Genetic Association of Solute Carrier Transporter Gene Variants with Metformin Response.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by elevated blood glucose levels and is influenced by both genetic and environmental factors. It is treated with various classes of oral antidiabetic drugs, however, response to treatment is highly variable with patients failing to achieve adequate glycemic control. Treatment response variability has been associated with single nucleotide polymorphisms (SNPs) which influence the pharma-cokinetics and pharmacodynamics of drug(s). The aim of this study was to evaluate the genetic association of 17 SNPs and the response to metformin therapy in patients diagnosed with diabetes from the indigenous Nguni population of South Africa. One hundred and forty indigenous African patients diagnosed with T2DM were recruited and genotyped using the MassARRAY® system. Therapeutic response of patients was ascertained by a change in Hb A1c. Two SNPs (rs1801282 and rs6265) were monomorphic. All other variants were within the Hardy-Weinberg equilibrium (HWE). The T allele of the SLC variant rs316009 [odds ratio (OR) = 0.25, 95% confidence interval (95% CI) = 0.01-0.09, p value = 0.044] and the CT genotype of the PCK1 variant rs4810083 (OR = 2.80, 95% CI = 1.01-7.79, p value = 0.049) were associated with an improved response to treatment after adjustment. No association was observed with post Bonferroni correction. Moreover, this study provides important additional data regarding possible associations between genetic variants and metformin therapy outcomes. In addition, this is one of the first studies providing genetic data from the understudied indigenous sub-Saharan African populations.

Intraoperative TOE guided management of newly diagnosed severe tricuspid regurgitation and pulmonary hypertension during orthotopic liver transplantation: a case report demonstrating the importance of reversibility as a favorable prognostic factor.

BACKGROUND: Tricuspid regurgitation (TR) and pulmonary hypertension (PHT) are highly dynamic cardiovascular lesions that may progress rapidly, particularly in the orthotopic liver transplantation (OLT) waitlist population. Severe TR and PHT are associated with poor outcomes in these patients, however it is rare for the two to be newly diagnosed intraoperatively at the time of OLT. Without preoperative information on pulmonary vascular and right heart function, the potential for reversibility of severe TR and PHT is unclear, making the decision to proceed to transplant fraught with difficulty. CASE PRESENTATION: We present a case of successful orthotopic liver transplantation (OLT) in a 48 year old female with severe (PHT) (mean pulmonary arterial pressure > 55 mmHg) and severe TR diagnosed post induction of anaesthesia. The degree of TR was associated with systemic venous pressures of > 100 mmHg resulting in massive haemorrhage during surgery and difficulty in distinguishing venous from arterial placement of vascular access devices. Intraoperative transoesophageal echocardiography (TOE) proved crucial in diagnosing functional TR due to tricuspid annular and right ventricular (RV) dilatation, and dynamically monitoring response to treatment. In response to positioning, judicious volatile anaesthesia administration, pulmonary vasodilator therapy and permissive hypovolemia during surgery we noted substantial improvement of the TR and pulmonary arterial pressures, confirming the reversibility of the TR and associated PHT. CONCLUSION: TR and PHT are co-dependent, dynamic, load sensitive right heart conditions that are interdependent with chronic liver disease, and may progress rapidly in patients waitlisted for OLT. Use of intraoperative TOE and pulmonary artery catheterisation on the day of surgery will detect previously undiagnosed severe TR and PHT, enable rapid assessment of the cause and the potential for reversibility. These dynamic monitors permit real-time assessment of the response to interventions or events affecting right ventricular (RV) preload and afterload, providing critical information for prognosis and management. Furthermore, we suggest that TR and PHT should be specifically sought when waitlisted OLT patients present with hepatic decompensation.

Synovial butorphanol concentrations and mechanical nociceptive thresholds after intravenous regional limb perfusion in standing sedated horses.

OBJECTIVE: To determine synovial butorphanol concentrations and mechanical nociceptive threshold (MNT) changes after butorphanol intravenous regional limb perfusion (IVRLP). STUDY DESIGN: Experimental ANIMALS: Six adult horses. METHODS: Cephalic IVRLP was performed with 10 mg butorphanol in sedated horses with a wide rubber tourniquet and a total volume of 30 mL. Radiocarpal synovial fluid and serum concentrations along with MNT were evaluated prior to and 0.5, 1, 2, 4, and 6 hours after IVRLP. Butorphanol concentrations were determined with liquid chromatography coupled to tandem mass spectrometry positive electrospray ionization. RESULTS: Butorphanol concentrations reached mean (SD) peak concentrations of 9.47 ng/mL (±12.00) in synovial fluid and 3.89 ng/mL (3.29) in serum 30 minutes after IVRLP. Concentrations remained above baseline for 4 hours in synovial fluid (P ≤ .017) and for 2 hours in serum (P ≤ .016). The only difference in MNT was detected 1 hour after IVRLP, when MNT were higher in controls than in treated horses (P = .047). CONCLUSION: Butorphanol IVRLP seemed well tolerated and resulted in measurable levels of butorphanol in the radiocarpal synovial fluid of five of six horses. CLINICAL SIGNIFICANCE: Intravenous regional limb perfusion appears to be a viable alternative to administer butorphanol, but additional investigation is required to evaluate the dose and local concentrations required for analgesia.

Meropenem synovial fluid concentrations after intravenous regional limb perfusion in standing horses.

OBJECTIVE: To determine meropenem concentrations in radiocarpal (RC) joint fluid and plasma after intravenous regional limb perfusion (IVRLP). STUDY DESIGN: In vivo experimental study. ANIMALS: Nine healthy adult mares. METHODS: Meropenem (500 mg) was injected in the forelimb of standing sedated horses via IVRLP with a pneumatic tourniquet inflated to 400 mmHg. Synovial fluid was collected from RC joints at 0, 0.5, 1, 2, 4, 6, 8, 12, and 18 hours after meropenem injection. Blood samples were collected from the jugular vein at the same time points and at 5 and 15 minutes following injection. Meropenem concentrations were determined by using a microbiological bioassay. RESULTS: Median synovial fluid concentrations reached a time of maximum synovial fluid concentration 0.5 hours after IVRLP. Synovial fluid concentrations varied greatly, with a mean maximum synovial fluid concentration of 25.6 µg/mL (range, below limit of quantitation to 75.5). Concentrations remained above the breakpoint for susceptibility (1 µg/mL) for 3 hours (last nonzero concentration measured, median) and 4.1 hours (predicted, mean). Concentrations >6 µg/mL were measured for 2 hours (observed, median) and 1.7 hours (predicted, mean). Six horses had mild swelling at the injection site. CONCLUSION: Administration of 500 mg meropenem resulted in highly variable concentrations between horses and achieved levels above clinically relevant minimum inhibitory concentration for a minor portion of a once-daily dosing interval. CLINICAL SIGNIFICANCE: If time-dependent pharmacodynamics apply, IVRLP with 500 mg of meropenem may be ineffective and would likely promote resistance.

The correlation between Toxoplasma gondii infection and prenatal depression in pregnant women.

Previous studies have demonstrated that latent toxoplasmosis is associated with neuropsychiatric disorders. We evaluated the correlation between Toxoplasma gondii infection and prenatal depression. In this case-control study, we enrolled 116 depressed pregnant women and 244 healthy controls. The Edinburgh Postpartum Depression Scale (EPDS) was used to evaluate the depression symptom severity in study participants. All participants were screened for the anti-Toxoplasma IgG by enzyme-linked immunosorbent assay. Seroprevalence of T. gondii did not significantly differ between the depressed pregnant women and healthy controls (OR = 1.4; 95 % CI = 0.9-2.19; P = 0.142). T. gondii IgG titer was significantly higher in depressed women (18.6 ± 10.9 IUs) than those in the control group (13.6 ± 8.1 IUs) (z = -5.36, P < 0.001). The T. gondii-positive depressed women showed a positive correlation of T. gondii IgG titer with the EPDS scores (r = 0.52; P < 0.01). The mean EPDS score was also significantly higher in the T. gondii-positive depressed women (20.7 ± 2.7) compared with the controls (18.36 ± 2.7) (P < 0.001). The results obtained from the current study revealed that T. gondii infection might affect susceptibility to depression and severity of depressive symptoms in pregnant women, particularly in those patients who have high antibody titers. Further study is required to fully elucidate the characteristics and mechanisms of this association.

Cardiopulmonary exercise testing before and after blood transfusion: a prospective clinical study.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is used to risk-stratify patients undergoing major elective surgery, with a poor exercise capacity being associated with an increased risk of complications and death. Patients with anaemia have a decreased exercise capacity and an increased risk of morbidity and mortality after major surgery. Blood transfusion is often used to correct anaemia in the perioperative period but the effect of this intervention on exercise capacity is not well described. We sought to measure the effect of blood transfusion on exercise capacity measured objectively with CPET. METHODS: Patients with stable haematological conditions requiring blood transfusion underwent CPET before and 2-6 days after transfusion. RESULTS: Twenty patients were enrolled and completed both pre- and post-transfusion tests. The mean (sd) haemoglobin (Hb) concentration increased from 8.3 (1.2) to 11.2 (1.4) g dl(-1) after transfusion of a median (range) of 3 (1-4) units of packed red cells. The anaerobic threshold increased from a mean (sd) of 10.4 (2.4) to 11.6 (2.5) ml kg(-1) min(-1) (P=0.018), a mean difference of 1.2 ml kg(-1) min(-1) (95% confidence interval (CI)=0.2-2.2). When corrected for the change in Hb concentration, the anaerobic threshold increased by a mean (sd) of 0.39 (0.74) ml kg(-1) min(-1) per g dl(-1) Hb. CONCLUSIONS: Transfusion of allogeneic packed red cells in anaemic adults led to a significant increase in their capacity to exercise. This increase was seen in the anaerobic threshold, and other CPET variables.

Australian radiographer roles in the emergency department; evidence of regulatory compliance to improve patient safety - A narrative review.

OBJECTIVES: Using a narrative approach, this paper aims to determine the extent of Australian radiographers' regulatory compliance to improve patient safety when performing appendicular X-ray and non-contrast brain computed tomography (CT) in the Emergency Department (ED). KEY FINDINGS: A narrative review explored relevant literature and key regulatory policy. Ten documents were identified, three main themes were developed related to the radiographer roles in X-ray request justification, dose optimisation and preliminary image evaluation (PIE). Radiographers were equally aware of justification and optimisation pre and post the introduction of a Medical Code of Practice. The collective PIE accuracy of radiographers remained unaffected by changes in mode of PIE delivery and regulatory factors but varied based on the anatomical region. CONCLUSION: While current Australian regulations mandate radiographer request justification, dose optimisation and PIE, the degree of compliance by Australian radiographers remains uncertain. Current literature provides evidence that radiographers can improve patient care and safety through justification, optimisation, and PIE delivery. Change in workplace practice, supported by key stakeholders including radiologists, is essential to integrate radiographers' functions into routine ED clinical practice. Further research is required to audit radiographers' regulatory compliance to improve patient safety. IMPLICATIONS FOR PRACTICE: Patient safety in ED can be improved with timely and accurate diagnosis provided by radiographers. Radiographers have a professional obligation to adhere to the capabilities and standards for safe medical radiation practice defined by Australian regulations. Therefore, radiographers must justify the X-ray request, optimise the radiation dose where appropriate and communicate urgent or unexpected findings to the referrer.

An evidence based conceptual framework for the multifactorial understanding of proximal junctional kyphosis.

Introduction: Adult spinal deformity (ASD) is a debilitating pathology that arises from a variety of etiologies. Spinal fusion surgery is the mainstay of treatment for those who do not achieve symptom relief with conservative interventions. Fusion surgery can be complicated by a secondary deformity termed proximal junctional kyphosis (PJK). Research question: This scoping review evaluates the modern body of literature analyzing risk factors for PJK development and organizes these factors according to a multifactorial framework based on mechanical, tissue or demographic components. Materials and methods: An extensive search of the literature was performed in PubMed and Embase back to the year 2010. Articles were assessed for quality. All risk factors that were evaluated and those that significantly predicted the development of PJK were compiled. The frequency that a risk factor was predictive compared to the number of times it was evaluated was calculated. Results: 150 articles were reviewed. 57.3% of papers were of low quality. 76% of risk factors analyzed were focusing on the mechanical contribution to development of PJK versus only 5% were focusing on the tissue-based contribution. Risk factors that were most frequently predictive compared to how often they were analyzed were Hounsfield Units of vertebrae, UIV disc degeneration, paraspinal muscle cross sectional area and fatty infiltration, ligament augmentation, instrument characteristics, postoperative hip and lower extremity radiographic metrics, and postoperative teriparatide supplementation. Discussion and conclusion: This review finds a multifactorial framework accounting for mechanical, patient and tissue-based risk factors will improve the understanding of PJK development.

Interdisciplinary Approach to Expedited Outpatient Gastrostomy Tube Placement in Head and Neck Cancer Patients: A Single Center Retrospective Study.

RATIONALE AND OBJECTIVE: Treatment for head and neck cancer (HNC) can lead to decreased oral intake which often requires gastrostomy tube (g-tube) placement to provide nutritional support. A multidisciplinary team (MDT) consisting of interventional radiology (IR), HNC oncology and surgery, nutrition, and speech language pathology departments implemented an expedited outpatient g-tube placement pathway to reduce hospital stays and associated costs, initiate feeds sooner, and improve communication between care teams. This single center study investigates differences in complications, time to procedure and costs savings with implementing this pathway. METHODS: 142 patients with HNC who underwent elective image guided g-tube placement by IR from 2015 to 2022 were identified retrospectively. 52 patients underwent the traditional pathway, and 90 patients underwent the expedited pathway. Patient demographics, procedure characteristics, periprocedural costs and 90-day complication rates were collected and compared statistically. RESULTS: The 90-day complication rate was comparable between groups (traditional=32.7%; expedited=22.2%; p-value=0.17). The expedited pathway decreased the time from consult to procedure by 11.1 days (95% CI 7.6 - 14.6; p < 0.001) and decreased charge per procedure by $2940 (95% CI $989-$4891; p < 0.001). CONCLUSION: A MDT for the treatment of patients with HNC successfully provided enteral nutrition support faster, with fewer associated costs, and in a more patient centered approach than previously done at this institution.

Dysregulated biomarkers induce distinct pathways in preterm birth.

OBJECTIVE: To document racial disparity in biomarker concentrations in maternal/fetal plasma and amniotic fluid between African Americans and European Americans with spontaneous preterm birth (PTB; cases) and normal term birth (controls), and their contribution to distinct pathophysiological pathways of PTB. DESIGN: Nested case-control study. SETTING: The Perinatal Research Center, Nashville, Tennessee, USA. SAMPLE: Maternal and fetal plasma and amniotic fluid samples were collected from 105 cases (59 African American and 46 European American) and 86 controls (40 African American and 46 European American). METHODS: Thirty-six biomarkers were analysed using the protein microarray approach. MAIN OUTCOME MEASURES: Differences in biomarker concentrations between cases and controls of different races in maternal, fetal and intra-amniotic compartments, and the risk of PTB. Dysregulated biomarker-induced PTB pathways associated with PTB in each race were determined using ingenuity pathway analysis (IPA). RESULTS: Racial disparity was observed in biomarker concentrations in each compartment between cases and controls: amniotic fluid, IL8 and MIP1α differed between case and controls in European Americans, whereas ANGPT2, Eotaxin, ICAM-1, IL-1ß, IL1RA, RANTES and TNFα differed between case and controls in African Americans. In both races the FAS ligand, MCP-3 and TNFR-I differed between cases and controls. For fetal plasma, ANGPT2, Eotaxin, FGF basic, ICAM-1, IGF-I, IL10, IL-1ß, IL2, IP10 KGF, MCP-3, MIP1α, PDGF-BB, TGFα, TGFß1, TIMP1, TNFα, TNFR-I, TNFR-II and VEGF differed between cases and controls in European Americans, whereas only MMP7 differed between cases and controls in African Americans. IL-8 differed between cases and controls in both races. For maternal plasma, IL1RA, MMP7 and VEGF differed between cases and controls in European Americans, whereas ANGPT2, FGF basic, IL-1ß, IL5, IL6R, KGF, MCP-3, MIP1α, TIMP1 and TNFα differed between cases and controls in African Americans. ANG, IL8 and TNFR-I differed between cases and controls in both races. CONCLUSIONS: We conclude that: (1) biomarker concentrations in maternal, fetal and intra-amniotic compartments differ between cases and controls; (2) there is racial disparity in the biomarker profile in each of the compartments; (3) substantial numbers of dysregulated fetal plasma biomarkers contribute to PTB in European Americans, whereas maternal plasma biomarkers contribute to PTB in African Americans; and (4) both inflammation and haematological functions are associated with PTB in European Americans, but maternal proinflammatory changes dominate PTB in African Americans. Biomarker analyses document racial disparity and the distinct pathophysiological contributions from different compartments that can determine pregnancy outcome.

Prediction of spontaneous preterm delivery in women with threatened preterm labour: a prospective cohort study of multiple proteins in maternal serum.

OBJECTIVE: To analyse whether specific proteins in maternal serum and cervical length, alone or in combination, can predict the likelihood that women with intact membranes with threatened preterm labour will deliver spontaneously within 7 days of sampling. DESIGN: Cohort study. SETTING: Sahlgrenska University Hospital, Gothenburg, Sweden. POPULATION: Women at between 22 and 33 weeks of gestation with threatened preterm labour (n = 142) admitted to the Sahlgrenska University Hospital, Gothenburg, Sweden, in 1995-2005. METHODS: Maternal serum was tested for 27 proteins using multiplex xMAP technology. Individual levels of each protein were compared, and calculations were performed to investigate potential associations between different proteins, cervical length and spontaneous preterm delivery. Receiver operating characteristic curves were used to find the best cut-off values for continuous variables in relation to spontaneous preterm delivery within 7 days of sampling. Prediction models were created based on a stepwise logistic regression using binary variables. MAIN OUTCOME MEASURE: Spontaneous preterm delivery within 7 days. RESULTS: In order to determine the best prediction model, we analysed models of serum proteins alone, cervical length alone, and the combination of serum proteins and cervical length. We found one multivariable combined model through the data analysis that more accurately predicted spontaneous preterm delivery within 7 days. This model was based on serum interleukin-10 (IL-10) levels, serum RANTES levels and cervical length (sensitivity 74%, specificity 87%, positive predictive value 76%, negative predictive value 86%, likelihood ratio 5.8 and area under the curve 0.88). CONCLUSIONS: A combination of maternal serum proteins and cervical length constituted the best prediction model, and would help determine whether women with threatened preterm labour are likely to deliver within 7 days of measurement.

Early origins of heart disease: low birth weight and determinants of cardiomyocyte endowment.

1. World-wide epidemiological and experimental animal studies demonstrate that adversity in fetal life, resulting in intrauterine growth restriction, programmes the offspring for a greater susceptibility to ischaemic heart disease and heart failure in adult life. 2. After cardiogenesis, cardiomyocyte endowment is determined by a range of hormones and signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of multinucleation/terminal differentiation. 3. The small fetus may have reduced cardiomyocyte endowment owing to the impact of a suboptimal intrauterine environment on the signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of terminal differentiation.

Dietary preference and feeding selectivity of common dragonet Callionymus lyra in U.K.

The gut contents of 90 individuals of common dragonet Callionymus lyra were analysed, of which 76 contained prey, along with 100 corresponding benthic grab samples in order to assess the diet of C. lyra in relation to the availability of its prey in the environment. Forty-five prey taxa were identified in the diet from 350 potential prey taxa identified in the environment. Calculation of the index of relative importance (I(RI)) found the main food components were crustaceans (%I(RI) = 86·3), mostly the porcelain crab Pisidia longicornis (%I(RI) = 43) and other decapods (%I(RI) = 18). Polychaetes played only a supplementary role in the overall diet (%I(RI) = 12·5). This study demonstrated that C. lyra is predominantly an opportunistic feeder that can modify its feeding behaviour to exploit alternative, more abundant prey.

Equine heel bulb lacerations: 62 cases (2004-2018).

OBJECTIVE: To characterize clinical findings and outcomes for horses with heel bulb lacerations. ANIMALS: Medical records of a teaching hospital were reviewed to identify horses treated for heel bulb lacerations between February 2004 and October 2018. Long-term outcome was assessed by telephone communication with owners. Results were analyzed to determine association with clinical outcome. RESULTS: 31 mares and 31 geldings of various ages, breeds, and uses were evaluated. Thirty-six horses had a wound of 0 to 2 days' duration, and 17 horses had a wound of > 2 days' duration. Horses with a wound duration of < 2 days had a significantly greater likelihood of a higher outcome score (P = .025; OR = 7.08; 95% CI = 1.28% to 39.08%). Synovial communication with the wound was confirmed in 21 of 62 (33.9%) horses. One synovial structure was involved in 17 horses, and > 1 synovial structure was involved in 4 horses. Fifty-nine horses survived to discharge, and follow-up information was available for 18 (30.5%) horses. Of the horses available for follow-up, 78% returned to the previous level of work (14/18). Degree of lameness at presentation, degree of wound contamination, treatment prior to presentation, treatment with foot casting, and involvement of synovial structures were not found to be significantly associated with clinical outcome. CLINICAL RELEVANCE: Results suggest that horses with heel bulb lacerations have a good prognosis for survival and a favorable prognosis for return to work. Clinical application of additional findings needs further investigation before clinical relevance can be ascertained.

Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection.

Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-gamma, TNF, IL-1alpha, and IL-6 were shown to be increased, but IL-1beta was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-gamma, TNF, and IL-6 responses were dramatic with peak levels reaching >150-10,000 pg/ml at 32-40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

Interrelationship of cytokines, hypothalamic-pituitary-adrenal axis hormones, and psychosocial variables in the prediction of preterm birth.

BACKGROUND/AIMS: To examine the relationship of biological mediators (cytokines, stress hormones), psychosocial, obstetric history, and demographic factors in the early prediction of preterm birth (PTB) using a comprehensive logistic regression model incorporating diverse risk factors. METHODS: In this prospective case-control study, maternal serum biomarkers were quantified at 9-23 weeks' gestation in 60 women delivering at <37 weeks compared to 123 women delivering at term. Biomarker data were combined with maternal sociodemographic factors and stress data into regression models encompassing 22 preterm risk factors and 1st-order interactions. RESULTS: Among individual biomarkers, we found that macrophage migration inhibitory factor (MIF), interleukin-10, C-reactive protein (CRP), and tumor necrosis factor-alpha were statistically significant predictors of PTB at all cutoff levels tested (75th, 85th, and 90th percentiles). We fit multifactor models for PTB prediction at each biomarker cutoff. Our best models revealed that MIF, CRP, risk-taking behavior, and low educational attainment were consistent predictors of PTB at all biomarker cutoffs. The 75th percentile cutoff yielded the best predicting model with an area under the ROC curve of 0.808 (95% CI 0.743-0.874). CONCLUSION: Our comprehensive models highlight the prominence of behavioral risk factors for PTB and point to MIF as a possible psychobiological mediator.

Acute liver failure following therapeutic paracetamol administration in patients with muscular dystrophies.

Clinically significant liver damage in patients taking therapeutic doses of paracetamol is very rare. We report two cases of fulminant hepatic failure caused by therapeutic (4 g x day(-1)) paracetamol administration on our Intensive Care Unit. Both patients had a muscular dystrophy and presented with a chest infection on a background of endstage neuromuscular respiratory failure. We also noted one further similar case in the literature and suggest a relationship between muscular dystrophy and paracetamol-induced hepatotoxicity. In this report we discuss in detail possible mechanisms that may account for this apparent association, which include altered pharmacokinetics, reduced glutathione stores, malnutrition and hypoxic injury.

Clinical contextualization and the assessment of adverse events in HBOC trials.

Establishing an acceptable safety and efficacy profile for hemoglobin based oxygen carriers, HBOCs, is essential. Understanding the data that describes an HBOC "safety profile" requires consideration beyond counting "events" typically associated with intent to treat analysis. The imputation of causation from numerical counts alone, without clinical context, is an incomplete description of a complex situation. Clinical contextualization provides a greater understanding of the clinico-pathological processes involved. Generating alternative hypotheses for the origin of the events, apart from the drug, patient co-morbidities, situational and disease demands, could include protocol design, failure to provide mitigation strategies, patient management issues, or inadequate education of investigators. How clinical contextualization can provide insight for the interpretation of significant safety profile events is discussed in the context of a large phase III clinical trial where an appreciation of factors underlying the differences between intent to treat analysis and other approaches is discussed.

Paenibacillus larvae Phage Tripp Genome Has 378-Base-Pair Terminal Repeats.

Paenibacillus larvae bacteriophage Tripp was isolated from an American foulbrood diseased honey bee hive in North Carolina, USA. The 54,439-bp genome is 48.3% G+C, encodes 92 proteins, no tRNAs, and has 378-bp direct terminal repeats. It is currently unique in Genbank.