A systematic review of tranexamic acid in hip fracture surgery

Aim: To systematically examine and quantify the efficacy and safety of Tranexamic acid in hip fracture surgery.  Methods: A systematic literature search was conducted using Medline, EMBASE, AMED, CiNAHL, and the Cochrane Central Registry of Controlled Trials. Two assessors independently screened search outputs for potentially relevant articles which met the eligibility criteria. The primary outcome measure was requirement of post-operative blood transfusion. Risk of bias assessment was performed using the Cochrane Collaboration’s risk of bias tool for RCT’s and the ROBINS-I tool for observational studies. Meta-analysis was performed to estimate risk ratio (RR), risk difference (RD) and mean difference (MD) values for dichotomous and continuous data outcomes respectively. The interpretation of each outcome was made using the GRADE approach.  Results: Of 102 studies identified, seven met the inclusion criteria including a total of 770 participants (TXA: 341; Control: 429). On meta-analysis, intra-venous TXA resulted in a 46% risk reduction in blood transfusion requirement compared to a placebo/control group (RR:0.54; 95% CI: 0.35 to 0.85; I2: 78%; Inconsistency (Chi2) p=<0.0001; N=750). There was also a significantly higher post-operative haemoglobin for TXA versus placebo/control (MD:0.81; 95% CI: 0.45 to 1.18; I2: 46%; Inconsistency (Chi2) p=0.10; N=638). There was no increased risk of thromboembolic events (RD:0.01; 95% CI: -0.03, 0.05; I2: 68%; Inconsistency (Chi2) p=0.007, N=683).  Conclusion: There is moderate quality evidence that TXA reduces blood transfusion in hip fracture surgery, with low quality evidence suggesting no increased risk of thrombotic events. These findings are consistent with TXA use in other orthopaedic procedures

The usefulness of confusion, urea, respiratory rate, and shock index or adjusted shock index criteria in predicting combined mortality and/or ICU admission compared to CURB-65 in community-acquired pneumonia

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Determinants of Length of Stay Following Total Anterior Circulatory Stroke

Identification of factors that determine length of stay (LOS) in total anterior circulatory stroke (TACS) has potential for targeted intervention to reduce the associated health care burden. This study aimed to determine which factors predict LOS following either ischaemic or haemorrhagic TACS. The study sample population was drawn from the Norfolk and Norwich Stroke and Transient Ischemic Attack (TIA) Register (1996 – 2012), a prospective registry. 2965 patients admitted with TACS verified by a stroke specialist team were included. Primary analysis identified predictors of length of stay (LOS) in either haemorrhagic or ischaemic TACS. Secondary analyses identified predictors of LOS in patients who were discharged alive or who died during admission separately. Moderate (p=0.014) to severe disability (p=0.015) and history of congestive heart failure (p=0.027) in the primary analysis and pre-stroke residence in a care facility among patients who survived to discharge (p=0.013) were associated with a shorter length of stay. Factors associated with increased length of stay included presence of neurological lateralisation in the primary analysis (p=0.004) and amongst patients who died (p=0.003 and p=0.014 for ischaemic and haemorrhagic stroke, respectively). Patients with advanced age (≥85 years) with haemorrhagic stroke had longer LOS regardless of mortality outcome. Patients with low pre-morbid disability (modified Rankin score ≤2 who died following haemorrhagic TACS also had longer LOS. Our study found predictors of LOS following TACS include neurological lateralisation, pre-stroke disability status, congestive heart failure, pre-morbid residence and age. The identification of such factors would assist in resource allocation and discharge planning

Challenges to replace ACT as first-line drug

The spread of artemisinin and partner drug resistance through Asia requires changes in first-line therapy. The traditional modus has been the replacement of one first-line anti-malarial regimen with another. The number of anti-malarial drug candidates currently in development may have given false confidence in the expectation that resistance to artemisinin-based combination therapy (ACT) can be solved with a switch to the next anti-malarial drug regimen. A number of promising anti-malarial drug regimens did not succeed in becoming first-line drugs due to safety concerns or rapid development of resistance. Currently promising candidates for inclusion in first-line regimens, such as KAE 609, KAF 156, OZ 439, and OZ 277, have already triggered safety concerns or fears that point mutations could render the drugs inefficacious. An additional challenge for a new first-line drug is finding an appropriate partner drug. There is hope that none of the above-mentioned concerns will be substantiated in larger, upcoming trials. Meanwhile, combining already licensed anti-malarials may be a promising stop-gap measure. Practitioners in Vietnam have empirically started to add mefloquine to the current dihydroartemisinin-piperaquine. Practitioners in Africa could do worse than empirically combine already licensed co-artemether and amodiaquine when treatment with ACT no longer clears Plasmodium falciparum. Both combinations are currently undergoing trials

Non-canonical functions of EZH2 in cancer

Mutations in chromatin modifying genes frequently occur in many kinds of cancer. Most mechanistic studies focus on their canonical functions, while therapeutic approaches target their enzymatic activity. Recent studies, however, demonstrate that non-canonical functions of chromatin modifiers may be equally important and therapeutically actionable in different types of cancer. One epigenetic regulator that demonstrates such a dual role in cancer is the histone methyltransferase EZH2. EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which plays a crucial role in cell identity, differentiation, proliferation, stemness and plasticity. While much of the regulatory functions and oncogenic activity of EZH2 have been attributed to its canonical, enzymatic activity of methylating lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark, recent studies suggest that non-canonical functions that are independent of H3K27me3 also contribute towards the oncogenic activity of EZH2. Contrary to PRC2\u27s canonical repressive activity, mediated by H3K27me3, outside of the complex EZH2 can directly interact with transcription factors and oncogenes to activate gene expression. A more focused investigation into these non-canonical interactions of EZH2 and other epigenetic/chromatin regulators may uncover new and more effective therapeutic strategies. Here, we summarize major findings on the non-canonical functions of EZH2 and how they are related to different aspects of carcinogenesis

Relationship of Job Design, Organizational Commitment on Compensations of Physicians In A Private Hospital, Philippines

The profession of a physician is one of the highly respected and challenging jobs in the world&nbsp;today. It is one of the fields where intelligence and hard decisions are made to save lives. This&nbsp;study examined the relationship between job design, organizational commitment, and&nbsp;compensations; if job design and organizational commitment are predictors of compensation&nbsp;of physicians of a private hospital in Manila, Philippines; and if there is a significant difference&nbsp;in compensation when physician’s gender and years of service are considered. The research&nbsp;design was correlational using a t-test, analysis of variance (ANOVA), regression, and Pearson&nbsp;Correlation. Fifty hospital physicians were conveniently selected to answer a self-constructed&nbsp;questionnaire. The study revealed that job design and organizational commitment has a positive&nbsp;correlation to compensation in a health facility. Sex and years of service of the physicians do&nbsp;not differ on compensation. The study also revealed that attention should be given to organizational commitment. Organizational commitment predicted a positive relationship to&nbsp;compensation, but job design in terms of prediction, could not predict compensation though it&nbsp;had a positive relationship, which requires future studies to further investigate using other&nbsp;variables.&nbsp

Use of Dexamethasone for Severe Fatigue in the Advanced Cancer Population: A Brief Report.

BACKGROUND: Fatigue is a common and distressing symptom for palliative care patients. Although the current literature emphasizes nonpharmacological management, dexamethasone is reportedly used in clinical practice. This study helps to characterize its use, efficacy, and adverse effects in a real-world setting. OBJECTIVE: To improve the evidence base by exploring the use, efficacy, and side effect profile of dexamethasone for fatigue management. METHODS: This international multisite prospective observational case series assessed the benefit and adverse effects of dexamethasone at baseline (T0) and at five to seven days postbaseline (T1). Fatigue scores were assessed using the symptom assessment scale (SAS) and visual analogue fatigue scale (VAFS). Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). The related samples Wilcoxon signed-rank test was used to compare before and after scores. RESULTS: All 18 patients (male-female, 11:7) had advanced metastatic cancer with most in the deteriorating palliative care phase (56%). The most common dose of dexamethasone was 4 mg daily orally. At T1 (n = 12), improvement was seen in all measures of fatigue; the median SAS scores decreased from 7 to 5.5 (p = 0.007), the median VAFS scores increased from 3 to 5 (p = 0.126), and the median NCI-CTCAE fatigue scores were reduced from 3 to 2.5 (p = 0.18). Dexamethasone was well tolerated; one participant experienced grade 3 delirium. CONCLUSION: The small number of participants recruited for this study suggests that dexamethasone is not widely used specifically for fatigue. Our results suggest an improvement in fatigue scores from T0 to T1

A new tool for the chemical genetic investigation of the Plasmodium falciparum Pfnek-2 NIMA-related kinase

Background: Examining essential biochemical pathways in Plasmodium falciparum presents serious challenges, as standard molecular techniques such as siRNA cannot be employed in this organism, and generating gene knock-outs of essential proteins requires specialized conditional approaches. In the study of protein kinases, pharmacological inhibition presents a feasible alternative option. However, as in mammalian systems, inhibitors often lack the desired selectivity. Described here is a chemical genetic approach to selectively inhibit Pfnek-2 in P. falciparum, a member of the NIMA-related kinase family that is essential for completion of the sexual development of the parasite. Results: Introduction of a valine to cysteine mutation at position 24 in the glycine rich loop of Pfnek-2 does not affect kinase activity but confers sensitivity to the protein kinase inhibitor 4-(6-ethynyl-9H-purin-2-ylamino) benzene sulfonamide (NCL-00016066). Using a combination of in vitro kinase assays and mass spectrometry, (including phosphoproteomics) the study shows that this compound acts as an irreversible inhibitor to the mutant Pfnek2 likely through a covalent link with the introduced cysteine residue. In particular, this was shown by analysis of total protein mass using mass spectrometry which showed a shift in molecular weight of the mutant kinase in the presence of the inhibitor to be precisely equivalent to the molecular weight of NCL-00016066. A similar molecular weight shift was not observed in the wild type kinase. Importantly, this inhibitor has little activity towards the wild type Pfnek-2 and, therefore, has all the properties of an effective chemical genetic tool that could be employed to determine the cellular targets for Pfnek-2. Conclusions: Allelic replacement of wild-type Pfnek-2 with the mutated kinase will allow for targeted inhibition of Pfnek-2 with NCL-00016066 and hence pave the way for comparative studies aimed at understanding the biological role and transmission-blocking potential of Pfnek-2. © 2016 The Author(s)

Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase

The Ageing Gut-Brain Study : Exploring the role of the gut microbiota in dementia

Alex Johnstone, Alison Donaldson, Karen Scott and Phyo Myint all contributed equally to the writing and preparation of the manuscript. This study is funded by Tenovus Scotland Research Project No. G16‐08 (start 1 June 2017, end date 31 January 2019) and NHS‐Grampian Research and Development Endowment Research Grants Project No: 16/11/043 (start date 1 April 2017, end date 31 January, 2019) and the Scottish government as part of the Strategic Research Programme at the Rowett Institute (start date 1 April 2016–31 March 2021).Peer reviewedPostprin