study is to examine the potential effects of a standardized and certified DBT-A therapy program on the identity development of adolescents in an inpatient setting. A total of 138 adolescents aged 13 to 18 years with symptoms of severe emotional instability were assessed before and after a certified and standardized 12-week in-patient DBT-A program targeting emotional regulation with the following standardized instruments: the Assessment of Identity Development in Adolescence (AIDA), Scale of the Experience of Emotions (SEE), and Symptom Checklist (SCL-90-R). The results indicate a significant change in identity development, emotion regulation, and general symptoms of psychopathology after treatment with DBT-A. In this large sample of adolescents, DBT-A significantly improved identity development and reduced identity diffusion, however, without a treatment-as-usual control group as a limitation. Nevertheless, our results may become clinically relevant for the prevention of chronic impairment in emotionally unstable adolescents.

Hypothetical framework for post-COVID 19 condition based on a fibromyalgia pathogenetic model.

There is a clear clinical overlap between fibromyalgia, myalgic encephalomyelitis, and post-COVID 19 condition. Chronic fatigue, cognitive impairment, and widespread pain characterize these 3 syndromes. A steady line of investigation posits fibromyalgia as stress-evoked sympathetically maintained neuropathic pain syndrome and places dorsal root ganglia dysregulation with the ensuing small fiber neuropathy at the epicenter of fibromyalgia pathogenesis. This article discusses emerging evidence suggesting that similar mechanism may operate in post-COVID 19 condition.

Synthesis, in silico, and evaluation of AChE inhibitory activity of N-phthaloylphenylglycine derivatives as potential anti-Alzheimer’s agents

Mental illnesses are one of the most relevant health problems today, among which Alzheimer’s disease (AD) stands out. This is a severe disease that entails different alterations such as chronic cognitive impairment. Commercial therapy drugs have not had the expected success due to their notable and rapid pharmacological efficacy reduction, therefore, we aimed to find new compounds capable of stopping the progression of this disease by cholinesterase inhibition. We synthesized and evaluated nine new racemic compounds (two precursors and their corresponding pyrrolo[2,1-a]isoindol-5-ones with different substituents) derived from phenylglycine as potential acetylcholinesterase inhibitors. Three of them (rac-4, rac-5, and rac-6) showed good enzyme inhibition (Ki 117.5, 90.62, and 77.30 µM, respectively), with a pattern of competitive inhibition type supported by in silico and in vitro experiments, being the rac-6 derivative the best inhibitor. The structural analysis showed that the presence of the ethyl ester group in the structure favors inhibition, likewise, the presence of double bonds increases the affinity of the inhibitor for the enzyme, so these new pyrrolo[2,1-a]isoindol-5-ones derivatives might be helpful for the treatment of Alzheimer’s disease.

Association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus: A prospective study of the Hong Kong Diabetes Register

AimsTo examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D). MethodsBetween July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia. ResultsAfter excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association. ConclusionsInsomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D.

Association of Neuroimaging Markers on Clinical CT Scans With Domain-Specific Cognitive Impairment in the Early and Later Post-Stroke Stages.

Post-stroke cognitive impairment (PSCI) is associated with neuroimaging markers, including cortical atrophy and white matter lesions (WMLs), on clinically acquired CT neuroimaging. To investigate the association between cortical atrophy/WMLs and PSCI in specific cognitive domains in the acute/subacute and chronic stages after stroke, in order to provide clarity on the relationship between these neuroimaging markers and the temporal evolution of PSCI. We visually assessed cortical atrophy using the Global Cortical Atrophy (GCA) scale and WMLs using the Fazekas scale. Oxford Cognitive Screen (OCS) or Birmingham Cognitive Screen (BCoS) assessed PSCI at two timepoints (acute/subacute and chronic) in six domains (language, memory, number processing, executive function, attention, praxis). We binarised domain-specific performance as impaired/unimpaired using normative cut-offs. Multivariable linear and logistic regression analyses evaluated associations between GCA/Fazekas scores with acute/subacute/chronic global and domain-specific PSCI, and ANCOVAs examined whether these scores were significantly different in patients with recovered versus persistent PSCI. Age, sex, education, NIHSS, lesion volume, and recurrent stroke were covariates in these analyses. Among 411 stroke patients (Mdn/IQR age= 76.16/16.64; 193 female; 346 ischaemic stroke; 107 recurrent stroke), GCA and Fazekas scores were not associated with global cognitive impairment in the acute/subacute stage after stroke, but GCA score was associated with chronic global PSCI (B = 0.01, p < .001, 95% CI [0.00 0.01]). In domain-specific analyses, GCA score was associated with chronic impairment in the memory (B = 0.06, p < .001, 95% CI [0.03 0.10]) and attention (B = 0.05, p = .003, 95% CI [0.02 0.09]) domains, and patients with persistent PSCI these domains showed significantly higher GCA scores than patients who had recovered (Memory: F(1,157) = 6.63, p = .01, η 2 G = .04; Attention: F(1,268) = 10.66, p = .001, η 2 G = .04). The present study highlights the potential impact of cortical atrophy on the cognitive recovery process after stroke and demonstrates the prognostic utility of CT neuroimaging for post-stroke cognitive outcomes. Clinical neuroimaging could help identify patients at long-term risk of PSCI during acute hospitalisation.