The Karolinska NeuroCOVID study protocol: Neurocognitive impairment, biomarkers and advanced imaging in critical care survivors

Background: This is the study plan of the Karolinska NeuroCOVID study, a study of neurocognitive impairment after severe COVID-19, relating post-intensive care unit (ICU) cognitive and neurological deficits to biofluid markers and MRI. The COVID-19 pandemic has posed enormous health challenges to individuals and health-care systems worldwide. An emerging feature of severe COVID-19 is that of temporary and extended neurocognitive impairment, exhibiting a myriad of symptoms and signs. The causes of this symptomatology have not yet been fully elucidated. Methods: In this study, we aim to investigate patients treated for severe COVID-19 in the ICU, as to describe and relate serum-, plasma- and cerebrospinal fluid-borne molecular and cellular biomarkers of immune activity, coagulopathy, cerebral damage, neuronal inflammation, and degeneration, to the temporal development of structural and functional changes within the brain as evident by serial MRI and extensive cognitive assessments at 3–12 months after ICU discharge. Results: To date, we have performed 51 3-month follow-up MRIs in the ICU survivors. Of these, two patients (~4%) have had incidental findings on brain MRI findings requiring activation of the Incidental Findings Management Plan. Furthermore, the neuropsychological and neurological examinations have so far revealed varying and mixed patterns. Several patients expressed cognitive and/or mental concerns and fatigue, complaints closely related to brain fog. Conclusion: The study goal is to gain a better understanding of the pathological mechanisms and neurological consequences of this new disease, with a special emphasis on neurodegenerative and neuroinflammatory processes, in order to identify targets of intervention and rehabilitation

Reproducibility of postural control measurement during unstable sitting in low back pain patients

<p>Abstract</p> <p>Background</p> <p>Postural control tests like standing and sitting stabilometry are widely used to evaluate neuromuscular control related to trunk balance in low back pain patients. Chronic low back pain patients have lesser postural control compared to healthy subjects. Few studies have assessed the reproducibility of the centre of pressure deviations and to our knowledge no studies have investigated the reproducibility of three-dimensional kinematics of postural control tests in a low back pain population. Therefore the aim of this study was to assess the test-retest reproducibility of a seated postural control test in low back pain patients.</p> <p>Methods</p> <p>Postural control in low back pain patients was registered by a three dimensional motion analysis system combined with a force plate. Sixteen chronic low back pain patients having complaints for at least six months, were included based on specific clinical criteria. Every subject performed 4 postural control tests. Every test was repeated 4 times and lasted 40 seconds. The force plate registered the deviations of the centre of pressure. A Vicon-612-datastation, equipped with 7 infra-red M1 camera's, was used to track 13 markers attached to the torso and pelvis in order to estimate their angular displacement in the 3 cardinal planes.</p> <p>Results</p> <p>All Intraclass Correlation Coefficients (ICC) calculated for the force plate variables did not exceed 0.73 (ranging between 0.11 and 0.73). As for the torso, ICC's of the mean flexion-extension and rotation angles ranged from 0.65 to 0.93 and of the mean lateral flexion angle from 0.50 to 0.67. For the pelvis the ICC of the mean flexion-extension angle varied between 0.66 and 0.83, the mean lateral flexion angle between 0.16 and 0.81 and the mean rotation angle between 0.40 and 0.62.</p> <p>Consecutive data suggest that the low test-retest reproducibility is probably due to a learning effect.</p> <p>Conclusion</p> <p>The test-retest reproducibility of these postural control tests in an unstable sitting position can globally be considered as rather moderate. In order to improve the test-retest reproducibility, a learning period may be advisable at the beginning of the test.</p

Medically certified sickness absence with insurance benefits in women with and without children

Background: Sickness absence in Sweden is high, particularly in young women and the reasons are unclear. Many Swedish women combine parenthood and work and are facing demands that may contribute to impaired health and well-being. We compared mothers and women without children under different conditions, assuming increased sickness absence in mothers, due to time-based stress and psychological strain. Methods: All women born in 1960–79 (1.2 million) were followed from 1993 to 2003. Information on children in the home for each year was related to medically certified sickness absence with insurance benefits the year after. We used age and time-stratified proportional hazard regression models accounting for the individual's changes on study variables over time. Data were retrieved from national administrative registers. Results: Sickness absence was higher in mothers than in women without children, the relative risks decreased by age, with no effect after the age of 35 years. An effect appeared in lonely women irrespective of age, while in cohabiting women only for the ages 20–25 years. Mothers showed increased sickness absence in all subgroups of country of birth, education, income, sector of employment and place of residence. The relation between number of children and sickness absence was nonlinear, with the highest relative risks for mothers of one child. The upward trend of sickness absence at the end of 1990s was steeper for mothers compared to women without children. Conclusion: Despite the well-developed social security system and child care services in Sweden, parenthood predicts increased sickness absence, particularly in young and in lone women

Lipopolysaccharides Impair Insulin Gene Expression in Isolated Islets of Langerhans via Toll-Like Receptor-4 and NF-κB Signalling

BACKGROUND:Type 2 diabetes is characterized by pancreatic β-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that the signalling cascade activated by lipopolysaccharides (LPS) binding to Toll-Like Receptor 4 (TLR4) exerts deleterious effects on pancreatic β-cell function; however, the molecular mechanisms of these effects are incompletely understood. In this study, we tested the hypothesis that LPS alters insulin gene expression via TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in islets. METHODOLOGY/PRINCIPAL FINDINGS:A 24-h exposure of isolated human, rat and mouse islets of Langerhans to LPS dose-dependently reduced insulin gene expression. This was associated in mouse and rat islets with decreased mRNA expression of pancreas-duodenum homebox-1 (PDX-1) and mammalian homologue of avian MafA/l-Maf (MafA). Accordingly, LPS exposure also decreased glucose-induced insulin secretion. LPS repression of insulin, PDX-1 and MafA expression, as well as its inhibition of insulin secretion, were not observed in islets from TLR4-deficient mice. LPS inhibition of β-cell gene expression in rat islets was prevented by inhibition of the NF-κB pathway, but not the p38 mitogen-activated protein kinase (p38 MAPK) pathway. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate that LPS inhibit β-cell gene expression in a TLR4-dependent manner and via NF-κB signaling in pancreatic islets, suggesting a novel mechanism by which the gut microbiota might affect pancreatic β-cell function

Non-specific psychological distress, smoking status and smoking cessation: United States National Health Interview Survey 2005

<p>Abstract</p> <p>Background</p> <p>It is well established that smoking rates in people with common mental disorders such as anxiety or depressive disorders are much higher than in people without mental disorders. It is less clear whether people with these mental disorders want to quit smoking, attempt to quit smoking or successfully quit smoking at the same rate as people without such disorders.</p> <p>Methods</p> <p>We used data from the 2005 Cancer Control Supplement to the United States National Health Interview Survey to explore the relationship between psychological distress as measured using the K6 scale and smoking cessation, by comparing current smokers who had tried unsuccessfully to quit in the previous 12 months to people able to quit for at least 7 to 24 months prior to the survey. We also used data from the 2007 Australian National Survey of Mental Health and Wellbeing to examine the relationship between psychological distress (K6) scores and duration of mental illness.</p> <p>Results</p> <p>The majority of people with high K6 psychological distress scores also meet diagnostic criteria for mental disorders, and over 90% of these people had first onset of mental disorder more than 2 years prior to the survey. We found that people with high levels of non-specific psychological distress were more likely to be current smokers. They were as likely as people with low levels of psychological distress to report wanting to quit smoking, trying to quit smoking, and to have used smoking cessation aids. However, they were significantly less likely to have quit smoking.</p> <p>Conclusions</p> <p>The strong association between K6 psychological distress scores and mental disorders of long duration suggests that the K6 measure is a useful proxy for ongoing mental health problems. As people with anxiety and depressive disorders make up a large proportion of adult smokers in the US, attention to the role of these disorders in smoking behaviours may be a useful area of further investigation for tobacco control.</p

Developmental expression of COE across the Metazoa supports a conserved role in neuronal cell-type specification and mesodermal development

The transcription factor COE (collier/olfactory-1/early B cell factor) is an unusual basic helix–loop–helix transcription factor as it lacks a basic domain and is maintained as a single copy gene in the genomes of all currently analysed non-vertebrate Metazoan genomes. Given the unique features of the COE gene, its proposed ancestral role in the specification of chemosensory neurons and the wealth of functional data from vertebrates and Drosophila, the evolutionary history of the COE gene can be readily investigated. We have examined the ways in which COE expression has diversified among the Metazoa by analysing its expression from representatives of four disparate invertebrate phyla: Ctenophora (Mnemiopsis leidyi); Mollusca (Haliotis asinina); Annelida (Capitella teleta and Chaetopterus) and Echinodermata (Strongylocentrotus purpuratus). In addition, we have studied COE function with knockdown experiments in S. purpuratus, which indicate that COE is likely to be involved in repressing serotonergic cell fate in the apical ganglion of dipleurula larvae. These analyses suggest that COE has played an important role in the evolution of ectodermally derived tissues (likely primarily nervous tissues) and mesodermally derived tissues. Our results provide a broad evolutionary foundation from which further studies aimed at the functional characterisation and evolution of COE can be investigated

Differences in the Properties and Mirna Expression Profiles between Side Populations from Hepatic Cancer Cells and Normal Liver Cells

AIMS: Because hepatic cancer stem cells (HCSCs) are believed to derive from the conversion of hepatic normal stem cells (HNSCs), the identification of the differences that distinguish HCSCs from HNSCs is important. METHODS: The HCC model was established in F344 rats by DEN induction. Using FACS analysis, side population cells from HCC (SP-HCCs) were isolated from the epithelial-like cells of HCC tissues, and the side population cells from normal liver (SP-NLCs) were isolated from syngeneic normal liver cells. The expression of stem cell markers was detected in both freshly isolated and amplified subpopulations. After induction with HGF, the differentiation of each subpopulation was analyzed by detection of early and late liver markers. In vivo, the biological characteristics of SP-HCCs and SP-NLCs were analyzed by repairing injured livers or forming tumors in nude mice. In addition, the expression of miRNAs was examined in both populations by miRNA array and QRT-PCR. RESULTS: SP-NLCs and SP-HCCs were 4.30±0.011% and 2.100±0.010% of the whole population, respectively. Both SP-NLCs and SP-HCCs displayed greater expression of stem cell markers (CD133 and EpCAM) than NSP-NLCs and NSP-HCCs, respectively (P<0.01), both after fresh isolation and amplification. Upon HGF induction, SP-NLCs generated many ALB positive cells and few CK-7 positive cells, but NSP-NLCs could generate only ALB positive cells. In contrast, SP-HCCs gave rise to only AFP positive cells. As few as 5 × 10⁵ SP-NLCs were capable of repairing liver injury, while the same number of NSP-NLCs could not repair the liver. Furthermore, only 1 × 10⁴ SP-HCCs were necessary to initiate a tumor, while NSP-HCCs could not form a tumor. Compared to SP-NLCs, 68 up-regulated and 10 down-regulated miRNAs were present in SP-HCCs (P<0.01). CONCLUSION: Based on the decisive roles of some miRNAs in the genesis of HCSCs, miRNAs may contribute to the different characteristics that distinguish SP-HCCs from SP-NLCs

More frequent, more costly? Health economic modelling aspects of monitoring glaucoma patients in England

BACKGROUND: Chronic open angle glaucoma (COAG) is an age-related eye disease causing irreversible loss of visual field (VF). Health service delivery for COAG is challenging given the large number of diagnosed patients requiring lifelong periodic monitoring by hospital eye services. Yet frequent examination better determines disease worsening and speed of VF loss under treatment. We examine the cost-effectiveness of increasing frequency of VF examinations during follow-up using a health economic model. METHODS: Two different VF monitoring schemes defined as current practice (annual VF testing) and proposed practice (three VF tests per year in the first 2 years after diagnosis) were examined. A purpose written health economic Markov model is used to test the hypothesis that cost effectiveness improves by implementing proposed practice on groups of patients stratified by age and severity of COAG. Further, a new component of the model, estimating costs of visual impairment, was added. Results were derived from a simulated cohort of 10000 patients with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) used as main outcome measures. RESULTS: An ICER of £21,392 per QALY was derived for proposed practice improving to a value of £11,382 once savings for prevented visual impairment was added to the model. Proposed practice was more cost-effective in younger patients. Proposed practice for patients with advanced disease at diagnosis generated ICERs > £60,000 per QALY; these cases would likely be on the most intensive treatment pathway making clinical information on speed of VF loss redundant. Sensitivity analysis indicated results to be robust in relation to hypothetical willingness to pay threshold identified by national guidelines, although greatest uncertainty was allied to estimates of implementation and visual impairment costs. CONCLUSION: Increasing VF monitoring at the earliest stages of follow-up for COAG appears to be cost-effective depending on reasonable assumptions about implementation costs. Our health economic model highlights benefits of stratifying patients to more or less monitoring based on age and stage of disease at diagnosis; a prospective study is needed to prove these findings. Further, this works highlights gaps in knowledge about long term costs of visual impairment

A randomised controlled trial linking mental health inpatients to community smoking cessation supports: A study protocol

<p>Abstract</p> <p>Background</p> <p>Mental health inpatients smoke at higher rates than the general population and are disproportionately affected by tobacco dependence. Despite the advent of smoke free policies within mental health hospitals, limited systems are in place to support a cessation attempt post hospitalisation, and international evidence suggests that most smokers return to pre-admission smoking levels following discharge. This protocol describes a randomised controlled trial that will test the feasibility, acceptability and efficacy of linking inpatient smoking care with ongoing community cessation support for smokers with a mental illness.</p> <p>Methods/Design</p> <p>This study will be conducted as a randomised controlled trial. 200 smokers with an acute mental illness will be recruited from a large inpatient mental health facility. Participants will complete a baseline survey and will be randomised to either a multimodal smoking cessation intervention or provided with hospital smoking care only. Randomisation will be stratified by diagnosis (psychotic, non-psychotic). Intervention participants will be provided with a brief motivational interview in the inpatient setting and options of ongoing smoking cessation support post discharge: nicotine replacement therapy (NRT); referral to Quitline; smoking cessation groups; and fortnightly telephone support. Outcome data, including cigarettes smoked per day, quit attempts, and self-reported 7-day point prevalence abstinence (validated by exhaled carbon monoxide), will be collected via blind interview at one week, two months, four months and six months post discharge. Process information will also be collected, including the use of cessation supports and cost of the intervention.</p> <p>Discussion</p> <p>This study will provide comprehensive data on the potential of an integrated, multimodal smoking cessation intervention for persons with an acute mental illness, linking inpatient with community cessation support.</p> <p>Trial Registration</p> <p>Australian and New Zealand Clinical Trials Registry ANZTCN: <a href="http://www.anzctr.org.au/ACTRN12609000465257.aspx">ACTRN12609000465257</a></p