Clinical and radiological correlates of apathy in multiple sclerosis.

BACKGROUND: Although apathy has been associated with fronto-striatal dysfunction in several neurological disorders, its clinical and magnetic resonance imaging (MRI) correlates have been poorly investigated in people with multiple sclerosis (PwMS). OBJECTIVES: To evaluate clinical variables and investigate microstructural integrity of fronto-striatal grey matter (GM) and white matter (WM) structures using diffusion tensor imaging (DTI). METHODS: A total of 123 PwMS (age: 40.25 ± 11.5; female: 60.9%; relapsing-remitting multiple sclerosis: 75.6%) were prospectively enrolled and underwent neurological and neuropsychological evaluation, including Expanded Disability Status Scale (EDSS), Apathy Evaluation Scale (AES-S), Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS) and brain 3T-MRI volumes of whole brain, frontal/prefrontal cortex (PFC) and subcortical regions were calculated. DTI-derived metrics were evaluated in the same GM regions and in connecting WM tracts. RESULTS: Apathetic PwMS (32.5%) showed lower education levels, higher HADS, MFIS scores and WM lesions volume than nonapathetic PwMS. Significant differences in DTI metrics were found in middle frontal, anterior cingulate and superior frontal PFC subregions and in caudate nuclei. Significant alterations were found in the right cingulum and left striatal-frontorbital tracts. CONCLUSIONS: Apathy in PwMS is associated with higher levels of physical disability, depression, anxiety and fatigue together with lower educational backgrounds. Microstructural damage within frontal cortex, caudate and fronto-striatal WM bundles is a significant pathological substrate of apathy in multiple sclerosis (MS).

Systematic review of cognitive reserve in multiple sclerosis: Accounting for physical disability, fatigue, depression, and anxiety.

BACKGROUND: Cognitive reserve (CR) describes an individual's ability to adapt cognitive processes in response to brain atrophy, and has been reported to explain some of the discrepancy between brain atrophy and cognitive functioning outcomes in multiple sclerosis (MS). CR in MS is typically investigated by assessing an individual's pre- and/or post-diagnosis enrichment, which includes premorbid intellectual abilities, educational level, occupational attainment, and engagement in cognitively enriching leisure activities. Common MS symptoms (e.g., physical disability, fatigue, depression, anxiety) may impact an individual's ability to engage in various CR-enhancing activities post-diagnosis. It is unknown to what extent these MS symptoms have been taken into account in MS research on CR. As such, we identified whether studies assessed CR using measures of premorbid or continuous (including post-diagnosis) enrichment. For studies investigating continuous enrichment, we identified whether studies accounted for MS-impact, which MS symptoms were accounted for, and how, and whether studies acknowledged MS symptoms as potential CR-confounds. METHODS: Three electronic databases (PsycINFO, PubMed, Scopus) were searched. Eligible studies investigated CR proxies (e.g., estimated premorbid intellectual abilities, vocabulary knowledge, educational level, occupational attainment, cognitively enriching leisure activities, or a combination thereof) in relation to cognitive, brain atrophy or connectivity, or daily functioning outcomes in adult participants with MS. We extracted data on methods and measures used, including any MS symptoms taken into account. Objectives were addressed using frequency analyses and narrative synthesis. RESULTS: 115 studies were included in this review. 47.8% of all studies investigated continuous enrichment. Approximately half of the studies investigating continuous enrichment accounted for potential MS-impact in their analyses, with only 31.0% clearly identifying that they treated MS symptoms as potential confounds for CR-enhancement. A narrative synthesis of studies which investigated CR with and without controlling statistically for MS-impact indicated that accounting for MS symptoms may impact findings concerning the protective nature of CR. CONCLUSION: Fewer than half of the studies investigating CR proxies in MS involved continuous enrichment. Just over half of these studies accounted for potential MS-impact in their analyses. To achieve a more complete and accurate understanding of CR in MS, future research should investigate both pre-MS and continuous enrichment. In doing so, MS symptoms and their potential impact should be considered. Establishing greater consistency and rigour across CR research in MS will be crucial to produce an evidence base for the development of interventions aimed at improving quality of care and life for pwMS.

Histological and contractile changes in the genioglossus muscle after nasal obstruction in growing rats.

The aim of the study was to address the genioglossus muscle physiological and histological changes after unilateral nasal obstruction in growing rats. Fifty-four 6-day-old male Wistar albino rats were randomly divided into control (n = 27) and experimental (n = 27) groups. Unilateral nasal obstruction was performed at 8 days old. Contractile properties of the genioglossus whole muscle were measured at 5-, 7- and 9-week-old, including the twitch and tetanic forces, contraction time, half-decay time, and fatigue index. The histological characteristics of the genioglossus were also evaluated at 5-, 7- and 9-week-old, analyzing the myosin heavy chain composition of the slow, fast, IIa and IIb muscle fiber type, by measuring the number, rate, diameter and cross-sectional area. The maximal twitch force, and tetanic force at 60 Hz and 80 Hz force was significantly increased at all ages after nasal obstruction. The fatigue index was decreased at 5 weeks-old after nasal obstruction. The diameter and cross-sectional area of the fast, IIa and IIb muscle fiber types were increased at 7 and 9 weeks after nasal obstruction, while only the diameter of IIa type and cross-sectional area of IIb type were increased at 5 weeks-old after nasal obstruction. Nasal obstruction during growth affects the whole genioglossus muscle contractile properties and histological characteristics, increasing its force, the diameter and area of its muscle fibers. These changes in the genioglossus muscle may affect the normal growth, development and function of the craniofacial complex.

Disruptions in Structural and Functional Connectivity Relate to Poststroke Fatigue.

Introduction: Poststroke fatigue (PSF) is a disabling condition with unclear etiology. The brain lesion is thought to be an important causal factor in PSF, although focal lesion characteristics such as size and location have not proven to be predictive. Given that the stroke lesion results not only in focal tissue death but also in widespread changes in brain networks that are structurally and functionally connected to damaged tissue, we hypothesized that PSF relates to disruptions in structural and functional connectivity. Materials and Methods: Twelve patients who incurred an ischemic stroke in the middle cerebral artery (MCA) territory 1-3 years prior, and currently experiencing a range of fatigue severity, were enrolled. The patients underwent structural and resting-state functional magnetic resonance imaging (MRI). The structural MRI data were used to measure structural disconnection of gray matter resulting from lesion to white matter pathways. The functional MRI data were used to measure network functional connectivity. Results: The patients showed structural disconnection in varying cortical and subcortical regions. Fatigue severity correlated significantly with structural disconnection of several frontal cortex regions in the ipsilesional (IL) and contralesional hemispheres. Fatigue-related structural disconnection was most severe in the IL rostral middle frontal cortex. Greater structural disconnection of a subset of fatigue-related frontal cortex regions, including the IL rostral middle frontal cortex, trended toward correlating significantly with greater loss in functional connectivity. Among identified fatigue-related frontal cortex regions, only the IL rostral middle frontal cortex showed loss in functional connectivity correlating significantly with fatigue severity. Conclusion: Our results provide evidence that loss in structural and functional connectivity of bihemispheric frontal cortex regions plays a role in PSF after MCA stroke, with connectivity disruptions of the IL rostral middle frontal cortex having a central role. Impact statement Poststroke fatigue (PSF) is a common disabling condition with unclear etiology. We hypothesized that PSF relates to disruptions in structural and functional connectivity secondary to the focal lesion. Using structural and resting-state functional connectivity magnetic resonance imaging (MRI) in patients with chronic middle cerebral artery (MCA) stroke, we found frontal cortex regions in the ipsilesional (IL) and contralesional hemispheres with greater structural disconnection correlating with greater fatigue. Among these fatigue-related cortices, the IL rostral middle frontal cortex showed loss in functional connectivity correlating with fatigue. These findings suggest that disruptions in structural and functional connectivity play a role in PSF after MCA stroke.

Structure and Function of the Mammalian Neuromuscular Junction.

The mammalian neuromuscular junction (NMJ) comprises a presynaptic terminal, a postsynaptic receptor region on the muscle fiber (endplate), and the perisynaptic (terminal) Schwann cell. As with any synapse, the purpose of the NMJ is to transmit signals from the nervous system to muscle fibers. This neural control of muscle fibers is organized as motor units, which display distinct structural and functional phenotypes including differences in pre- and postsynaptic elements of NMJs. Motor units vary considerably in the frequency of their activation (both motor neuron discharge rate and duration/duty cycle), force generation, and susceptibility to fatigue. For earlier and more frequently recruited motor units, the structure and function of the activated NMJs must have high fidelity to ensure consistent activation and continued contractile response to sustain vital motor behaviors (e.g., breathing and postural balance). Similarly, for higher force less frequent behaviors (e.g., coughing and jumping), the structure and function of recruited NMJs must ensure short-term reliable activation but not activation sustained for a prolonged period in which fatigue may occur. The NMJ is highly plastic, changing structurally and functionally throughout the life span from embryonic development to old age. The NMJ also changes under pathological conditions including acute and chronic disease. Such neuroplasticity often varies across motor unit types. © 2022 American Physiological Society. Compr Physiol 12:1-36, 2022.

Review of human supraspinatus tendon mechanics. Part II: tendon healing response and characterization of tendon health.

Overuse injuries of the rotator cuff, particularly of the supraspinatus tendon (SST), are highly prevalent and debilitating in work, sport, and daily activities. Despite the clinical significance of these injuries, there remains a large degree of uncertainty regarding the pathophysiology of injury, optimal methods of nonoperative and operative repair, and how to adequately assess tendon injury and healing. The tendon response to fatigue damage resulting from overuse is different from that of acute rupture and results in either an adaptive (healing) or a maladaptive (degenerative) response. Factors associated with the degenerative response include increasing age, smoking, hypercholesterolemia, biological sex (variable by tendon), diabetes mellitus, and excessive load post fatigue damage. After injury, the average healing rate of tendon is approximately 1% per day and may be significantly influenced by biologic sex (females have lower collagen synthesis rates) and excessive load after damage. Although magnetic resonance imaging (MRI) is considered the gold standard in assessing acute tears as well as tendinopathic change in the SST, ultrasonography has proven to be a valuable tool to measure tendinopathic change in real time. Ultrasonography can determine multiple mechanical and structural parameters of the SST that are altered in fatigue loading. Thus, ultrasonography may be utilized to understand how these parameters change in response to SST overuse, and may aid in determining the activity level that places the SST at greater risk of rupture.

Brain predictors of fatigue in rheumatoid arthritis: A machine learning study.

BACKGROUND: Fatigue is a common and burdensome symptom in Rheumatoid Arthritis (RA), yet is poorly understood. Currently, clinicians rely solely on fatigue questionnaires, which are inherently subjective measures. For the effective development of future therapies and stratification, it is of vital importance to identify biomarkers of fatigue. In this study, we identify brain differences between RA patients who improved and did not improve their levels of fatigue based on Chalder Fatigue Scale variation (ΔCFS≥ 2), and we compared the performance of different classifiers to distinguish between these samples at baseline. METHODS: Fifty-four fatigued RA patients underwent a magnetic resonance (MR) scan at baseline and 6 months later. At 6 months we identified those whose fatigue levels improved and those for whom it did not. More than 900 brain features across three data sets were assessed as potential predictors of fatigue improvement. These data sets included clinical, structural MRI (sMRI) and diffusion tensor imaging (DTI) data. A genetic algorithm was used for feature selection. Three classifiers were employed in the discrimination of improvers and non-improvers of fatigue: a Least Square Linear Discriminant (LSLD), a linear Support Vector Machine (SVM) and a SVM with Radial Basis Function kernel. RESULTS: The highest accuracy (67.9%) was achieved with the sMRI set, followed by the DTI set (63.8%), whereas classification performance using clinical features was at the chance level. The mean curvature of the left superior temporal sulcus was most strongly selected during the feature selection step, followed by the surface are of the right frontal pole and the surface area of the left banks of the superior temporal sulcus. CONCLUSIONS: The results presented evidence a superiority of brain metrics over clinical metrics in predicting fatigue changes. Further exploration of these methods may support clinicians to triage patients towards the most appropriate fatigue alleviating therapies.

Acute cold stress induces transient MuRF1 upregulation in the skeletal muscle of zebrafish.

Cryotherapy is one of the most common treatments for trauma or fatigue in the field of sports medicine. However, the molecular biological effects of acute cold exposure on skeletal muscle remain unclear. Therefore, we used zebrafish, which have recently been utilized as an animal model for skeletal muscle, to comprehensively investigate and selectively clarify the time-course changes induced by cryotherapy. Zebrafish were exposed intermittently to cold stimulation three times for 15 min each. Thereafter, skeletal muscle samples were collected after 15 min and 1, 2, 4, and 6 h. mRNA sequencing revealed the involvement of trim63a, fbxo32, fbxo30a, and klhl38b in "protein ubiquitination" from the top 10 most upregulated genes. Subsequently, we examined the time-course changes of the four genes by quantitative PCR, and their expression peaked 2 h after cryotherapy and returned to baseline after 6 h. Moreover, the proteins encoded by trim63a and fbxo32 (muscle-specific RING finger protein 1 [MuRF1] and muscle atrophy F-box, respectively), which are known to be major genes encoding E3 ubiquitin ligases, were examined by western blotting, and MuRF1 expression displayed similar temporal changes as trim63a expression. These findings suggest that acute cold exposure transiently upregulates E3 ubiquitin ligases, especially MuRF1; thus, cryotherapy may contribute to the treatment of trauma or fatigue by promoting protein processing.

Structural Basal Ganglia Correlates of Subjective Fatigue in Middle-Aged and Older Adults.

OBJECTIVE: Fatigue is among the most common complaints in community-dwelling older adults, yet its etiology is poorly understood. Based on models implicating frontostriatal pathways in fatigue pathogenesis, we hypothesized that smaller basal ganglia volume would be associated with higher levels of subjective fatigue and reduced set-shifting in middle-aged and older adults without dementia or other neurologic conditions. METHODS: Forty-eight non-demented middle-aged and older adults (Mage = 68.1, SD = 9.4; MMMSE = 27.3, SD = 1.9) completed the Fatigue Symptom Inventory, set-shifting measures, and structural MRI as part of a clinical evaluation for subjective cognitive complaints. Associations were examined cross-sectionally. RESULTS: Linear regression analyses showed that smaller normalized basal ganglia volumes were associated with more severe fatigue (ß = -.29, P = .041) and poorer Trail Making Test B-A (TMT B-A) performance (ß = .30, P = .033) controlling for depression, sleep quality, vascular risk factors, and global cognitive status. Putamen emerged as a key structure linked with both fatigue (r = -.43, P = .003) and TMT B-A (ß = .35, P = .021). The link between total basal ganglia volume and reduced TMT B-A was particularly strong in clinically fatigued patients. CONCLUSION: This study is among the first to show that reduced basal ganglia volume is an important neurostructural correlate of subjective fatigue in physically able middle-aged and older adults without neurological conditions. Findings suggest that fatigue and rapid set-shifting deficits may share common neural underpinnings involving the basal ganglia, and provide a framework for studying the neuropathogenesis and treatment of subjective fatigue.

Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness.

AIMS: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. MAIN METHODS: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). KEY FINDINGS: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SIGNIFICANCE: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.

Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment.

AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.

Building a biopsychosocial model of cancer-related fatigue: the BIOCARE FActory cohort study protocol.

BACKGROUND: Cancer-related fatigue (CRF) is the most common side effect of cancer and cancer treatment. CRF prevalence is up to 50% in breast cancer patients and can continue several years after cancer remission. This persistent subjective sense of exhaustion is multifactorial. Numerous parameters have been evidenced to be related to CRF across biological, physical, psychological, social and/or behavioral dimensions. Although CRF has been studied for many years, the majority of previous studies focused on only one dimension, i.e., physical function. Moreover, few studies investigated CRF longitudinally with repeated measures. These are the two main obstacles that limit the understanding of CRF mechanisms. The purpose of this study is to create a biopsychosocial model of CRF with simultaneous and longitudinal anthropometric, clinical, biological, physical, psychological and sociological parameters. METHODS: BIOCARE FActory is a multicentric prospective study that will consist of an 18-month follow-up of 200 women diagnosed with breast cancer. Four visits will be scheduled at diagnosis, after treatments, and 12 and 18 months after diagnosis. The same procedure will be followed for each visit. Each session will be composed of anthropometric data collection, a semi-structured interview, cognitive tests, postural control tests, neuromuscular fatigability tests and a cardiorespiratory fitness test. Clinical and biological data will be collected during medical follow-ups. Participants will also complete questionnaires to assess psychological aspects and quality of life and wear an actigraphy device. Using a structural equation modeling analysis (SEM), collected data will build a biopsychosocial model of CRF, including the physiological, biological, psychological, behavioral and social dimensions of CRF. DISCUSSION: This study aims to highlight the dynamics of CRF and its correlates from diagnosis to post treatment. SEM analysis could examine some relations between potential mechanisms and CRF. Thus, the biopsychosocial model will contribute to a better understanding of CRF and its underlying mechanisms from diagnosis to the aftermaths of cancer and its treatments. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov ( NCT04391543 ), May 2020.

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

Perception, magnitude, and implications of cancer-related fatigue in breast cancer survivors: Study from a developing country.

BACKGROUND: We have analyzed perceptions, magnitude, interventions adopted, and overall implications of cancer-related fatigue (CRF) in breast cancer survivors (BCSs). METHODOLOGY: BCSs who attended follow-up clinic at our institute between January and June 2018 were asked to fill a questionnaire focused on assessing an individual's perception, severity, potential causes, implications on quality of life, and measures taken to deal with CRF. RESULTS: Sixty-five patients were included. Fifty-four (83%) had undergone surgery, 59 (91%) chemotherapy, 43 (66%) radiation therapy, and 36 (55%) hormonal/targeted therapy. Sixty-two (95%) patients experienced any grade CRF. Fifty-five (85%) patients experienced moderate to severe CRF affecting work (58%) and activities of daily living (27%). CRF was perceived as generalized weakness by 54 (83%) patients, diminished concentration/attention span by 24 (37%) patients, decreased motivation and interest in usual activities by 29 (45%) patients, and emotional labiality by 16 (25%) patients. Fifty-six patients (86%) believed that fatigue was due to the effect of cancer treatment on the body, while only 8 (12%) attributed it to underlying cancer. CRF had negative impact on mood, daily activities, interpersonal relationships, and professional work in 40 (62%), 39 (60%), 13 (20%), and 10 (15%) patients, respectively. Measures taken to overcome CRF were increased physical exercise, psychosocial interventions, mind-body interventions, and pharmacological interventions in 32 (49%), 8 (12%), 28 (43), and 17 (26%) patients, respectively. Thirty-nine (60%) patients reported persistence of CRF after completion of treatment while it took up to 6 months, 6-12 months, and more than 12 months for resolution of CRF in 13, 10, and 3 patients, respectively. CONCLUSION: Development and persistence of CRF remains a major health concern, and current interventions are not able to mitigate this problem. Further research in this field is warranted.

Clinical and laboratory factors associated with coronavirus disease 2019 (Covid-19): A systematic review and meta-analysis.

SARS Coronavirus-2 is one of the most widespread viruses globally during the 21st century, whose severity and ability to cause severe pneumonia and death vary. We performed a comprehensive systematic review of all studies that met our standardised criteria and then extracted data on the age, symptoms, and different treatments of Covid-19 patients and the prognosis of this disease during follow-up. Cases in this study were divided according to severity and death status and meta-analysed separately using raw mean and single proportion methods. We included 171 complete studies including 62,909 confirmed cases of Covid-19, of which 148 studies were meta-analysed. Symptoms clearly emerged in an escalating manner from mild-moderate symptoms, pneumonia, severe-critical to the group of non-survivors. Hypertension (Pooled proportion (PP): 0.48 [95% Confident interval (CI): 0.35-0.61]), diabetes (PP: 0.23 [95% CI: 0.16-0.33]) and smoking (PP: 0.12 [95% CI: 0.03-0.38]) were highest regarding pre-infection comorbidities in the non-survivor group. While acute respiratory distress syndrome (PP: 0.49 [95% CI: 0.29-0.78]), (PP: 0.63 [95% CI: 0.34-0.97]) remained one of the most common complications in the severe and death group respectively. Bilateral ground-glass opacification (PP: 0.68 [95% CI: 0.59-0.75]) was the most visible radiological image. The mortality rates estimated (PP: 0.11 [95% CI: 0.06-0.19]), (PP: 0.03 [95% CI: 0.01-0.05]), and (PP: 0.01 [95% CI: 0-0.3]) in severe-critical, pneumonia and mild-moderate groups respectively. This study can serve as a high evidence guideline for different clinical presentations of Covid-19, graded from mild to severe, and for special forms like pneumonia and death groups.

Exposure to Gulf War Illness-related agents leads to the development of chronic pain and fatigue.

AIMS: A substantial contingent of veterans from the first Gulf War continues to suffer from a number of Gulf War-related illnesses (GWI) affecting the neurological and musculoskeletal systems; the most common symptoms include chronic pain and fatigue. Although animal models have recapitulated several aspects of cognitive impairments in GWI, the pain and fatigue symptoms have not been well documented to allow examination of potential pathogenic mechanisms. MAIN METHODS: We used a mouse model of GWI by exposing mice repeatedly to a combination of Gulf War chemicals (pyridostigmine bromide, permethrin, DEET, and chlorpyrifos) and mild immobilization stress, followed by investigating their pain susceptibilities and fatigue symptoms. To assess whether enhanced antioxidant capacity can counter the effects of GW agents, transgenic mice overexpressing extracellular superoxide dismutase (SOD3OE) were also examined. KEY FINDINGS: The mouse model recapitulated several aspects of the human illness, including hyperalgesia, impaired descending inhibition of pain, and increased tonic pain. There is a close association between chronic pain and fatigue in GWI patients. Consistent with this observation, the mouse model showed a significant reduction in physical endurance on the treadmill. Examination of skeletal muscles suggested reduction in mitochondrial functions may have contributed to the fatigue symptoms. Furthermore, the negative impacts of GW agents in pain susceptibilities were largely diminished in SOD3OE mice, suggesting that increased oxidative stress was associated with the emergence of these Gulf War symptoms. SIGNIFICANCE: the mouse model will be suitable for delineating specific defects in the pain pathways and mechanisms of fatigue in GWI.

Neurological symptoms and axonal damage in COVID-19 survivors: are there sequelae?

The persistence of neurological symptoms after SARS-CoV-2 infection, as well as the presence of late axonal damage, is still unknown. We performed extensive systemic and neurological follow-up evaluations in 107 out of 193 consecutive patients admitted to the COVID-19 medical unit, University Hospital of Verona, Italy between March and June 2020. We analysed serum neurofilament light chain (NfL) levels in all cases including a subgroup (n = 29) of patients with available onset samples. Comparisons between clinical and biomarker data were then performed. Neurological symptoms were still present in a significant number (n = 49) of patients over the follow-up. The most common reported symptoms were hyposmia (n = 11), fatigue (n = 28), myalgia (n = 14), and impaired memory (n = 11) and were more common in cases with severe acute COVID-19. Follow-up serum NfL values (15.2 pg/mL, range 2.4-62.4) were within normal range in all except 5 patients and did not differentiate patients with vs without persistent neurological symptoms. In patients with available onset and follow-up samples, a significant (p < 0.001) decrease of NfL levels was observed and was more evident in patients with a severe acute disease. Despite the common persistence of neurological symptoms, COVID-19 survivors do not show active axonal damage, which seems a peculiar feature of acute SARS-CoV-2 infection.

Possible inflammatory mechanisms and predictors of Parkinson's disease patients with fatigue (Brief Review).

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the substantia nigra and the abnormal cytoplasmic accumulation of proteinaceous aggregates called Lewy bodies (LBs), mainly composed of α-synuclein (α-syn). In recent years, it has been gradually recognized that fatigue is one of the most common and disabling symptoms in PD patients, with a prevalence of approximately 50%. Although neuroinflammation, a pathological hallmark of PD, is closely associated with fatigue, present mechanisms of fatigue in PD patients have not yet been systematically summarized, with their inflammatory predictors remaining controversial. Therefore, the aim of this brief review is to fill in the gaps in our understanding on the inflammatory factors involved in the pathophysiological mechanisms of fatigue and predicting its occurrence in PD patients. The determination of fatigue is mainly assessed using the Parkinson Fatigue Scale 16 (PFS-16) and Fatigue Severity Scale 9 (FSS-9). Several studies have reported that inflammatory marker levels, such as interleukin-6 (IL-6), and other inflammatory predictors closely associated with fatigue, such as soluble IL-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), and red blood cell distribution width (RDW), may help detect fatigue. Moreover, the following inflammatory mechanisms may be involved. (1) Abnormal aggregation of α-syn undergoes a conformational change, which then activates toll-like receptor 4 (TLR4) to release a large number of proinflammatory cytokines, causing fatigue symptoms. (2) Chronic peripheral inflammation and immune activation responses induce elevated levels of proinflammatory cytokines in PD patients, which enter the brain mainly through the traditional endocrine route or via direct vagus nerve transmission. The rising levels of proinflammatory cytokines cause the destruction of the blood-brain barrier (BBB) by combining with BBB endothelial cells, allowing many proinflammatory cytokines to cross the destroyed BBB and enter the brain, preventing astrocytes from reuptaking glutamate and laying foundations for the occurrence of fatigue. Furthermore, studies have suggested that fatigue symptoms in PD patients often represent a poor prognosis. Nevertheless, if the aforementioned inflammatory markers can effectively predict the occurrence of fatigue and allow early intervention, the prognosis of PD patients could be significantly improved. At present, its management mainly includes medical treatment (levodopa, dopamine receptor agonists, rasagiline, and antidepressants) and non-medical treatment (acupuncture and yoga). Thus, it is of great significance to be able to practice early detection and intervention in fatigue and improve the prognosis of patients with PD.

Bridging the research to practice gap: a systematic scoping review of implementation of interventions for cancer-related fatigue management.

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common and distressing symptoms in people with cancer. Although efficacy of interventions for CRF have been extensively investigated, less has been done to ensure successful translation into routine clinical practice. The aim of this systematic scoping review was to synthesise knowledge surrounding the implementation of CRF interventions, summarise the processes and outcomes of implementation strategies used, and identify opportunities for further research. METHODS: PubMed, Cochrane CENTRAL, EMBASE and CINAHL databases were searched (up to December 2020). The Cochrane Effective Practice and Organisation of Care (EPOC) Group taxonomy and the RE-AIM Framework were used to guide the evaluation of implementation strategies and outcomes, respectively. RESULTS: Six studies were included. Three used an implementation framework (PARIHS, KTA, Cullens & Adams' Implementation Guide) to guide implementation. Overall, the implementation strategies used across all studies were reported to have directly resulted in immediate changes at the clinician level (e.g., increased clinician behaviours, self-efficacy, attitudes, knowledge of CRF management). No clear relationship was found between the use of implementation models and the number or type of implementation strategies used. For outcomes, Effectiveness and Implementation were the most highly reported RE-AIM measures followed by Reach then Maintenance. Adoption was the least reported. CONCLUSIONS: Despite the high prevalence of CRF and evidence-based interventions for managing CRF, there is limited evidence informing the sustainable implementation of these interventions. This systematic scoping review emphasises the lack of quality CRF implementation studies presently available in the literature leading to a disconnect between effective CRF interventions, routine clinical care, and cancer survivors at present. This review highlights the need for robust study designs guided by established frameworks to methodically design and evaluate the implementation of CRF management interventions in the future.

Understanding Fatigue in Sjögren's Syndrome: Outcome Measures, Biomarkers and Possible Interventions.

Sjögren's syndrome (SS) is an autoimmune disease affecting the salivary and lacrimal glands. Symptoms range from dryness to severe extra-glandular disease involving manifestations in the skin, lungs, nervous system, and kidney. Fatigue occurs in 70% of patients, characterizing primary SS (pSS) and significantly impacting the patient's quality of life. There are some generic and specific instruments used to measure fatigue in SS. The mechanisms involved with fatigue in SS are still poorly understood, but it appears fatigue signaling pathways are more associated with cell protection and defense than with pro-inflammatory pathways. There are no established pharmacological treatment options for fatigue in pSS. So far, exercise and neuromodulation techniques have shown positive effects on fatigue in pSS. This study briefly reviews fatigue in pSS, with special attention to outcome measures, biomarkers, and possible treatment options.