RePHILL: protocol for a randomised controlled trial of pre-hospital blood product resuscitation for trauma.

OBJECTIVES: To describe the 'Resuscitation with Pre-HospItaL bLood products' trial (RePHILL) - a multi-centre randomised controlled trial of pre-hospital blood product (PHBP) administration vs standard care for traumatic haemorrhage. BACKGROUND: PHBP are increasingly used for pre-hospital trauma resuscitation despite a lack of robust evidence demonstrating superiority over crystalloids. Provision of PHBP carries additional logistical and regulatory implications, and requires a sustainable supply of universal blood components. METHODS: RePHILL is a multi-centre, two-arm, parallel group, open-label, phase III randomised controlled trial currently underway in the UK. Patients attended by a pre-hospital emergency medical team, with traumatic injury and hypotension (systolic blood pressure <90 mmHg or absent radial pulse) believed to be due to traumatic haemorrhage are eligible. Exclusion criteria include age <16 years, blood product receipt on scene prior to randomisation, Advanced Medical Directive forbidding blood product administration, pregnancy, isolated head injury and prisoners. A total of 490 patients will be recruited in a 1 : 1 ratio to receive either the intervention (up to two units of red blood cells and two units of lyophilised plasma) or the control (up to four boluses of 250 mL 0.9% saline). The primary outcome measure is a composite of failure to achieve lactate clearance of ≥20%/h over the first 2 hours after randomisation and all-cause mortality between recruitment and discharge from the primary receiving facility to non-acute care. Secondary outcomes include pre-hospital time, coagulation indices, in-hospital transfusion requirements and morbidity. RESULTS: Pilot study recruitment began in December 2016. Approval to proceed to the main trial was received in June 2017. Recruitment is expected to continue until 2020. CONCLUSIONS: RePHILL will provide high-quality evidence regarding the efficacy and safety of PHBP resuscitation for trauma.

Deviation from expected cognitive ability across psychotic disorders.

Patients with schizophrenia show a deficit in cognitive ability compared to estimated premorbid and familial intellectual abilities. However, the degree to which this pattern holds across psychotic disorders and is familial is unclear. The present study examined deviation from expected cognitive level in schizophrenia, schizoaffective disorder, and psychotic bipolar disorder probands and their first-degree relatives. Using a norm-based regression approach, parental education and WRAT-IV Reading scores (both significant predictors of cognitive level in the healthy control group) were used to predict global neuropsychological function as measured by the composite score from the Brief Assessment of Cognition in Schizophrenia (BACS) test in probands and relatives. When compared to healthy control group, psychotic probands showed a significant gap between observed and predicted BACS composite scores and a greater likelihood of robust cognitive decline. This effect was not seen in unaffected relatives. While BACS and WRAT-IV Reading scores were themselves highly familial, the decline in cognitive function from expectation had lower estimates of familiality. Thus, illness-related factors such as epigenetic, treatment, or pathophysiological factors may be important causes of illness related decline in cognitive abilities across psychotic disorders. This is consistent with the markedly greater level of cognitive impairment seen in affected individuals compared to their unaffected family members.

Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10-11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10-8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10-10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10-8) and LMO7 (13q22.2, P=7.3x10-8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10-9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10-2-9.8 × 10-4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.

Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes.

Genetic factors may underlie beneficial and adverse responses to antipsychotic treatment. These relationships may be easier to identify among patients early in the course of disease who have limited exposure to antipsychotic drugs. We examined 86 first episode patients (schizophrenia, psychotic bipolar disorder and major depressive disorder with psychotic features) who had minimal to no prior antipsychotic exposure in a 6-week pharmacogenomic study of antipsychotic treatment response. Response was measured by change in Brief Psychiatric Rating Scale total score. Risperidone monotherapy was the primary antipsychotic treatment. Pharmacogenomic association studies were completed to (1) examine candidate single-nucleotide polymorphisms (SNPs) in genes known to be involved with glutamate signaling, and (2) conduct an exploratory genome-wide association study of symptom response to identify potential novel associations for future investigation. Two SNPs in GRM7 (rs2069062 and rs2014195) were significantly associated with antipsychotic response in candidate gene analysis, as were two SNPs in the human glutamate receptor delta 2 (GRID2) gene (rs9307122 and rs1875705) in genome-wide association analysis. Further examination of these findings with those from a separate risperidone-treated study sample demonstrated that top SNPs in both studies were overrepresented in glutamate genes and that there were similarities in neurodevelopmental gene categories associated with drug response from both study samples. These associations indicate a role for gene variants related to glutamate signaling and antipsychotic response with more broad association patterns indicating the potential importance of genes involved in neuronal development.

Paracetamol-associated acute liver failure in Australian and New Zealand children: high rate of medication errors.

BACKGROUND: In children, paracetamol overdose due to deliberate self-poisoning, accidental exposure or medication errors can lead to paediatric acute liver failure and death. In Australia and New Zealand, the nature of ingestion and outcomes of paracetamol-associated paediatric acute liver failure have not been described. OBJECTIVE: To describe the nature and outcomes of paracetamol-associated paediatric acute liver failure. DESIGN: Retrospective analysis of paracetamol-associated paediatric acute liver failure cases presenting 2002-2012. SETTING: New Zealand and Queensland Paediatric Liver Transplant Services. RESULTS: 14 of 54 cases of paediatric acute liver failure were attributed to paracetamol, the majority were secondary to medication errors. 12 of the 14 children were under the age of 5 years. Seven children received doses in excess of 120 mg/kg/day. Many of the other children received either a double dose, too frequent administration, coadministration of other medicines containing paracetamol or regular paracetamol for up to 24 days. Three children underwent transplant. One of these and one other child died. CONCLUSIONS: In Australia and New Zealand, paracetamol overdose secondary to medication errors is the leading cause of paediatric acute liver failure. A review of regional safety practices surrounding paracetamol use in children is indicated.

Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder.

Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).

Insight into the mechanism of trypanosome lytic factor-1 killing of Trypanosoma brucei brucei.

It has been known for almost a century that normal human serum can lyse the extracellular blood parasite Trypanosoma brucei brucei. This process is a result of a non-immune killing factor in human sera known as trypanosome lytic factor (TLF). In this work, we demonstrate that killing of T. b. brucei by trypanosome lytic factor-1 (TLF-1) in vitro is inhibited by the lipophyllic iron chelator, LI, the lipophyllic antioxidant DPPD, and the protease inhibitors antipain and E64. Thus TLF-1 killing likely requires iron, oxidants, and serine and cysteine proteases. Furthermore, we demonstrate that TLF-1 mediated lysis causes measurable peroxidation in T. brucei lipids via a reaction that is inhibited by DPPD, weak bases, and human haptoglobin. We hypothesize that TLF-1 lysis requires intracellular factors within the trypanosome including high intracellular H2O2 and high polyenoic lipid concentrations, lysosomal acidification and proteases, and intracellular iron sources. The data presented supports the hypothesis that the combination of these factors with TLF-1 inside the lysosome results in lysosomal membrane breakdown, release of the lysosomal contents, and subsequent autodigestion of the cell.

Transitional cell carcinomatous meningitis after M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy.

The M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen has been utilized at our two institutions to treat 17 patients with advanced stage transitional cell carcinoma of the bladder. We report 2 cases of carcinomatous meningitis resulting from metastatic transitional cell carcinoma which occurred in patients treated with M-VAC. Review of the literature suggests that our experience with central nervous system metastases is not unique, and that treatment of advanced stage transitional cell carcinoma of the bladder with M-VAC may enhance the incidence of meningeal metastases. Carcinomatous meningitis, although rare, is a rapidly fatal manifestation of metastatic transitional cell carcinoma if left untreated. However, prompt diagnosis and early aggressive therapy may result in palliation and stabilization of neurologic status. We review the pathophysiology, diagnosis, and treatment of transitional cell carcinomatous meningitis.

Iloperidone for the treatment of schizophrenia.

Iloperidone is a recently approved antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone is characterized as a serotonin 5-HT(2A) and dopamine D(2) receptor antagonist, which makes its core mechanism of action similar to other second-generation antipsychotic agents. The affinity (or lack thereof) of iloperidone for other receptors (e.g., histamine, muscarinic, α(1)-adrenoceptors, serotonin) results in a unique side effect and perhaps response profile that may make it an additional option for patients who have previously not tolerated or adequately responded to other available agents. Iloperidone has been studied in over 3,200 patients throughout its development. Its efficacy appears to be similar to haloperidol, risperidone and ziprasidone. It appears to be safe with minimal extrapyramidal side effects, weight gain and prolactin elevation. A cautious dosing and titration schedule is recommended at the initiation of therapy due to the potential for orthostatic hypotension and dizziness. Drug interactions through the CYP3A4 and CYP2D6 enzymes, along with the potential for QT prolongation, may influence its use in certain patients. Genetic studies conducted during drug development may facilitate the clinical use of pharmacogenomic tests to aid clinicians in optimizing the risk-benefit ratio of iloperidone. The purpose of this review is to summarize the chemistry, pharmacology and clinical aspects of iloperidone, with the goals of identifying key scientific and clinical issues for its use, as well as assessing the potential utility of iloperidone for the treatment of schizophrenia.

Complementary medicines in pediatric bipolar disorder.

The increasing number and availability of various complementary and alternative medicines (CAM) has resulted in an exponentially growing utilization of these products for everything from minor aches and pains to the treatment of mental illness. Difficulties in treating mental illnesses in children, averseness to having children take psychiatric medications, and stigma all drive patients and their families to research alternative treatments. As a result, there has been an increased utilization of CAM in psychiatry, particularly for hard to treat conditions like pediatric BD. It is important for the health care providers to be aware of the alternative treatments by some of their patients. A review of studies investigating the utility of complementary and alternative medicines in bipolar patients was conducted and selected studies were included. Omega-3 fatty acids and lecithin/ choline have preliminary data indicating potential utility in the CAM treatment for bipolar disorder while S-adenosyl methionine (SAM-e) and inositol have some data supporting their efficacy in the treatment of depressive symptoms. Some data for CAM suggest they may be useful adjunctive treatments but only little data are available to support their use as stand-alone therapy. Thus, the conventional medicines remain the first choice in pediatric bipolar management. Healthcare providers need to routinely inquire about the utilization of these treatments by their patients and become familiar with the risks and benefits involved with their use in children.

Atmospheric lead and the related blood-levels of workers in high-speed can-making.

Any lead in the atmosphere around high-speed can-making lines consists wholly of solid particulate lead metal or lead oxidation products. The working temperature is below the boiling-point of lead, and so none of it is the result of condensation of lead vapor. Level of lead in blood does not appear to be related to the level of total lead in atmosphere or with the worker's proximity to the can-line. There may however perhaps be some relation between blood-lead level and the atmospheric concentration of the respirable part of the lead in the air breathed; investigation is therefore now directed into comparing blood-lead level with atmospheric lead-level measured by analytical procedures which select the particle-size of the sample taken. The paper presents an interim report, with data, on results so far obtained. The whole research program will study the individual operations of can-making.

Estimation of Potential Shelf-life of Pasteurized Fluid Milk Utilizing Bacterial Numbers and Metabolites.

A study was conducted on use of bacterial numbers and their metabolites, and any possible interaction thereof, as estimators of the potential shelf-life of pasteurized fluid milk. Whole and skim milk samples were obtained on the day of processing. Samples of each milk were inoculated in duplicate with 0, 1,000, or 100,000 bacteria/ml with a pure strain of Pseudomonas fluorescens P27. Samples, stored at 7°C, were analyzed for microbiological and bioichemical parameters every 5 d for up to 20 d, with organoleptic evaluations conducted on a daily basis. On days of analysis, each sample was subjected to various preliminary incubations. Bacterial enumerations conducted were psychrotrophic bacteria count, standard plate count, gram-negative bacteria count, and modified psychrotrophic bacteria count. Lipopolysaccharide (endotoxin) concentrations, degree of proteolysis and impedance detection were also determined. All bacterial enumerations and proteolysis were significantly related to potential shelf-life of pasteurized fluid milk (whole, skim, and combined) but were of little predictive value. Endotoxin concentration and impedance detection were highly significantly related to shelf-life, and provided predictive regression equations. Using combined data from whole and skim milk, impedance detection resulted in the preferred prediction equation suitable for pasteurized fluid milks.

Estimation of Potential Shelf Life of Cottage Cheese Utilizing Bacterial Numbers and Metabolites.

A study was conducted to investigate the use of bacterial numbers and their metabolites as estimators of the potential shelf life of cottage cheese. Dry cottage cheese curd and cream dressing were obtained on the day of processing. Portions of the cream dressing were inoculated with Pseudomonas fluorescens P27 to result in approximate levels of 0, 1,000 and 100,000 bacteria per g in finished cottage cheese after combining the curd and cream. Samples, stored at 7°C, were sensorially evaluated on a daily basis and analyzed every 7 d for up to 35 d. On days of analysis each sample was subjected to preliminary incubation (PI) as follows: none, 21°C for 7 h, 21°C for 14 h, 13°C for 18 h and 18°C for 18 h. For each PI, samples were enumerated by aerobic plate count, modified psychrotrophic bacteria count and gram-negative (CVT) count. Samples were enumerated for the standard psychrotrophic bacteria count without PI. Samples were also exposed to 18°C for 18 h PI in plate count broth for impedance detection measurements. Endotoxin (lipopolysaccharide) concentration and proteolysis were determined by the Limulus amebocyte lysate assay and the o-phthaldialdehyde method, respectively. Bacterial enumerations proved to be of little estimative value as the highest correlation coefficient obtained was -0.61. Endotoxin, proteolysis and impedance detection methods resulted in high correlation coefficients as related to potential shelf life of cottage cheese, with values of -0.81, -0.87 and -0.90, respectively. A prediction equation was formulated from the data.

Quality assessment of pasteurized fluid milk as related to lipopolysaccharide content.

A study was conducted to investigate any relationship between lipopolysaccharide (endotoxin) concentration in milk and parameters associated with the keeping quality of milk. Parameters investigated were flavor intensity, standard plate count, coliform count, psychrotrophic count, and gram-negative count. Lipopolysaccharide content was determined using the Limulus Amoebocyte Lysate assay. Pasteurized whole milk samples were obtained the day of processing in .94-L containers with samples analyzed on d 0 through 21. Significant linear relationships were detected between lipopolysaccharide concentration and days storage at 7 degrees C, flavor intensity, and psychrotrophic count.

Sanitizer Efficacy Against Attached Bacteria in a Milk Biofilm.

Pseudomonas fluorescens , Yersinia enterocolitica , and Listeria monocytogenes were shown to readily attach to both rubber and Teflon® surfaces. Sanitizer efficacy testing done in the laboratory with nonadherent bacteria could lead to false assumptions as to the sanitizer's true effectiveness under processing conditions where cells may be attached. The objectives in this study were: (a) evaluate the efficacy of in-use concentrations of sanitizers on bacteria attached to gasket materials, (b) compare bacterial attachment to rubber and Teflon® gaskets, (c) examine different methods of enumeration, and (d) compare sanitizer efficacy on attached and suspended bacteria. The goal reduction for all of the sanitizers tested was ≥3 log cycles or 99.9%. Results indicated that iodophor, hypochlorite, acid anionic, peroxyacetic acid, fatty acid, and quaternary ammonium sanitizers failed to provide an adequate reduction in the numbers of attached bacteria at levels of 104 to 105/mm2 in most cases. The test organisms attached in slightly higher numbers to the rubber surface versus Teflon®. Plate counts, impedance microbiology, and the direct epifluorescent filter technique were tested as methods of enumeration. Impedance microbiology was the best method of enumeration, since it allowed the estimation of both reversibly and irreversibly attached bacteria. The efficacy of sanitizers versus a bacterial suspensions resulted in a ≥ 5 log-cycle reduction. The same concentrations were relatively ineffective against the attached bacteria. The goal reduction was reached on the Teflon® surface with the iodophor, hypochlorite, and fatty acid sanitizers with a log-cycle reduction in the number of Yersinia enterocolitica of 3.09, 3.19, and 3.31, respectively. Pseudomonas fluorescens was reduced by 3.16 on both the rubber and Teflon® surfaces when exposed to the hypochlorite sanitizer.

Assessment of Dairy Product Quality and Potential Shelf-Life - A Review.

Over the years, many tests and assays have been developed to estimate the quality and potential shelf-life of dairy products. These have ranged from simple, standard bacterial enumerations to more complex metabolite detections. This paper is a review of the parameters that have been used to estimate, or indicate the inherent quality of dairy products.

Evaluation of a Dry Medium Culture Plate (3M Petrifilm AC) for Laboratory Pasteurized Counts.

In this study Petrifilm AC was evaluated for its ability to enumerate thermoduric bacteria in raw milk by the laboratory pasteurized count (LPC). LPC's were conducted on agar pour plates and Petrifilm plates. Both plating techniques were conducted immediately following laboratory pasteurization, and plating was also conducted after incubations of 2 and 4 h at room temperature. Uninoculated raw milk samples, raw milk inoculated with Bacilluscereus , Micrococcus luteus , and raw milk isolates ( Streptococcus , Corynebacterium , and Micrococcus species) were enumerated. A total of 270 samples was analyzed. Uninoculated raw milk samples and raw milk samples inoculated with B. cereus , Corynebacterium , Streptococcus , and some Micrococcus species showed no significant difference between agar pour plates and Petrifilm AC. Other Micrococcus species were recovered at lower numbers on the Petrifilm after laboratory pasteurization. Some of these were comparable to the agar plates after a 4-h incubation at room temperature. This study indicates that Petrifilm AC could be used in place of agar pour plates to conduct the LPC.

Antibiotic Residue Detection in Milk - A Review.

Methods for antibiotic residue detection in dairy products, especially raw milk, have greatly improved as to their rapidity, accuracy and sensitivity over the past 30 years. An assay requiring overnight coagulation was available in the mid-1950's, whereas now there is an immunologically-based test using monoclonal antibody technology requiring only 6 min. These advances have not come about without extensive research efforts. The following is an overview of the developments and their significance to the dairy industry.