The spectrum of bacterial infections in febrile neutropenic patients: effect on empiric antibiotic therapy

The aim of this retrospective analysis was to look at the spectrum of bacterial isolates and their resistance patterns to the commonly used antIbiotics in the settmg of febrile neutropenia. A total of 127 bacteria were isolated from patients with acute leukemias, lymphoproliferative disorders, aplastic anaemia and various solid tumours. Fifty-four percent organisms were gram negative; while the rest were gram positive. E. coli, pseudomónas aeruginosa, staphylococcus aureus, enterococcus and streptococci were the commonly isolated organisms. Forty-eight percent organisms were isolated from blood, 16% from urine, 13% from wounds and superficial abscesses and 11% from respiratory tract. E. coli exhibited a great degree of resistance to the commonly used antibiotics, such as pipericillin (70%), ofloxacin (50%) and aztreonam (50%). Pseudomonas and kiebsiella also showed varying degree of resistance against the antibiotics. Staphylococcus aureus and staphylococcus epidennidis were almost universally resistant to penicillin and showed a variable degree of resistance to other antibiotices too. Compared to the previous reports, the pattern of bacterial isolates and their resistance to antibiotics has changed over the past years. Aminolgy­cosides and third generation cephalosporins seem to be the choice of antibiotics for the upfront manage­ment of febrile neutropenic patients (JPMA 48:364,1998)

Severe thrombocytopenia in a man with prostatic cancer

A 66 year old gentleman was diagnosed to have metastatic adenocarcinoma of the prostate in 1990, following a CT scan of the abdomen and trans-uretheral resection of prostate (TLJRP). He was started on estrogen therapy (Fos­festerol sodium). Two years later he presented to the emer­gency room with breathlessness and edema of the left ann of a week’s duration. He admitted to persistence of symptoms of pmstatism and was found to have bilateral axillary lymphade­nopathy and pitting edema of the left arm. A doppler scan revealed left subclavian vein thrombosis. The patient was started on i.v. heparin and was maintained on it until the resolution of arm edema and was subsequently switched to oral anticoagulation. The serum Prostate Specific Antigen (PSA) level was found to be 1460 ng/ml. Fosfesterol was discontinued and the patient was started on antiandrogen therapy (Cyproterone acetate). The patient was sent home on anticoagulation, but had to be readmitted shortly thereafter because of the sudden onset of shortness of breath. This time he was found to have bilateral pitting pedal edema and :tenderness in the right calf. Intravenous heparin was reinsti­tuted. An infçrior venacavagram revealed extensive thrombo­sis of the right popliteal vein and the left common iliac vein. A clinical diagnosis of pulmonary embolism was made. Despite continuous i.v. heparin in adequate doses, the patient experi­enced recurrent episodes of shortness of breath. A greenfield filter was placed in the inferior vena cava to prevent further episodes of pulmonary embolism. The patient remained heparinized for more than two weeks, until complete resolu­tionofsyniptoms had occured. Subsequently oral anticoagula­tion was started and the dose of coumarin was adjusted to maintain an international normalized ratio (INR) between 1.8 and2.0

The longitudinal association of sleep and 24-hour activity rhythms with cortisol response to a very low dose of dexamethasone

Objectives: Poor sleep is common in the general population, with hyperarousal and stress often suggested as causal factors. Conversely, sleep might also affect the stress response, in which the hypothalamic-pituitary-adrenal (HPA) axis plays a key role. We assessed the longitudinal association of sleep and 24-hour activity rhythms with functioning of the negative feedback loop of the HPA axis, as indicated by the cortisol response to a very low dose of dexamethasone. Design: Longitudinal cohort. Setting: Population-based. Participants: This study included 410 participants (mean age: 56.1 ± 5.5 years, 59% women) from the Rotterdam Study. For 217 participants, the cortisol response to dexamethasone was assessed again after a median follow-up of 5.7 years (IQR = 5.5-5.8). Measurements: Between 2004 and 2007, sleep and 24-hour activity rhythms were estimated with actigraphy (mean duration: 146 ± 19.6 hours) and sleep quality with the Pittsburgh Sleep Quality Index. To assess the negative feedback loop of the HPA axis we measured cortisol before and after the intake of a very low-dose of dexamethasone (0.25 mg). Results: Unstable (B = 1.64, 95% CI = 0.78; 2.50) and fragmented (B = -1.31, 95% CI = -2.17; -0.45) 24-hour activity rhythms, and a poor self-rated sleep quality (B = -0.02, 95% CI = -0.04; 0.00) were associated with an enhanced cortisol response to dexamethasone over time, also in those without clinically relevant depressive symptoms and those not using psychoactive medication. Conclusions: This study demonstrates a longitudinal association of disturbed 24-hour activity rhythms and poor self-rated sleep quality with an enhanced cortisol response to dexamethasone, in other words stronger suppression of cortisol. Statement of significance: This study shows that disturbed 24-hour activity rhythms and a poor self-rated sleep quality are associated with functioning of the negative feedback loop over a period of years.</p

Are C-Reactive Protein Associated Genetic Variants Associated with Serum Levels and Retinal Markers of Microvascular Pathology in Asian Populations from Singapore?

Introduction:C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations.Methods:Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry.Results:Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10-8) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058).Conclusions:Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease

Mediation of the Association Between <i>APOE </i>ε4 Genotype, Cognition, and Dementia by Neuropathology Imaging Markers in the Rotterdam Study

Background and ObjectivesInsight into APOE-related pathways is important to unravel pathophysiology and identify therapeutic targets against late-life cognitive decline. We aimed to estimate mediators of APOE ϵ4 on cognition and dementia through different disease markers on structural in vivo brain imaging.MethodsAll participants from the population-based Rotterdam Study who underwent brain MRI between 2005 and 2009 were included. Cognition was assessed cross-sectionally during center visits, and participants were followed up for incident dementia until January 1, 2020. Imaging markers included hippocampal volume (HV), volume of white matter hyperintensities (WMHs), Alzheimer disease-specific regional cortical thickness, and presence of ≥2 cerebral microbleeds. We performed causal mediation analyses to decompose the total effect of APOE ϵ4 carriership on cognition and dementia into natural direct and indirect effects and corresponding percentage mediated. We adjusted models for potential confounders.ResultsAmong 5,510 participants (mean age at time of MRI scan: 65.0 [±10.9] years, 55.0% women), 349 developed dementia, of whom 148 were ϵ4 carriers. Carriers of ϵ4 had slightly lower Z-scores for global cognition (β = -0.02 [-0.07 to 0.02], age-related cognitive decline = 4.4 months), with 7% (β = -0.00 [0.00-0.00]) of this association mediated by HV and 4% (β = -0.00 [-0.01 to 0.00]) by cortical thickness. In total, an estimated 25% of the effect of ϵ4 on cognition was mediated by microbleeds (p value = 0.24, [β = -0.00 {-0.01 to 0.00}]) and 12% by WMHs (p value = 0.44, [β = -0.00 {-0.01 to 0.00}]). In multiple mediator analyses, WMHs and microbleeds together accounted for 27% of the mediated effect of APOE ϵ4 on cognition (p value = 0.48). Carriers of ϵ4 had higher risk of incident dementia (HR 2.35 [95% CI 2.06-2.65]). For dementia, there was little to no evidence of mediation by either HV (3%, p value = 0.09, OR = 1.01 [1.00-1.03]) or regional cortical thickness (0%, p value = 0.79, OR = 1.00 [0.99-1.02]). In total, 1% of the effect of ϵ4 on dementia was mediated by WMHs (p value 0.29, OR = 1.00 [1.00-1.02]) and 5% by microbleeds (p value = 0.06), OR = 1.03 (1.00-1.07). In multiple mediator analyses, all 4 imaging markers together explained 6% of the mediated effect on incident dementia (p value = 0.04).DiscussionIn this population-based cohort study, we found that an estimated one-fourth of the effect of APOE ϵ4 on cognition is mediated by structural brain imaging markers, driven mainly by cerebral microbleeds. For dementia, mediation by these markers was limited. Glossary FLAIR = fluid-attenuated inversion recovery; GMS = Geriatric Mental Schedule; HV = hippocampal volume; IQR = interquartile range; MMSE = Mini-Mental State Examination; PPB = Purdue Pegboard test; WMH = white matter hyperintensity.</p

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179

Genetic evidence for the most common risk factors for chronic axonal polyneuropathy in the general population

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. METHODS: This study was performed within the population‐based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6–78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome‐wide association studies. RESULTS: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR](diabetes, p < 1.0) = 1.21, 95% confidence interval [CI] = 1.05–1.39 and OR(BMI, p < 1.0) = 1.21, 95% CI = 1.04–1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR (vitamin B12, p < 5e‐6) = 0.79, 95% CI = 0.68–0.92 and OR(alcohol, p < 5e‐8) = 1.17, 95% CI = 1.02–1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGS (p ) (< 5e‐8) and polyneuropathy. CONCLUSIONS: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well‐known clinical risk factors and polyneuropathy