Multiple Physiological Systems Research Articles

Burnout and allostatic load among health workers engaged in human resourced-constrained hospitals in Accra, Ghana

BackgroundBurnout syndrome is a psycho-social disorder which develops in an individual exposed to chronic stress on the job. Health workers in sub-Saharan Africa (SSA) are at increased risk of burnout due to job-related challenges. Burnout does not only affect the job performance of employees, but could result in dysregulation of multiple physiological systems (allostatic load) in victims and predispose them to non-communicable diseases (NCDs). This study examined the association between burnout and allostatic load among health workers engaged in human resourced-constrained hospitals in Accra, Ghana.MethodThis study was a hospital-based cross-sectional study involving 1264 health workers (clinicians and non-clinicians) from three public hospitals in Accra, Ghana who were recruited using a proportionate stratified random sampling technique. The participants completed a questionnaire which collected general and burnout information. In addition, each participant’s anthropometric; biochemical and hemodynamic indices were measured. The allostatic load in the participants was determined using eleven (11) biomarkers from the neuro-endocrine, cardiovascular, metabolic and anthropometric measures. The relationship between burnout and allostatic overload (high allostatic load) was determined at the bivariate and multivariable levels. The data analysis was done with the aid of Stata 15.0 at a 95% confidence level.ResultsThe prevalence of burnout was 20.57%, higher in non-clinicians than clinicians (26.74% vs 15.64, p < 0.001). Also, non-clinical participants had higher levels of emotional exhaustion and depersonalization than the clinical participants. Over a quarter (26.27%) of the participants had allostatic overload manifesting as high allostatic load. Furthermore, for a one unit increase in overall burnout, the odds of experiencing allostatic overload was increased by 17.59 times (AOR = 17.59, 95% CI: 11.7-26.4) as compared to those without burnout and similar findings were found for the individual components of burnout syndrome with high allostatic load.ConclusionBurnout among health workers is associated with multi-system physiological dysregulation manifesting as high allostatic load; a major risk factor for NCDs. It is recommended that measures aimed at reducing burnout and allostatic overload such as structured psychological counseling and healthy lifestyle patterns are recommended for health workers engaged in stressful work settings to reduce their risk of NCDs.

Association between Frailty and Depression among Elderly in Nursing Home

Background: Frailty is described by the collective decline of multiple physiological systems and increased vulnerability to multiple stressors. It is also linked to emotional distress and mental illness, especially depression. Both frailty and depression are correlated with many harmful consequences in the elderly, including decreased quality of life, escalated utilization of health services, and elevated morbidity and mortality. Given the prominence of frailty and depression in the elderly, and the deleterious consequences when they coexist, understanding the association between these factors is essential. Aim: This study aims to analyze the association between frailty and depression among the elderly in the nursing home. Material and Methods: This research was cross-sectional, and conducted at 3 nursing homes in South Sulawesi. Frailty and depression were measured. Frailty was assessed by Edmonton Frail Scale (EFS), while depression was evaluated by Geriatric Depression Scale (GDS). The data were analyzed with the Pearson test in SPSS 25. Results: There were 27 participants, consisting of females 19 (70.3%), and males 8 (29.6%) with a mean age was 73.15±8, included in this study. The mean EFS was 5.89±3.15. The mean GDS result was 3.74±3.14. Frailty has positive strong association with depression (r=0.6, p=0.001). Conclusion: There was a strong and substantial association between frailty and depression among the elderly in the nursing home.

Frailty among people with multiple sclerosis who are wheelchair users.

Frailty is a biological syndrome arising from cumulative declines across multiple physiologic systems. Although recent reports have described elevated frailty levels in people with multiple sclerosis (MS) with minimal to moderate disability, very little is known about frailty in individuals with severe disability. The objective of the current investigation was to evaluate frailty through the deficit accumulation model and to explore the relationship of frailty with MS clinical subtypes, disease duration and fall-history in wheelchair users living with MS. Standard validated procedures were used to calculate a frailty index in 45 wheelchair and scooter users living with MS (median age = 60.0[16.0] years, 82.2% female, patient determined disease steps score = 7.0). Information on demographics, MS clinical subtypes, disease duration, and six-month fall-history were collected as part of a standardized medical survey. The mean frailty index score was 0.54 (standard deviation = 0.13). Overall, 91.1% and 8.9% of participants met objective diagnostic criteria for severe and moderate frailty, respectively. A one-way ANOVA revealed no significant differences (F = 0.054, p = 0.948) in the frailty index among participants with relapsing-remitting MS, primary progressive, and secondary progressive MS. No relationship between frailty and disease duration (r = -0.058, p = 0.706) was found. A univariable negative binomial regression analysis revealed a significant association between frailty index scores and the number of falls experienced in the previous six months (IRR = 1.75, 95% CI [1.06-2.91], p = 0.030). The current study suggests that individuals with MS with advanced disability also live with coexisting frailty and that the frailty index may be a valuable tool in evaluating fall-risk in wheelchair users living with MS. The significant overlap observed between severe disability and severe frailty highlights the emerging need to untangle this bi-directional relationship to identify appropriate therapeutic pathways in the MS population living with advanced disability.

SEMA4D/PlexinB1 promotes AML progression via activation of PI3K/Akt signaling

BackgroundAcute myeloid leukemia (AML) is the most common type of acute leukemia in adults. SEMA4D is a 150 kDa transmembrane protein that belongs to the IV class of the subfamily of semaphorin family. Previous studies have reported that SEMA4D is a multifunctional target in many solid tumors, involving multiple physiological systems, and there are emerging therapies to target these pathways. The role of SEMA4D in AML has not yet been explored.MethodsThe SEMA4D expression prolile, clinical data and potential prognostic analysis were acquired via the cBioPortal and GEPIA databases. SEMA4D expression was measured using real-time quantitative PCR and western blot. Cell counting kit-8 (CCK8) and flow cytometry were used to evaluate the malignant biological characteristics.ResultsWe observed that SEMA4D was increased in AML patients and correlated with risk stratification and prognosis. Moreover, SEMA4D promotes the proliferation and inhibits apoptosis of AML cells by binding to its receptor, PlexinB1, and reduces the sensitivity of AML cells to daunorubicin. In addition, SEMA4D/PlexinB1 promotes the proliferation and survival of AML cells by activating the PI3K/Akt signaling pathway. VX15/2503, an anti-SEMA4D antibody, can inhibit the proliferation of AML cells in xenograft mouse models, thereby inhibiting the development of AML.ConclusionSEMA4D will serve as a unique predictive biomarker and a possible therapeutic target in AML.

Seasonality of prolactin in birds and mammals.

In most animals, annual rhythms in environmental cues and internal programs regulate seasonal physiology and behavior. Prolactin, an evolutionarily ancient hormone, serves as a molecular correlate of seasonal timing in most species. Prolactin is highly pleiotropic with a wide variety of well-documented physiological effects; in a seasonal context prolactin is known to regulate annual changes in pelage and molt. While short-term homeostatic variation of prolactin secretion is under the control of the hypothalamus, long-term seasonal rhythms of prolactin are programmed by endogenous timers that reside in the pituitary gland. The molecular basis of these rhythms is generally understood to be melatonin dependent in mammals. Prolactin rhythmicity persists for several years in many species, in the absence of hypothalamic signaling. Such evidence in mammals has supported the hypothesis that seasonal rhythms in prolactin derive from an endogenous timer within the pituitary gland that is entrained by external photoperiod. In this review, we describe the conserved nature of prolactin signaling in birds and mammals and highlight its role in regulating multiple diverse physiological systems. The review will cover the current understanding of the molecular control of prolactin seasonality and propose a mechanism by which long-term rhythms may be generated in amniotes.

Clinical Frailty Assessment and Associated Outcomes Through COVID-19 Outbreak in a Long-Term Care Facility

Frailty is a syndrome characterized by decreased physiologic reserve resulting from decline across multiple physiologic systems. It is a common condition among elderly patients in nursing homes and has been linked to increased risk of adverse health outcomes. The association of frailty with health and quality of life outcomes in these living in nursing homes during the COVID-19 pandemic is not well understood. Evaluation of Frailty in nursing home residents might help provide an identification tool to recognize patients who are likely to have poor outcomes including rapid deterioration or significant functional decline. Demographics, weights, and functional measures were collected from the electronic medical records and physical therapy records of the residents at a single nursing home in West Virginia. Data was collected from prior to the first positive case at the facility and at the 6-month mark after the first case. A clinical frailty assessment was created using a modified FRAIL-NH scale. Weight loss values were chosen at 2.5% and 5% for the scale. Fatigue was measured using patients’ ability to maintain static balance in sitting and standing positions. The remaining measures were obtained using data from the Modified Barthel Index. Frailty scores were compared pre and post COVID-19 outbreak and infection status to assess risk factors for worsening of frailty status. Preliminary results showed that half of the facility met the cutoffs for frailty initially, with a quarter of the total being pre-frial and a quarter being non-frail. Using Mantel-Haenszel Chi-Square testing, Frailty was compared against sex, dementia, CHF, CVA, CAD, diabetes, asthma, COVID-19 infection, and severe COVID-19 symptoms for pre and post COVID outbreak frailty scores. Only patients with dementia met statistical significance for increased risk of frailty (P= 0.0022). Frailty scores before and after the COVID-19 outbreak at the facility did not show any significant change. COVID-19 infection and/or symptoms were not linked to worsening of or the development of frailty. Further analysis of the subset of patients who did show a decline in frailty score is currently underway. *Finalized data will be presented on the final poster. Frail elderly adults in nursing homes are at high risk for clinical decline and mortality, especially in the setting of a global pandemic. Early recognition of these patients could help identify those at risk for rapid deterioration if they acquire the virus. This study identified nursing home patients who were pre-frail and frail and followed their medical outcome to identify if they were at increased risk for a negative outcome. This objective version of the Frail-NH scale did help identify frail individuals in this facility, but it did not show any correlation between COVID-19 severity and worsening of frailty. Further investigation into those with frailty decline is ongoing to develop a better understanding of what places those patients at higher risk so a targeted intervention can be made.

Schizophrenia in Translation: Why the Eye?

Schizophrenia is increasingly recognized as a systemic disease, characterized by dysregulation in multiple physiological systems (eg, neural, cardiovascular, endocrine). Many of these changes are observed as early as the first psychotic episode, and in people at high risk for the disorder. Expanding the search for biomarkers of schizophrenia beyond genes, blood, and brain may allow for inexpensive, noninvasive, and objective markers of diagnosis, phenotype, treatment response, and prognosis. Several anatomic and physiologic aspects of the eye have shown promise as biomarkers of brain health in a range of neurological disorders, and of heart, kidney, endocrine, and other impairments in other medical conditions. In schizophrenia, thinning and volume loss in retinal neural layers have been observed, and are associated with illness progression, brain volume loss, and cognitive impairment. Retinal microvascular changes have also been observed. Abnormal pupil responses and corneal nerve disintegration are related to aspects of brain function and structure in schizophrenia. In addition, studying the eye can inform about emerging cardiovascular, neuroinflammatory, and metabolic diseases in people with early psychosis, and about the causes of several of the visual changes observed in the disorder. Application of the methods of oculomics, or eye-based biomarkers of non-ophthalmological pathology, to the treatment and study of schizophrenia has the potential to provide tools for patient monitoring and data-driven prediction, as well as for clarifying pathophysiology and course of illness. Given their demonstrated utility in neuropsychiatry, we recommend greater adoption of these tools for schizophrenia research and patient care.

γδ T Cells in Brain Homeostasis and Diseases.

γδ T cells are a distinct subset of T cells expressing γδ T cell receptor (TCR) rather than αβTCR. Since their discovery, the critical roles of γδ T cells in multiple physiological systems and diseases have been investigated. γδ T cells are preferentially located at mucosal surfaces, such as the gut, although a small subset of γδ T cells can circulate the blood. Additionally, a subset of γδ T cells reside in the meninges in the central nervous system. Recent findings suggest γδ T cells in the meninges have critical roles in brain function and homeostasis. In addition, several lines of evidence have shown γδ T cells can infiltrate the brain parenchyma and regulate inflammatory responses in multiple diseases, including neurodegenerative diseases. Although the importance of γδ T cells in the brain is well established, their roles are still incompletely understood due to the complexity of their biology. Because γδ T cells rapidly respond to changes in brain status and regulate disease progression, understanding the role of γδ T cells in the brain will provide critical information that is essential for interpreting neuroimmune modulation. In this review, we summarize the complex role of γδ T cells in the brain and discuss future directions for research.

Sleep Disruption and Cancer: Chicken or the Egg?

Sleep is a nearly ubiquitous phenomenon across the phylogenetic tree, highlighting its essential role in ensuring fitness across evolutionary time. Consequently, chronic disruption of the duration, timing, or structure of sleep can cause widespread problems in multiple physiological systems, including those that regulate energy balance, immune function, and cognitive capacity, among others. Many, if not all these systems, become altered throughout the course of cancer initiation, growth, metastatic spread, treatment, and recurrence. Recent work has demonstrated how changes in sleep influence the development of chronic diseases, including cancer, in both humans and animal models. A common finding is that for some cancers (e.g., breast), chronic disruption of sleep/wake states prior to disease onset is associated with an increased risk for cancer development. Additionally, sleep disruption after cancer initiation is often associated with worse outcomes. Recently, evidence suggesting that cancer itself can affect neuronal circuits controlling sleep and wakefulness has accumulated. Patients with cancer often report difficulty falling asleep, difficulty staying asleep, and severe fatigue, during and even years after treatment. In addition to the psychological stress associated with cancer, cancer itself may alter sleep homeostasis through changes to host physiology and via currently undefined mechanisms. Moreover, cancer treatments (e.g., chemotherapy, radiation, hormonal, and surgical) may further worsen sleep problems through complex biological processes yet to be fully understood. This results in a “chicken or the egg” phenomenon, where it is unclear whether sleep disruption promotes cancer or cancer reciprocally disrupts sleep. This review will discuss existing evidence for both hypotheses and present a framework through which the interactions between sleep and cancer can be dissociated and causally investigated.

Measurement of Sarcopenia in Head and Neck Cancer Patients and Its Association With Frailty.

In head and neck cancer (HNC) there is a need for more personalized treatment based on risk assessment for treatment related adverse events (i.e. toxicities and complications), expected survival and quality of life. Sarcopenia, defined as a condition characterized by loss of skeletal muscle mass and function, can predict adverse outcomes in HNC patients. A review of the literature on the measurement of sarcopenia in head and neck cancer patients and its association with frailty was performed. Skeletal muscle mass (SMM) measurement only is often used to determine if sarcopenia is present or not. SMM is most often assessed by measuring skeletal muscle cross-sectional area on CT or MRI at the level of the third lumbar vertebra. As abdominal scans are not always available in HNC patients, measurement of SMM at the third cervical vertebra has been developed and is frequently used. Frailty is often defined as an age-related cumulative decline across multiple physiologic systems, with impaired homeostatic reserve and a reduced capacity of the organism to withstand stress, leading to increased risk of adverse health outcomes. There is no international standard measure of frailty and there are multiple measures of frailty. Both sarcopenia and frailty can predict adverse outcomes and can be used to identify vulnerable patients, select treatment options, adjust treatments, improve patient counselling, improve preoperative nutritional status and anticipate early on complications, length of hospital stay and discharge. Depending on the definitions used for sarcopenia and frailty, there is more or less overlap between both conditions. However, it has yet to be determined if sarcopenia and frailty can be used interchangeably or that they have additional value and should be used in combination to optimize individualized treatment in HNC patients.

Mild‐to‐Moderate Chronic Hypercapnia Impairs Adaptation of Acute CO2/H+ Chemosensitivity but Not Steady‐State Ventilation

CO2 retention (hypercapnia, CH) presents in a number of etiologies including sedative use, chronic lung disease, and central/peripheral neuromuscular disorders. Acute‐on‐chronic hypercapnia can develop in these disorders during times of acute stress (i.e., infection and postoperative states). Recurrent acute‐on‐chronic CH may lead to respiratory failure and transient, life‐threatening worsening of the hypercapnia. We previously established in awake goats that exposure to mild CH (PaCO2 ~55mmHg) elicits changes across multiple physiologic systems but does not impair the response to acute increases in inspired CO2(InCO2).Herein, we test the hypothesis that progressive exposure from mild‐to‐moderate CH (~55‐to‐65mmHg CO2) results in secondary adaptations across several physiologic systems but increases the risk of pathological responses during acute‐on‐chronic exacerbations. Utilizing our established large animal model of CH, female goats (n=7) were exposed to 7 days (d) of 6% InCO2 followed by 7d of 8% InCO2. Throughout the protocol, we regularly assessed steady‐state cardiorespiratory function (i.e., VI, f, VT, HR, and BP) and acute CO2/H+ chemosensitivity. During 6% InCO2, the temporal pattern of physiologic adaptations was consistent with that previously reported (J. Physiol. 2018). As expected, increasing steady‐state (SS) InCO2 resulted in a sustained 10 mmHg increase in PaCO2 and an increase in arterial [H+] that decreased over the 7d at 6%. During 6% InCO2 there was a transient decrease (6%‐Day 2) in acute chemosensitivity (DVI/DCO2) that returned to control values by Day 5 at 6%. Upon increasing SS InCO2from 6% to 8%, minute ventilation (VI) increased from 23±3.4L/min on Day 7 at 6% InCO2 to 34±2.2L/min on Day 1 at 8% InCO2,which was primarily driven by an increase in breathing frequency. By 24h at 8% InCO2, VIhad declined from the 8%‐Day 1 values and remained at or near that level thereafter. This temporal pattern of adaptation is comparable to that observed during 6% CO2. A similar pattern of adaptation in [H+] occurred during 8% as occurred at 6%, while [HCO3‐] continually increased. PaCO2remained elevated throughout the 8% InCO2 exposure, compared to 6% InCO2. Finally, when SS InCO2 was increased to 8% the acute chemoreflex remained suppressed throughout the 7d. Our results suggest that progressive worsening of chronic hypercapnia results in similar SS adaptations compared to initial hypercapnic exposure. However, more severe levels of CH, such as 8% InCO2, perturb the acute chemoreflex, creating a risk for consequences such as CO2 narcosis and cardiorespiratory failure in patients with pre‐existing CH.

Time‐of‐Day Influence on Central Nervous System Autoimmunity

Circadian rhythms are a characteristic of most living organisms and describe biological processes experiencing an oscillation of about 24h. These rhythms regulate multiple physiological systems, including innate and adaptive immune responses. Circadian disruption is an important risk factor in neuroinflammation such as multiple sclerosis (MS), a T‐cell mediated autoimmune disease affecting around 2.8 million people worldwide. In the central nervous system (CNS), autoimmune T cells attack oligodendrocytes leading to progressive demyelination and neurological impairment. Studies performed by our lab demonstrate that the circadian clock plays an important role in the severity of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. However, the mechanisms responsible for this time‐of‐day difference are unknown. We investigated time‐of‐day differences in adhesion molecule expression and immune cell infiltration to the CNS that could explain differences in disease phenotype. Our results indicate a time‐of‐day‐dependent infiltration of cells into spinal cords during EAE development that correlates with expression of the adhesion molecules VCAM‐1 and ICAM‐1 in the CNS vasculature. Targeting leukocyte‐endothelial cell interactions in a time‐of‐day dependent manner with an anti‐VLA4 antibody that blocks VLA‐4/VCAM‐1 engagement reduces leukocyte infiltration and disease severity. This study shows the importance of circadian oscillations in adhesion molecule expression and cell infiltration in the CNS, and identifies an axis to target for chronotherapy purposes in MS patients.

Hiding in Plain Sight: Factors Influencing the Neuroinflammatory Response to Sport-Related Concussion.

Sport-related concussion (SRC) is a major concern among athletes and clinicians around the world. Research into fluid biomarkers of SRC has made significant progress in understanding the complex underlying pathophysiology of concussion. However, little headway has been made toward clinically validating any biomarkers to improve the clinical management of SRC. A major obstacle toward clinical translation of any fluid biomarker is the heterogeneity of SRC overlapping with multiple physiological systems involved in pathology and recovery. Neuroinflammation post-SRC is one such system that may confound fluid biomarker data on many fronts. Neuroinflammatory processes consist of cell mediators, both within the central nervous system and the periphery, that play vital roles in regulating the response to brain injury. Further, neuroinflammation is influenced by many biopsychosocial variables present in most athletic populations. In this commentary, we propose that future fluid biomarker research should take a systems biology approach in the context of the neuroinflammatory response to SRC. We highlight how biological variables, such as age, sex, immune challenges, and hypothalamic-pituitary-adrenal (HPA)-axis responses to stress, may alter neuroinflammation. Further, we underscore the importance of accounting for health and lifestyle variables, such as diet, exercise, sleep, and pre-morbid medical factors, when measuring inflammatory markers of SRC. To successfully move toward clinical translation, fluid biomarker research should take a more holistic approach in study design and data interpretation, collecting information on hidden variables that may be influencing the neuroinflammatory response to SRC.

The Structural and Functional Correlates of Frailty in Persons With Human Immunodeficiency Virus.

Persons with HIV (PWH) are at increased risk of frailty, a clinically recognizable state of increased vulnerability resulting from aging-associated decline in multiple physiologic systems. Frailty is often defined by the Fried criteria, which includes subjective and objective standards concerning health resiliency. However, these frailty metrics do not incorporate cognitive performance or neuroimaging measures. We compared structural (diffusion tensor imaging [DTI]) and functional (cerebral blood flow [CBF]) neuroimaging markers in PWH with frailty and cognitive performance. Virologically controlled PWH were dichotomized as either frail (≥3) or nonfrail (<3) using the Fried criteria. Cognitive Z-scores, both domain (executive, psychomotor speed, language, and memory) and global, were derived from a battery of tests. We identified three regions of reduced CBF, based on a voxel-wise comparison of frail PWH compared with nonfrail PWH. These clusters (bilateral frontal and posterior cingulate) were subsequently used as seed regions of interest (ROIs) for DTI probabilistic white matter tractography. White matter integrity connecting the ROIs was significantly decreased in frail compared with nonfrail PWH. No differences in cognition were observed between frail and nonfrail PWH. However, reductions in white matter integrity among these ROIs was significantly associated with worse psychomotor speed and executive function across the entire cohort. We conclude that frailty in PWH can lead to structural and functional brain changes, including subtle changes that are not detectable by standard neuropsychological tests. Multimodal neuroimaging in conjunction with frailty assessment could identify pathological brain changes observed in PWH.

Consumer-grade wearables identify changes in multiple physiological systems during COVID-19 disease progression

SummaryConsumer-grade wearables are needed to track disease, especially in the ongoing pandemic, as they can monitor patients in real time. We show that decomposing heart rate from low-cost wearable technologies into signals from different systems can give a multidimensional description of physiological changes due to COVID-19 infection. We find that the separate physiological features of basal heart rate, heart rate response to physical activity, circadian variation in heart rate, and autocorrelation of heart rate are significantly altered and can classify symptomatic versus healthy periods. Increased heart rate and autocorrelation begin at symptom onset, while the heart rate response to activity increases soon after symptom onset and increases more in individuals exhibiting cough. Symptom onset is associated with a blunting of circadian variation in heart rate, as measured by the uncertainty in the phase estimate. This work establishes an innovative data analytic approach to monitor disease progression remotely using consumer-grade wearables.

Ageing and exercise-induced motor unit remodelling.

A motor unit (MU) comprises the neuron cell body, its corresponding axon and each of the muscle fibres it innervates. Many studies highlight age‐related reductions in the number of MUs, yet the ability of a MU to undergo remodelling and to expand to rescue denervated muscle fibres is also a defining feature of MU plasticity. Remodelling of MUs involves two coordinated processes: (i) axonal sprouting and new branching growth from adjacent surviving neurons, and (ii) the formation of key structures around the neuromuscular junction to resume muscle–nerve communication. These processes rely on neurotrophins and coordinated signalling in muscle–nerve interactions. To date, several neurotrophins have attracted focus in animal models, including brain‐derived neurotrophic factor and insulin‐like growth factors I and II. Exercise in older age has demonstrated benefits in multiple physiological systems including skeletal muscle, yet evidence suggests this may also extend to peripheral MU remodelling. There is, however, a lack of research in humans due to methodological limitations which are easily surmountable in animal models. To improve mechanistic insight of the effects of exercise on MU remodelling with advancing age, future research should focus on combining methodological approaches to explore the in vivo physiological function of the MU alongside alterations of the localised molecular environment.

Association Between Homocysteine, Frailty and Biomechanical Response of the CNS in NPH-Suspected Patients.

Frailty is a geriatric syndrome that combines physiological decline, disruptions of homeostatic mechanisms across multiple physiologic systems and thus, strong vulnerability to further pathological stress. Previously, we provided the first evidence that increased risk of poor health outcomes, as quantified by a frailty index (FI), is associated with an alteration of the central nervous system (CNS) biomechanical response to blood pulsatility. In this study, we explored correlation between 14 biological parameters, the CNS elastance coefficient and FI. We included 60 adults (52-92 years) suspected of normal pressure hydrocephalus and presenting with markers of multiple coexisting brain pathologies, including Parkinson disease, Alzheimer disease, and vascular dementia. We showed that the homocysteine (Hcy) level was independently and positively associated with both the FI and the CNS elastance coefficient (adjusted R² of 10% and 6%). We also demonstrated that creatinine clearance and folate level were independently associated with Hcy level. Based on previous literature results describing the involvement of Hcy in endothelial dysfunction, glial activation, and neurodegeneration, we discuss how Hcy could contribute to the altered biomechanical response of the CNS and frailty.

Neural networks for anatomical therapeutic chemical (ATC) classification

PurposeAutomatic anatomical therapeutic chemical (ATC) classification is progressing at a rapid pace because of its potential in drug development. Predicting an unknown compound's therapeutic and chemical characteristics in terms of how it affects multiple organs and physiological systems makes automatic ATC classification a vital yet challenging multilabel problem. The aim of this paper is to experimentally derive an ensemble of different feature descriptors and classifiers for ATC classification that outperforms the state-of-the-art.Design/methodology/approachThe proposed method is an ensemble generated by the fusion of neural networks (i.e. a tabular model and long short-term memory networks (LSTM)) and multilabel classifiers based on multiple linear regression (hMuLab). All classifiers are trained on three sets of descriptors. Features extracted from the trained LSTMs are also fed into hMuLab. Evaluations of ensembles are compared on a benchmark data set of 3883 ATC-coded pharmaceuticals taken from KEGG, a publicly available drug databank.FindingsExperiments demonstrate the power of the authors’ best ensemble, EnsATC, which is shown to outperform the best methods reported in the literature, including the state-of-the-art developed by the fast.ai research group. The MATLAB source code of the authors’ system is freely available to the public at https://github.com/LorisNanni/Neural-networks-for-anatomical-therapeutic-chemical-ATC-classification.Originality/valueThis study demonstrates the power of extracting LSTM features and combining them with ATC descriptors in ensembles for ATC classification.

A Personalized Multidisciplinary Approach to Evaluating and Treating Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder without a known cure. Current standard-of-care treatments focus on addressing core symptoms directly but have provided limited benefits. In many cases, individuals with ASD have abnormalities in multiple organs, including the brain, immune and gastrointestinal system, and multiple physiological systems including redox and metabolic systems. Additionally, multiple aspects of the environment can adversely affect children with ASD including the sensory environment, psychosocial stress, dietary limitations and exposures to allergens and toxicants. Although it is not clear whether these medical abnormalities and environmental factors are related to the etiology of ASD, there is evidence that many of these factors can modulate ASD symptoms, making them a potential treatment target for improving core and associated ASD-related symptoms and improving functional limitation. Additionally, addressing underlying biological disturbances that drive pathophysiology has the potential to be disease modifying. This article describes a systematic approach using clinical history and biomarkers to personalize medical treatment for children with ASD. This approach is medically comprehensive, making it attractive for a multidisciplinary approach. By concentrating on treatable conditions in ASD, it is possible to improve functional ability and quality of life, thus providing optimal outcomes.

Physiological Network Is Disrupted in Severe COVID-19.

The human body is a complex system maintained in homeostasis thanks to the interactions between multiple physiological regulation systems. When faced with physical or biological perturbations, this system must react by keeping a balance between adaptability and robustness. The SARS-COV-2 virus infection poses an immune system challenge that tests the organism’s homeostatic response. Notably, the elderly and men are particularly vulnerable to severe disease, poor outcomes, and death. Mexico seems to have more infected young men than anywhere else. The goal of this study is to determine the differences in the relationships that link physiological variables that characterize the elderly and men, and those that characterize fatal outcomes in young men. To accomplish this, we examined a database of patients with moderate to severe COVID-19 (471 men and 277 women) registered at the “Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán” in March 2020. The sample was stratified by outcome, age, and sex. Physiological networks were built using 67 physiological variables (vital signs, anthropometric, hematic, biochemical, and tomographic variables) recorded upon hospital admission. Individual variables and system behavior were examined by descriptive statistics, differences between groups, principal component analysis, and network analysis. We show how topological network properties, particularly clustering coefficient, become disrupted in disease. Finally, anthropometric, metabolic, inflammatory, and pulmonary cluster interaction characterize the deceased young male group.