Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)

Purpose Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4–46.1) had thrombocytopenia; 23.4% (20–26) had thrombocytopenia at ICU admission, and 19.8% (17.6–22.2) developed thrombocytopenia during their ICU stay. Non-AIDS-, non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19–2.42). Conclusion Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.publishedVersio

The association between cervical degenerative MRI findings and self-reported neck pain, disability and headache: a cross-sectional exploratory study

Abstract Background Neck pain and headache are highly prevalent conditions and leading causes of disability worldwide. Although MRI is widely used in the management of these conditions, there is uncertainty about the clinical significance of cervical MRI findings in patients with neck pain or headache. Therefore, this study aims to investigate the association between cervical degenerative MRI findings and self-reported neck pain, neck disability, and headache. Methods This study was a secondary analysis of a cohort of patients with low back pain aged 18–40 years recruited from a non-surgical outpatient spine clinic. The cervical MRI and outcome measures used in this analysis were collected at a four-year follow-up (2014–2017). Self-reported outcome measures included neck pain intensity, neck disability as measured by the Neck Disability Index, and headache as measured by a single NDI item. Cervical MRI findings included disc degeneration, disc contour changes, and vertebral endplate signal changes (VESC). Multivariable logistic regression analyses, adjusted for age and sex, were used to analyse the associations between MRI findings and neck pain, neck disability, and headache. Results A total of 600 participants who underwent MRI and completed the relevant questionnaires at follow-up were included. The median age was 37 years (interquartile range 31–41) and 325 (54%) were female. Of the included participants, 181 (31%) had moderate or severe neck pain, 274 (59%) had moderate or severe neck disability, 193 (42%) reported headaches, and 211 (35%) had one or more cervical degenerative MRI findings. Cervical disc degeneration and disc contour changes were positively associated with moderate or severe neck pain with odds ratio 1.6 (95% CI 1.1–2.4) and 1.6 (1.1–2.3), respectively. VESC was associated with moderate or severe neck disability with odds ratio 3.3 (1.3–8.4). No statistically significant associations were found between the MRI findings assessed and headache. Conclusions In this cross-sectional exploratory study, we found that cervical disc degeneration and disc contour changes were associated with neck pain, and VESC was associated with neck disability. None of the MRI findings were associated with headache. The results suggest that cervical degenerative changes may contribute to the aetiology of neck symptoms, but the associations are modest and cannot guide clinical decisions

Additional file 1 of The association between cervical degenerative MRI findings and self-reported neck pain, disability and headache: a cross-sectional exploratory study

Additional file 1. Number of cervical degenerative MRI findings, stratified by neck pain, neck disability and headache, and graphical representation of the distribution of outcomes and age

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia.

Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6) or chemokines (CXCL1, CXCL10, CCL2); however, protein expression of TNF, IL-1β, IL-6 and CXCL1 was reduced in membrane-anchored tumor necrosis factor(Δ/Δ) compared to membrane-anchored tumor necrosis factor(wt/wt) mice one day after experimental stroke. This was paralleled by reduced MHCII expression and a reduction in macrophage infiltration in the ipsilateral cortex of membrane-anchored tumor necrosis factor(Δ/Δ) mice. Collectively, these findings indicate that membrane-anchored tumor necrosis factor mediates the protective effects of tumor necrosis factor signaling in experimental stroke, and therapeutic strategies specifically targeting soluble tumor necrosis factor could be beneficial in clinical stroke therapy

Selective mGAT2 (BGT-1) GABA Uptake Inhibitors: Design, Synthesis, and Pharmacological Characterization

β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1–4. The parent amino acids were also characterized. Compounds <b>13a</b>, <b>13b</b>, and <b>17b</b> displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound <b>17b</b> displayed anticonvulsive properties inferring a role of mGAT2 in epileptic disorders. These results provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors

Radiosynthesis and Evaluation of [¹¹C]3-Hydroxycyclopent-1-enecarboxylic Acid as Potential PET Ligand for the High-Affinity γ‑Hydroxybutyric Acid Binding Sites

γ-Hydroxybutyric acid (GHB) is an endogenous neuroactive substance and proposed neurotransmitter with affinity for both low- and high-affinity binding sites. A radioligand with high and specific affinity toward the high-affinity GHB binding site would be a unique tool toward a more complete understanding of this population of binding sites. With its high specific affinity and monocarboxylate transporter (MCT1) mediated transport across the blood-brain barrier in pharmacological doses, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) seems like a suitable PET radiotracer candidate. Here, we report the ¹¹C-labeling and subsequent evaluation of [¹¹C]­HOCPCA in a domestic pig, as a PET-radioligand for visualization of the high-affinity GHB binding sites in the live pig brain. To investigate the regional binding of HOCPCA in pig brain prior to in vivo PET studies, in vitro quantitative autoradiography on sections of pig brain was performed using [³H]­HOCPCA. In vivo evaluation of [¹¹C]­HOCPCA showed no brain uptake, possibly due to a limited uptake of HOCPCA by the MCT1 transporter at tracer doses of [¹¹C]­HOCPCA