Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case–control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1–3 and n = 36 with CRP >3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.

Objectives: Antidepressants are among the most prescribed medications in older adults. In this study we aimed to explore the trends in the use of antidepressants in older Swedish adults between 2006 and 2020. Methods: We conducted a retrospective repeated cross-sectional study, where we included all older adults (65 years and older) registered in the Swedish National Prescribed Drug Register between 2006 and 2020. We estimated the use of antidepressants in older people for each year, across the 21 Swedish regions. Results: The Swedish population of older adults increased from 1.2 million in 2006 to 1.7 million in 2020. There was an increase in antidepressant use from 12.4% in 2006 to 13.2% in 2019 and 13.8% in 2020. We found that the use of antidepressants varied across age groups, older adults 85+ had a higher use (18.2% in 2006, 18.2% in 2019 and 19.4% in 2020) compared to those 65-74 years of age (9.6% in 2006, 11.7% in 2019 and 12.2% in 2020). Individuals who used antidepressants were generally older (mean age = 77.7) and more often women, compared to individuals who did not use antidepressants (mean age =75.7). Moreover, individuals who used antidepressants also had a higher use of benzodiazepine compared to non-users (25.1% vs. 6.4% in 2006; 16.0% vs. 2.7% in 2019 and 15.6% vs. 2.5% in 2020), sleeping drugs (27.7% vs. 10.9% in 2006; 25.2% vs. 9.3% in 2019 and 24.6% vs. 8.9% in 2020), first generation antipsychotics (1.1% vs. 4.0% in 2006 and 0.3% vs. 1.3% in 2020) and second-generation antipsychotics (1.0% vs. 6.3% in 2006 and 0.8% vs. 6.3% in 2020). Citalopram was the most frequently used antidepressant. However, its use declined from 2006 to 2020 and instead we observed an increase in the use of mirtazapine and sertraline. The prescription of tricyclic antidepressants (TCA), selective monoamine-A inhibitors and lithium was relative stable over time. Overall, antidepressants were prescribed at doses close to the defined daily doses (DDD), except for TCA, mianserin, bupropion and venlafaxine which were often prescribed at lower doses. Conclusions: We found a slight increase in antidepressant prescription in Sweden between 2006 and 2020, with older adults 85 years and older using more antidepressants compared to those 65-74 years of age. Use of antidepressants was associated with increased use of benzodiazepines, sleeping drugs (zolpidem and zopiclone), as well as first- and second-generation antipsychotics. Citalopram was the most prescribed antidepressant, but its use has declined over time.

AbstractBackgroundDepression and overweight are each associated with abnormal immune system activation. We sought to disentangle the extent to which depressive symptoms and overweight status contributed to increased inflammation and abnormal cortisol levels.MethodsParticipants were recruited through the Wellcome Trust NIMA Consortium. The sample of 216 participants consisted of 69 overweight patients with depression; 35 overweight controls; 55 normal-weight patients with depression and 57 normal-weight controls. Peripheral inflammation was measured as high-sensitivity C-Reactive Protein (hsCRP) in serum. Salivary cortisol was collected at multiple points throughout the day to measure cortisol awakening response and diurnal cortisol levels.ResultsOverweight patients with depression had significantly higher hsCRP compared with overweight controls (p = 0.042), normal-weight depressed patients (p < 0.001) and normal-weight controls (p < 0.001), after controlling for age and gender. Multivariable logistic regression showed that comorbid depression and overweight significantly increased the risk of clinically elevated hsCRP levels ⩾3 mg/L (OR 2.44, 1.28–3.94). In a separate multivariable logistic regression model, overweight status contributed most to the risk of having hsCRP levels ⩾3 mg/L (OR 1.52, 0.7–2.41), while depression also contributed a significant risk (OR 1.09, 0.27–2). There were no significant differences between groups in cortisol awakening response and diurnal cortisol levels.ConclusionComorbid depression and overweight status are associated with increased hsCRP, and the coexistence of these conditions amplified the risk of clinically elevated hsCRP levels. Overweight status contributed most to the risk of clinically elevated hsCRP levels, but depression also contributed to a significant risk. We observed no differences in cortisol levels between groups.

Background: Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive disorder is more prevalent in females than in males, with sex differences present in antidepressant treatment response and in immune system regulation. To explore sex differences in inflammatory profiles and treatment responses, we investigated a cohort of patients with treatment resistant depression (TRD), for which they received an adjunctive, anti-inflammatory treatment with minocycline - the Minocycline in Depression (MINDEP) study. Methods: The MINDEP study is a 4-week double-blind, randomised, placebo-controlled clinical trial (stratified by sex) with 39 TRD participants, which demonstrated the efficacy of minocycline, an antibiotic with antiinflammatory properties, in TRD patients with major depressive disorder (MDD) and evidence of low-grade inflammation measured with C-reactive protein (CRP) >= 3 mg/L. In these secondary analyses, we investigated the differential effects of minocycline in females (N = 22, 10 randomised to minocycline and 12 randomised to placebo) and in males (N = 17, 8 randomised to minocycline and 9 randomised to placebo) on changes in depressive symptoms (Delta-Hamilton Rating Scale for Depression (HAMD)-17), taking also into consideration CRP levels (CRP >= 3 mg/L vs. CRP <3 mg/L). Additionally, we investigated the role of serum IL-6 in predicting treatment response to minocycline, using sex-specific medians of IL-6, in novel exploratory analyses. Results: Sex differences in Delta-HAMD-17 indicate that only females (F =10.49, p = 0.005), but not males (F = 1.64, p = 0.22), presented an effect of CRP levels on the response to minocycline. Also, we detected sex differences in the relationship between serum CRP and IL-6 levels: CRP was strongly correlated with IL-6 in females (Spearman's rho = 0.658, P < 0.001) but not in males (rho = 0.007, p = 0.979). Exploratory analyses found that IL-6 was indeed a better predictor of response than minocycline than CRP, as we found an interaction between study arms and IL-6 groups (above and below the IL-6 sex-specific median) in females (F = 4.435 p = 0.050) and, at trend statistical level, in males (F = 4.258 p = 0.060). Moreover, Delta-HAMD-17 was numerically comparable in the two high-IL-6 group taking minocycline (females, mean 9.20 +/- SD 7.80; males, mean 8.80 +/- SD 5.97), confirming that high IL-6, differently from high CRP, identified responders to minocycline both in males and females. Conclusion: Our findings highlight the need of sex-specific inflammatory biomarkers in predicting antidepressant response to anti-inflammatories in TRD patients, with the possibility of CRP being a relevant predictor of treatment response only for females, and IL-6 being relevant for both sexes.

Synaptic dysfunction is an early event in Alzheimer's disease. Post-mortem studies suggest that alterations in synaptic proteins are associated with cognitive decline in Alzheimer's disease. We measured the concentration of three synaptic proteins, zinc transporter protein 3, dynamin1 and AMPA glutamate receptor 3 in cerebrospinal fluid of subjects with mild cognitive impairment (n = 18) and Alzheimer's disease (n = 18) and compared the levels to cognitively and neurologically healthy controls (n = 18) by using ELISA assay. In addition, we aimed to assess the translational potential of these synaptic proteins in two established amyloid precursor protein knock-in Alzheimer's disease mouse models by assessing the cerebrospinal fluid, hippocampal and cortical synaptic protein concentrations. Using ELISA, we measured in parallel these three proteins in cerebrospinal fluid and/or brain of 12- and 24-month-old AppNL-F and AppNL-G-F knock-in mice and AppWt control mice. The regional distribution and expression of these proteins were explored upon aging of the App knock-in models by quantitative immunofluorescence microscopy. Notably, we found a significant increase in concentrations of zinc transporter protein 3 and AMPA glutamate receptor 3 in cerebrospinal fluid of both patient groups compared with cognitively healthy controls. Dynamin1 concentration was significantly higher in Alzheimer's disease patients. Remarkably, patients with mild cognitive impairment who converted to Alzheimer's disease (n = 7) within 2 years exhibited elevated baseline cerebrospinal fluid zinc transporter protein 3 concentrations compared with mild cognitive impairment patients who did not convert (n = 11). Interestingly, similar to the alterations in Alzheimer's disease subjects, cerebrospinal fluid AMPA glutamate receptor 3 concentration was significantly higher in AppNL-G-F knock-in mice when compared with wild-type controls. Furthermore, we have detected age and brain regional specific changes of the three synaptic proteins in the hippocampus and prefrontal cortex of both AppNL-F and AppNL-G-F knock-in mice. Notably, all the three cerebrospinal fluid synaptic protein concentrations correlated negatively with concentrations in hippocampal lysates. The elevated zinc transporter protein 3 concentrations in the cerebrospinal fluid of converter versus non-converter mild cognitive impairment patients suggests a prospective role of zinc transporter 3 in differentiating dementia patients of the biological continuum of Alzheimer's disease. The increased cerebrospinal fluid concentrations of synaptic proteins in both patient groups, potentially reflecting synaptic alterations in the brain, were similarly observed in the amyloid precursor protein knock-in mouse models highlighting the translational potential of these proteins as markers for synaptic alterations. These synaptic markers could potentially help reduce the current disparities between human and animal model-based studies aiding the translation of preclinical discoveries of pathophysiological changes into clinical research.

Processing-in-memory (PIM) proposes to move computational components inside memory units to alleviate the high cost of data movement in big data processing. This approach has been recently utilized to reach high performance and energy-efficiency in large-scale graph processing. This paper analyzes a state-of-the-art PIM accelerator for graph processing and identifies message queue management as a significant bottleneck for system efficiency. Two metrics were introduced for representing the waiting time and processor utilization. We then present a lightweight solution for reducing waiting time caused by the message queue while increasing resource utilization in the system. Our simulation results on a set of real-world graph examples indicate that the enhanced graph processing system achieves 40% reduction in the overall execution time and 15% system energy savings over the baseline PIM based accelerator.

BACKGROUND:Peripheral immune markers have previously been linked to a poor response to antipsychotic medication and more severe negative symptoms at the onset of psychosis. The present study investigated the association of blood cytokines and complement markers with the presence of antipsychotic non-response and symptom severity in patients with psychosis. METHODS:This cross-sectional study recruited 94 patients with schizophrenia and other psychoses, of whom 47 were defined as antipsychotic responders and 47 as antipsychotic non-responders. In all subjects we measured plasma levels of cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, and IFN-γ), complement markers (C1-inhibitor, C3, C4, C3a, C3b, Bb, factor D, C5a, terminal complement complex) and high sensitivity C-reactive protein (hsCRP). Symptom severity was recorded using the Positive and Negative Syndrome scale for Schizophrenia (PANSS). Binary logistic regression tested each immune marker as predictor of response status while covarying for relevant socio-demographic variables. Correlation analyses tested the association between immune markers and the severity of symptoms. RESULTS:Interleukin (IL)-8 significantly predicted antipsychotic non-response (OR=24.70, 95% CI, 1.35-453.23, p = 0.03). Other immune markers were not associated with antipsychotic response. IL-6, IL-8, IL-10 and TNF-α significantly positively correlated with negative psychotic symptoms. CONCLUSIONS:Higher levels of IL-8 are associated with a poor response to antipsychotic treatment. Increased cytokines levels are specifically associated with more severe negative symptoms in patients with schizophrenia and other psychoses.

Inflammatory processes in the Central Nervous System (CNS) have been proposed to mediate the association between peripheral inflammation and the development of psychiatric disorders, but we currently lack sensitive measures of CNS inflammation for human studies in vivo. Here we used quantitative MRI (qMRI) to explore the in vivo central response to a peripheral immune challenge in healthy humans, and we assessed whether changes in quantitative relaxometry MRI parameters were associated with changes in peripheral inflammation. Quantitative relaxation times (T1 & T2) and Proton Density (PD) were measured in n = 6 healthy males (mean age = 30.5 +/- 6.8 years) in two MRI assessments collected before and 24 hours after a subcutaneous injection of the proinflammatory cytokine and immune activator, interferon-alpha (IFN-alpha). Serum levels of immune markers and markers of blood-brain barrier integrity (S100B) were also measured before and after the injection. Region of interest and histogram-based analyses (optimized for the small sample size) showed a statistically significant increase of both T1 (t(5) = 3.78, p = 0.013) and PD (t(5) = 2.91, p = 0.033) parameters in the bilateral hippocampus after IFN-alpha administration. T1 peak values in bilateral hippocampus were positively correlated with serum Tumour Necrosis Factor-alpha levels at 24 h after the injection, when this cytokine peaked (Spearman's rho = 0.67, p = 0.018) and negatively correlated with S100B levels (Spearman's rho =-0.826, p = 0.001). Our data suggest that peripheral administration of IFN-alpha produces acute changes in brain qMRI which might indicate a brain immune response. This is supported by the association of such changes with low-grade peripheral inflammation.

To characterize features and outcomes of intravenous drug use (IVDU)-associated endophthalmitis.Retrospective cross-sectional study.A retrospective chart review of all cases of endophthalmitis seen between September 2006 and November 2014 at a single academic referral center was performed. All cases of IVDU-associated endophthalmitis were identified and characterized.Ophthalmic examination findings, microbial results, visual outcomes, and secondary ocular sequelae.Thirty patients (32 eyes) with IVDU-associated endophthalmitis were identified, which represented 9% of all endophthalmitis patients (n = 338) and 44% of all endogenous endophthalmitis patients (n = 68). Mean follow-up was 11 months. All eyes had vitritis, 6 had hypopyon, and 2 had subretinal abscesses. Twenty eyes had macular involvement, 8 eyes had no macular involvement, and media opacities precluded macular assessment in 4 eyes. Initial treatment was needle vitreous biopsy with intravitreal antibiotics ("tap and inject") in 25 eyes (78%) and pars plana vitrectomy (PPV) in 6 eyes (19%); 1 patient refused ocular treatment. An organism was identified from at least 1 source in 75% of eyes (24/32): 59% fungal, 16% bacterial, 22% negative cultures, and 3% refused ocular cultures. Mean visual acuity improved significantly between initial examination and final follow-up (1.64 logMAR to 0.91 logMAR, P < 0.0001). At final follow-up, 90% of eyes had improved vision compared with presentation, 31% of eyes had 20/40 or better vision, and 25% of eyes had 20/200 or worse vision. Twenty-one eyes (66%) required PPV for their infection—6 initially and 15 secondarily after tap and inject. Sixty-nine percent of eyes (9/13) that had cultures sent from a secondary PPV had positive cultures, despite almost all receiving appropriate intravitreal antibiotic therapy at the time of the tap and inject. Eight patients (27%) had extraocular signs of infection. Twenty eyes (63%) suffered secondary ocular sequelae.This represents the largest series of IVDU-associated endophthalmitis. Bacterial etiologies constitute an important share of cases. A majority of patients eventually required PPV and there was frequent culture positivity even after tap and inject with appropriate antibiotics; therefore, early PPV may have an important role in management.

Background: Cognitive deficits arising in the course of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease with dementia (PDD) are directly linked to synaptic loss. Postmortem studies suggest that zinc transporter protein 3 (ZnT3), AMPA glutamate receptor 3 (GluA3), and Dynamin1 are associated with cognitive decline in AD and Lewy body dementia patients. Objective: We aimed to evaluate the diagnostic value of ZnT3, GluA3, and Dynamin 1 in the cerebrospinal fluid (CSF) of patients with dementia due to AD, DLB, and PDD compared to cognitively normal subjective cognitive decline (SCD) patients in a retrospective study. In addition, we assessed the relationship between synaptic markers and age, sex, cognitive impairment, and depressive symptoms as well as CSF amyloid, phosphorylated tau (p-tau), and total tau (T-tau). Methods: Commercially available ELISA immunoassay was used to measure the levels of proteins in a total of 97 CSF samples from AD (N = 24), PDD (N =18), DLB (N = 27), and SCD (N = 28) patients. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE). Results: We found a significant increase in the concentrations of ZnT3, GluA3, and Dynamin1 in AD (p = 0.002) and of ZnT3 and Dynamin 1 in DLB (p = 0.001, p = 0.002) when compared to SCD patients. Changes in ZnT3 concentrations correlated with MMSE scores in AD (p = 0.011), and with depressive symptoms in SCD (p = 0.041). Conclusion: We found alteration of CSF levels of synaptic proteins in AD, PDD, and DLB. Our results reveal distinct changes in CSF concentrations of ZnT3 that could reflect cognitive impairment in AD with implications for future prognostic and diagnostic marker development.

The corneal endothelium state is verified on the basis of an in vivo specular microscope image from which the shape and density of cells are exploited for data description. Due to the relatively low image quality resulting from a high magnification of the living, non-stained tissue, both manual and automatic analysis of the data is a challenging task. Although, many automatic or semi-automatic solutions have already been introduced, all of them are prone to inaccuracy.This work presents a comparison of four methods (fully-automated or semi-automated) for endothelial cell segmentation, all of which represent a different approach to cell segmentation; fast robust stochastic watershed (FRSW), KH method, active contours solution (SNAKE), and TOPCON ImageNET. Moreover, an improvement framework is introduced which aims to unify precise cell border location in images pre-processed with differing techniques. Finally, the influence of the selected methods on clinical parameters is examined, both with and without the improvement framework application.The experiments revealed that although the image segmentation approaches differ, the measures calculated for clinical parameters are in high accordance when CV (coefficient of variation), and CVSL (coefficient of variation of cell sides length) are considered. Higher variation was noticed for the H (hexagonality) metric. Utilisation of the improvement framework assured better repeatability of precise endothelial cell border location between the methods while diminishing the dispersion of clinical parameter values calculated for such images. Finally, it was proven statistically that the image processing method applied for endothelial cell analysis does not influence the ability to differentiate between the images using medical parameters.

Classic arterial and venous anatomy of the upper extremity are presented in this chapter. Congenital variants are discussed, as well as clinical correlates.

Depression is associated with peripheral inflammation, but its link with brain microglial activity remains unclear. In seven healthy males, we used repeated translocator protein-Positron Emission Tomography (TSPO-PET) dynamic scans with [11C]PBR28 to image brain microglial activation before and 24 h after the immune challenge interferon (IFN)-α. We also investigated the association between changes in peripheral inflammation, changes in microglial activity, and changes in mood. IFN-α administration decreased [11C]PBR28 PET tissue volume of distribution (Vt) across the brain (−20 ± 4%; t6 = 4.1, p = 0.01), but after correction for radioligand free-plasma fraction there were no longer any changes (+23 ± 31%; t = 0.1, p = 0.91). IFN-α increased serum IL-6 (1826 ± 513%, t6 = −7.5, p < 0.001), IL-7 (39 ± 12%, t6 = −3.6, p = 0.01), IL-10 (328 ± 48%, t6 = −12.8, p < 0.001), and IFN-γ (272 ± 64%, t6 = −7.0, p < 0.001) at 4–6 h, and increased serum TNF-α (49 ± 7.6%, t6 = −7.5, p < 0.001), IL-8 (39 ± 12%, t6 = −3.5, p = 0.013), and C-reactive protein (1320 ± 459%, t6 = −7.2, p < 0.001) at 24 h. IFN-α induced temporary mood changes and sickness symptoms after 4–6 h, measured as an increase in POMS-2 total mood score, confusion and fatigue, and a decrease in vigor and friendliness (all p ≤ 0.04). No association was found between changes in peripheral inflammation and changes in PET or mood measures. Our work suggests that brain TSPO-PET signal is highly dependent of inflammation-induced changes in ligand binding to plasma proteins. This limits its usefulness as a sensitive marker of neuroinflammation and consequently, data interpretation. Thus, our results can be interpreted as showing either that [11C]PBR28 is not sensitive enough under these conditions, or that there is simply no microglial activation in this model.

We have corrected this Article post-publication, because Dr. Cattaneo's affiliation details were originally incorrect (she was affiliated with three institutions but is in fact only linked to one: Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia). These changes reflect in both the PDF and HTML versions of this Article.

Matching pedestrians across disjoint camera views, known as person re-identification (re-id), is a challenging problem that is of importance to visual recognition and surveillance. Most existing methods exploit local regions with spatial manipulation to perform matching in local correspondences. However, they essentially extract fixed representations from pre-divided regions for each image and then perform matching based on these extracted representations. For models in this pipeline, local finer patterns that are crucial to distinguish positive pairs from negative ones cannot be captured, and thus making them underperformed. In this paper, we propose a novel deep multiplicative integration gating function, which answers the question of what-and-where to match for effective person re-id. To address what to match, our deep network emphasizes common local patterns by learning joint representations in a multiplicative way. The network comprises two Convolutional Neural Networks (CNNs) to extract convolutional activations, and generates relevant descriptors for pedestrian matching. This leads to flexible representations for pair-wise images. To address where to match, we combat the spatial misalignment by performing spatially recurrent pooling via a four-directional recurrent neural network to impose spatial dependency over all positions with respect to the entire image. The proposed network is designed to be end-to-end trainable to characterize local pairwise feature interactions in a spatially aligned manner. To demonstrate the superiority of our method, extensive experiments are conducted over three benchmark data sets: VIPeR, CUHK03 and Market-1501.

•Patients depression have higher CSF levels of IL-6 and TNF-α than controls.•Patients with depression have higher PET TSPO expression in different brain regions.•Post-mortem data suggest a reduction in astrocytes and oligodendrocytes in depression.•There is little correlation between central and peripheral markers of inflammation.