Compounded Cyclophosphamide and Piroxicam for the Treatment of a Canine Peripheral Nerve Sheath Tumor: A Case Report.

For many people, companion animals are family members and partners in life. The diagnosis of a life-threatening illness in a beloved pet can present challenges for the patient and cause stress and grief for its owner. A successful therapeutic outcome often requires the use of commercially manufactured medications that are not produced in the doses or dosage forms tolerated by veterinary patients or are unavailable to, unaffordable for, and/or inaccessible by owners. In those cases, the use of customized compounded preparations is often the best option. In this report, we describe the successful use of 2 compounds (cyclophosphamide and piroxicam) to treat an aggressive peripheral nerve sheath tumor in an older male dog. Formulations for those medications are provided.

Correction: Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0160064.].

Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

BACKGROUND: Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (>3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE. METHODS: Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted. RESULTS: Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0-3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of 'major or clinically relevant non-major bleed' compared with warfarin INR 2.0-3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed. CONCLUSIONS: Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0-3.0, and aspirin.

Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

BACKGROUND: Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and prevention. Although novel oral anti-coagulants (NOACs) have been compared with SOC in this indication, no head-to-head randomised controlled trials (RCTs) have directly compared NOACs. A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of NOACs for the initial and long-term treatment of VTE. METHODS: Electronic databases (accessed July 2014) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus SOC. Eligible patients included adults with an objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as relative risks (RR) and 95% credible intervals (Crl). RESULTS: Six Phase III RCTs met criteria for inclusion: apixaban (one RCT; n = 5,395); rivaroxaban (two RCTs; n = 3,423/4,832); dabigatran (two RCTs; n = 2,539/2,568); edoxaban (one RCT; n = 8,240). There were no statistically significant differences between the NOACs with regard to the risk of 'VTE and VTE-related death. Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]). Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]). CONCLUSIONS: Indirect comparisons showed statistically similar reductions in the risk of 'VTE or VTE-related death for all NOACs. In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban. Results from the current analysis indicate that the NOACs offer clinical benefit over conventional therapy while highlighting relative differences in their bleeding profile.

Acute kidney injury among HIV-infected patients admitted to the intensive care unit.

We describe the incidence, associations and outcomes of acute kidney injury (AKI) among HIV-infected patients admitted to the intensive care unit (ICU). We retrospectively analysed 223 admissions to an inner-London, University-affiliated ICU between 1999 and 2012, and identified those with AKI and performed multivariate analysis to determine associations with AKI. Of all admissions, 66% were affected by AKI of any severity and 35% developed stage 3 AKI. In multivariate analysis, AKI was associated with chronic kidney disease (odds ratio [OR] = 3.19; p = 0.014), a previous AIDS-defining illness (OR = 1.93; p = 0.039) and the Acute Physiology and Chronic Health Evaluation (APACHE) II score, (OR = 3.49; p = 0.018, if > 30). No associations were demonstrated with use of anti-retroviral medication (including tenofovir), or an individual's HIV viral load or CD4 count. AKI was associated with higher inpatient mortality and longer duration of ICU admission. Among patients with stage 3 AKI, only 41% were alive 90 days after ICU admission. Among survivors, 74% regained good renal function, the remainder were dependent on renal replacement therapy or were left with significant ongoing renal dysfunction. Of note, many patients had baseline serum creatinine concentrations well below published reference ranges. AKI among HIV-infected patients admitted to ICU carries a poor prognosis.

Survival of HIV-infected patients admitted to the intensive care unit in the era of highly active antiretroviral therapy.

We retrospectively studied outcomes for HIV-infected patients admitted to the intensive care unit (ICU) between January 1999 and June 2009. Patient demographics, receipt of highly active antiretroviral therapy (HAART), reason for ICU admission and survival to ICU and hospital discharge were recorded. Comparison was made against outcomes for general medical patients contemporaneously admitted to the same ICU. One hundred and ninety-two HIV-infected patients had 222 ICU admissions; 116 patients required mechanical ventilation (MV) and 43 required renal replacement therapy. ICU admission was due to an HIV-associated diagnosis in 113 patients; 37 had Pneumocystis pneumonia. Survival to ICU discharge and hospital discharge for HIV-infected patients was 78% and 70%, respectively, and was 75% and 68% among 2065 general medical patients with 2274 ICU admissions; P = 0.452 and P = 0.458, respectively. HIV infection was newly diagnosed in 42 patients; their ICU and hospital survival was 69% and 57%, respectively. From multivariable analysis, factors associated with ICU survival were patient's age (odds ratio [OR] = 0.74 [95% confidence interval (CI) = 0.53-1.02] per 10-year increase), albumin (OR = 1.05 [1.00-1.09] per 1 g/dL increase), Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR = 0.55 [0.35-0.87] per 10 unit increase), receipt of HAART (OR = 2.44 [1.01-4.94]) and need for MV (OR = 0.14 [0.06-0.36]). In the era of HAART, HIV-infected patients should be offered ICU admission if it is likely to be of benefit.

Survival of HIV-infected patients in the intensive care unit in the era of highly active antiretroviral therapy.

BACKGROUND: Several studies have described improved outcomes for HIV-infected patients admitted to the intensive care unit (ICU) since the introduction of highly active antiretroviral therapy (HAART). A study was undertaken to examine the outcome from the ICU for HIV-infected patients and to identify prognostic factors. METHODS: A retrospective study of HIV-infected adults admitted to a university affiliated hospital ICU between January 1999 and December 2005 was performed. Information was collected on patient demographics, receipt of HAART (no patient began HAART on the ICU), reason for ICU admission and hospital course. Outcomes were survival to ICU discharge and to hospital discharge. RESULTS: 102 patients had 113 admissions to the ICU; HIV infection was newly diagnosed in 31 patients. Survival (first episode ICU discharge and hospital discharge) was 77% and 68%, respectively, compared with 74% and 65% for general medical patients. ICU and hospital survival was 78% and 67% in those receiving HAART, and 75% and 66% in those who were not. In univariate analysis, factors associated with survival were: haemoglobin (OR = 1.25, 95% CI 1.03 to 1.51, for an increase of 1 g/dl), CD4 count (OR = 1.59, 95% CI 0.98 to 2.58, for a 10-fold increase in cells/microl), APACHE II score (OR = 0.51, 95% CI 0.29 to 0.90, for a 10 unit increase) and mechanical ventilation (OR = 0.29, 95% CI 0.10 to 0.83). CONCLUSIONS: The outcome for HIV-infected patients admitted to the ICU was good and was comparable to that in general medical patients. More than a quarter of patients had newly diagnosed HIV infection. Patients receiving HAART did not have a better outcome.

Acute renal failure after cardiothoracic surgery: a review of three years experience.

2,683 cardiothoracic operations were carried out over a 3-year period. Patients requiring haemofiltration after surgery had a much greater mortality than those not haemofiltered. Of the 1,177 cardiothoracic intensive care unit (ICU) patients, 91 required haemofiltration for acute renal failure (ARF; 7.7%). Of the 1,506 cardiothoracic high-dependency unit patients 13 were transferred to the renal unit for dialysis (0.86%). Mortality for cardiothoracic patients overall was 14.4% and for those who required haemofiltration 58.7%. 74 of these haemofiltered patients had normal renal function preoperatively; mortality 61%. 15 patients had pre-existing renal impairment; mortality 53.3%. 15 patients were on dialysis prior to surgery; mortality 60%. Age was not a predictor of requirement for renal replacement therapy or of mortality. Operation type was a risk factor for ARF: of patients having a coronary artery bypass graft (CABG) 2.4% were filtered (mortality 37.8%), of patients having valve replacements 14.2% were haemofiltered (mortality 60.9%), and of the patients having redo-CABGs or redo-valve replacements 12.3% required haemofiltration (mortality 100%).

Comparison of a specialist retrieval team with current United Kingdom practice for the transport of critically ill patients.

OBJECTIVE: The inter-hospital transfer of critically ill patients in the United Kingdom is commonly undertaken using standard ambulance under junior doctor escort, despite recommendations for the use of specialist retrieval teams. Patients are transferred into University College London Hospitals (UCLH) intensive care unit (ICU) by both methods. We undertook to evaluate the effect of transfer method on acute physiology (within 2 h of ICU admission) and early mortality ( < 12 h after ICU admission). DESIGN: Retrospective review of all transfers over 1 year. SETTING: UCLH ICU. SUBJECTS: 259 transfers; 168 by specialist retrieval team (group A) and 91 by standard ambulance with doctor provided by referring hospital (group B). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Acute physiology (pH, PaO2, PaCO2, heart rate (HR), mean arterial blood pressure (MAP), 24 h severity of illness scores (APACHE II, SAPS II), length of stay and mortality. RESULTS: There were no differences in demographic characteristics or severity of illness between the two groups; nevertheless significantly more patients in group B than in group A were severely acidotic (pH < 7.1: 11% vs. 3%, p < 0.008) and hypotensive (MAP < 60: 18 % vs. 9%, p < 0.03) upon arrival. In addition, there were more deaths within the first 12 h after admission with 7.7 % deaths (7/91) in group B transfers vs. 3% (5/168) in group A. CONCLUSIONS: The use of a specialist transfer team may significantly improve the acute physiology of critically ill patients and may reduce early mortality in ICU.

Human immunodeficiency virus type 1 nucleocapsid protein specifically stimulates Mg2+-dependent DNA integration in vitro.

The integrase (IN) protein of the human immunodeficiency virus mediates integration of the viral DNA into the cellular genome. In vitro, this reaction can be mimicked by using purified recombinant IN and model DNA substrates. IN mediates two reactions: an endonucleolytic cleavage at each 3' end of the proviral DNA (terminal cleavage) and the joining of the linear viral DNA to 5' phosphates in the target DNA (strand transfer). Previous investigators have shown that purified IN requires Mn2+ or Mg2+ to promote strand transfer in vitro, although Mg2+ is the likely metal cofactor in vivo. IN activity in the presence of Mg2+ in vitro requires high IN concentrations and low concentrations of salt. Here, we show that the viral nucleocapsid protein NCp7 allows efficient IN-mediated strand transfer in the presence of Mg2+ at low enzyme concentrations. This potentiating effect appears to be unique to NCp7, as other small DNA-binding proteins, while capable of stimulating integration in the presence of Mn2+, all failed to stimulate strand transfer in the presence of Mg2+.

A study of problems associated with the delivery of enteral feed in critically ill patients in five ICUs in the UK.

OBJECTIVES: To describe the incidence of problems associated with enteral feeding in different patient groups and intensive care units (ICUs). To compare this incidence with specific feeding protocols and volumes of feed delivered. To identify for future study any interventions likely to improve delivery of enteral feed and to manage or eliminate problems. DESIGN: A prospective, descriptive study of problems associated with enteral feeding in five ICUs over a period of 9 months. SETTING: ICUs in two district general and three university hospitals. PATIENTS: ICU patients (age > 18 years) who received enteral feeding for a period > 24 h. MEASUREMENTS AND RESULTS: 193 patients were studied for a total of 1929 patient-days. On average, only 76% of the quantity of feed prescribed was delivered to the patient. The two main problems preventing delivery of feed were gut dysfunction and elective stoppage for procedures. ICUs with well-defined feeding protocols delivered significantly greater volumes of feed (p < 0.0001) than those without. Feeding was abandoned in 11% of patients, half of these due to gastric dysfunction. Only 2 of 193 patients were fed jejunally. CONCLUSIONS: The major factors associated with the interruption in delivery of feed are problems with gut function and stopping feed prior to a procedure. Use of specific feeding protocols is clearly associated with a greater volume of feed delivered and a greater percentage of the prescription delivered. These should be an integral part of all ICU protocols.

Stimulation of RNA polymerase II elongation by chromosomal protein HMG-14.

The high-mobility group protein 14 (HMG-14) is a non-histone chromosomal protein that is preferentially associated with transcriptionally active chromatin. To assess the effect of HMG-14 on transcription by RNA polymerase II, in vivo-assembled chromatin with elevated amounts of HMG-14 was obtained. Here it is shown that HMG-14 enhanced transcription on chromatin templates but not on DNA templates. This protein stimulated the rate of elongation by RNA polymerase II but not the level of initiation of transcription. These findings suggest that the association of HMG-14 with nucleosomes is part of the cellular process involved in the generation of transcriptionally active chromatin.

Childhood abuse in first-episode psychosis.

Of 38 adult patients admitted for first-episode psychosis, 20 reported childhood abuse, with equal prevalence in men and women. Patients with histories of childhood abuse had significantly more dissociative symptoms, but not more severe psychiatric symptoms. Childhood abuse was not related to rate of recovery and was only marginally related to longer stays in hospital. Although childhood abuse did not affect recovery during first-episode psychosis, it may contribute to a chronic course in some patients.

The development of a pressure area scoring system for critically ill patients: a pilot study.

At present no suitably sensitive scoring system is available to differentiate degrees of risk of developing pressure sores in critically ill people. The object of this study is to produce a tool that has been validated to identify and weight risk factors associated with critically ill patients. In a pilot study data were collected on 50 patients and analysed, using multiple regression analysis, to produce a set of weighted coefficients (C) suitable for use as a scoring system. The feasibility of the technique is demonstrated and five highly significant factors are described: adrenaline infusions (C = 14), noradrenaline infusions (C = 15), diabetes (C = 15), restricted movement (traction, post-operative pain, intra-aortic balloon pump and haemofiltration) (C = 8) and patients too unstable to turn (C = 17). All coefficients not equal to 0 with p < 0.05. Risk factors which may become significant in a larger study are identified. In order to develop the full tool a further multi-centre study is proposed.

Association of nucleosome-free regions and basal transcription factors with in vivo-assembled chromatin templates active in vitro.

Using SV40 minichromosomes assembled in vivo, we have studied the relationship between a nucleosome-free promoter-region and initiation of transcription by RNA polymerase II on chromatin templates in vitro. Our data suggest that accessibility of DNA to transcription factors, programmed into the structure of the chromatin, is crucial for initiation of transcription. First, minichromosomes competent to be transcribed in vitro contained nucleosome-free promoter regions. Second, tsC219 minichromosomes, most of which contain the nucleosome-free promoter region, supported transcription more efficiently both in vivo and in vitro than wild-type minichromosomes, in which only a subset contain the nucleosome-free region. We have also identified basal transcription factors associated with the in vivo-assembled chromatin templates. A striking correlation was observed between minichromosomes associated with in vivo initiated RNA polymerases and those associated with the basal transcription factors TFIID and TFIIE/F, and to a lesser extent, TFIIB. Of these associated factors, only TFIID was poised for ready assembly into preinitiation complexes and therefore for subsequent initiation of transcription. However, an active chromatin template could also be maintained in the absence of the binding of TFIID. Finally, our data are consistent with the presence of TFIIF in elongating ternary complexes on the chromatin templates.

In vitro initiation of transcription by RNA polymerase II on in vivo-assembled chromatin templates.

We have studied the initiation of transcription in vitro by RNA polymerase II on simian virus 40 (SV40) minichromosomal templates isolated from infected cells. The efficiency and pattern of transcription from the chromatin templates were compared with those from viral DNA templates by using two in vitro transcription systems, either HeLa whole-cell extract or basal transcription factors, RNA polymerase II, and one of two SV40 promoter-binding transcription factors, LSF and Sp1. Dramatic increases in numbers of transcripts upon addition of transcription extract and different patterns of usage of the multiple SV40 initiation sites upon addition of Sp1 versus LSF strongly suggested that transcripts were being initiated from the minichromosomal templates in vitro. That the majority of transcripts from the minichromosomes were due to initiation de novo was demonstrated by the efficient transcription observed in the presence of alpha-amanitin, which inhibited minichromosome-associated RNA polymerase II, and an alpha-amanitin-resistant RNA polymerase II, which initiated transcription in vitro. The pattern of transcription from the SV40 late and early promoters on the minichromosomal templates was similar to the in vivo pattern of transcription during the late stages of viral infection and was distinct from the pattern of transcription generated from viral DNA in vitro. In particular, the late promoter of the minichromosomal templates was transcribed with high efficiency, similar to viral DNA templates, while the early-early promoter of the minichromosomal templates was inhibited 10- to 15-fold. Finally, the number of minichromosomes competent to initiate transcription in vitro exceeded the amount actively being transcribed in vivo.

Proteolysis at the 2A/2B junction in Theiler's murine encephalomyelitis virus.

Processing at the 2A/2B junction in Theiler's murine encephalomyelitis virus (TMEV) was studied using in vitro transcription and translation. A plasmid which contained only the P2 region of TMEV was used. The protein products obtained after in vitro transcription/translation indicated that proteolysis at the 2A/2B junction occurs even if templates coding for only the 2A and 2B proteins are used. Time-course experiments indicated that 2A/2B proteolysis was cotranslational. The plasmid described will allow further definition of the sequences involved in this proteolytic event.