Effect modification of dosing strategy (AUC or trough) on AKI associated with vancomycin in combination with piperacillin/tazobactam or cefepime and meropenem.

Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

To Block or Not: Updates in Neuromuscular Blockade in Acute Respiratory Distress Syndrome.

Objective: To review and evaluate neuromuscular blocking agents (NMBAs) in critically ill patients with acute respiratory distress syndrome (ARDS). Data Sources: A literature search utilizing PubMed was performed (January 1991 to January 2020) using the following search terms: (neuromuscular blocking agents OR neuromuscular blockade OR cisatracurium OR rocuronium OR vecuronium OR pancuronium OR atracurium) AND *acute respiratory distress syndrome OR acute lung injury). Publications in English were evaluated. Study Selection and Data Extraction: Relevant clinical studies in humans were considered. Data Synthesis: Although NMBAs have been used for decades in the setting of ARDS, questions regarding mortality benefit remain. Early NMBA, within 48 hours of lung injury, have been historically used in critically ill patients with ARDS to aid in increasing alveolar recruitment, improving patient-ventilator synchrony, and promoting oxygenation by the prevention of contraction of respiratory muscles. Until recently, the literature showed an improvement in 90-day adjusted mortality. However, recent literature has demonstrated the lack of a mortality benefit. The continued receipt of NMBAs, with no clear benefit, could potentially lead to increased costs, skin breakdown, corneal abrasions, venous thromboembolisms, intensive care unit acquired weakness, and awareness with inappropriate sedation. Relevance to Patient Care and Clinical Practice: This review aims at discussing the preferred NMBA based on mechanism of action and reviews specific clinical trial data for the use of NMBAs in ARDS, clinical implications of these trial data, complications for the use of NMBAs, and needed future directions. Conclusions: The mortality benefit of NMBAs in ARDS has contradicting evidence with potentially serious adverse effects and notable controversies.

First detection of Edwardsiella ictaluri (Proteobacteria: Enterobacteriaceae) in wild Australian catfish.

The bacterium Edwardsiella ictaluri is considered to be one of the most significant pathogens of farmed catfish in the United States of America and has also caused mortalities in farmed and wild fishes in many other parts of the world. E. ictaluri is not believed to be present in wild fish populations in Australia, although it has previously been detected in imported ornamental fishes held in quarantine facilities. In an attempt to confirm freedom from the bacterium in Australian native fishes, we undertook a risk-based survey of wild catfishes from 15 sites across northern Australia. E. ictaluri was detected by selective culturing, followed by DNA testing, in Wet Tropics tandan (Tandanus tropicanus) from the Tully River, at a prevalence of 0.40 (95% CI 0.21-0.61). The bacterium was not found in fishes sampled from any of the other 14 sites. This is the first report of E. ictaluri in wild fishes in Australia.

Comparative Biology of Cycad Pollen, Seed and Tissue - A Plant Conservation Perspective.

Cycads are the most endangered of plant groups based on IUCN Red List assessments; all are in Appendix I or II of CITES, about 40% are within biodiversity 'hotspots,' and the call for action to improve their protection is long-standing. We contend that progress in this direction will not be made until there is better understanding of cycad pollen, seed and tissue biology, which at the moment is limited to relatively few (<10%) species. We review what is known about germplasm (seed and pollen) storage and germination, together with recent developments in the application of contemporary technologies to tissues, such as isotype labelling, biomolecular markers and tissue culture. Whilst progress is being made, we conclude that an acceleration of comparative studies is needed to facilitate the integration of in situ and ex situ conservation programmes to better safeguard endangered cycads.

Urinary C-peptide analysis in an intervention study: experience from the DEFEND-2 otelixizumab trial.

AIMS: To demonstrate that analysis of urinary C-peptide across multiple study sites in the context of an intervention trial (DEFEND-2) is a viable alternative to mixed meal testing and delivers results that correlate to mixed meal testing estimation of endogenous insulin production. METHODS: Second morning void urine was collected for analysis and was available from 161 subjects at baseline (55 placebo, 106 otelixizumab), and 146 subjects (47 placebo, 99 otelixizumab) at month 12. Urinary C-peptide concentration was corrected for urinary creatinine [urinary C-peptide/creatinine ratio (UCPCR)] and serum C-peptide from the mixed meal tolerance test was calculated using area under the plasma concentration-time curve (AUC) normalized over 120 min. The correlation between mixed meal stimulated C-peptide AUC (mmol/l/min) and UCPCR (nmol/mmol), as well as the correlation between insulin use (IU/kg), and HbA1c (%) with UCPCR, was determined. RESULTS: UCPCR and mixed meal testing C-peptide AUC were correlated, with a correlation coefficient of 0.4172. UCPCR was not correlated with exogenous insulin use (r = -0.089) or with HbA1c (r = -0.032). CONCLUSIONS: Urinary C-peptide estimation should be considered as a measure of endogenous insulin production in future Type 1 diabetes mellitus outcome trials. A change in the timing for urine collection (to 120 min post standard meal) may provide a tighter correlation to C-peptide measured via a traditional mixed meal test.

Rapidly enlarging neck masses of the thyroid with Horner's syndrome: a concise clinical review.

BACKGROUND: Horner's syndrome (HS) presenting with a neck mass is a rare but challenging clinical scenario which may be caused by malignant thyroid disease. METHODS: A concise review of the literature (PubMED database; 1990-2013) on the clinical management of neck masses with HS. An example case is also discussed. RESULTS: 1.3% of HS is caused by thyroid pathology. Thyroid pathology is the commonest cause of a neck mass associated with HS: the majority are caused by benign pathology; with carcinoma and lymphoma accounting for the remainder. Anaplastic thyroid carcinoma (ATC), thyroid lymphoma (TL) and thyroid sarcoma (TS) typically present with rapidly enlarging anterior neck masses in the elderly and are difficult to distinguish clinically. Although fine needle aspirate cytology (FNAC) is the diagnostic tool of choice for thyroid masses, core or incisional biopsy may be necessary when FNAC is inconclusive. CONCLUSION: Differentiation between ATC, TL and TS is imperative as their treatment and prognoses differ greatly. Where feasible a combination of surgical debulking, radiotherapy and chemotherapy is the treatment of choice in ATC. Advanced cases benefit from 2 monthly endoscopic surveillance ± tracheostomy, stenting or Nd-YAG laser therapy. Aggressive oncological resection alone is recommended in TS. Treatment regimes in thyroid lymphoma (typically chemotherapy ± radiotherapy) differ for histological sub-types. 5-year failure-free survival is 90% in TL compared with a mean survival of 6-8 months in ATC and 10 months in TS.

The effect of different high-fat diets on erythrocyte osmotic fragility, growth performance and serum lipid concentrations in male, Japanese quail (Coturnix coturnix japonica).

Poultry diets are formulated with additional animal fat or vegetable oils to improve growth rate and feed conversion efficiency. High-fat diet feeding in rats and fish has been shown to result in alterations in the phospholipid composition and cholesterol content of the erythrocyte membrane, in turn affecting erythrocyte osmotic fragility. In contrast, the few studies performed using high-fat diet feeding in avian species show no changes in erythrocyte osmotic fragility. This study made use of the Japanese quail as no data exists on investigation of this species with respect to high-fat diet feeding and erythrocyte osmotic fragility. Fifty-seven male quail were randomly divided into six groups and fed either a standard diet (commercial poultry feed) or one of five high-fat diets (commercial poultry feed with 22% of either coconut oil, lard, palm oil, soya bean oil or sunflower oil on a weight/weight basis) for 12 weeks. All birds on the high-fat diets were significantly heavier (p < 0.05) after the 12-week feeding period, than when commencing the dietary intervention. Serum triglyceride concentrations of birds in all high-fat diet groups were significantly lower (p < 0.05) than birds in the standard diet group, whereas only birds in the palm oil group had significantly lower (p < 0.05) serum cholesterol concentrations compared to the standard diet group. Fragiligrams of erythrocytes from birds in the various dietary groups were similar. High-fat diet feeding with different types of additional fat did not affect the osmotic fragility of the quail erythrocytes. Feeding quail high-energy diets of varying degrees of fatty acid saturation was well tolerated and did not seem to affect the overall health status of the birds. Resistance of avian erythrocytes to modification by excess dietary fat may be a general characteristic of avian erythrocytes.

The UK prevalence of hereditary haemorrhagic telangiectasia and its association with sex, socioeconomic status and region of residence: a population-based study.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder of aberrant blood vessel development characterised by arteriovenous malformations. HHT is associated with significant morbidity due to complications including epistaxis, gastrointestinal bleeding and stroke. We explored the hypothesis that a diagnosis of HHT is associated with sex, socioeconomic status and geographical location. METHODS: We used The Health Improvement Network, a longitudinal, computerised general practice database covering 5% of the UK population to calculate prevalence estimates for HHT stratified by age, sex, socioeconomic status and geographical location. RESULTS: The 2010 UK point prevalence for HHT was 1.06/10 000 person years (95% CI 0.95 to 1.17) or 1 in 9400 individuals. The diagnosed prevalence of HHT was significantly higher in women compared with men (adjusted prevalence rate ratio (PRR) 1.53, 95% CI 1.24 to 1.88) and in those from the most affluent socioeconomic group compared with the least (adjusted PRR 1.74, 95% CI 1.14 to 2.64). The PRR varied between different regions of the UK, being highest in the South West and lowest in the West Midlands (adjusted PRR for former compared with latter 1.86, 95% CI 1.61 to 2.15). CONCLUSIONS: HHT prevalence is more common in the UK population than previously demonstrated, though this updated figure is still likely to be an underestimate. HHT appears to be significantly under-diagnosed in men, which is likely to reflect their lower rates of consultation with primary care services. There is under-diagnosis in patients from lower socioeconomic groups and a marked variation in the prevalence of diagnosis between different geographical regions across the UK that requires further investigation.

Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study.

AIMS: Phase III DEFEND-2 investigated whether otelixizumab (3.1 mg over 8 days) preserved C-peptide secretion in patients with new-onset Type 1 diabetes, focusing on adolescents (12-17 years). METHODS: One hundred and seventy-nine patients (54 adolescents) were randomized to otelixizumab or placebo. The primary endpoint was change in 2-h mixed-meal-stimulated C-peptide area under the curve at month 12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND-1. DEFEND-2 terminated early after 12 months' efficacy and safety follow-up. RESULTS: Change from baseline C-peptide was not significantly different [∆ = -0.09 nmol/l (95% CI -0.17 to 0; P = 0.051)]. No differential C-peptide effect was seen for otelixizumab in adolescents and more adverse events were reported. CONCLUSIONS: Efficacy and tolerability of otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required. Clinical Trials Registry No: NCT 00763451.

The progressive effects of a high-fat diet on erythrocyte osmotic fragility, growth performance and serum triglyceride and cholesterol levels in Guinea fowl (Numida meleagris) and Muscovy duck (Cairina moschata).

To investigate the progressive effects of a high-fat diet on erythrocyte osmotic fragility, growth performance and serum lipid concentrations in Guinea fowl and Muscovy ducks, 36 Guinea fowl and 36 Muscovy ducks were divided into two groups, for each species, and fed either a standard (STD = commercial poultry feed) or high-fat diet (HFD = commercial poultry feed with 20% palm oil and 2% lard) for up to 12 weeks. After 4, 8 and 12 weeks on the diets, six birds from each group were euthanized and blood samples collected. Osmotic fragility was assessed by measuring the haemoglobin released by erythrocytes placed in serially diluted solutions of phosphate-buffered saline, spectrophotometrically. Serum triglyceride and cholesterol concentrations were also determined. Fragiligrams from erythrocytes from both species of birds on the HFD were not different to those on the STD. However, Muscovy duck erythrocytes were more resistant to haemolysis compared with Guinea fowl erythrocytes. Final body mass and serum triglyceride levels were not significantly different (p > 0.05, anova) between the birds in the HFD and STD groups, for both species of birds. In contrast, serum cholesterol levels were significantly higher in birds on the HFD compared with those on the STD, after 4, 8 and 12 weeks of feeding, for both species of birds. Feeding Guinea fowl and Muscovy ducks a high-fat diet for up to 12 weeks resulted in hypercholesterolaemia but had no effect on final body mass, erythrocyte osmotic fragility or serum triglyceride concentrations in either bird species.

Posterior reversible encephalopathy syndrome in liver transplant patients: clinical presentation, risk factors and initial management.

Posterior reversible encephalopathy syndrome (PRES) is an uncommon but well-known complication after transplantation diagnosed by characteristic radiological features. As limited data on this complex syndrome exist we sought to better define the incidence, clinical presentation and risk factors for PRES in liver transplant (LTx) patients. We conducted a retrospective analysis of 1923 adult LTx recipients transplanted between 2000 and 2010. PRES was diagnosed radiologically in 19 patients (1%), with 84% of cases occurring within 3 months post-LTX. We compared this cohort of PRES patients to 316 other LTx recipients also requiring radiographic imaging within 3 months after LTx for neurological symptoms. Seizure was the most common clinical manifestation in the PRES group (88% vs. 16%, p< 0.001) and 31% had an intracranial hemorrhage. Those with hemorrhage on imaging were more likely to be coagulopathic. PRES patients were significantly more likely to have had alcoholic liver disease and infection/sepsis. These factors may be related to a common pathway of vascular dysregulation/damage that appears to characterize this complex syndrome. Intracranial bleeding and seizures may be the end result of these phenomena. The relationship of these associated factors to the hypothesized pathophysiology of PRES is discussed.

Pulmonary thromboembolism during adult liver transplantation: incidence, clinical presentation, outcome, risk factors, and diagnostic predictors.

BACKGROUND: Intraoperative pulmonary thromboembolism (PTE) is an often overlooked cause of mortality during adult liver transplantation (LT) with diagnostic challenge. The goals of this study were to investigate the incidence, clinical presentation, and outcome of PTE and to identify risk factors or diagnostic predictors for PTE. METHODS: Four hundred and ninety-five consecutive, isolated, deceased donor LTs performed in an institution for a 3 yr period (2004-6) were analysed. The standard technique was a piggyback method with veno-venous bypass without prophylactic anti-fibrinolytics. The clinical diagnosis of PTE was made with (i) acute cor pulmonale, and (ii) identification of blood clots in the pulmonary artery or observation of acute right heart pressure overload with or without intracardiac clots with transoesophageal echocardiography. RESULTS: The incidence of PTE was 4.0% (20 cases); cardiac arrest preceded the diagnosis of PTE [75% (15)] and PTE occurred during the neo-hepatic phase [85% (17)], especially within 30 min after graft reperfusion [70% (14)]. Operative and 60 day mortalities of patients with PTE were higher (P<0.001) than those without PTE (30% vs 0.8% and 45% vs 6.5%). Comparison of perioperative data between the PTE group (n=20) and the non-PTE group (n=475) revealed cardiac arrest and flat-line thromboelastography in three channels (natural, amicar, and protamine) at 5 min after graft reperfusion as the most significant risk factors or diagnostic predictors for PTE with an odds ratio of 154.32 [95% confidence interval (CI): 44.82-531.4] and 49.44 (CI: 15.6-156.57), respectively. CONCLUSIONS: These findings confirmed clinical significance of PTE during adult LT and suggested the possibility of predicting this devastating complication.

Integrating diverse scientific and practitioner knowledge in ecological risk analysis: a case study of biodiversity risk assessment in South Africa.

Ecological risk analysis (ERA) is a structured evaluation of threats to species, natural communities, and ecosystem processes from pollutants and toxicants and more complicated living stressors such as invasive species, genetically modified organisms, and biological control agents. Such analyses are typically conducted by a narrowly-focused group of scientific experts using technical information. We evaluate whether the inclusion of more diverse experts and practitioners in ERA improved the ecological knowledge base about South African biodiversity and the potential impacts of genetically modified (GM) crops. We conducted two participatory ERA workshops in South Africa, analyzing potential impacts of GM maize on biodiversity. The first workshop involved only four biological scientists, who were joined by 18 diverse scientists and practitioners in the second, and we compared the ERA process and results between the two using descriptive statistics and semi-structured interview responses. The addition of diverse experts and practitioners led to a more comprehensive understanding of biological composition of the agro-ecosystem and a more ecologically relevant set of hazards, but impeded hazard prioritization and the generation of precise risk assessment values. Results suggest that diverse participation can improve the scoping or problem formulation of the ERA, by generating an ecologically robust set of information on which to base the subsequent, more technical risk assessment. The participatory ERA process also increased the transparency of the ERA by exposing the logic and rationale for decisions made at each step.

The use of gold in dentistry: an historical overview.

Gold was first used in dentistry over 2500 years ago, and its dental applications have increased steadily, especially during the past 100 years, to the point where they now absorb over 80 tons of gold per annum. Course of these developments is outlined in this review.

Prenatal acrylamide exposure results in time-dependent changes in liver function and basal hematological, and oxidative parameters in weaned Wistar rats.

Acrylamide (ACR) is a toxic compound commonly found in fried, baked and heat-processed starchy foods. The current study investigated the time-dependent effects of maternal exposure to non-toxic ACR doses on the oxidative stress, liver function, and basal blood morphology of the rat offspring. Pregnant, Wistar rats were randomly divided into the control group or the groups administrated with ACR (3 mg/kg b.w./day): long exposure for 15 days, medium exposure for 10 days and short exposure for 5 days during pregnancy. Body mass, blood morphology and hematology, serum concentrations of growth hormone, IGF-1, TNF-α, IL-1ß, IL-6 and insulin, liver histomorphometry, liver activity of beclin1, LC2B and caspase3, markers of oxidative stress and the activity of antioxidative enzymes in blood serum and the liver were measured in offspring at weaning (postnatal day 21). Even short prenatal exposure to ACR led to oxidative stress and resulted in changes in liver histomorphometry and upregulation of autophagy/apoptosis. However, the most significant changes were observed following the long period of ACR exposure. This study has shown for the first time that ACR is responsible for changes in body mass in a time-dependent manner, which could lead to more serious illnesses like overweight and diabetes later in life.

Treatment outcomes of bladder stones in children with intact bladders in developing countries: A systematic review of >1000 cases on behalf of the European Association of Urology Bladder Stones Guideline panel.

INTRODUCTION: Bladder stones (BS) are still endemic in children in developing nations and account for a high volume of paediatric urology workload in these areas. The aim of this systematic review is to comparatively assess the benefits and risks of minimally invasive and open surgical interventions for the treatment of bladder stones in children. METHODS: This systematic review was conducted in accordance with Cochrane Guidance. Database searches (January 1970- March 2021) were screened, abstracted, and assessed for risk of bias for comparative randomised controlled trials (RCTs) and non-randomised studies (NRSs) with >10 patients per group. Open cystolithotomy (CL), transurethral cystolithotripsy (TUCL), percutaneous cystolithotripsy (PCCL), extracorporeal shock wave lithotripsy (ESWL) and laparoscopic cystolithotomy (LapCL) were evaluated. RESULTS: In total, 3040 abstracts were screened, and 8 studies were included. There were 7 retrospective non-randomised studies (NRS's) and 1 quasi-RCT with 1034 eligible patients (CL: n=637, TUCL: n=196, PCCL: n=138, ESWL: n=63, LapCL n=0). Stone free rate (SFR) was given in 7 studies and measured 100%, 86.6%-100%, and 100% for CL, TUCL and PCCL respectively. CL was associated with a longer duration of inpatient stay than PCCL and TUCL (p<0.05). One NRS showed that SFR was significantly lower after 1 session with outpatient ESWL (47.6%) compared to TUCL (93.5%) and CL (100%) (p<0.01 and p<0.01 respectively). One RCT compared TUCL with laser versus TUCL with pneumatic lithotripsy and found that procedure duration was shorter with laser for stones <1.5cm (n=25, p=0.04). CONCLUSION: In conclusion, CL, TUCL and PCCL have comparable SFRs but ESWL is less effective for treating stones in paediatric patients. CL has the longest duration of inpatient stay. Information gathered from this systematic review will enable paediatric urologists to comparatively assess the risks and benefits of all urological modalities when considering surgical intervention for bladder stones.

Regulators and effectors of the ARF GTPases.

The small G proteins of the ARF family are key regulators of membrane dynamics. Many functions of ARF proteins in cells are being revealed by studies of their regulators and effectors. Significant progress has been made over the past year, with the identification of a surprisingly large family of novel ARF GTPase-activating proteins. In addition, two new classes of effectors, the PIP kinases and a novel family of monomeric coat-like proteins have been discovered.

ARF: a key regulatory switch in membrane traffic and organelle structure.

The small GTP-binding protein ADP ribosylation factor (ARF) regulates, through a GTP cycle, the reversible binding of cytosolic coat proteins to Golgi membranes. By determining the binding and release of coat proteins from membranes, ARF controls the production and lifetime of coated-membrane structures. In the past year, studies suggesting a role for ARF in phospholipid metabolism have broadened our perspective on ARF function within the cell.

Membrane-cytoskeletal dynamics in a new dimension.

The recent Airlie House meeting on 'Cytoplasmic Organization and Membrane Traffic' (22-25 March 2001), sponsored by the Keith Porter Endowment, proved not to be the typical exchange of advances among specialists familiar with each other's work, but rather a series of interesting and diverse presentations that together illuminated the pace and pattern of membrane and cytoskeletal interactions in living cells.