Utility of the 4Ts score in excluding heparin-induced thrombocytopenia in lung transplant recipients.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic complication following heparin exposure. Data is limited on the incidence of HIT and validity of 4Ts score in the solid organ transplant population. This retrospective observational cohort included patients who underwent lung transplant between August 2015 and June 2018 and had a clinical suspicion of HIT with heparin-PF4 testing. The 4Ts score was correlated with the heparin-PF4 antibody and serotonin release assay (SRA) results, with positive SRA considered confirmed HIT. Of 146 patients evaluated, the overall incidence of HIT was low (2(1%)). Fifty-one patients had heparin-PF4 testing and were included in the cohort; 5 (10%) had positive heparin-PF4 and 1 (2%) had confirmed HIT. The median 4Ts score was 3 (3-4). Thirty (59%), 17 (33%), and 4 (8%) patients had low, intermediate, and high risk, respectively. The intermediate/high risk group compared to the low risk group had a higher use of alternative non-heparin anticoagulation [13 (62%) vs 7 (23%); p = 0.0086)] and a higher incidence of thrombosis [13 (62%) vs 1 (3%); p < 0.0001]. No patient with a low 4Ts score had confirmed HIT, supporting the utility of low 4Ts score to exclude HIT diagnosis in lung transplant recipients.

Impact of Potentially Unwarranted Intravenous Antibiotics Targeting Pulmonary Infections in Acute Decompensated Heart Failure.

BACKGROUND: Acute decompensated heart failure (ADHF) can present similarly to pulmonary infections. The additional volume and sodium received from intravenous antibiotics (IVAB) can be counterproductive, especially when strong evidence of infection is lacking. OBJECTIVE: The objective was to evaluate the impact of potentially unwarranted IVAB on clinical outcomes in patients with ADHF. METHODS: This multicenter, retrospective, cohort study evaluated adults admitted with ADHF, a chest radiograph within 24 hours, B-natriuretic peptide >100 pg/mL, and either received no IVAB or IVAB for at least 48 hours. Subjects with recent antibiotics, justification for antibiotics, or transferred to the intensive care unit (ICU) within 24 hours of admission were excluded. The primary outcome was hospital length of stay (LOS). Secondary outcomes included utilization of loop diuretics, administration of fluid and sodium, mortality, and 30-day readmissions. RESULTS: Out of 240 subjects included, 120 received IVAB. LOS was significantly longer in the IVAB group (5.12 days vs 3.73 days; P < .001). LOS remained significantly longer in the IVAB group in a propensity score matched cohort (5.26 days vs 3.70 days; P < .001). The IVAB group received more volume and sodium from intravenous fluids (P < .001). ICU admission greater than 24 hours after admission was higher with IVAB (20% vs 7.5%; P = .049). No significant differences in total loop diuretics, intubation rate, mortality, and 30-day readmissions were identified. CONCLUSION: ADHF patients who received potentially unwarranted IVAB had longer hospital LOS and were more likely to be admitted to the ICU after 24 hours of hospitalization.

National park development in China: conservation or commercialization?

The rapid development of parks and ecotourism in China has attracted worldwide attention, not only for the beauty of the landscape that the parks are protecting but also for their abundant and often unique biodiversity. However, in some areas, the development of ecotourism has actually led to the degradation of local ecological, economic, and social systems. Using National Forest Parks for demonstration, this article analyzes the current political, institutional, legal, environmental, and economic issues concerning National Parks in China, and examines their potential future development. Although the intention of National Park systems in China is to raise environmental quality, and to protect biodiversity and social livelihoods, their success has varied. Future success will be measured by their capacity to reduce poverty, to promote long-term rehabilitation of wildlife habitats, and to simultaneously protect Chinese culture and biodiversity.

Impact of inter-hospital transfer on success of angioembolization for lower gastrointestinal bleeding.

BACKGROUND: Angioembolization is a useful therapeutic tool for lower gastrointestinal bleeding (LGIB) however is only available at centres with specialist interventional radiology departments. Delay in angioembolization of greater than 120-150 minutes is associated with higher rates of non-therapeutic angioembolization. METHODS: This retrospective review analysed the impact of interhospital transfer on timing and success of angioembolization in adults with LGIB. RESULTS: Of the 121 patients who underwent CTMA at a peripheral hospital for LGIB, only 20.7% had positive CTMA (n = 25). Of the 24 patients who were transferred for the purpose of angioembolization, only five ultimately had successful embolisation (20.1%). Patients who had unsuccessful angioembolization had a significantly longer mean time from arrival at the tertiary hospital to angioembolization compared to patients who had successful angioembolization (mean 375 versus 175 min, P = 0.001). There was no association of patient haemodynamics, use of anticoagulant or antiplatelet therapy, and transfusion requirement with success of angioembolization. CONCLUSION: Interhospital transfer is associated with delay in angioembolization. Delay after arrival at the receiving hospital is associated with unsuccessful angioembolization.

Binge ethanol consumption-associated behavioral impairments in male mice using a gelatin-based drinking-in-the dark model.

BACKGROUND: Acute intoxication caused by binge ethanol drinking is linked to widespread impairments in brain functions. Various alcohol administration paradigms have been used in animals to model the heterogeneous clinical manifestation of intoxication in people. It is challenging to model a procedure that produces "visible intoxication" in rodents; however, manipulation of variables such as route of alcohol administration, time of availability, frequency, and duration and amount of ethanol exposure has achieved some success. In the current study, we employed a modified drinking-in-the-dark model to assess the validity of this model in producing "post-ethanol consumption intoxication" impairments following prolonged repeated daily voluntary "binge" ethanol consumption. METHODS: Adult male C57BL/6J mice were allowed a daily 3-h access to non-alcoholic plain or ethanol-containing gel during the dark cycle for a total of 83 days. After the initial 2-month daily DID, ethanol intake patterns were intensely characterized during the next 3 weeks. Immediately following the last DID session (day 83), plain and ethanol gel-consuming mice were then subjected to behavioral tests of locomotor ability and/or anxiety (cylinder, wire grip, open field) followed by blood ethanol concentration measurement. RESULT: Mice exhibited a relatively consistent ethanol consumption pattern during and across daily access periods. Ethanol intake of individual mice positively correlated with blood ethanol concentration that averaged 61.64 ± 2.84 mg/dL (n = 12). Compared to the plain gel-consuming control mice, ethanol gel mice exhibited significant locomotor impairment as well as anxiety-like behavior, with the magnitude of impairments of key indices well correlated with blood ethanol levels. CONCLUSION: The gelatin vehicle-based voluntary ethanol drinking-in-the-dark model reliably produced post consumption acute movement impairments as well as anxiety-like behaviors even after 2 months of daily binge ethanol consumption in male mice. Taken together, this mouse binge ethanol model should facilitate the investigation of mechanisms of binge drinking in subjects chronically abusing ethanol and the search for effective novel treatment strategies.

Overcoming the Challenges of Low Drug Solubility in the Intravenous Formulation of Solithromycin.

Solithromycin is a fluoro-ketolide (a fourth-generation macrolide) antibiotic that has been undergoing clinical trials for the treatment of community-acquired bacterial pneumonia. In this study, development of the tri-amino acid-buffered solithromycin intravenous (IV) formulation was performed to minimize the occurrence of infusion-associated local adverse events (infusion-site pain or phlebitis) observed in patients who received the tartaric acid-buffered IV formulation with a lower buffered capacity during phase I clinical trials. Development of the tri-amino acids-buffered solithromycin IV formulation was achieved using a dynamic in vitro precipitation model. Computational modeling also supports the superiority of the amino acid-buffered formulation over the tartaric aid-buffered formulation.

The role of neurogenesis in neurodegenerative diseases and its implications for therapeutic development.

Neurodegenerative diseases are characterised by a net loss of neurons from specific regions of the central nervous system (CNS). Until recently, research has focused on identifying mechanisms that lead to neurodegeneration, while therapeutic approaches have been primarily targeted to prevent neuronal loss. This has had limited success and marketed pharmaceuticals do not have dramatic benefits. Here we suggest that the future success of therapeutic strategies will depend on consideration and understanding of the role of neurogenesis in the adult CNS. We summarize evidence suggesting that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's, Alzheimer's and Amyotrophic Lateral Sclerosis, while it is enhanced in stroke. We review studies where stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important. We show that many current therapeutics, developed to block degeneration or to provide symptomatic relief, serendipitously stimulate neurogenesis or, at least, do not interfere with it. Importantly, many receptors, ion channels and ligand-gated channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors, also play an important role in neurogenesis and regeneration. Therefore, new therapeutics targeted to block degeneration by antagonizing these channels may have limited benefit as they may also block regeneration. Our conclusion is that future drug development must consider neurogenesis. It appears unlikely that drugs being developed to treat neurodegenerative diseases will be beneficial if they impair neurogenesis. And, most tantalizing, therapeutic approaches that stimulate neurogenesis might stimulate repair and even recovery from these devastating diseases.

Recent advances of MEK inhibitors and their clinical progress.

The RAS/RAF/MEK/ERK signaling pathway has been a major clinical focus in oncology research in recent years. A clearer association of B-RAF mutations to cancers such as melanoma, papillary thyroid cancer and others has brought an increasing interest in chemotherapeutics that target this cellular signaling pathway. In this review, the authors summarize the current understanding of science and therapeutic use of the MEK inhibitors targeting the RAS/RAF/ MEK/ERK pathway. Clinical progresses of PD0325901 and AZD6244 are highlighted in addition to developments of new MEK inhibitors. Recently disclosed MEK inhibitors in two sub-divided classes, ATP noncompetitive and ATP competitive inhibitors are discussed.