Warfarin-induced skin necrosis in HIV-1-infected patients with tuberculosis and venous thrombosis

Background. At the turn of the century, only 300 cases of warfarin-induced skin necrosis (WISN) had been reported. WISN is a rare but potentially fatal complication of warfarin therapy. There are no published reports of WISN occurring in patients with HIV-1 infection or tuberculosis (TB).Methods. We retrospectively reviewed cases of WISN presenting from April 2005 to July 2008 at a referral hospital in Cape Town, South Africa.Results. Six cases of WISN occurred in 973 patients receiving warfarin therapy for venous thrombosis (0.62%, 95% CI 0.25 - 1.37%). All 6 cases occurred in HIV-1-infected women (median age 30 years, range 27 - 42) with microbiologically confirmed TB and venous thrombosis. All were profoundly immunosuppressed (median CD4+ count at TB diagnosis49 cells/μl, interquartile range 23 - 170). Of the 3 patients receiving combination antiretroviral therapy, 2 had TB-IRIS (immune reconstitution inflammatory syndrome). The median interval from initiation of antituberculosis treatment to venous thrombosis was 37 days (range 0 - 150). The median duration of parallel heparin and warfarin therapy was 2days (range 1 - 6). WISN manifested 6 days (range 4 - 8) after initiation of warfarin therapy. The international normalised ratio (INR) at WISN onset was supra-therapeutic, median 5.6 (range 3.8 - 6.6). Sites of WISN included breasts, buttocks and thighs. Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extendedspectrumβ-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 - 37 days after WISN onset. In 4 patients, the median interval from WISN onset to death was 43 days (range 25 - 45). One of the 2 patients who survived underwent bilateral mastectomies and extensive skin graftingat a specialist centre. Conclusion. This is one of the largest case series of WISN. We report a novel clinical entity: WISN in HIV-1 infected patients with TB and venous thrombosis. The occurrence of 6 WISN cases in a 40-month period may be attributed to (i) hypercoagulability, secondary to HIV-1 and TB; (ii) shortconcurrent heparin and warfarin therapy; and (iii) high loading doses of warfarin. Active prevention and appropriate management of WISN are likely to improve the dire morbidity and mortality of this unusual condition.S Afr Med J 2010; 100: 372-377

Lenvatinib and its use in the treatment of unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver accounting for approximately 90% of cases. Patients often present at an advanced stage when treatment options are limited. Sorafenib, a multitargeted tyrosine kinase inhibitor, has been the first-line treatment in this setting for almost a decade. Several subsequent targeted therapies have failed to demonstrate significant improvement in survival. The results of the REFLECT study suggest that lenvatinib, a multikinase inhibitor, may have promised as a first-line treatment in patients with advanced HCC. This article will review the development of lenvatinib and the evidence behind its potential use in patients with advanced HCC

Dynorphin is expressed primarily by GABAergic neurons that contain galanin in the rat dorsal horn

Background The opioid peptide dynorphin is expressed by certain neurons in the superficial dorsal horn of the spinal cord, but little is known about the types of cell that contain dynorphin. In this study, we have used an antibody against the dynorphin precursor preprodynorphin (PPD), to reveal the cell bodies and axons of dynorphin-expressing neurons in the rat spinal cord. The main aims were to estimate the proportion of neurons in each of laminae I-III that express dynorphin and to determine whether they are excitatory or inhibitory neurons. Results PPD-immunoreactive cells were concentrated in lamina I and the outer part of lamina II (IIo), where they constituted 17% and 8%, respectively, of all neurons. Around half of those in lamina I and 80% of those in lamina II were GABA-immunoreactive. We have previously identified four non-overlapping neurochemical populations of inhibitory interneurons in this region, defined by the presence of neuropeptide Y, galanin, parvalbumin and neuronal nitric oxide synthase. PPD co-localised extensively with galanin in both cell bodies and axons, but rarely or not at all with the other three markers. PPD was present in around 4% of GABAergic boutons (identified by the presence of the vesicular GABA transporter) in laminae I-II. Conclusions These results show that most dynorphin-expressing cells in the superficial dorsal horn are inhibitory interneurons, and that they largely correspond to the population that is defined by the presence of galanin. We estimate that dynorphin is present in ~32% of inhibitory interneurons in lamina I and 11% of those in lamina II. Since the proportion of GABAergic boutons that contain PPD in these laminae was considerably lower than this, our findings suggest that these neurons may generate relatively small axonal arborisations

Galanin-immunoreactivity identifies a distinct population of inhibitory interneurons in laminae I-III of the rat spinal cord

Background: Inhibitory interneurons constitute 30-40% of neurons in laminae I-III and have an important anti-nociceptive role. However, because of the difficulty in classifying them we know little about their organisation. Previous studies have identified 3 non-overlapping groups of inhibitory interneuron, which contain neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) or parvalbumin, and have shown that these differ in postsynaptic targets. Some inhibitory interneurons contain galanin and the first aim of this study was to determine whether these form a different population from those containing NPY, nNOS or parvalbumin. We also estimated the proportion of neurons and GABAergic axons that contain galanin in laminae I-III. Results: Galanin cells were concentrated in laminae I-IIo, with few in laminae IIi-III. Galanin showed minimal co-localisation with NPY, nNOS or parvalbumin in laminae I-II, but most galanin-containing cells in lamina III were nNOS-positive. Galanin cells constituted similar to 7%, 3% and 2% of all neurons in laminae I, II and III, and we estimate that this corresponds to 26%, 10% and 5% of the GABAergic neurons in these laminae. However, galanin was only found in similar to 6% of GABAergic boutons in laminae I-IIo, and similar to 1% of those in laminae IIi-III. Conclusions: These results show that galanin, NPY, nNOS and parvalbumin can be used to define four distinct neurochemical populations of inhibitory interneurons. Together with results of a recent study, they suggest that the galanin and NPY populations account for around half of the inhibitory interneurons in lamina I and a quarter of those in lamina I

Estimating the impact of HIV PrEP regimens containing long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate/emtricitabine among men who have sex with men in the United States: a mathematical modelling study for HPTN 083

Background: The HPTN 083 trial demonstrated superiority of HIV pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB) to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) among men who have sex with men (MSM). We compared the potential population-level impact of TDF/FTC and CAB among MSM in Atlanta, Georgia. Methods: An MSM HIV transmission model was calibrated to Atlanta-specific data on HIV prevalence and PrEP usage (percentage of uninfected MSM on PrEP), assuming only PrEP-indicated MSM used PrEP. CAB effectiveness (efficacy × adherence) of 91% was estimated using data from HPTN 083 and previous TDF/FTC trials. We estimated HIV infections averted over 5/10 years if TDF/FTC use were maintained, or if all TDF/FTC users switched to CAB in January 2022 (vs. no PrEP or continued TDF/FTC use). CAB scenarios with 10%/20% more users were also considered. Progress towards Ending the HIV Epidemic (EHE) goals (75%/90% fewer HIV infections in 2025/2030 vs. 2017) was estimated. Findings: We predicted TDF/FTC at current usage (∼28%) would avert 36.3% of new HIV infections (95% credible interval 25.6–48.7%) among all Atlanta MSM over 2022–2026 vs. no PrEP. Switching to CAB with similar usage may prevent 44.6% (33.2–56.6%) infections vs. no PrEP and 11.9% (5.2–20.2%) infections vs. continued TDF/FTC. Increasing CAB usage 20% could increase the incremental impact over TDF/FTC to 30.0% over 2022–2026, getting ∼60% towards reaching EHE goals (47%/54% fewer infections in 2025/2030). Reaching the 2030 EHE goal would require 93% CAB usage. Interpretation: If CAB effectiveness were like HPTN 083, CAB could prevent more infections than TDF/FTC at similar usage. Increased CAB usage could contribute substantially towards reaching EHE goals, but the usage required to meet EHE goals is unrealistic

Neural correlates of enhanced visual short-term memory for angry faces: An fMRI study

Copyright: © 2008 Jackson et al.Background: Fluid and effective social communication requires that both face identity and emotional expression information are encoded and maintained in visual short-term memory (VSTM) to enable a coherent, ongoing picture of the world and its players. This appears to be of particular evolutionary importance when confronted with potentially threatening displays of emotion - previous research has shown better VSTM for angry versus happy or neutral face identities.Methodology/Principal Findings: Using functional magnetic resonance imaging, here we investigated the neural correlates of this angry face benefit in VSTM. Participants were shown between one and four to-be-remembered angry, happy, or neutral faces, and after a short retention delay they stated whether a single probe face had been present or not in the previous display. All faces in any one display expressed the same emotion, and the task required memory for face identity. We find enhanced VSTM for angry face identities and describe the right hemisphere brain network underpinning this effect, which involves the globus pallidus, superior temporal sulcus, and frontal lobe. Increased activity in the globus pallidus was significantly correlated with the angry benefit in VSTM. Areas modulated by emotion were distinct from those modulated by memory load.Conclusions/Significance: Our results provide evidence for a key role of the basal ganglia as an interface between emotion and cognition, supported by a frontal, temporal, and occipital network.The authors were supported by a Wellcome Trust grant (grant number 077185/Z/05/Z) and by BBSRC (UK) grant BBS/B/16178

Facile Synthesis of High Quality Graphene Nanoribbons

Graphene nanoribbons have attracted attention for their novel electronic and spin transport properties1-6, and because nanoribbons less than 10 nm wide have a band gap that can be used to make field effect transistors. However, producing nanoribbons of very high quality, or in high volumes, remains a challenge. Here, we show that pristine few-layer nanoribbons can be produced by unzipping mildly gas-phase oxidized multiwalled carbon nanotube using mechanical sonication in an organic solvent. The nanoribbons exhibit very high quality, with smooth edges (as seen by high-resolution transmission electron microscopy), low ratios of disorder to graphitic Raman bands, and the highest electrical conductance and mobility reported to date (up to 5e2/h and 1500 cm2/Vs for ribbons 10-20 nm in width). Further, at low temperature, the nanoribbons exhibit phase coherent transport and Fabry-Perot interference, suggesting minimal defects and edge roughness. The yield of nanoribbons was ~2% of the starting raw nanotube soot material, which was significantly higher than previous methods capable of producing high quality narrow nanoribbons1. The relatively high yield synthesis of pristine graphene nanoribbons will make these materials easily accessible for a wide range of fundamental and practical applications.Comment: Nature Nanotechnology in pres

The validity of using ICD-9 codes and pharmacy records to identify patients with chronic obstructive pulmonary disease

Background: Administrative data is often used to identify patients with chronic obstructive pulmonary disease (COPD), yet the validity of this approach is unclear. We sought to develop a predictive model utilizing administrative data to accurately identify patients with COPD. Methods: Sequential logistic regression models were constructed using 9573 patients with postbronchodilator spirometry at two Veterans Affairs medical centers (2003-2007). COPD was defined as: 1) FEV1/FVC <0.70, and 2) FEV1/FVC < lower limits of normal. Model inputs included age, outpatient or inpatient COPD-related ICD-9 codes, and the number of metered does inhalers (MDI) prescribed over the one year prior to and one year post spirometry. Model performance was assessed using standard criteria. Results: 4564 of 9573 patients (47.7%) had an FEV1/FVC < 0.70. The presence of ≥1 outpatient COPD visit had a sensitivity of 76% and specificity of 67%; the AUC was 0.75 (95% CI 0.74-0.76). Adding the use of albuterol MDI increased the AUC of this model to 0.76 (95% CI 0.75-0.77) while the addition of ipratropium bromide MDI increased the AUC to 0.77 (95% CI 0.76-0.78). The best performing model included: ≥6 albuterol MDI, ≥3 ipratropium MDI, ≥1 outpatient ICD-9 code, ≥1 inpatient ICD-9 code, and age, achieving an AUC of 0.79 (95% CI 0.78-0.80). Conclusion: Commonly used definitions of COPD in observational studies misclassify the majority of patients as having COPD. Using multiple diagnostic codes in combination with pharmacy data improves the ability to accurately identify patients with COPD.Department of Veterans Affairs, Health Services Research and Development (DHA), American Lung Association (CI- 51755-N) awarded to DHA, the American Thoracic Society Fellow Career Development AwardPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84155/1/Cooke - ICD9 validity in COPD.pd