Thermally stable Peltier controlled vacuum chamber for electrical transport measurements.

The design, manufacture, and characterization of an inexpensive, temperature-controlled vacuum chamber with millikelvin stability for electrical transport measurements at and near room temperature is reported. A commercially available Peltier device and a high-precision temperature controller are used to actively heat and cool the sample space. The system was designed to minimize thermal fluctuations in spintronic and semiconductor transport measurements, but the general principle is relevant to a wide range of electrical measurement applications. The main issues overcome are the mounting of a sample with a path of high thermal conductivity through to the Peltier device and the heat sinking of the said Peltier device inside a vacuum. A copper slug is used as the mount for a sample, and a large copper block is used as a thermal feedthrough before a passive heat sink is used to cool this block. The Peltier device provides 20 W of heating and cooling power, achieving a maximum range of 30 K below and 40 K above the ambient temperature. The temperature stability is within 5 mK at all set points with an even better performance above the ambient temperature. A vacuum pressure of 10-8 hPa is achievable. As a demonstration, we present experimental results from current-induced electrical switching of a CuMnAs thin film. Transport measurements with and without the Peltier control emphasize the importance of a constant temperature in these applications. The thermal lag between the sample space measurement and the sample itself is observed through magnetoresistance values measured during a temperature sweep.

Oxidative stress and histopathological effects by microplastic beads, in the crayfish Procambarus clarkii, and fiddler crab Leptuca pugilator.

The present study was aimed at evaluating the in vivo effects of microplastics (MP), in terms of oxidative stress and histopathological effects, in two crustacean species: Procambarus clarkii and Leptuca pugilator. In addition, MP accumulation in the hepatopancreas (HP) of both species was also determined. Adults of both crayfish and crabs were exposed for one month to fluorescent polystyrene beads (size: 1 µm) at nominal concentrations of 1000 or 5000 particles/mL. During the exposure, animals were maintained under controlled feeding, aeration, temperature, and photoperiod conditions. At the end of the exposure, HP and hemolymph (HL) samples were harvested for analysis of oxidative damage and total antioxidant levels. Additionally, the presence of MPs in both tissues was confirmed. Significant differences with the control groups were observed in lipid peroxidation levels in HP in animals exposed to the lowest concentration in P. clarkii and to the highest concentration in L. pugilator. A marked increase in antioxidant levels was also observed in the HL at both concentrations in P. clarkii, and at the highest MPs concentration in L. pugilator. Moreover, several histopathological changes were detected in both gills and HP, including hypertrophied lamellae, lifting or collapse of gill epithelia, loss of normal shape of hepatopancreatic tubules, and epithelial atrophy in the HP tissue. We conclude that exposure to MP beads at selected concentrations results in oxidative damage, induces histopathological changes in gills and HP, and triggers an antioxidant response in two crustacean species.

Antiferromagnetic half-skyrmions electrically generated and controlled at room temperature.

Topologically protected magnetic textures are promising candidates for information carriers in future memory devices, as they can be efficiently propelled at very high velocities using current-induced spin torques. These textures-nanoscale whirls in the magnetic order-include skyrmions, half-skyrmions (merons) and their antiparticles. Antiferromagnets have been shown to host versions of these textures that have high potential for terahertz dynamics, deflection-free motion and improved size scaling due to the absence of stray field. Here we show that topological spin textures, merons and antimerons, can be generated at room temperature and reversibly moved using electrical pulses in thin-film CuMnAs, a semimetallic antiferromagnet that is a testbed system for spintronic applications. The merons and antimerons are localized on 180° domain walls, and move in the direction of the current pulses. The electrical generation and manipulation of antiferromagnetic merons is a crucial step towards realizing the full potential of antiferromagnetic thin films as active components in high-density, high-speed magnetic memory devices.

Risk factors for persistent abnormality on chest radiographs at 12-weeks post hospitalisation with PCR confirmed COVID-19.

BACKGROUND: The long-term consequences of COVID-19 remain unclear. There is concern a proportion of patients will progress to develop pulmonary fibrosis. We aimed to assess the temporal change in CXR infiltrates in a cohort of patients following hospitalisation for COVID-19. METHODS: We conducted a single-centre prospective cohort study of patients admitted to University Hospital Southampton with confirmed SARS-CoV2 infection between 20th March and 3rd June 2020. Patients were approached for standard-of-care follow-up 12-weeks after hospitalisation. Inpatient and follow-up CXRs were scored by the assessing clinician for extent of pulmonary infiltrates; 0-4 per lung (Nil = 0, < 25% = 1, 25-50% = 2, 51-75% = 3, > 75% = 4). RESULTS: 101 patients with paired CXRs were included. Demographics: 53% male with a median (IQR) age 53.0 (45-63) years and length of stay 9 (5-17.5) days. The median CXR follow-up interval was 82 (77-86) days with median baseline and follow-up CXR scores of 4.0 (3-5) and 0.0 (0-1) respectively. 32% of patients had persistent CXR abnormality at 12-weeks. In multivariate analysis length of stay (LOS), smoking-status and obesity were identified as independent risk factors for persistent CXR abnormality. Serum LDH was significantly higher at baseline and at follow-up in patients with CXR abnormalities compared to those with resolution. A 5-point composite risk score (1-point each; LOS ≥ 15 days, Level 2/3 admission, LDH > 750 U/L, obesity and smoking-status) strongly predicted risk of persistent radiograph abnormality (0.81). CONCLUSION: Persistent CXR abnormality 12-weeks post COVID-19 was common in this cohort. LOS, obesity, increased serum LDH, and smoking-status were risk factors for radiograph abnormality. These findings require further prospective validation.

"Time Variable Earth Gravity Field Models From the First Spaceborne Laser Ranging Interferometer".

The Gravity Recovery and Climate Experiment Follow-On (GRACE-FO), launched May 22, 2018 and collecting science data since June 2018, is extending the 15-year data record of Earth mass change established by its predecessor GRACE mission (2002-2017). The GRACE-FO satellites carry onboard a novel technology demonstration instrument for intersatellite ranging, the Laser Ranging Interferometer (LRI), in addition to the microwave interferometer (MWI) carried on GRACE. The LRI has out-performed its in-orbit performance requirements both in terms of accuracy as well as the duration of tracking. Here, we compare and validate LRI-based gravity solutions for January 2019 to September 2020 against the MWI solutions. The comparison between the two sets of gravity solutions shows great similarities in general and nearly perfect consistency at a large hydrologic basin spatial scale (100,000 km2 and above), commonly viewed as the spatial resolution established by GRACE. The comparison in the spectral domain shows differences at the higher degrees of the spectrum, with lower error in the zonal and near zonal terms for the LRI solutions. We conclude that the LRI observations can be used to recover time-varying gravity signals to at least the level of accuracy established by the MWI-based solutions. This is a promising finding, especially when considering the benefits of using the LRI over the MWI, such as the great stability of the instrument and the low occurrence of instrument reboot events.

Evaluation of the immunogenicity and protective efficacy of a recombinant CS6-based ETEC vaccine in an Aotus nancymaae CS6 + ETEC challenge model.

Colonization factors or Coli surface antigens (CFs or CS) are important virulence factors of Enterotoxigenic E. coli (ETEC) that mediate intestinal colonization and accordingly are targets of vaccine development efforts. CS6 is a highly prevalent CF associated with symptomatic ETEC infection both in endemic populations and amongst travelers. In this study, we used an Aotus nancymaae non-human primate ETEC challenge model with a CS6 + ETEC strain, B7A, to test the immunogenicity and protective efficacy (PE) of a recombinant CS6-based subunit vaccine. Specifically, we determined the ability of dscCssBA, the donor strand complemented recombinant stabilized fusion of the two subunits of the CS6 fimbriae, CssA and CssB, to elicit protection against CS6 + ETEC mediated diarrhea when given intradermally (ID) with the genetically attenuated double mutant heat-labile enterotoxin LT(R192G/L211A) (dmLT). ID vaccination with dscCssBA + dmLT induced strong serum antibody responses against CS6 and LT. Importantly, vaccination with dscCssBA + dmLT resulted in no observed diarrheal disease (PE = 100%, p = 0.03) following B7A challenge as compared to PBS immunized animals, with an attack rate of 62.5%. These data demonstrate the potential role that CS6 may play in ETEC infection and that recombinant dscCssBA antigen can provide protection against challenge with the homologous CS6 + ETEC strain, B7A, in the Aotus nancymaae diarrheal challenge model. Combined, these data indicate that CS6, and more specifically, a recombinant engineered derivative should be considered for further clinical development.

Pathway-Based Approaches for Assessing Biological Hazards of Complex Mixtures of Contaminants: A Case Study in the Maumee River.

Assessment of ecological risks of chemicals in the field usually involves complex mixtures of known and unknown compounds. We describe the use of pathway-based chemical and biological approaches to assess the risk of chemical mixtures in the Maumee River (OH, USA), which receives a variety of agricultural and urban inputs. Fathead minnows (Pimephales promelas) were deployed in cages for 4 d at a gradient of sites along the river and adjoining tributaries in 2012 and during 2 periods (April and June) in 2016, in conjunction with an automated system to collect composite water samples. More than 100 industrial chemicals, pharmaceuticals, and pesticides were detected in water at some of the study sites, with the greatest number typically found near domestic wastewater treatment plants. In 2016, there was an increase in concentrations of several herbicides from April to June at upstream agricultural sites. A comparison of chemical concentrations in site water with single chemical data from vitro high-throughput screening (HTS) assays suggested the potential for perturbation of multiple biological pathways, including several associated with induction or inhibition of different cytochrome P450 (CYP) isozymes. This was consistent with direct effects of water extracts in an HTS assay and induction of hepatic CYPs in caged fish. Targeted in vitro assays and measurements in the caged fish suggested minimal effects on endocrine function (e.g., estrogenicity). A nontargeted mass spectroscopy-based analysis suggested that hepatic endogenous metabolite profiles in caged fish covaried strongly with the occurrence of pesticides and pesticide degradates. These studies demonstrate the application of an integrated suite of measurements to help understand the effects of complex chemical mixtures in the field. Environ Toxicol Chem 2021;40:1098-1122. © 2020 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Inflammatory phenotyping predicts clinical outcome in COVID-19.

BACKGROUND: The COVID-19 pandemic has led to more than 760,000 deaths worldwide (correct as of 16th August 2020). Studies suggest a hyperinflammatory response is a major cause of disease severity and death. Identitfying COVID-19 patients with hyperinflammation may identify subgroups who could benefit from targeted immunomodulatory treatments. Analysis of cytokine levels at the point of diagnosis of SARS-CoV-2 infection can identify patients at risk of deterioration. METHODS: We used a multiplex cytokine assay to measure serum IL-6, IL-8, TNF, IL-1ß, GM-CSF, IL-10, IL-33 and IFN-γ in 100 hospitalised patients with confirmed COVID-19 at admission to University Hospital Southampton (UK). Demographic, clinical and outcome data were collected for analysis. RESULTS: Age > 70 years was the strongest predictor of death (OR 28, 95% CI 5.94, 139.45). IL-6, IL-8, TNF, IL-1ß and IL-33 were significantly associated with adverse outcome. Clinical parameters were predictive of poor outcome (AUROC 0.71), addition of a combined cytokine panel significantly improved the predictability (AUROC 0.85). In those ≤70 years, IL-33 and TNF were predictive of poor outcome (AUROC 0.83 and 0.84), addition of a combined cytokine panel demonstrated greater predictability of poor outcome than clinical parameters alone (AUROC 0.92 vs 0.77). CONCLUSIONS: A combined cytokine panel improves the accuracy of the predictive value for adverse outcome beyond standard clinical data alone. Identification of specific cytokines may help to stratify patients towards trials of specific immunomodulatory treatments to improve outcomes in COVID-19.

Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenic Escherichia coli as a prophylactic against diarrhea.

BACKGROUND: . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. METHODS: . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). RESULTS: . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. CONCLUSIONS: . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Integrating smoking cessation into routine care in hospitals--a randomized controlled trial.

AIMS: To evaluate the effectiveness of a pharmacist-led multi-component smoking cessation programme (GIVE UP FOR GOOD) compared with usual care in hospitalized smokers. DESIGN: Randomized, assessor-blinded, parallel-group trial. SETTING: Three tertiary public hospitals in Australia. PARTICIPANTS: A total of 600 adult in-patient smokers [mean ± standard deviation (SD), age 51 ± 14 years; 64% male] available for 12 months follow-up. INTERVENTIONS: Multi-component hospital pharmacist-led behavioural counselling and/or pharmacotherapy provided during hospital stay, on discharge and 1 month post-discharge, with further support involving community health professionals (n = 300). Usual care comprised routine care provided by hospitals (n = 300). MEASUREMENTS: Two primary end-points were tested using intention-to-treat analysis: carbon monoxide (CO)-validated 1-month sustained abstinence at 6-month follow-up and verified 6-month sustained abstinence at 12-month follow-up. Smoking status and pharmacotherapy usage were assessed at baseline, discharge, 1, 6 and 12 months. FINDINGS: Sustained abstinence rates for intervention and control groups were not significantly different at both 6 months [11.6% (34 of 294) versus 12.6% (37 of 294); odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.55-1.50] and 12 months [11.6% (34 of 292) versus 11.2% (33 of 294); OR = 1.04, 95% CI = 0.63-1.73]. Secondary end-points, self-reported continuous abstinence at 6 and 12 months, also agreed with the primary end-points. Use of pharmacotherapy was higher in the intervention group, both during hospital stay [52.3% (157 of 300) versus 42.7% (128 of 300); P = 0.016] and after discharge [59.6% (174 of 292) versus 43.5% (128 of 294); P < 0.001]. CONCLUSIONS: A pharmacist-led multi-component smoking cessation intervention provided during hospital stay did not improve sustained abstinence rates at either 6 or 12 months compared with routine hospital care.

Relationship between dietary energy density and dietary quality in overweight young children: a cross-sectional analysis.

BACKGROUND: Observational research has found that lower energy density (ED) diets are related to reduced intake of fat and greater intake of fruits and vegetables. No study has examined the relationship between dietary ED and dietary quality, as determined by the Healthy Eating Index-2005 (HEI), in children who are overweight and obese. OBJECTIVE: Examine the relationship between dietary ED and HEI, determined from 3-d food records, in 156 children, aged 4-9 years, who had ≥85th percentile body mass index presenting for family-based obesity treatment. METHOD: Dietary ED, in kcal/g, was calculated using two methods: food and all beverages consumed (food+bev) and food only consumed (food). For calculation of HEI, all components of the HEI were included except oils. RESULTS: Participants were classified as consuming a low-ED, medium-ED or high-ED diet using tertile cut-off points with ED calculated using food and beverages(food+bev) or food only(food) . After controlling for group difference in child sex and race and parent sex, LOW(food+bev) and LOWfood had significantly (P < 0.05) higher total HEI scores, and total fruit, total vegetable and saturated fat HEI scores than HIGH(food+bev) and HIGHfood , with higher scores indicating greater quality. CONCLUSIONS: Lower dietary ED is associated with higher dietary quality in children presenting for obesity treatment. Additional research investigating an ED prescription on dietary quality in children who are overweight or obese is needed to better understand this relationship.

Offering statins to a population attending health checks with a 10-year cardiovascular disease risk between 10% and 20.

BACKGROUND: In 2014 the UK National Institute for Health and Care Excellence recommended reducing the threshold for offering statin therapy to patients from a 10-year modelled risk of cardiovascular disease (CVD) of 20% to 10%. AIM: To describe the response of patients in UK primary care with a CVD risk between 10% and 20% to an invitation to attend a consultation to discuss statins. DESIGN AND SETTING: Review of electronic medical records at one GP practice in the East of England. METHOD: We invited all patients who had attended an NHS Health Check at the practice, had a QRisk(®) score between 10% and 20%, and were not prescribed statins to attend designated clinics in the practice to discuss starting statins. We reviewed the medical records to identify those who had attended the clinics and those who had chosen to start a statin. RESULTS: Of 410 patients invited, 100 (24.4%) patients attended the designated clinics and 45 (11%) chose to start a statin. Those who chose to start a statin were older and with a higher QRisk(®) than those who did not. Among those who attended, individuals who started a statin had a higher QRisk(®) than those who did not and were more likely to be current or ex-smokers. CONCLUSIONS: The proportion choosing to start a statin was substantially lower than previously estimated. Large population-based studies with long-term follow-up are needed to assess the impact on health and workload of this change in guidance.

Emergency medicine resident physicians' perceptions of electronic documentation and workflow: a mixed methods study.

OBJECTIVE: To understand emergency department (ED) physicians' use of electronic documentation in order to identify usability and workflow considerations for the design of future ED information system (EDIS) physician documentation modules. METHODS: We invited emergency medicine resident physicians to participate in a mixed methods study using task analysis and qualitative interviews. Participants completed a simulated, standardized patient encounter in a medical simulation center while documenting in the test environment of a currently used EDIS. We recorded the time on task, type and sequence of tasks performed by the participants (including tasks performed in parallel). We then conducted semi-structured interviews with each participant. We analyzed these qualitative data using the constant comparative method to generate themes. RESULTS: Eight resident physicians participated. The simulation session averaged 17 minutes and participants spent 11 minutes on average on tasks that included electronic documentation. Participants performed tasks in parallel, such as history taking and electronic documentation. Five of the 8 participants performed a similar workflow sequence during the first part of the session while the remaining three used different workflows. Three themes characterize electronic documentation: (1) physicians report that location and timing of documentation varies based on patient acuity and workload, (2) physicians report a need for features that support improved efficiency; and (3) physicians like viewing available patient data but struggle with integration of the EDIS with other information sources. CONCLUSION: We confirmed that physicians spend much of their time on documentation (65%) during an ED patient visit. Further, we found that resident physicians did not all use the same workflow and approach even when presented with an identical standardized patient scenario. Future EHR design should consider these varied workflows while trying to optimize efficiency, such as improving integration of clinical data. These findings should be tested quantitatively in a larger, representative study.

Collaborative study for the establishment of the WHO 3(rd) International Standard for Endotoxin, the Ph. Eur. endotoxin biological reference preparation batch 5 and the USP Reference Standard for Endotoxin Lot H0K354.

An international collaborative study was organised jointly by the World Health Organization (WHO)/National Institute for Biological Standards and Control (NIBSC), the United States Pharmacopeia (USP) and the European Directorate for the Quality of Medicines & HealthCare (EDQM/Council of Europe) for the establishment of harmonised replacement endotoxin standards for these 3 organisations. Thirty-five laboratories worldwide, including Official Medicines Control Laboratories (OMCLs) and manufacturers enrolled in the study. Three candidate preparations (10/178, 10/190 and 10/196) were produced with the same material and same formulation as the current reference standards with the objective of generating a new (3(rd)) International Standard (IS) with the same potency (10 000 IU/vial) as the current (2(nd)) IS, as well as new European Pharmacopoeia (Ph. Eur.). and USP standards. The suitability of the candidate preparations to act as the reference standard in assays for endotoxin performed according to compendial methods was evaluated. Their potency was calibrated against the WHO 2(nd) IS for Endotoxin (94/580). Gelation and photometric methods produced similar results for each of the candidate preparations. The overall potency estimates for the 3 batches were comparable. Given the intrinsic assay precision, the observed differences between the batches may be considered unimportant for the intended use of these materials. Overall, these results were in line with those generated for the establishment of the current preparations of reference standards. Accelerated degradation testing of vials stored at elevated temperatures supported the long-term stability of the 3 candidate preparations. It was agreed between the 3 organisations that batch 10/178 be shared between WHO and EDQM and that batches 10/190 and 10/196 be allocated to USP, with a common assigned value of 10 000 IU/vial. This value maintains the continuity of the global harmonisation of reference materials and unitage for the testing of endotoxins in parenteral pharmaceutical products. Based on the results of the collaborative study, batch 10/178 was established by the European Pharmacopoeia Commission as the Ph. Eur. Endotoxin Biological Reference Preparation (BRP) batch 5. The same batch was also established by the Expert Committee on Biological Standardisation (ECBS) of WHO as the WHO 3(rd) IS for Endotoxin. Batch 10/190 was adopted as the USP Endotoxin Reference Standard, lot H0K354 and vials from this same batch (10/190) will serve as the United States Food and Drug Administration (USFDA) Endotoxin Standard, EC-7.

Dosing of cytotoxic chemotherapy: impact of renal function estimates on dose.

BACKGROUND: Oncology clinicians are now routinely provided with an estimated glomerular filtration rate on pathology reports whenever serum creatinine is requested. The utility of using this for the dose determination of renally excreted drugs compared with other existing methods is needed to inform practice. PATIENTS AND METHODS: Renal function was determined by [Tc(99m)]DTPA clearance in adult patients presenting for chemotherapy. Renal function was calculated using the 4-variable Modification of Diet in Renal Disease (4v-MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Cockcroft and Gault (CG), Wright and Martin formulae. Doses for renal excreted cytotoxic drugs, including carboplatin, were calculated. RESULTS: The concordance of the renal function estimates according to the CKD classification with measured Tc(99m)DPTA clearance in 455 adults (median age 64.0 years: range 17-87 years) for the 4v-MDRD, CKD-EPI, CG, Martin and Wright formulae was 47.7%, 56.3%, 46.2%, 56.5% and 60.2%, respectively. Concordance for chemotherapy dose for these formulae was 89.0%, 89.5%, 85.1%, 89.9% and 89.9%, respectively. Concordance for carboplatin dose specifically was 66.4%, 71.4%, 64.0%, 73.8% and 73.2%. CONCLUSION: All bedside formulae provide similar levels of concordance in dosage selection for the renal excreted chemotherapy drugs when compared with the use of a direct measure of renal function.

Naturopaths and Western herbalists' attitudes to evidence, regulation, information sources and knowledge about popular complementary medicines.

BACKGROUND: The practice of naturopathy and Western herbal medicine (WHM) was built on traditional evidence but may be undergoing change with the advent of scientific evidence. The aims of this research were to provide a better understanding of practitioners' attitudes towards evidence, information sources, professional regulation and their knowledge about the evidence of commonly used complementary medicines (CMs). METHOD: Naturopaths and WHM practitioners were invited to participate in an anonymous, self-administered, on-line survey. Participants were recruited using the mailing lists and websites of CM manufacturers and professional associations. RESULTS: Four hundred and seventy nine practitioners participated; 95% currently in practice. The majority (99%) thought well documented traditional evidence was essential or important, 97% patient reports and feedback, 97% personal experience, 94% controlled randomised trials and 89% published case reports. Significantly more recent graduates (less than 5 years) rated randomised trials as essential compared to others. Most (82%) respondents want information sources containing both traditional and scientific evidence. They currently use several resources; 74% CM textbooks, 67% conferences/seminars, 57% CM journals, 48% databases and 40% manufacturers' information. The mean knowledge score was 61.5% with no significant differences between respondents with diploma or degree level education or by graduating year. Eighty-five percent of practitioners strongly agreed or agreed that practitioners should be formally registered to safeguard the public, 8% were unsure and 8% disagreed or strongly disagreed. CONCLUSION: Naturopaths and WHM practitioners accept the importance of scientific evidence whilst maintaining the importance and use of traditional evidence. The majority are in favour of professional registration.

After TGN1412: recent developments in cytokine release assays.

The failure of regulatory science to keep pace with and support the development of new biological medicines was very publically highlighted in March 2006 when the first-in-man Phase I clinical trial of the immunomodulatory CD28-specific monoclonal antibody (mAb) TGN1412 ended in disaster when all six volunteers suffered a life-threatening adverse reaction termed a 'Cytokine Storm'. The poor predictive value of standard pre-clinical safety tests and animal models applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays and animal models that are both sensitive and predictive of clinical outcome in man. The non-predictive result obtained from pre-clinical safety testing in cynomolgus macaques has now been attributed to a lack of CD28 expression on CD4+ effector memory T-cells that therefore cannot be stimulated by TGN1412. In contrast, high levels of CD28 are expressed on human CD4+ effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines. Standard in vitro safety tests with human cells were also non-predictive as they did not replicate in vivo presentation of TGN1412. It was subsequently shown that, if an immobilized therapeutic mAb-based assay or endothelial cell co-culture assay was used to evaluate TGN1412, then these would have predicted a pro-inflammatory response in man. New in vitro assays based on these approaches are now being applied to emerging therapeutics to hopefully prevent a repeat of the TGN1412 incident. It has emerged that the mechanism of pro-inflammatory cytokine release stimulated by TGN1412 is different to that of other therapeutic mAbs, such that standard pro-inflammatory markers such as TNFα and IL-8 are not discriminatory. Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response.

Estimation of body weight in hospitalized patients.

AIM: To examine the bias and precision of different methods of estimating body mass and height in hospitalized adult patients. METHODS: Patients were enrolled at the Alfred and Caulfield hospitals, Melbourne, Australia following verbal consent. Estimates were made using the Lorenz formula (that utilizes height, waist and hip circumference), the Crandell formula (that utilizes height and arm circumference) and visual estimation of weight based on the average results obtained by two pharmacy interns. Statistical error was calculated as the ratio of estimated to actual weight; bias was assessed as the mean error and precision as the proportion of estimates within 10 and 20% of measured weight and standard deviation of the error. RESULTS: In a 5-week period July to August 2010, 198 patients were enrolled. The median age was 64 years (range 19-91) and 52% were female. Thirty-four (17%) patients were obese (BMI >30 kg/m(2)) and 8 (4%) were underweight (BMI <18 kg/m(2)). With the Lorenz formula an estimate within 10% was obtained for 56% of patients; with the Crandell formula prediction was poor. Documentation of body weight in notes and patient self-reporting were both accurate. Seventy-two patients (43%) were prescribed one or more drugs for which dosing potentially should be adjusted for body weight. CONCLUSION: In adult hospitalized patients, the estimation of body weight by anthropomorphic measures is not accurate. This supports the need for equipment to be made widely available to accurately weigh patients directly in hospital, including in unconscious and immobile patients.

Emerging tropical diseases in Australia. Part 2. Ciguatera fish poisoning.

Ciguatera poisoning is a food-borne neuro-intoxication caused by consumption of finfish that have accumulated ciguatoxins in their tissues. Ciguatera is a distressing and sometimes disabling condition that presents with a self-limiting though occasionally severe gastro-intestinal illness, progressing to a suite of aberrant sensory symptoms. Recovery can take from days to years; second and subsequent attacks may manifest in a more severe illness. Ciguatera remains largely a pan-tropical disease, although tourism and export fish markets facilitate increased presentation in temperate latitudes. While ciguatera poisoning in the South Pacific was recognised and eloquently described by seafarers in the 18th Century, it remains a public-health challenge in the 21st Century because there is neither a confirmatory diagnostic test nor a reliable, low-cost screening method to ascertain the safety of suspect fish prior to consumption. A specific antidote is not available, so treatment is largely supportive. The most promising pharmacotherapy of recent decades, intravenous mannitol, has experienced a relative decline in acceptance after a randomized, double-blind trial failed to confirm its efficacy. Some questions remain unanswered, however, and the use of mannitol for the treatment of acute ciguatera poisoning arguably deserves revisiting. The immunotoxicology of ciguatera is poorly understood, and some aspects of the epidemiology and symptomatology of ciguatera warrant further enquiry.