Miracle-dz/UniFAR-FTUs huggingface dataset:
The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site of demyelination by microglia is critically important to achieve adequate remyelination and to slow the progression of the disease. However, how microglia phagocytose the myelin debris, and why clearance is impaired in MS, is not fully known; likewise, the role of the microglia in remyelination remains unclear. Recent studies using cuprizone (CPZ) as an animal model of central nervous system demyelination revealed that the up‐regulation of signaling proteins in microglia facilitates effective phagocytosis of myelin debris. Moreover, during demyelination, protective mediators are released from activated microglia, resulting in the acceleration of remyelination in the CPZ model. In contrast, inadequate microglial activation or recruitment to the site of demyelination, and the production of toxic mediators, impairs remyelination resulting in progressive demyelination. In addition to the microglia‐mediated phagocytosis, astrocytes play an important role in the phagocytic process by recruiting microglia to the site of demyelination and producing regenerative mediators. The current review is an update of these emerging findings from the CPZ animal model, discussing the roles of microglia and astrocytes in phagocytosis and myelination.
Validation of the Danish version of the Quality of Life in Hand Eczema Questionnaire (QOLHEQ)

Katie Bechman, Emma S. Cook iD , Nick Dand iD , Zenas Z.N. Yiu iD , Teresa Tsakok iD , Freya Meynell, Bolaji Coker, Alexandra Vincent, Herve Bachelez iD , Ines Barbosa, Matthew A. Brown iD , Francesca Capon iD , Claudia R. Contreras iD , Claudia De La Cruz iD , Paola Di Meglio iD , Paolo Gisondi iD , Denis Jullien iD , Jade Kelly, Jo Lambert iD , Camille Lancelot, Sinead M. Langan iD , Kayleigh J. Mason, Helen McAteer iD , Lucy Moorhead, Luigi Naldi iD , Sam Norton iD , Llu ıs Puig iD , Phyllis I. Spuls iD , Tiago Torres iD , Dominic Urmston, Amber Vesty, Richard B. Warren iD , Hoseah Waweru, John Weinman iD , Christopher E.M. Griffiths iD , Jonathan N. Barker iD , Catherine H. Smith iD , James B. Galloway iD , Satveer K. Mahil iD 5,6 and on behalf of the PsoProtect study group
Single-cell imaging of ERK and Akt activation dynamics and heterogeneity induced by G-protein-coupled receptors

ABSTRACT Kinases play key roles in signaling networks that are activated by G-protein-coupled receptors (GPCRs). Kinase activities are generally inferred from cell lysates, hiding cell-to-cell variability. To study the dynamics and heterogeneity of ERK and Akt proteins, we employed high-content biosensor imaging with kinase translocation reporters. The kinases were activated with GPCR ligands. We observed ligand concentration-dependent response kinetics to histamine, α2-adrenergic and S1P receptor stimulation. By using G-protein inhibitors, we observed that Gq mediated the ERK and Akt responses to histamine. In contrast, Gi was necessary for ERK and Akt activation in response to α2-adrenergic receptor activation. ERK and Akt were also strongly activated by S1P, showing high heterogeneity at the single-cell level, especially for ERK. Cluster analysis of time series derived from 68,000 cells obtained under the different conditions revealed several distinct populations of cells that display similar response dynamics. ERK response dynamics to S1P showed high heterogeneity, which was reduced by the inhibition of Gi. To conclude, we have set up an imaging and analysis strategy that reveals substantial cell-to-cell heterogeneity in kinase activity driven by GPCRs.
Effect of pretreatment with dexamethasone on the efficacy and immune-related adverse events of immunotherapy in first-line treatment for advanced non-small cell lung cancer: a network meta-analysis of randomized control trials.

BACKGROUND The pretreatment of dexamethasone on the efficacy and immune-related adverse events of immunotherapy involving programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PDL1) inhibitors is an effective option for the first-line treatment of advanced non-small-cell lung cancer (NSCLC). With the immunosuppressive effect, corticosteroids may be used to reduce the efficacy of PDL1 blockade, as well as prevent overactive immune responses, thereby reducing the occurrence of immune-related adverse events (irAEs). This study quantitatively summarized the current evidence, and compared the efficacy and toxicity of therapies involving chemotherapy plus PDL1 inhibitors plus dexamethasone pretreatment (I+C+D) with chemotherapy plus PDL1 inhibitors (I+C) and therapies involving PDL1 inhibitors or chemotherapy alone (I or C). METHODS The protocol of this study was registered with PROSPERO (CRD42021227281). By using a network meta-analysis approach, the different treatments were compared and ranked based on their effectiveness and rates of irAEs at the different grades. Risk rates were determined through direct meta-analysis and indirect treatment comparison. RESULTS 12 randomized clinical trials were included with a total of 7155 NSCLC patients. Network meta-analysis generated 15 comparisons. The combination treatment of I+C+D showed a longer progression-free survival and overall survival, while I+C was less toxic, and the toxicity of I+C+D or that of I+C had been significantly decreased, compared to that of monotherapy with either drug. According to the ranking analysis, I+C+D is consistently proved to be the most effective therapeutic strategy, while I+C is linked to the lowest rate of irAEs, with the rate of grade value of ≥3 irAEs. CONCLUSION The combination treatment of I+C+D is the most effective approach for the first-line treatment of NSCLC patients treated with I+C, I, or C.
A Direct Test of Competitive Versus Cooperative Episodic-Procedural Network Dynamics in Human Memory.

Classical lesion studies led to a consensus that episodic and procedural memory arises from segregated networks identified with the hippocampus and the caudate nucleus, respectively. Neuroimaging studies, however, show that competitive and cooperative interactions occur between networks during memory tasks. Furthermore, causal experiments to manipulate connectivity between these networks have not been performed in humans. Although nodes common to both networks, such as the precuneus and ventrolateral thalamus, may mediate their interaction, there is no experimental evidence for this. We tested how network-targeted noninvasive brain stimulation affects episodic-procedural network interactions and how these network manipulations affect episodic and procedural memory in healthy young adults. Compared to control (vertex) stimulation, hippocampal network-targeted stimulation increased within-network functional connectivity and hippocampal connectivity with the caudate. It also increased episodic, relative to procedural, memory, and this persisted one week later. The differential effect on episodic versus procedural memory was associated with increased functional connectivity between the caudate, precuneus, and ventrolateral thalamus. These findings provide direct evidence of episodic-procedural network competition, mediated by regions common to both networks. Enhanced hippocampal network connectivity may boost episodic, but decrease procedural, memory by co-opting resources shared between networks.
The prevalence and clinical manifestations of IgA deficiency among blood donors at transfusion centers in Shiraz, Southern Iran.

BACKGROUND IgA deficiency is the most common immunodeficiency disorder. Most affected individuals are asymptomatic, and since there are no routine diagnostic screening programs the prevalence of this disease has remained uncertain. METHODS AND MATERIALS Seven thousand blood donors who attended Fars Blood Transfusion Center, from September 2017 to March 2018, were selected randomly, and their serum IgA levels were checked by Immunoturbidimetry method. Cases with IgA levels <10 mg/dL were considered as serum IgA deficient patients. Serum IgM and IgG levels of IgA deficient cases were measured to determine selective IgA deficiency. The prevalent clinical findings of IgA deficiency were also investigated. RESULTS Ten blood donors had selective IgA deficiency: 0.14% (CI 95%: 0.001, 0.002). All cases were male, with a mean age of 36.10±9.70 years. Investigating common clinical findings in the IgA deficient cases revealed the most prevalent symptoms were recurrent upper respiratory tract infections (50%) which were significantly higher in the study group compared to the control group (P-value =0.008) and allergic disorders (40%) with no statistical difference from the control cases. CONCLUSION The prevalence of selective IgA deficiency (SIgAD) among blood donors at Fars Transfusion Center was 0.14%. The most common clinical finding among the patients with SIgAD was recurrent upper respiratory infections, followed by allergic diseases.
Risk of hepato‐pancreato‐biliary cancer is increased by primary sclerosing cholangitis in patients with inflammatory bowel disease: A population‐based cohort study

Abstract Background There is continued uncertainty regarding the risks of hepato‐pancreato‐biliary cancers in patients with inflammatory bowel disease (IBD) with or without concomitant primary sclerosing cholangitis (PSC). Objective To give updated estimates on risk of hepato‐pancreato‐biliary cancers in patients with IBD, including pancreatic cancer, hepatocellular carcinoma, gall bladder cancer, and intra – and extrahepatic cholangiocarcinoma. Methods In a population‐based cohort study, we included all patients diagnosed with IBD in Norway and Sweden from 1987 to 2016. The cohort comprised of 141,960 patients, identified through hospital databases and the National Patient Register. Participants were followed through linkage to national cancer, cause of death, and population registries. We calculated absolute risk and standardized incidence ratios (SIRs) of hepato‐pancreato‐biliary cancers by PSC and other clinical characteristics. Results Of the 141,960 IBD patients, 3.2% were diagnosed with PSC. During a median follow‐up of 10.0 years, we identified 443 biliary tract cancers (SIR 5.2, 95% confidence interval [CI] 4.8–5.7), 161 hepatocellular carcinomas (SIR 2.4, 95% CI 2.0–2.7) and 282 pancreatic cancers (SIR 1.3, 95% CI 1.2–1.5). The relative risks were considerably higher in PSC‐IBD patients, with SIR of 140 (95% CI 123–159) for biliary tract, 38.6 (95% CI 29.2–50.0) for hepatocellular, and 9.0 (95% CI 6.3–12.6) for pancreatic cancer. The SIRs were still slightly increased in non‐PSC‐IBD patients, compared to the general population. For biliary tract cancer, the cumulative probability at 25 years was 15.6% in PSC‐IBD patients, and 0.4% in non‐PSC‐IBD patients. Conclusions The dramatically increased risks of hepato‐pancreato‐biliary cancers in PSC‐IBD patients support periodic surveillance for these malignancies. While much lower, the excess relative risks in non‐PSC‐IBD patients were not trivial compared to non‐IBD related risk factors.
How patients with multiple sclerosis acquire disability

Abstract Patients with multiple sclerosis acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins and the extent to which multiple sclerosis therapies delay disability accumulation. Using the Novartis-Oxford multiple sclerosis (NO.MS) data pool spanning all multiple sclerosis phenotypes and paediatric multiple sclerosis, we evaluated ∼200 000 Expanded Disability Status Scale (EDSS) transitions from >27 000 patients with ≤15 years follow-up. We analysed three datasets: (i) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (n = 27 328); (ii) all phase 3 clinical trials (n = 8346); and (iii) all placebo-controlled phase 3 clinical trials (n = 4970). We determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening using Andersen-Gill models and observed the impact of the mechanism of worsening and disease-modifying therapies on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in the disease process, occurred in all phenotypes and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events; following a year in which relapses occurred (versus a year without relapses), the hazard increased by 31–48% (all P < 0.001). Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1), it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with disease-modifying therapies delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and 3.09 years (2.60, 3.72), respectively. In patients with relapsing-remitting multiple sclerosis, those who worsened exclusively due to RAW events took a similar length of time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses. Our data confirm that relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA begins in relapsing-remitting multiple sclerosis and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. The use of disease-modifying therapies delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.
Electrophysiological Evidence for the Suppression of Highly Salient Distractors

Abstract There has been a longstanding debate as to whether salient stimuli have the power to involuntarily capture attention. As a potential resolution to this debate, the signal suppression hypothesis proposes that salient items generate a bottom–up signal that automatically attracts attention, but that salient items can be suppressed by top–down mechanisms to prevent attentional capture. Despite much support, the signal suppression hypothesis has been challenged on the grounds that many prior studies may have used color singletons with relatively low salience that are too weak to capture attention. The current study addressed this by using previous methods to study suppression but increased the set size to improve the relative salience of the color singletons. To assess whether salient distractors captured attention, electrophysiological markers of attentional allocation (the N2pc component) and suppression (the PD component) were measured. The results provided no evidence of attentional capture, but instead indicated suppression of the highly salient singleton distractors, as indexed by the PD component. This suppression occurred even though a computational model of saliency confirmed that the color singleton was highly salient. Altogether, this supports the signal suppression hypothesis and is inconsistent with stimulus-driven models of attentional capture.
Adaptive immune responses in vaccinated patients with symptomatic SARS-CoV-2 Alpha infection

Benchmarks for protective immunity from infection or severe disease after SARS-CoV-2 vaccination are still being defined. Here, we characterized virus neutralizing and ELISA antibody levels, cellular immune responses, and viral variants in 4 separate groups: healthy controls (HCs) weeks (early) or months (late) following vaccination in comparison with symptomatic patients with SARS-CoV-2 after partial or full mRNA vaccination. During the period of the study, most symptomatic breakthrough infections were caused by the SARS-CoV-2 Alpha variant. Neutralizing antibody levels in the HCs were sustained over time against the vaccine parent virus but decreased against the Alpha variant, whereas IgG titers and T cell responses against the parent virus and Alpha variant declined over time. Both partially and fully vaccinated patients with symptomatic infections had lower virus neutralizing antibody levels against the parent virus than the HCs, similar IgG antibody titers, and similar virus-specific T cell responses measured by IFN-γ. Compared with HCs, neutralization activity against the Alpha variant was lower in the partially vaccinated infected patients and tended to be lower in the fully vaccinated infected patients. In this cohort of breakthrough infections, parent virus neutralization was the superior predictor of breakthrough infections with the Alpha variant of SARS-CoV-2.
Cystatin C-based equations for estimating glomerular filtration rate do not require race or sex coefficients

Abstract Estimation or measurement of glomerular filtration rate (GFR) is generally required for optimal treatment of patients. Plasma creatinine has been used for estimation of GFR since 1926 and plasma cystatin C since 1979. The creatinine level is strongly dependent upon muscle mass and as the average muscle mass of different populations may vary, creatinine-based GFR-estimating equations have since 1999 used more than 10 different race coefficients to improve the diagnostic performance of such equations. But ‘race’ cannot be determined by biological measurements and is thus an ill-defined biological entity and controversial as it involves self-reporting and social considerations. In contrast, cystatin C-levels are virtually independent of muscular mass and cystatin C-based GFR-estimating equations do not require race coefficients for reliable estimation of GFR. The use of cystatin C-based GFR-estimating equations, alone or in conjunction with creatinine-based GFR-estimating equations, is therefore highly recommended to eliminate the use of race coefficients in estimating GFR. Although sex is a more biology-oriented parameter than race, sex terms may in some cases be controversial, involving self-reporting and social considerations. However, sex terms are not required for adequate estimation of GFR using cystatin C-based equations.
Encoding contexts are incidentally reinstated during competitive retrieval and track the temporal dynamics of memory interference

Abstract The ability to remember an episode from our past is often hindered by competition from similar events. For example, if we want to remember the article a colleague recommended during the last lab meeting, we may need to resolve interference from other article recommendations from the same colleague. This study investigates if the contextual features specifying the encoding episodes are incidentally reinstated during competitive memory retrieval. Competition between memories was created through the AB/AC interference paradigm. Individual word-pairs were presented embedded in a slowly drifting real–word-like context. Multivariate pattern analysis (MVPA) of high temporal-resolution electroencephalographic (EEG) data was used to investigate context reactivation during memory retrieval. Behaviorally, we observed proactive (but not retroactive) interference; that is, performance for AC competitive retrieval was worse compared with a control DE noncompetitive retrieval, whereas AB retrieval did not suffer from competition. Neurally, proactive interference was accompanied by an early reinstatement of the competitor context and interference resolution was associated with the ensuing reinstatement of the target context. Together, these findings provide novel evidence showing that the encoding contexts of competing discrete events are incidentally reinstated during competitive retrieval and that such reinstatement tracks retrieval competition and subsequent interference resolution.
High-value decisions are fast and accurate, inconsistent with diminishing value sensitivity

Significance What information about economic value is incorporated into decision-makers’ choices? Across the decision sciences, several prominent models ignore average value, assuming that only value differences are incorporated into the decision-making process, while others assume diminishing sensitivity to value, suggesting that it should be more difficult to choose between high-value options. Other models suggest that high-value decisions should, if anything, be treated as less important (holding value difference constant). Across three experiments with very different types of choices (food, art, and learned stimuli), we find violations of these predictions. Contrary to expectations, the presence of high-value options makes decisions easier while also inducing more effort to get them right. It is a widely held belief that people’s choices are less sensitive to changes in value as value increases. For example, the subjective difference between $11 and $12 is believed to be smaller than between $1 and $2. This idea is consistent with applications of the Weber-Fechner Law and divisive normalization to value-based choice and with psychological interpretations of diminishing marginal utility. According to random utility theory in economics, smaller subjective differences predict less accurate choices. Meanwhile, in the context of sequential sampling models in psychology, smaller subjective differences also predict longer response times. Based on these models, we would predict decisions between high-value options to be slower and less accurate. In contrast, some have argued on normative grounds that choices between high-value options should be made with less caution, leading to faster and less accurate choices. Here, we model the dynamics of the choice process across three different choice domains, accounting for both discriminability and response caution. Contrary to predictions, we mostly observe faster and more accurate decisions (i.e., higher drift rates) between high-value options. We also observe that when participants are alerted about incoming high-value decisions, they exert more caution and not less. We rule out several explanations for these results, using tasks with both subjective and objective values. These results cast doubt on the notion that increasing value reduces discriminability.
Palliative vertical vein stenting in a critical neonate with obstructed infradiaphragmatic total anomalous pulmonary venous connection

Abstract Neonatal total anomalous pulmonary venous connection has an incidence of about ∼1–2%. 1 The clinical presentation of total anomalous pulmonary venous connection in the neonatal period is dependent on the presence or absence of pulmonary venous obstruction, which is usual when the veins connect to the umbilicovitelline system, as in infradiaphragmatic total anomalous pulmonary venous connection. Obstructed total anomalous pulmonary venous connection presents with severe respiratory distress, metabolic acidosis, and cyanosis and requires urgent surgical intervention. However, critically ill neonates with obstructed total anomalous pulmonary venous connection have a higher surgical morbidity and mortality, and pre-operative stabilisation can improve outcomes in them. We present a case of a septic term neonate with obstructed infradiaphragmatic total anomalous pulmonary venous connection who underwent emergency palliative stent placement for immediate relief of pulmonary venous obstruction.