Controls Of Similar Age Research Articles

Adjusted global antiphospholipid syndrome score (aGAPSS) is useful to predict relapses in patients with retinal vein occlusion

BackgroundA significant proportion of patients with retinal vein occlusion (RVO) are antiphospholipid antibodies (aPL) carriers. Relapsing disease occurs in nearly 10 % of cases and the role of aPL has not been established. The adjusted global antiphospholipid syndrome score (aGAPSS) was developed to assess the risk of clinical events in aPL carriers and its role in the management of RVO patients is unknown. ObjectiveTo analyze the values of aGAPSS in a large cohort of patients with RVO and population-based controls, and to assess its usefulness to predict RVO relapses. MethodsCase-control study of RVO patients and population-based controls of similar age and sex. We have assessed and compared the aPL profile and the aGAPSS score in patients with and without relapsing disease and controls. ResultsFour-hundred and seventy-two RVO patients and 346 controls were included. Fifty-seven RVO patients had antiphospholipid syndrome (RVO-APS). Of them, 75.4 % had a high-risk profile compared to 3 % in controls (p = 0.0001). The median aGAPSS values were 8 [7–13], 3 [1–4], and 3 [0–4], in RVO-APS, RVO no-APS, and controls. Nineteen patients had had a recurrence of RVO before inclusion and 8 during the follow-up. APS was more prevalent in relapsing patients. In the adjusted multivariable regression model, the best predictor for RVO recurrence during the follow-up was an aGAPSS score ≥6 (OR 5.5, CI95% 1.3–23.7; p = 0.023). ConclusionsIn patients with RVO, once the control of vascular risk factors has been optimized, the aGAPSS might help to identify those at risk of relapsing disease.

The relationship of biochemical factors related to calcium metabolism with temporomandibular disorders

ObjectiveThe aim of this study is to investigate the relationship between calcium metabolism-related biochemical factors (alkaline phosphatase, vitamin D, parathyroid hormone (PTH), calcium, phosphorus and magnesium), and temporomandibular joint (TMJ) disk displacement with reduction (DDWR). Materials and MethodsThis prospective observational study included patients with temporomandibular disorders (TMDs) (n = 50) and healthy controls (n = 50) of similar age and sex. The diagnosis of TMJ DDWR was made using the diagnostic criteria for temporomandibular joint disorders (DC/TMD). Both groups were compared in terms of serum alkaline phosphatase, 25 (OH) vitamin D, PTH, calcium, magnesium, and phosphorus levels. P<0.005 was accepted as a significant difference. ResultsThere was no significant difference between the groups in terms of age, gender, and body mass index (BMI). Calcium levels of patients with TMD were statistically significantly lower than control patients (p<0.05). While there was no significant difference between the two groups in terms of mean VIT D, the number of people with severe Vit D deficiency (<10 ng) in the TMD group was significantly higher than in the control group (p<0.05). There was no statistically significant difference between the groups in terms of serum alkaline phosphatase, magnesium, phosphorus and PTH levels. ConclusionThe differences in serum calcium and vitamin D levels seen in the study indicate that biochemical factors related to calcium metabolism may be associated with TMJ DDWR. These results suggest that calcium and vitamin D deficiency should be evaluated and corrected in patients with TMD.

Metabolomic Signatures of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is associated with many variations in metabolism, but the ex-act correlates of these metabolic disturbances with behavior and development and their links to other core metabolic disruptions are understudied. In this study, large-scale targeted LC-MS/MS metabolomic analysis was conducted on fasting morning plasma samples from 57 children with ASD (29 with neurodevelopmental regression, NDR) and 37 healthy controls of similar age and gender. Linear model determined the metabolic signatures of ASD with and without NDR, measures of behavior and neurodevelopment, as well as markers of oxidative stress, inflammation, redox, methylation, and mitochondrial metabolism. MetaboAnalyst ver 5.0 (the Wishart Research Group at the University of Alberta, Edmonton, Canada) identified the pathways associated with altered metabolic signatures. Differences in histidine and glutathione metabolism as well as aromatic amino acid (AAA) biosynthesis differentiated ASD from controls. NDR was associated with disruption in nicotinamide and energy metabolism. Sleep and neurodevelopment were associated with energy metabolism while neurodevelopment was also associated with purine metabolism and aminoacyl-tRNA biosynthesis. While behavior was as-sociated with some of the same pathways as neurodevelopment, it was also associated with alternations in neurotransmitter metabolism. Alterations in methylation was associated with aminoacyl-tRNA biosynthesis and branched chain amino acid (BCAA) and nicotinamide metabolism. Alterations in glutathione metabolism was associated with changes in glycine, serine and threonine, BCAA and AAA metabolism. Markers of oxidative stress and inflammation were as-sociated with energy metabolism and aminoacyl-tRNA biosynthesis. Alterations in mitochondrial metabolism was associated with alterations in energy metabolism and L-glutamine. Using behavioral and biochemical markers, this study finds convergent disturbances in specific metabolic pathways with ASD, particularly changes in energy, nicotinamide, neurotransmitters, and BCAA, as well as aminoacyl-tRNA biosynthesis.

Clinical use of mean platelet volume and neutrophil-to-lymphocyte ratio to predict prognosis in heart failure with preserved ejection fraction patients

Abstract Background Over the last decade, a new paradigm for heart failure with preserved ejection (HFpEF) development has been proposed. High burden of comorbidities would lead to a systemic inflammatory state and enhanced platelet activation. High platelet reactivity could be associated with higher mean platelet volume (MPV) due increased circulating immature platelets. Moreover, neutrophil-to-lymphocyte (NLR) reflects systemic inflammation. Both parameters have been associated with morbidity and mortality in heart failure (HF). However, data in HFpEF are limited. Purpose We aim to investigate the use of MPV and NLR to predict clinical outcome in HFpEF patients. Methods We prospectively enrolled 228 patients with HFpEF (79±9 years, 66% female patients) and 38 controls of similar age and gender (78±5, 63% female patients). All subjects underwent a complete two-dimensional echocardiography. Mean platelet volume and NLR were measured at baseline. Patients were followed over time for a primary end point of all-cause mortality or first HF hospitalization. The prognosis impact of MPV and NLR were determined with Cox proportional hazard models. Results Mean MPV and median NLR were significantly higher in HFpEF patients compared to controls (MPV: 11.7±1.1 fL vs 10.0±1.1 fL, p=0.005; NLR: 3.3 [2.2; 5.0] vs 2.2 [1.9; 2.9], p&amp;lt;0.001). HFpEF patients with MPV &amp;gt;75th percentile (n=56) had more frequently a history of ischemic cardiomyopathy (46%, p=0.04). HFpEF patients with NLR &amp;gt;75th percentile (n=57) were more frequently in New York Heart Association functional (NYHA) III or IV class (58%, p=0.02) and had higher levels of NT-proBNP (2152 [1336; 6397] pg/mL vs 1690 [705; 3304] pg/mL, p=0.02). Over a median follow-up of 26 months [11.5–56.7 months], 136 HFpEF patients (60%) reached the composite end point (87 deaths and 107 hospitalizations for HF). In univariate Cox regression analysis for the primary end point, MPV &amp;gt;75th percentile (HR: 1.45 [0.99; 2.13], p=0.05) and NLR &amp;gt;75th percentile (HR: 1.59 [1.11; 2.28], p=0.01) were predictors of the primary composite endpoint. In multivariate Cox regression analysis, mean platelet volume &amp;gt;75th percentile (χ2=8.11, P=0.004), continuous MPV (χ2=4.64, P=0.03) provided significant additional prognostic value over a baseline model created using independent predictors of the primary composite end point: body mass index (BMI), NYHA class III or IV, chronic obstructive pulmonary disease (COPD), loop diuretics, estimated glomerular filtration rate (eGFR) and NT-proBNP. By contrast, NLR did not provide any additional information (Figure 1 and 2). Conclusion MPV level and NLR were significantly higher in HFpEF patients compared with controls of similar age and gender. Elevated MPV offers an additional prognostic indication for clinicians and more interestingly it supports the hypothesis that of platelet activation could be involved in disease pathophysiology in HFpEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Fondation Saint-Luc

Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy.

ObjectivesRecent studies suggested that the expansion of long‐standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus may be linked to chronic inflammation and microglial activation. We investigated the potential association between plexus volume and subsequent lesion expansion in patients with relapsing‐remitting MS.MethodsPre‐ and post‐gadolinium 3D‐T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients. Choroid plexus (CP) volume (normalised by Total Intracranial Volume, TIV) and lesion activity were analysed between baseline and 48 months. In addition, plexus volume was measured in 40 healthy controls of similar age and gender.ResultsBaseline CP/TIV ratio was significantly larger in RRMS patients compared to normal controls (p < 0.001). CP/TIV ratio remained stable in RRMS patients during follow‐up period. There was a strong correlation between baseline CP/TIV ratio and subsequent rate of chronic lesion expansion (p < 0.001), which was stronger in close proximity to CSF. A cut‐off of 98 × 10−5 CP/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. CP/TIV ratio larger than a cut‐off was associated with >8‐fold increased risk of chronic lesion expansion. Baseline CP/TIV ratio was also associated with change in Mean Diffusivity (MD) inside of chronic lesions. Furthermore, baseline CP/TIV ratio significantly correlated with central brain atrophy. There was, however, no correlation between CP/TIV ratio and volume of new lesions.InterpretationOur data demonstrate that baseline CP/TIV ratio predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage within and outside of chronic lesions.

1439P Sexual health in long-term breast cancer survivors: A comparative study

Sexual challenges are frequently reported by women diagnosed with breast cancer (BC), but knowledge of their long-term sexual health is limited. We aimed to compare sexual health among BC survivors (BCSs) eight years after diagnosis to that of population controls, and to explore the effects of age and systemic BC treatment. Women aged 20-65 years when diagnosed with early BC in 2011-2012 were identified by the Cancer Registry of Norway (n=2803) and invited to participate in a questionnaire survey. In total, 1241 BCSs responded and were eligible to this study. Controls were similar aged women (n=17751 of the 36395 invited) from the Trøndelag Health Study. Sexual health was measured by subscales from the EORTC QLQ-BR23 (sexual enjoyment and sexual function) scored from 0-100, and from the Sexual Activity Questionnaire (sexual discomfort) scored from 0-6. Linear regression analyzes with adjustments for sociodemographic variables were performed. Compared to similar aged controls: • Sexual enjoyment was poorer (B -14.4, CI -16.4, -12.5) and discomfort higher (B 1.0, CI 0.9, 1.1) among BCSs in total • There were no differences in sexual health when assessing BCSs diagnosed at postmenopausal age (≥ 55 years) • BCSs with current use of endocrine treatment had poorer sexual function (B -11.9, CI -14.7, -9.1), poorer enjoyment (B -17.6, CI -21.4, -13.9) and higher discomfort (B 1.4, CI 1.2, 1.7) • BCSs treated with adjuvant chemotherapy had poorer sexual function (B -11.1, CI -12.7, -9.5), poorer enjoyment (B -16.7, CI -19.0, -14.5) and higher discomfort (B 1.3, CI 1.1, 1.4) • BCSs formerly treated with aromatase inhibitor had poorer sexual function (B -10.1, CI -12.9, -7.4), poorer enjoyment (B -16.9, CI -21.0, -12.9) and higher discomfort (B 1.3, CI 1.0, 1.5). There were no differences in sexual health when comparing BCSs diagnosed at postmenopausal age with similar aged controls - a reassuring finding for postmenopausal women diagnosed with BC. Premenopausal age, adjuvant chemotherapy, current endocrine therapy, and former aromatase inhibitor therapy are risk factors for sexual health challenges in long-term BCSs. During follow-up, special attention with regards to sexual health should be given to BCSs with these risk factors.

Identifying Protective Drugs for Parkinson's Disease in Health-Care Databases Using Machine Learning.

Available treatments for Parkinson's disease (PD) are only partially or transiently effective. Identifying existing molecules that may present a therapeutic or preventive benefit for PD (drug repositioning) is thus of utmost interest. We aimed at detecting potentially protective associations between marketed drugs and PD through a large-scale automated screening strategy. We implemented a machine learning (ML) algorithm combining subsampling and lasso logistic regression in a case-control study nested in the French national health data system. Our study population comprised 40,760 incident PD patients identified by a validated algorithm during 2016 to 2018 and 176,395 controls of similar age, sex, and region of residence, all followed since 2006. Drug exposure was defined at the chemical subgroup level, then at the substance level of the Anatomical Therapeutic Chemical (ATC) classification considering the frequency of prescriptions over a 2-year period starting 10 years before the index date to limit reverse causation bias. Sensitivity analyses were conducted using a more specific definition of PD status. Six drug subgroups were detected by our algorithm among the 374 screened. Sulfonamide diuretics (ATC-C03CA), in particular furosemide (C03CA01), showed the most robust signal. Other signals included adrenergics in combination with anticholinergics (R03AL) and insulins and analogues (A10AD). We identified several signals that deserve to be confirmed in large studies with appropriate consideration of the potential for reverse causation. Our results illustrate the value of ML-based signal detection algorithms for identifying drugs inversely associated with PD risk in health-care databases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder: Shared or Unique Neurocognitive Profiles?

Attention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders are commonly co-occurring conditions characterized by neurocognitive impairments. Few studies have directly compared neurocognitive profiles in ADHD and ASD and fewer still have controlled for comorbidity of ADHD and ASD. All direct comparisons have been in clinic samples, leaving the question of generalizability of results unaddressed. We compared neurocognitive performance in clinically ascertained ASD (n = 261) and ADHD (n = 423) cases and controls (n = 162), 6.0–17.9 years of age. We also compared ASD (n = 190) and ADHD (n = 926) cases ascertained in the community with controls (n = 14,842) of similar age. Using the stop-signal task (SST), we measured response inhibition (stop-signal reaction time–SSRT), sustained attention (defined as reaction time variability–RTV), and reaction time (RT). We controlled for comorbidity using ADHD and ASD trait scores and categorically-defined ADHD. Compared with controls, both clinic ADHD and ASD had significantly longer SSRT and RTV than controls and did not differ from each other. ADHD traits accounted for neurocognitive impairment in ASD, but not vice versa. There were no group differences for RT. Similar patterns of neurocognitive impairment were observed in the community sample. In the largest direct comparison of ADHD and ASD to date, we found impaired response inhibition and sustained attention in both disorders. However, neurocognitive impairment in ASD was almost completely accounted for by comorbid ADHD. Results generalized in the community sample indicating that referral bias alone did not drive results. Response inhibition and sustained attention likely play a role in ADHD and ASD.

Astrogliosis in aging and Parkinson's disease dementia: a new clinical study with 11C-BU99008 PET.

The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls and patients with established Parkinson’s disease dementia. Eighteen healthy controls (age: 45–78 years) and six patients with Parkinson’s disease dementia (age: 64–77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3 T MRI brain scan to facilitate the analysis of the PET data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution were calculated for each subject by the two-tissue compartmental modelling. Positive correlations between 11C-BU99008 volumes of distribution values and age were found for all tested regions across the brain within healthy controls (P < 0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 volumes of distribution values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 volumes of distribution values between Parkinson’s disease dementia (n = 6; mean age = 71.97 ± 4.66 years) and older healthy controls (n = 9; mean age = 71.90 ± 5.51 years). Our data set shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with Parkinson’s disease dementia from healthy controls of similar age.

Assessment of depression, anxiety, and stress levels in prehypertensive females

Background: it is needed to assess the depression, anxiety, and stress in these individuals as a part of the intervention. Earlier studies in this area assessed only with less sample size.&#x0D; Objective: The present study was undertaken to assess depression, anxiety, and stress in the pre hypertensives with large sample size. Materials and methods: A total of 100 cases with pre-hypertension and 100 controls of similar ages and gender were recruited in the present study. Depression, anxiety, and stress are negative emotional states. They can be assessed using DASS 42 questionnaire which is a standard questionnaire and available freely to use. Results: Age is significantly different between the groups. Other demographic data were not significant between the cases and controls. Depression, anxiety, and stress scores were significantly high in the cases when compared with the control group (P&lt;0.001). Conclusion: The study highlights that negative emotional states like depression, anxiety and stress are significantly high in the prehypertensive when compared with healthy controls.

Pain and health-related quality of life in patients with hypophosphatasemia with and without ALPL gene mutations.

BackgroundLow serum alkaline phosphatase levels are the hallmark of hypophosphatasia, a disorder due to pathogenic variants of the ALPL gene. However, some patients do not carry ALPL variants and the cause of low alkaline phosphatase remains unknown. We aimed to determine health-related quality of life in adults with low alkaline phosphatase and explore the differences between patients with and without ALPL mutations.MethodsWe studied 35 adult patients with persistently low alkaline phosphatase unrelated to secondary acquired causes who had ALPL sequenced, and 35 controls of similar age. Three questionnaires about body pain (Brief Pain Inventory, BPI), physical disability (Health Assessment Questionnaire Disability Index, HAQ-DI), and health-related quality of life (36-item Short-Form Health Survey, SF-36) were delivered by telephone interviews.ResultsThe mean BPI intensity and interference scores were higher in the patient group (p=0.04 and 0.004, respectively). All domains of the HAQ instrument tended to score better in the control group, with significant differences in the “reach” score (p=0.037) and the overall mean score (0.23 vs 0.09; p=0.029). Patients scored worse than controls in several SF-36 dimensions (Role physical, p=0.039; Bodily pain p=0.046; Role emotional, p=0.025). Patients with and without pathogenic variants scored similarly across all tests, without between-group significant differences.ConclusionsPatients with persistently low levels of alkaline phosphatase have significantly worse scores in body pain and other health-related quality of life dimensions, without differences between patients with and without pathogenic variants identified in ALPL gene. This is consistent with the latter ones carrying mutations in regulatory regions.

Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome.

Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (CTC1). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1–STN1–TEN1 which promotes telomere DNA synthesis and inhibits telomerase-mediated telomere elongation. However, it is unclear how CTC1 mutations may have an effect on telomere structure and function. For that purpose, we established the very first induced pluripotent stem cell lines (iPSCs) from a compound heterozygous patient with CP carrying deleterious mutations in both alleles of CTC1. Telomere dysfunction and chromosomal instability were assessed in both circulating lymphocytes and iPSCs from the patient and from healthy controls of similar age. The circulating lymphocytes and iPSCs from the CP patient were characterized by their higher telomere length heterogeneity and telomere aberrations compared to those in control cells from healthy donors. Moreover, in contrast to iPSCs from healthy controls, the high levels of telomerase were associated with activation of the alternative lengthening of telomere (ALT) pathway in CP-iPSCs. This was accompanied by inappropriate activation of the DNA repair proteins γH2AX, 53BP1, and ATM, as well as with accumulation of DNA damage, micronuclei, and anaphase bridges. CP-iPSCs presented features of cellular senescence and increased radiation sensitivity. Clonal dicentric chromosomes were identified only in CP-iPSCs after exposure to radiation, thus mirroring the role of telomere dysfunction in their formation. These data demonstrate that iPSCs derived from CP patients can be used as a model system for molecular studies of the CP syndrome and underscores the complexity of telomere dysfunction associated with the defect of DNA repair machinery in the CP syndrome.

Elevated heart rate as sympathetic biomarker in human obesity

Background and aimThe present study was aimed at determining whether and to what extent a specific heart rate (HR) cutoff value allows to identify in obeses a more pronounced level of adrenergic overdrive. Methods and resultsIn 86 obese subjects aged 44.7 ± 0.9 (mean ± SEM) years and in 45 heathy lean controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in 3 different groups according to their resting clinic and 24-h HR values (<70, 70–79 and 80–89 beats/minute). MSNA and plasma NE values detected in the three obese groups were almost superimposable each other, no significant difference between groups being observed. A similar behavior was observed when HR values were assessed during the 24-h Holter monitoring. In the group as a whole no significant relationship was detected between MSNA, plasma NE and clinic HR, this being the case also when 24-h HR replaced clinic HR in the correlation analysis. In contrast lean controls displayed a progressive significant increase in MSNA values form the group with clinic (and 24 Holter) values below 70 beats/minute to the ones with HR values between 70 and 79 and above 80 beats/minute. ConclusionsIn the obese state measurement of resting HR may allow to provide some general information on the functional status of the adrenergic cardiovascular drive. When the information required, however, are more subtle the sensitivity of the approach appears to be reduced and HR cannot be regarded as a faithful sympathetic biomarker.

Level of β-defensin among Iraqi patients with COVID-19 in relation to oral health status

Background: Innate immunity plays an important role in deciding the severity of coronavirus disease 2019 (COVID-19) and disease outcomes. Defensins are antimicrobial peptides that are produced by epithelial cells in mucosal locations and play a key role in innate immunity. Understanding COVID-19 mucosal agents and their role in disease severity is critical for developing therapeutic options and identification of prognostic markers for COVID-19. Objective: In this study, we aimed to determine the role of β-defensin-1 in patients with COVID-19 and compare it with that of the control group, as well as to look into the link between β-defensin-1 and oral hygiene and disease severity. Methods: This case-control study included 50 patients with COVID-19 and 35 controls of similar ages and sexes. From November 2020 to January 2021, the patients were admitted to Baghdad Teaching Hospital/Medical City. The simplified oral hygiene index was used to determine oral hygiene status. Blood samples were obtained from all subjects (patients and controls), and the serum levels of β-defensin-1 were measured using enzyme-linked immunosorbent assay (ELISA). Results: Findings showed a non-significant reduction (P&gt;0.05) in the β-defensin-1 level among patients compared with that of the controls. In addition, patients with severe disease had a significantly lower level of β-defensin-1 than those with mild disease. There were no significant variations in the levels of β-defensin-1 between patients with good oral hygiene and those with poor oral hygiene (P&gt;0.05). Conclusions: The reduction in β-defensin-1 levels indicates an abnormal immune response in these patients and may require a new treatment option for this condition in the future. Furthermore, in patients with severe disease, a considerable drop in β-defensin-1 might be used as an indicator of illness severity.

Differential perivascular microglial activation in the deep white matter in vascular dementia developed post-stroke.

With the hypothesis that perivascular microglia are involved as neuroinflammatory components of the gliovascular unit contributing to white matter hyperintensities on MRI and pathophysiology, we assessed their status in stroke survivors who develop dementia. Immunohistochemical and immunofluorescent methods were used to assess the distribution and quantification of total and perivascular microglial cell densities in 68 brains focusing on the frontal lobe WM and overlying neocortex in post-stroke dementia (PSD), post-stroke non-dementia (PSND) and similar age control subjects. We primarily used CD68 as a marker of phagocytic microglia, as well as other markers of microglia including Iba-1 and TMEM119, and the myeloid cell marker TREM2 to assess dementia-specific changes. We first noted greater total densities of CD68+ and TREM2+ cells per mm2 in the frontal WM compared to the overlying cortex across the stroke cases and controls (p=0.001). PSD subjects showed increased percentage of activated perivascular CD68+ cells distinct from ramified or primed microglia in the WM (p < 0.05). However, there was no apparent change in perivascular TREM2+ cells. Total densities of TREM2+ cells were only ~10% of CD68+ cells but there was high degree of overlap (>70%) between them in both the WM and the cortex. CD68 and Iba-1 or CD68 and TMEM119 markers were colocalised by ~55%. Within the deep WM, ~30% of CD68+ cells were co-localised with fragments of degraded myelin basic protein. Among fragmented CD68+ cells in adjacent WM of PSD subjects, >80% of the cells expressed cleaved caspase-3. Our observations suggest although the overall repertoire of perivascular microglial cells is not changed in the parenchyma, PSD subjects accrue more perivascular-activated CD68+ microglia rather than TREM2+ cells. This implies there is a subset of CD68+ cells, which are responsible for the differential response in perivascular inflammation within the gliovascular unit of the deep WM.

Subclinical atherosclerosis profiles in rheumatoid arthritis and primary Sjögren's syndrome: the impact of BAFF genetic variations.

RA and primary SS carry increased atherosclerotic risk, while B-cell activating factor holds a vital role in disease pathogenesis and atherosclerosis. We aimed to compare subclinical atherosclerosis profiles between the two clinical entities and define whether BAFF genetic variants alter atherosclerotic risk. DNA from 166 RA, 148 primary SS patients and 200 healthy controls of similar age and sex distribution was subjected to PCR-based assay for the detection of five single nucleotide polymorphisms of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and rs9514827). Genotype and haplotype frequencies were determined by SNPStats software and statistical analysis was performed by SPSS and Graphpad Software. Subclinical atherosclerosis was defined by the presence of carotid/femoral plaque formation and arterial wall thickening. Atherosclerotic plaque formation was more frequently detected in the RA vs primary SS group (80.7% vs 62.2%, P-value <0.001), along with higher rates of family CVD history, current steroid dose and serum inflammatory markers. The TT genotype of the rs1224141 variant was more prevalent in RA but not primary SS patients with plaque and arterial wall thickening vs their counterparts without. Regarding the rs1014569 variant, among RA patients the TT genotype increased the risk for plaque formation while in primary SS patients the AT genotype conferred increased risk. Haplotype GTTTT was protective in the RA cohort, while TATTT and TTCTT haplotypes increased susceptibility for arterial wall thickening in the primary SS cohort. Increased inflammatory burden, higher steroid doses and distinct BAFF gene variations imply chronic inflammation and B-cell hyperactivity as key contributors for the augmented atherosclerotic risk among autoimmune patients.

Relationships between sympathetic markers and heart rate thresholds for cardiovascular risk in chronic heart failure

BackgroundResults of recent clinical trials have shown that in heart failure (HF) heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk. No information is available on whether the sympathetic nervous system is differently activated in HF patients displaying resting HR values above or below this cutoff.MethodsIn 103 HF patients aged 62.7 ± 0.9 (mean ± SEM) years and in 62 heathy controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in different groups according to their resting clinic and 24-h HR values.ResultsIn HF progressively greater values of clinic or 24-h HR were associated with a progressive increase in both MSNA and NE. HR cutoff values adopted in large scale clinical trials for determining cardiovascular risk, i.e., 70 beats/minute, were associated with MSNA values significantly greater than the ones detected in patients with lower HR, this being the case also for NE. In HF both MSNA and NE were significantly related to clinic (r = 0.92, P < 0.0001 and r = 0.81, P < 0.0001, respectively) and 24-h (r = 0.91, P < 0.0001 and r = 0.79, P < 0.0001, respectively) HR. The behavior of sympathetic markers described in HF was specific for this clinical condition, being not observed in healthy controls.ConclusionsBoth clinic and 24-h HR values greater than 70 beats/minute are associated with an increased sympathetic activation, which parallels for magnitude the HR elevations. These findings support the relevance of using in the therapeutic approach to HF drugs exerting sympathomoderating properties.Graphical abstract

MO004: Hidden Patterns of T Cell and B Cell Phenotypes seen Through Machine Learning Algorithms in End-Stage Renal Disease

Abstract BACKGROUND AND AIMS End-stage renal disease (ESRD) is essentially a chronic inflammatory state and, consequently, it engenders detrimental effects on the immune system. Due to the specific uremic environment, multiple phenotypic lymphocyte alterations are described, similar but not identical to ageing. We aimed to evaluate these changes through simple unsupervised dimensionality reduction algorithms in order to reveal unique phenotypical lymphocyte patterns in ESRD patients. METHOD A wide panel of senescent and exhaustion-related lymphocyte markers, including CD45RA, CCR7, CD31, CD28, CD57, and PD1 on T cells and CD27 and IgD on B cells, was assessed by flow cytometry in 30 ESRD patients and 20 healthy controls of similar age, sex and ethnicity. The resulting immunological multidimensional phenotype was projected at lower dimensions using two algorithms: principal component analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP). RESULTS The plane defined by the two first eigenvectors of PCA showed two clusters, patients and controls, with PCA variable loadings of non-senescent markers pointing towards the controls' centroid. Indeed, ‘naïve’ lymphocytes were reduced in ESRD patients compared with controls [CD4+CD45RA+CCR7+200(150–328) versus 426(260–585) cells/μL, respectively; P = .001] and [CD19+IgD+CD27–54(26–85) versus 130(83–262) cells/μL, respectively; P &amp;lt; .0001]. Also, PCA projections of the multidimensional ESRD immune phenotype suggested a more senescent phenotype in haemodialysis compared with haemodiafiltration treated patients. Finally, clustering based on UMAP projections revealed three distinct patients groups (UMAP 1–3), exhibiting gradual changes for naive, senescent and exhausted lymphocyte markers. Out of these, the UMAP 1 group was characterized by a predominance of CD8 senescent T cell subsets, in contrast, to groups UMAP 2 and 3, which showed a gradual decrease of all T cell subsets, in comparison to healthy controls. These groups were found to differ in the type of dialyzer used, with polysulfone or derivatives alone more often prescribed in UMAP 2–3 patients (13 out of 17) compared with 4 out of 13 in UMAP 1, P = .012. CONCLUSION Simple machine learning algorithms may help to unravel hidden lymphocyte markers and define patterns characteristic of ESRD. Moreover, significant connections of immune changes with dialysis methods and dialyzers were revealed and described.

Are Pedobarographic and Gait Analyses Useful Tools to Evaluate Outcomes of Anterograde Calcaneo-Stop Procedure in Pediatric Symptomatic Flexible Flatfoot?

Background: Flexible flatfoot is a frequent condition in childhood that needs to be treated when symptomatic. The aim of this study was to analyze pedobarographic and gait outcomes of patients with painful flexible flatfoot who underwent the anterograde calcaneo-stop procedure. Methods: All patients scheduled for surgical correction of painful flexible flatfoot between April and September 2011 were offered to participate in a study of dynamic pedobarographic and gait analyses before surgery and 3, 12, and 24 months after surgery. A healthy control group of similar age and physical characteristics also underwent dynamic pedobarographic and gait analyses. Results: Fifteen patients accepted to undergo dynamic pedobarography and gait analyses. The data were compared with fifteen controls of similar age and BMI. No significant differences were found on dynamic pedobarography within patients at different endpoints, except for a decreased percentage of plantigrade phase and increased percentage of digitigrade phase at 12 months post-op in comparison with 3 months post-op, nor when compared with control. Similarly, when range of motion was taken into consideration, no significant differences were found within patients at different endpoints, nor when compared with control, except for a decrease in ankle joint range of motion 24 months post-op in comparison with the controls. The stride was significantly decreased before surgery and became like controls 24 months after the procedure. The cadence, significantly decreased 24 months after surgery in comparison with the pre-surgical set, was similar to the controls. No significant differences were seen in the walking speed within patients at different endpoints and the controls. The cycle time significantly increased 24 months after surgery when compared to the pre-op situation, and was similar to the controls. Conclusion: Dynamic pedobarographic and gait analyses were useful not only to identify the gait impairment in patients with symptomatic flexible flatfoot, but also to measure the treatment outcome through the analysis of the surgery’s impact on the gait quality.

Compromised future thinking: another cognitive cost of temporal lobe epilepsy.

The ability to mentally travel forward through time allows humans to envisage a diverse array of possible events taking place in the future, helping us to choose which pathway to take in life. In epilepsy, we assume that patients use this cognitive ability when deciding between various treatment options, but this assumption has not been robustly tested. The temporal lobes are key contributors to this ‘future thinking’ and its building blocks include cognitive functions commonly impaired in temporal lobe epilepsy such as memory and language, giving rise to a hypothesis that ‘future thinking’ is impaired in this patient cohort. Participants were 68 adults: 37 with neurosurgically-naïve, unilateral temporal lobe epilepsy (51% right lateralized) and 31 healthy controls of similar age, sex and intellectual ability to the participants with epilepsy. Future thinking was measured using an imagined experiences task validated in other neurological populations. Tools well-established in temporal lobe epilepsy were used to measure potential cognitive correlates of future thinking. Analysis of variance revealed significantly impoverished future thinking in both left and right temporal lobe epilepsy relative to controls (P = 0.001, ηp2=0.206), with no difference between temporal lobe epilepsy groups (P > 0.05). Future thinking deficits in left temporal lobe epilepsy were paralleled by deficits in scene construction, whereas impoverished future thinking in right temporal lobe epilepsy occurred in the setting of intact scene construction. Deficits in future thinking were associated with reductions in lexical access and episodic autobiographic memory in both epilepsy groups. In sum, future thinking is compromised in both left and right temporal lobe epilepsy. The deficit in left temporal lobe epilepsy is largely explainable by dysfunction in verbal cognitive processes including scene construction. While the basis of the deficits observed with right temporal foci shares features with that of left temporal lobe epilepsy, their intact scene construction raises questions about the role of the left and right temporal lobes in future thinking and scene construction and the relationship between these two constructs, including whether right temporal lobe might play a specific role in future thinking in terms of creative processing. Clinicians should take impaired future thinking into account when counselling temporal lobe epilepsy patients about various treatment options, as they may struggle to vividly imagine what different outcomes might mean for their future selves.