ResearchPad - inflammatory-diseases https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment]]> https://www.researchpad.co/article/elastic_article_11232 The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility–both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation.

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<![CDATA[Increased 14-3-3β and γ protein isoform expressions in parasitic eosinophilic meningitis caused by Angiostrongylus cantonensis infection in mice]]> https://www.researchpad.co/article/5c8acccdd5eed0c484990014

The 14-3-3 proteins are cerebrospinal fluid (CSF) markers of neuronal damage during infectious meningitis and Creutzfeldt-Jakob disease. Little is known about dynamic changes in the individual isoforms in response to parasitic eosinophilic meningitis. The purposes of this study were to determine the 14-3-3 protein isoform patterns, examine the kinetics and correlate the severity of blood brain barrier (BBB) damage with the expressions of these markers in mice with eosinophilic meningitis.

Mice were orally infected with 50 A. cantonensis L3 via an oro-gastric tube and sacrificed every week for 3 consecutive weeks after infection. The Evans blue method and BBB junctional protein expressions were used to measure changes in the BBB. Hematoxylin and eosin staining was used to analyze pathological changes in the mice brains following 1–3 weeks of infection with A. cantonensis. The levels of 14-3-3 protein isoforms in serum/CSF and brain homogenates were analyzed by Western blot, and immunohistochemistry (IHC) was used to explore the different isoform distributions of 14-3-3 proteins and changes in BBB junctional proteins in the mice brain meninges. Dexamethasone was injected intraperitoneally from the seventh day post infection (dpi) until the end of the study (21 dpi) to study the changes in BBB junctional proteins. The amounts of Evans blue, tight junction and 14-3-3 protein isoforms in the different groups of mice were compared using the nonparametric Kruskal-Wallis test.

There were significant increases in 14-3-3 protein isoforms β and γ in the CSF in the second and third weeks after infection compared to the controls and first week of infection, which were correlated with the severity of BBB damage in brain histology, and Evans blue extravasation. Using IHC to assess the distribution of 14-3-3 protein isoforms and changes in BBB junctional proteins in the mice brain meninges, the expressions of isoforms β, γ, ε, and θ and junctional proteins occludin and claudin-5 in the brain meninges increased over a 3-week period after infection compared to the controls and 1 week after infection. The administration of dexamethasone decreased the expressions of BBB junctional proteins occludin and claudin-5 in the mice brain meninges.

Our findings support that 14-3-3 proteins β and γ can potentially be used as a CSF marker of neuronal damage in parasitic eosinophilic meningitis caused by A. cantonensis.

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<![CDATA[High-resolution contrast-enhanced vessel wall imaging in patients with suspected cerebral vasculitis: Prospective comparison of whole-brain 3D T1 SPACE versus 2D T1 black blood MRI at 3 Tesla]]> https://www.researchpad.co/article/5c8c1948d5eed0c484b4d33a

Purpose

Vessel wall imaging (VWI) using T1 dark blood MRI can depict inflammation of intracranial arteries in patients with cerebral vasculitis. Recently, 3D VWI sequences were introduced at 3 Tesla. We aimed to compare 2D and 3D VWI for detection of intracranial vessel wall enhancement (VWE) in patients suspected of cerebral vasculitis.

Methods

44 MRI scans of 39 patients were assessed that included bi-planar 2D T1 and whole-brain 3D T1 SPACE dark blood VWI pre and post contrast. Visibility and VWE were analyzed in 31 pre-specified intracranial artery segments. Additionally, leptomeningeal and parenchymal contrast enhancement was assessed.

Results

Overall, more arterial segments were visualized with 3D VWI (p<0.0001). Detection of VWE showed fair agreement between 2D and 3D VWI (κ = 0.583). On segmental level, more VWE was detected in intradural ICA by 2D VWI (p<0.001) and in VA V4 segment by 3D VWI (p<0.05). 3D VWI showed more leptomeningeal (p<0.05) and parenchymal (p<0.01) contrast enhancement. In patients with positive diagnosis of cerebral vasculitis, sensitivity was of 67% (2D and 3D VWI) and specificity was 44% (2D VWI) and 48% (3D VWI); more VWE was seen in arteries distal to VA and ICA compared to non-vasculitic patients.

Conclusion

2D and 3D VWI differed in the ability to detect VWE. Whole brain coverage with better evaluability of VAs and distal intracranial artery segments, and depiction of more parenchymal and leptomeningeal enhancement make 3D VWI more favorable. As VWE in arteries distal to VA and ICA may be used for discrimination of vasculitic and non-vasculitic patients, future increase in spatial resolution of 3D VWI sequences may be beneficial.

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<![CDATA[The effect of a transient immune activation on subjective health perception in two placebo controlled randomised experiments]]> https://www.researchpad.co/article/5c8977a8d5eed0c4847d3294

Background

Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status.

Methods

Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD = 3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once (28.6 years; SD = 7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin-6, interleukin-8 and tumour necrosis factor-α, before and after injection.

Results

Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b = 1.88 for 0.8 ng/kg) and current health (Experiment 1 b = -3.00; and Experiment 2 b = -1.79) 1.5h after injection (p’s<0.01), effects that remained after 4.5 to 5 hours (p’s<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (β = -0.28, p = 0.01).

Conclusion

Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity.

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<![CDATA[Combination of colonoscopy and magnetic resonance enterography is more useful for clinical decision making than colonoscopy alone in patients with complicated Crohn's disease]]> https://www.researchpad.co/article/5c76fe3fd5eed0c484e5b78a

Background/aims

The small bowel is affected in more than half of patients with Crohn’s disease (CD) at the time of diagnosis, and small bowel involvement has a negative impact on the long-term outcome. Many patients reportedly have active lesions in the small intestine even in patients in clinical remission. This study was performed to compare findings of magnetic resonance enterography (MRE) and ileocolonoscopy.

Methods

A single-center retrospective study was conducted in 50 patients (60 imaging series) with CD, for whom MRE was additionally performed during the bowel preparation for subsequent ileocolonoscopy. Endoscopic remission was defined as a Simple Endoscopic Score for CD (SES-CD) of <5. MRE remission was defined as a Magnetic Resonance Index of Activity (MaRIA) score of <50. The time to treatment escalation was assessed by the log-rank test.

Results

Importantly, 7 of 29 patients (24.1%) with endoscopic remission had a MaRIA score of ≥50. Both SES-CD and MaRIA correlated with the need for treatment escalation (P = 0.025, P = 0.009, respectively). MRE predicted the need for treatment escalation even in patients with endoscopic remission. Although no correlation was present between SES-CD and MaRIA score in patients with structuring/penetrating disease, or insufficient ileal insertion (<10cm), a high MaRIA score still correlated with the need for treatment escalation in stricturing or penetrating disease (P = 0.0306).

Conclusions

The MaRIA score predicts the need for treatment escalation even in patients with endoscopic remission, indicating that addition of MRE to conventional ileocolonoscopy alone can be a useful, noninvasive tool for monitoring CD especially in stricturing or penetrating disease.

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<![CDATA[The dynamic association between Frailty, CD4 and CD4/CD8 ratio in people aging with HIV]]> https://www.researchpad.co/article/5c6f1532d5eed0c48467aeb2

Objective

To investigate the association between current CD4+ T-cell count and CD4/CD8+ ratio with severity of frailty among people aging with HIV.

Methods

Cross-sectional observational study analysing data from all study visits in the ongoing prospective Modena HIV Metabolic Clinic Cohort between 2006 and 2015. Frailty severity was assessed using a frailty index (FI). We visualized the relationships between frailty index score and current CD4 cell count and CD4/CD8 ratio on two different curves adjusted for age, sex, and duration of HIV infection.

Results

Frailty index scores exhibited an inverse relationship with current CD4 count, up to 900 cells/μL. The CD4/CD8 ratio was inversely correlated with frailty index both below and above the cut-off of 900 CD4 cells/μL.

Conclusions

Frailty in PLWH is inversely associated with both immune-activation, depicted by CD4/CD8 ratio and immune-deficit depicted by CD4 count. The first association shows a linear shape while the second shows a hook-shape with a turning point at 900 cells. Above this cut off level CD4 do not represent a significant risk factor for frailty.

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<![CDATA[Efficient design and analysis of randomized controlled trials in rare neurological diseases: An example in Guillain-Barré syndrome]]> https://www.researchpad.co/article/5c76fe48d5eed0c484e5b7f7

Background

Randomized controlled trials (RCTs) pose specific challenges in rare and heterogeneous neurological diseases due to the small numbers of patients and heterogeneity in disease course. Two analytical approaches have been proposed to optimally handle these issues in RCTs: covariate adjustment and ordinal analysis. We investigated the potential gain in efficiency of these approaches in rare and heterogeneous neurological diseases, using Guillain-Barré syndrome (GBS) as an example.

Methods

We analyzed two published GBS trials with primary outcome ‘at least one grade improvement’ on the GBS disability scale. We estimated the treatment effect using logistic regression models with and without adjustment for prognostic factors. The difference between the unadjusted and adjusted estimates was disentangled in imbalance (random differences in baseline covariates between treatment arms) and stratification (change of the estimate due to covariate adjustment). Second, we applied proportional odds regression, which exploits the ordinal nature of the GBS disability score. The standard error of the estimated treatment effect indicated the statistical efficiency.

Results

Both trials were slightly imbalanced with respect to baseline characteristics, which was corrected in the adjusted analysis. Covariate adjustment increased the estimated treatment effect in the two trials by 8% and 18% respectively. Proportional odds analysis resulted in lower standard errors indicating more statistical power.

Conclusion

Covariate adjustment and proportional odds analysis most efficiently use the available data and ensure balance between the treatment arms to obtain reliable and valid treatment effect estimates. These approaches merit application in future trials in rare and heterogeneous neurological diseases like GBS.

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<![CDATA[Effects of microbiota-driven therapy on inflammatory responses in elderly individuals: A systematic review and meta-analysis]]> https://www.researchpad.co/article/5c648cddd5eed0c484c81990

Current evidence suggests that age-associated inflammation, a strong risk factor for the health status of elderly individuals, is closely associated with gut microbiota. Previous animal studies have demonstrated a benefit of microbiota-driven therapy in decreasing low-grade chronic inflammation in elderly individuals; however, it remains controversial in clinical studies. Therefore, the present systematic review and meta-analysis were designed to assess the effects of microbiota-driven therapy on inflammatory markers in elderly individuals. PubMed, EMBASE, and the Cochrane Library were searched with no language restrictions from the inception of the database to November 11th, 2018 to identify all existing literature. We calculated pooled standard mean difference (SMD) using fixed effect model or random effect model to assess the effects of microbiota-driven therapy on elderly individuals. The methodological quality of the studies was determined according to the Cochrane Handbook. The publication bias was evaluated by funnel plot and Egger regression test. Ten randomized controlled studies, with 689 elderly individuals (347 individuals in the microbiota-driven therapy group and 342 individuals in the placebo group), were included in the analysis. Compared with placebo, microbiota-driven therapy did not decrease the levels of tumor necrosis factor-α (SMD, -0.24; 95% CI, -0.69 to 0.21; p = 0.30; I2 = 82.7%), interleukin-6 (SMD, -0.13; 95% CI, -0.74 to 0.49; p = 0.69; I2 = 90.7%) and interleukin-10 (SMD, 1.00; 95% CI, -0.15 to 2.15; p = 0.09; I2 = 96.3%). In addition, the microbiota-driven therapy also did not decrease the levels of C reactive protein (SMD, -1.28; 95% CI, -2.62 to 0.06; p = 0.06; I2 = 96.2%), interleukin-1β (SMD, -0.22; 95% CI, -0.81 to 0.37; p = 0.46; I2 = 73.8%), interleukin-8 (SMD, -0.03; 95% CI, -0.67 to 0.61; p = 0.93; I2 = 88.0%) and monocyte chemoattractant protein-1 (SMD, -0.11; 95% CI, -0.41 to 0.20; p = 0.49; I2 = 0%) when compared with placebo. No obvious publication bias was observed (p>0.05). In conclusion, the present meta-analysis of available randomized controlled studies did not suggest any significant benefit of microbiota-driven therapy in decreasing the inflammatory responses of elderly individuals.

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<![CDATA[Individual and area-level determinants associated with C-reactive protein as a marker of cardiometabolic risk among adults: Results from the German National Health Interview and Examination Survey 2008-2011]]> https://www.researchpad.co/article/5c6730d2d5eed0c484f381b9

Background

High-sensitivity C-reactive protein (hsCRP) is a sensitive biomarker of systemic inflammation and is related to the development and progression of cardiometabolic diseases. Beyond individual-level determinants, characteristics of the residential physical and social environment are increasingly recognized as contextual determinants of systemic inflammation and cardiometabolic risks. Based on a large nationwide sample of adults in Germany, we analyzed the cross-sectional association of hsCRP with residential environment characteristics. We specifically asked whether these associations are observed independent of determinants at the individual level.

Methods

Data on serum hsCRP levels and individual sociodemographic, behavioral, and anthropometric characteristics were available from the German Health Interview and Examination Survey for Adults (2008–2011). Area-level variables included, firstly, the predefined German Index of Socioeconomic Deprivation (GISD) derived from the INKAR (indicators and maps on spatial and urban development in Germany and Europe) database and, secondly, population-weighted annual average concentration of particulate matter (PM10) in ambient air provided by the German Environment Agency. Associations with log-transformed hsCRP levels were analyzed using random-intercept multi-level linear regression models including 6,768 participants aged 18–79 years nested in 162 municipalities.

Results

No statistically significant association of PM10 exposure with hsCRP was observed. However, adults residing in municipalities with high compared to those with low social deprivation showed significantly elevated hsCRP levels (change in geometric mean 13.5%, 95%CI 3.2%-24.7%) after adjusting for age and sex. The observed relationship was independent of individual-level educational status. Further adjustment for smoking, sports activity, and abdominal obesity appeared to markedly reduce the association between area-level social deprivation and hsCRP, whereas all individual-level variables contributed significantly to the model.

Conclusions

Area-level social deprivation is associated with higher systemic inflammation and the potentially mediating role of modifiable risk factors needs further elucidation. Identifying and assessing the source-specific harmful components of ambient air pollution in population-based studies remains challenging.

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<![CDATA[Salivary and plasma levels of matrix metalloproteinase-9 and myeloperoxidase at rest and after acute physical exercise in patients with coronary artery disease]]> https://www.researchpad.co/article/5c648d46d5eed0c484c82427

Background

Low-grade systemic inflammation is a predictor of recurrent cardiac events in patients with coronary artery disease (CAD). Plasma proteins such as matrix metalloproteinase (MMP)-9 and myeloperoxidase (MPO) have been shown to reflect basal as well as stress-induced inflammation in CAD. Measurements of MMP-9 and MPO in saliva might pose several advantages. Therefore, we investigated whether salivary levels of MMP-9 and MPO corresponded to plasma levels in patients with coronary artery disease (CAD), both at rest and after acute physical exercise.

Methods

A bicycle ergometer test was used as a model for stress-induced inflammation. Twenty-three CAD patients performed the test on two occasions 3–6 months apart. Whole unstimulated saliva was collected before, directly after and 30 min after exercise while plasma was collected before and after 30 min. MMP-9 and MPO in saliva and plasma were determined by Luminex.

Results

MMP-9 and MPO levels were 2- to 4-fold higher in saliva than in plasma. Amongst the saliva samples, and also to a great extent amongst the plasma samples, the levels of both types of protein showed strong intercorrelations between the levels at rest and after exercise during the two visits. However, there were no (or weak) correlations between salivary and plasma MMP-9 and none between salivary and plasma MPO.

Conclusion

We conclude that salivary diagnostics cannot be used to assess systemic levels of MMP-9 and MPO in CAD patients, neither at rest nor after acute physical exercise.

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<![CDATA[Fc gamma RIIb expression levels in human liver sinusoidal endothelial cells during progression of non-alcoholic fatty liver disease]]> https://www.researchpad.co/article/5c59fedbd5eed0c48413572f

Liver sinusoidal endothelial cells (LSECs) play a pivotal role in hepatic function and homeostasis. LSEC dysfunction has been recognized to be closely involved in various liver diseases, including non-alcoholic steatohepatitis (NASH), but not much is known about the fate of the scavenger receptors in LSECs during NASH. Fc gamma receptor IIb (FcγRIIb), known as a scavenger receptor, contributes to receptor-mediated endocytosis and immune complexes clearance. In this study, to elucidate the fate of FcγRIIb in the progression of non-alcoholic fatty liver disease (NAFLD), we examined FcγRIIb levels in NAFLD biopsy specimens by immunohistochemistry, and investigated their correlation with the exacerbation of biological indexes and clinicopathological scores of NASH. The FcγRIIb expression levels indicated significant negative correlations with serum levels of blood lipids (triglyceride, total cholesterol, high-density lipoprotein-cholesterol), type 4 collagen and hyaluronic acid, which are involved in hepatic lipid metabolism disorder, fibrosis, and inflammation, respectively. However, there was no significant difference of FcγRIIb expression levels among the pathological grades of NAFLD. During NAFLD progression, inflammation and fibrosis may influence the expression of FcγRIIb and their scavenger functions to maintain hepatic homeostasis.

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<![CDATA[Leg muscle strength is reduced and is associated with physical quality of life in Antineutrophil cytoplasmic antibody-associated vasculitis]]> https://www.researchpad.co/article/5c61e902d5eed0c48496f649

Objective

Physical quality of life is reduced in ANCA-associated vasculitis (AAV). This study aims to investigate whether this may be explained by reduced muscle strength and physical activity resulting from disease damage and steroid myopathy.

Methods

Forty-eight AAV patients were sequentially included from the outpatient clinic. Patients in different stages of disease and treatment underwent measurements of muscle strength and anthropometric parameters. Patients filled in physical activity (Baecke) and quality of life questionnaires (RAND-36) and carried an accelerometer for a week. Muscle strength and physical activity were compared to quality of life, prednisolone use and disease duration.

Results

Most AAV patients had lower knee extension (76%) and elbow flexion (67%) forces than expected based on healthy norms. Also, physical (P<0.001) and mental (P = 0.01) quality of life were significantly reduced compared to healthy norm values. Lower knee extension force (P = 0.009), younger age <70 (P<0.001) and relapse of vasculitis (P = 0.003) were associated with lower age-adjusted physical quality of life. Lower Baecke index (P = 0.006), higher prednisolone dose (P = 0.005) and ENT involvement (P = 0.006) were associated with lower age-adjusted mental quality of life. Leg muscle strength showed no association with current or cumulative prednisolone use. Disease duration was longer in patients with knee extension force below healthy norms (P = 0.006).

Conclusion

Knee extension force and physical activity are positively associated with quality of life in AAV. Knee extension force decreases with longer disease duration, suggesting that disease- and treatment-related damage have a cumulative negative effect on muscle strength.

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<![CDATA[Prevalence and treatment of gout among patients with chronic kidney disease in the Irish health system: A national study]]> https://www.researchpad.co/article/5c644870d5eed0c484c2e6d4

Background

Gout is a common inflammatory arthritis associated with adverse clinical outcomes. Under treatment is common in the general population. The aim of this study was to determine the prevalence of gout and its treatment among patients with chronic kidney disease (CKD).

Methods

We conducted a multi-centre cross sectional study of patients (n = 522) who attended specialist nephrology clinics in Ireland. Standardized data collection tool recorded clinical characteristics and medication use at clinic visits and kidney function was assessed with standardised creatinine measurements and Estimated Glomerular Filtration Rate (eGFR). The prevalence of gout and the corresponding use of urate lowering therapies (ULT) were determined. Multivariate logistic regression explored correlates of gout expressed as Odds Ratios (OR) and 95% Confidence Intervals (CI) adjusting for demographic and clinical characteristics.

Results

Overall prevalence of gout was 16.6% and increased significantly from 7.5% in Stage 1–2 CKD to 22.8% in stage 4–5 CKD, P< 0.005. Prevalence increased with age (P < 0.005) and was higher in men than women (19.1% versus 10.3% P< 0.005). Overall, 67.9% of gout patients with CKD were treated with ULT, and the percentage increased with advancing stage of CKD from 55.6% in Stage 1–2 to 77.4% in Stage 4–5, P<0.005. Multivariable modelling identified men (vs women), OR, 1.95 (0.95–4.03), serum albumin, OR 1.09 (1.02–1.16) per 1 g/L lower, poorer kidney function, OR 1.11 (1.01–1.22) per 5 ml/min/1.73m2 lower, and rising parathyroid hormone levels, OR 1.38 (1.08–1.77) per 50 pg/ml higher as disease correlates.

Conclusions

Gout is common in CKD and increases with worsening kidney function in the Irish health system. Over two thirds of patients with gout were receiving ULT, increasing to 77% of patients with advanced CKD. Greater awareness of gout in CKD, its treatment and the effectiveness of treatment strategies should be vigorously monitored to improve patient outcomes.

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<![CDATA[Evaluation of a national cryptococcal antigen screening program for HIV-infected patients in Uganda: A cost-effectiveness modeling analysis]]> https://www.researchpad.co/article/5c40f7dad5eed0c484386afb

Background

Cryptococcal meningitis accounts for 15% of AIDS-related mortality. Cryptococcal antigen (CrAg) is detected in blood weeks before onset of meningitis, and CrAg positivity is an independent predictor of meningitis and death. CrAg screening for patients with advanced HIV and preemptive treatment is recommended by the World Health Organization, though implementation remains limited. Our objective was to evaluate costs and mortality reduction (lives saved) from a national CrAg screening program across Uganda.

Methods

We created a decision analytic model to evaluate CrAg screening. CrAg screening was considered for those with a CD4<100 cells/μL per national and international guidelines, and in the context of a national HIV test-and-treat program where CD4 testing was not available. Costs (2016 USD) were estimated for screening, preemptive therapy, hospitalization, and maintenance therapy. Parameter assumptions were based on large prospective CrAg screening studies in Uganda, and clinical trials from sub Saharan Africa. CrAg positive (CrAg+) persons could be: (a) asymptomatic and thus eligible for preemptive treatment with fluconazole; or (b) symptomatic with meningitis with hospitalization.

Results

In the base case model for 1 million persons with a CD4 test annually, 128,000 with a CD4<100 cells/μL were screened, and 8,233 were asymptomatic CrAg+ and received preemptive therapy. Compared to no screening and treatment, CrAg screening and treatment in the base case cost $3,356,724 compared to doing nothing, and saved 7,320 lives, for a cost of $459 per life saved, with the $3.3 million in cost savings derived from fewer patients developing fulminant meningitis. In the scenario of a national HIV test-and-treat program, of 1 million HIV-infected persons, 800,000 persons were screened, of whom 640,000 returned to clinic, and 8,233 were incident CrAg positive (CrAg prevalence 1.4%). The total cost of a CrAg screening and treatment program was $4.16 million dollars, with 2,180 known deaths. Conversely, without CrAg screening, the cost of treating meningitis was $3.09 million dollars with 3,806 deaths. Thus, despite the very low CrAg prevalence of 1.4% in the general HIV-infected population, and inadequate retention-in-care, CrAg screening averted 43% of deaths from cryptococcal meningitis at a cost of $662 per death averted.

Conclusion

CrAg screening and treatment programs are cost-saving and lifesaving, assuming preemptive treatment is 77% effective in preventing death, and could be adopted and implemented by ministries of health to reduce mortality in those with advanced HIV disease. Even within HIV test-and-treat programs where CD4 testing is not performed, and CrAg prevalence is only 1.4%, CrAg screening is cost-effective.

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<![CDATA[No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study]]> https://www.researchpad.co/article/5c478c44d5eed0c484bd134e

Background

Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).

Methods and findings

We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: −1.99 ml/min/1.73 m2; 95% CI −2.86 to −1.11; P = 8.08 × 10−6; odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10−11). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10−3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.

Conclusions

Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.

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<![CDATA[Diagnosis of bacterial meningitis in Ghana: Polymerase chain reaction versus latex agglutination methods]]> https://www.researchpad.co/article/5c6059efd5eed0c4847cc4c7

Bacterial meningitis is a public health crisis in the northern part of Ghana, where it contributes to very high mortality and morbidity rates. Early detection of the causative organism will lead to better management and effective treatment. Our aim was to evaluate the diagnostic accuracy of Pastorex and Wellcogen latex agglutination tests for the detection of bacterial meningitis in a resource-limited setting. CSF samples from 330 suspected meningitis patients within the northern zone of Ghana were analysed for bacterial agents at the zonal Public Health Reference Laboratory in Tamale using polymerase chain reaction (PCR) and two latex agglutination test kits; Pastorex and Wellcogen. The overall positivity rate of samples tested for bacterial meningitis was 46.4%. Streptococcus pneumoniae was the most common cause of bacterial meningitis within the sub-region, with positivity rate of 25.2%, 28.2% and 28.8% when diagnosed using Wellcogen, Pastorex and PCR respectively. The Pastorex method was 97.4% sensitive while the Wellcogen technique was 87.6% sensitive. Both techniques however produced the same specificity of 99.4%. Our study revealed that the Pastorex method has a better diagnostic value for bacterial meningitis than the Wellcogen method and should be the method of choice in the absence of PCR.

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<![CDATA[The salivary levels of leptin and interleukin-6 as potential inflammatory markers in children obesity]]> https://www.researchpad.co/article/5c37b7b5d5eed0c484490a01

Background

Obesity among children is an alarming issue due to an increased incidence over the last years with devastating physiological and psychological consequences. Current available medical diagnostic tools use invasive methods to evaluate and monitor the lipid profile, glycaemia or liver status for determining the overweight/ obesity complications. The standard methods proposed for the assay of IL6 and leptin from saliva cannot detect these two biomarkers in children saliva; the levels of IL6 and leptin in children’s saliva are lower than the limit of determination of the standard methods. Therefore, we proposed a method based on utilization of stochastic sensors, able to simultaneously perform a qualitative and quantitative determination of these two biomarkers within minutes, in the range able to cover healthy and obese children.

Methods

Children from the urban area monitored for annual standard analyses and health status assessment at National Institute of Endocrinology C.I. Parhon within University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania were included in the study. In the same day, for all participants of the study, blood analyses were performed and saliva samples were collected for the determination of the IL-6 and leptin levels.

Findings/ Results

The children diagnosed with overweight/ obesity presented not significantly different blood lipid profile and glycaemia comparing to the control group. Only few cases of the children presented high levels of cholesterol, low level of HDL-cholesterol, a slightly increased level of triglycerides and transaminases. No correlation with the body mass index could be established with the blood analyses results. In case of the overweight/obese children, the salivary level of the proinflammatory citokynes IL-6 (41ng/mL±21) and leptin (40.4ng/mL±28.8), were significantly increased comparing to normal weight children (IL-6 8.1±4.6, leptin 9.58±3.1). Moreover, the saliva level of the IL-6 was positively correlated with the body mass index. Salivary leptin level was highly variable in case of obese children, 6 patients presenting similar levels with the control group.

Conclusions

Increased levels of salivary IL-6 and leptin sustain a systemic inflammation status despite normal range of standard blood analyses. The results were positively correlated in case of IL-6 with the body mass index the general accepted method used for the assessment of the obesity or overweight degree The determination of these markers in saliva samples by a stochastic method proved the utility within the medical examination for a better evaluation of the health status in obesity. The method has some advantages like: easy collection of the biological sample, fast determination of low concentrations and could be promising in case of no associated oral cavity infections or inflammations which could interfere the results.

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<![CDATA[Permissive underfeeding, cytokine profiles and outcomes in critically ill patients]]> https://www.researchpad.co/article/5c3d017cd5eed0c48403bceb

Background

During critical illness in humans, the effects of caloric restriction on the inflammatory response are not well understood. The aim of this study is to examine the associations of caloric restriction, inflammatory response profiles and outcomes in critically ill patients.

Methods

This is a sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998). Serum samples were collected on study days 1, 3, 5, 7 and 14 and analyzed for a panel of 29 cytokines. We used principal component analysis to convert possibly correlated variables (cytokine levels) into a limited number of linearly uncorrelated variables (principal components). We constructed repeated measures mixed linear models to assess whether permissive underfeeding compared to standard feeding was associated with difference cytokine levels over time.

Results

A total of 72 critically ill patients were enrolled in this study (permissive underfeeding n = 36 and standard feeding n = 36). Principal component analysis identified 6 components that were responsible for 78% of the total variance. When adjusted to principal components, permissive underfeeding was not associated with 90-day mortality (adjusted odds ratio 1.75, 95% confidence interval 0.44, 6.95, p = 0.43) or with incident renal replacement therapy. The cytokines did not differ with time between permissive underfeeding and standard feeding groups.

Conclusions

The association of permissive underfeeding compared to standard feeding with mortality was not influenced by the inflammatory profile. Permissive underfeeding compared to standard feeding was not associated with differences in the serum levels of cytokines in critically ill patients.

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<![CDATA[Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment]]> https://www.researchpad.co/article/5c269727d5eed0c48470ec6b

Background

Brain volume loss is an important surrogate marker for assessing disability in MS; however, contribution of gray and white matter to the whole brain volume loss needs further examination in the context of specific MS treatment.

Objectives

To examine whole and segmented gray, white, thalamic, and corpus callosum volume loss in stable patients receiving natalizumab for 2–5 years.

Methods

This was a retrospective study of 20 patients undergoing treatment with natalizumab for 24–68 months. Whole brain volume loss was determined with SIENA. Gray and white matter segmentation was done using FAST. Thalamic and corpus callosum volumes were determined using Freesurfer. T1 relaxation values of chronic hypointense lesions (black holes) were determined using a quantitative, in-house developed method to assess lesion evolution.

Results

Over a mean of 36.6 months, median percent brain volume change (PBVC) was -2.0% (IQR 0.99–2.99). There was decline in gray (p = 0.001) but not white matter (p = 0.6), and thalamic (p = 0.01) but not corpus callosum volume (p = 0.09). Gray matter loss correlated with PBVC (Spearman’s r = 0.64, p = 0.003) but not white matter (Spearman’s r = 0.42, p = 0.07). Age significantly influenced whole brain volume loss (p = 0.010, multivariate regression), but disease duration and baseline T2 lesion volume did not. There was no change in T1 relaxation values of lesions or T2 lesion volume over time. All patients remained clinically stable.

Conclusions

These results demonstrate that brain volume loss in MS is primarily driven by gray matter changes and may be independent of clinically effective treatment.

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<![CDATA[Toll-like receptor 4 in acute viral infection: Too much of a good thing]]> https://www.researchpad.co/article/5c25454ad5eed0c48442c43d ]]>