Frailty is associated with reduced prospect of discharge home after in-hospital cardiac arrest.

BACKGROUND: Frailty is common among acute hospital patients and might adversely affect recovery from inpatient cardiac arrest. AIM: To assess the relationship between hospital admission characteristics, including frailty, and discharge outcome after in-hospital cardiac arrest. METHODS: Prospectively collected data were retrospectively analysed for all separations from a tertiary hospital during 2008-2017 that involved rapid response team attendance for cardiac arrest. Hospital Frailty Risk Score (HFRS) and Charlson index of comorbidity were calculated from 'primary' and 'associated' International Classification of Diseases, 10th revision, Australian Modification diagnoses. HFRS ≥5 was taken to signify frailty. Discharge home from hospital and death in hospital were modelled using logistic regression. RESULTS: There were 388 in-hospital arrest patients: 91% were aged ≥50 years, 34% were previously discharged in the past 6 months, 66% were unplanned admissions, 63% were non-cardiology-cardiothoracic admissions, 45% had a Charlson comorbidity index ≥2 and 19% were identified as frail. Discharge home occurred in 22%, discharge to another hospital 17% and death 62%. Of the frail patients, only 3 (4%) were discharged home, 12 (17%) were discharged to another hospital and 57 (79%) died in hospital. Fewer frail patients were discharged home compared with non-frail patients (4 vs 26%; odds ratio (OR) 0.13, P = 0.001). On multivariable analysis, patients were less likely to be discharged home if they had frailty (OR 0.24, P = 0.02), age ≥ 50 years (OR 0.36, P = 0.01), non-cardiology-cardiothoracic unit admission (OR 0.40, P = 0.001) and unplanned admission (OR 0.57, P = 0.04). Frail patients discharged to another hospital spent a median of 15 days (interquartile range 11-23) in the hospital post-arrest before leaving to continue inpatient care elsewhere. Frailty was associated with death in hospital on univariate analysis (79 vs 58%; OR 2.80, P = 0.001) but not after controlling for other factors. CONCLUSION: Frail patients are unlikely to make a good recovery after in-hospital arrest. This should be taken into account when planning care with patients and their families.

Use of resuscitation plans at a tertiary Australian hospital: room for improvement.

BACKGROUND: The 'Acute Resuscitation Plan' (ARP) is a document for recording the resuscitation plans of patients at a tertiary hospital for adult patients. The ARP was introduced at the hospital in September 2014, superseding the 'Not for Cardiopulmonary Resuscitation (CPR)' form. Unlike the Not for CPR form, the ARP was relevant to patients with and without resuscitation limits. AIM: To evaluate the introduction of the ARP. METHODS: This study is a retrospective audit of the records of all admissions to the hospital from January to June 2014 (Not for CPR period) and January to June 2015 (ARP period). The main outcomes are the incidence of resuscitation plans, the proportion of ARP specifying consultation with the patient (or representative) and with senior medical staff, and the proportion of ARP among older patients and those with significant comorbidity. RESULTS: Resuscitation plans were present for 453 of 23 325 (1.9%) admissions in the Not for CPR period versus 1801 of 24 037 (7.5%) in the ARP period (odds ratio (OR) 4.1, 95% confidence interval (CI) 3.7-4.5, P < 0.001). A total of 42% of ARP specified 'care of the dying' in the event of arrest. Acknowledgement of the views of the patient (or representative) was indicated on 37% of ARP and of a senior physician on 28%. An ARP was not present for 67% of patients aged ≥90 years, 59% from aged care, 90% with metastatic cancer and 64% aged ≥80 years and with a Charlson comorbidity index ≥3. CONCLUSIONS: More patients had resuscitation plans after introducing the ARP. However, patients and senior physicians were often remote from the consultation process, and an ARP was not present for many patients likely to have a poor outcome from cardiopulmonary arrest.

Changing clinical guidelines from delayed to early aperient administration for enterally fed intensive care patients was associated with increased diarrhoea: a before-and-after, intention-to-treat evaluation.

BACKGROUND: The 14-bed intensive care unit of a tertiary referral hospital adopted a guideline to start docusate sodium with sennosides when enteral nutrition was started. This replaced a guideline to start aperients after 24h of enteral nutrition if no bowel action had occurred. We sought to determine the effect of this change on the incidence of diarrhoea and constipation in intensive care. METHODS: Retrospective audit of the medical records of consecutive adult patients admitted to intensive care and given enteral nutrition, excluding those with a primary gastrointestinal system diagnosis, between Jan-Aug 2011 (the delayed group, n=175) and Jan-Aug 2012 (the early group, n=175). The early aperient guideline was implemented during Sep-Dec 2011. RESULTS: The early and delayed groups were similar in age (median 62 years vs. 64 years; P=0.17), sex (males 65% vs. 63%; P=0.91), and postoperative cases (31% vs. 33%; P=0.82) and had similar proportions who received mechanical ventilation (95% vs. 95%; P=1.00), an inotrope or vasopressor (63% vs. 70%; P=0.17), renal replacement therapy (8% vs. 10%; P=0.71), opiates (77% vs. 80%; P=0.60), antibiotics (89% vs. 91%; P=0.72) and metoclopramide (46% vs. 55%; P=0.11). A significantly larger proportion of the early group received an aperient (54% vs. 29%, P<0.001) and experienced diarrhoea (38% vs. 27%, P=0.04), but the groups had similar proportions affected by constipation (42% vs. 43%, P=0.91). CONCLUSIONS: Changing guidelines from delayed to early aperient administration was associated with an increase in the incidence of diarrhoea but was not associated with the incidence of constipation. These findings do not support changing guidelines from delayed to early aperient administration.

Do outlier inpatients experience more emergency calls in hospital? An observational cohort study.

OBJECTIVE: To determine the effect of spending time as an outlier (ie, an inpatient who spends time away from his or her "home" ward) on the frequency of emergency calls for patients admitted to a tertiary referral hospital. DESIGN, SETTING AND PATIENTS: Observational cohort study of all patients admitted to a university-affiliated tertiary referral hospital in Melbourne, Victoria, between 1 July 2009 and 30 November 2011. MAIN OUTCOME MEASURE: The number of emergency calls per hospital admission, with reference to location within the hospital. RESULTS: There were 58,158 admissions during the study period. The median age of admitted patients was 61 years, 55% were male, and the inhospital mortality was 1.40%. In 11,034 admissions (18.97%), patients spent time as outliers. Inhospital mortality was 2.57% in the outlier group versus 1.12% in the non-outlier group (P < 0.001). After adjusting for age, same-day admission, 10-year predicted mortality, interhospital transfer and high-risk clinical units, outlier status was associated with a 53% increase in emergency calls (P < 0.001). CONCLUSIONS: This study found a strong association between time spent away from a patient's home ward and the number of emergency calls. We postulate that outlier patients are at risk as they may have therapeutic and monitoring needs that are only available on their home ward. With increasing pressure to move patients out of the emergency department, the number of outlier patients may increase.

Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS: The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS: Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION: In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING: Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.

Validation of putative genomic biomarkers of nephrotoxicity in rats.

Drug-induced renal injury is a common finding in the early preclinical phase of drug development. But the specific genes responding to renal injury remain poorly defined. Identification of drug-induced gene changes is critical to provide insights into molecular mechanisms and detection of renal damage. To identify genes associated with the development of drug-induced nephrotoxicity, a literature survey was conducted and a panel of 48 genes was selected based on gene expression changes in multiple published studies. Male Sprague-Dawley rats were dosed daily for 1, 3 or 5 days to the known nephrotoxicants gentamicin, bacitracin, vancomycin and cisplatin, or the known hepatotoxicants ketoconazole, 1-naphthyl isothiocyanate and 4,4-diaminodiphenylmethane. Histopathological evaluation and clinical chemistry revealed renal proximal tubular necrosis in rats treated with the nephrotoxicants, but not from those treated with the hepatotoxicants. RNA was extracted from the kidney, and RT-PCR was performed to evaluate expression profiles of the selected genes. Among the genes examined, 24 genes are confirmed to be highly induced or repressed in rats treated with nephrotoxicants; further investigation identified that 5 of the 24 genes were also altered by hepatotoxicants. These data led to the identification of a set of genomic biomarker candidates whose expression in kidney is selectively regulated only by nephrotoxicants. Among those genes displaying the highest expression changes specifically in nephrotoxicant-treated rats were kidney injury molecule 1 (Kim1), lipocalin 2 (Lcn2), and osteopontin (Spp1). The establishment of such a genomic marker set offers a new tool in our ongoing quest to monitor nephrotoxicity.

Temporal evaluation of CYP mRNA in mice administered with prototypical P450 inducers: comparison with conventional protein/enzyme methods.

Assessment of cytochrome P450 (CYP) induction at the mRNA level in preclinical rodent studies has gained interest in recent years, but there are still concerns regarding correlations between the mRNA and the enzyme activity levels, especially in mice. The purpose of the present study was to systematically evaluate patterns of temporal changes of CYPs 1a1, 1a2, 2b10, 3a11, and 4a10 at mRNA, protein, and activity levels in order to determine to what extent mRNA levels could be used either qualitatively or quantitatively for the assessment of CYP enzyme induction. In this study, livers from male CD-1 mice treated daily with beta-naphthoflavone, phenobarbital, dexamethasone, clofibrate, and control vehicles were collected for RNA and microsomal analysis after 0.5, 1, 2, 4, and 8 days of daily dose. The results revealed a good correlation among mRNA, protein, and enzyme activity levels, with the best correlation at the time points between Days 2 and 8, suggesting that the appropriate time to monitor CYP mRNA may be beyond Day 2 of chemical treatments. Based on these results, we concluded that the mRNA approach is a useful tool to monitor CYP induction in mice, particularly when treatment duration is beyond 2 days.

Rapid response team diagnoses: frequencies and related hospital mortality.

OBJECTIVES: To describe the frequency and hospital mortality of problems (diagnoses) encountered by a rapid response team (RRT), and to identify the most common diagnoses for RRT triggers and for treating units. DESIGN: For each RRT event in 2015 at a tertiary hospital for adults, we chose the diagnosis that best explained the RRT event from a pre-defined list after reviewing relevant test results and clinical notes. RESULTS: There were 937 RRT events during 700 admissions and there were 58 different RRT diagnoses in 11 diagnosis groups. The largest groups were neurological and consciousness problems (22.9%), circulatory problems (19.0%) and breathing problems (16.0%). The most common diagnoses were rapid atrial fibrillation (7.6%) and oversedation or narcosis (4.8%). When SpO2 < 90% triggered RRT review, the leading diagnoses were complex respiratory failure (25.9%) and pneumonia (11.4%). When decreased conscious state triggered review, the main problems were neurological, but there were 39 different diagnoses among these cases. The main problems among orthopaedic cases were post-operative hypovolaemia (19.0%) and spinal anaesthetic-related or epidural analgesicrelated hypotension (15.2%). Hospital mortality was 101/700 (14.4%). Diagnoses with high mortality included gastrointestinal bleeding (4/17, 23.5%), complex respiratory failure (8/33, 24.2%), intracranial event (8/28, 28.6%), cardiogenic shock or acute heart failure (5/17, 29.4%), pneumonia (7/21, 33.3%), chest sepsis (5/11, 45.5%) and cardiac arrest (18/26, 69.2%). CONCLUSIONS: The RRT activation trigger provides only a general indication of the diagnosis. Some problems appear preventable and could provide a focus for unit-based quality initiatives. The mortality of some diagnoses is substantial, and this may help in setting treatment goals, but more work is needed to understand the association of RRT diagnosis and outcome.

The duration of hospitalization before review by the rapid response team: A retrospective cohort study.

PURPOSE: The purpose of this study is to compare cases of rapid response team (RRT) review for early deterioration (<48 hours after admission), intermediate deterioration (48 to <168 hours after admission), late deterioration (≥168 hours after admission), and cardiac arrest and to determine the association between duration of hospitalization before RRT review and mortality. METHODS: This is a retrospective cohort study of RRT cases from a single hospital over 5 years (2009-2013) using administrative data and data for the first RRT attendance of each hospital episode. RESULTS: Of 2843 RRT cases, 971 (34.2%) were early deterioration, 917 (32.3%) intermediate, 775 (27.3%) late, and 180 (6.3%) cardiac arrest. Compared with early deterioration patients, late deterioration patients were older (median, 71 vs 69 years; P = .005), had a higher Charlson comorbidity index (median, 2 vs 1; P < .001), more often had RRT review for respiratory distress (32.5% vs 23.5%; P < .001), more often received RRT-initiated not for resuscitation orders (8.4% vs 3.9%; P < .001), less often were discharged directly home (27.9% vs 58.4%; P < .001), and more often died in hospital (30.6% vs 12.8%; P < .001). Compared with early deterioration and adjusted for confounders, the odds ratio of death in hospital for late deterioration was 2.36 (1.81-3.08; P < .001). CONCLUSIONS: Late deterioration is frequently encountered by the RRT and, compared with early deterioration, is associated with greater clinical complexity and a worse hospital outcome.

Quantitative PCR deconstruction of discrepancies between results reported by different hybridization platforms.

Differences in hybridization platforms used in gene array analysis experiments can lead to significant differences in hybridization results. In this study we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to investigate discrepant results between the National Institute of Environmental Health Sciences cDNA and Affymetrix oligo platforms used to evaluate hepatic gene expression changes in rats exposed to methapyrilene. Caldesmon cDNA platform hybridization results showed decreases in gene expression levels for the high-dose methapyrilene 7-day pooled samples compared with their controls. By contrast, the Affymetrix oligonucleotide platform showed increases in expression levels for these samples. Quantitative gene expression measurements provide an explanation for the discrepancies observed for these samples. In the case of caldesmon, there is a 74-base sequence in the cDNA clone that is absent in the Affymetrix sequence. The amplicon based on the cDNA clone shows > 100-fold suppression relative to the day 7 high-dose methapyrilene-pooled control. These data demonstrate the importance of using a "gold standard," such as qRT-PCR to confirm key hybridization results as well as to understand the sources of discrepancies resulting from different hybridization platforms.

The mortality associated with review by the rapid response team for non-arrest deterioration: a cohort study of acute hospital adult patients.

OBJECTIVES: To compare the admission characteristics, discharge destination and mortality of patients reviewed by the rapid response team (RRT) for deterioration with those of other hospital patients; and to determine the association between RRT review for deterioration and mortality. DESIGN, SETTING AND PATIENTS: Acute admissions of adult patients to a tertiary hospital between 1 January 2008 and 31 December 2011 were identified from administrative data. Data for each patient's first admission were merged with RRT data on the first RRT event of each admission, if any. RRT events involving cardiac arrest were classified as arrest events and all others as deterioration events. RESULTS: Of 43 385 patients in the cohort, 1117 (2.57%) had RRT review for deterioration and 91 (0.21%) for cardiac arrest. Deterioration events occurred a median of 3.23 days after admission. Advanced treatments were instituted in 38.59% of deterioration events, and a new not-for resuscitation order for 5.55%. Compared with those not reviewed by the RRT, patients in the deterioration group were older (median, 70 v 60 years, P < 0.001) and had a higher Charlson comorbidity index (median, 1 v 0, P < 0.001). They also more often died in hospital (18.80% v 1.42%, P < 0.001) or were discharged to another hospital (37.51% v 13.39%, P < 0.001) and more often died in the 90 days after admission (24.44% v 3.48%, P < 0.001). Their adjusted odds ratio of death in the 90 days after admission was 5.85 (95% CI, 4.97-6.89, P < 0.001). CONCLUSION: Patients reviewed for deterioration were older and had greater comorbidity than patients the RRT was not called to review. RRT review for deterioration was an independent risk factor for mortality.

Automated external defibrillators and in-hospital cardiac arrest: patient survival and device performance at an Australian teaching hospital.

AIMS: To evaluate the effect of automated external defibrillators (AEDs) on patient survival and to describe the performance of AEDs after in-hospital cardiac arrest. METHODS: Prospectively collected data were analysed for cardiac arrests in the general patient care areas of a teaching hospital during the 3 years before and the 3 years after the deployment of AEDs. The association between availability of an AED and survival to hospital discharge was assessed using multivariate logistic regression. AED performance during automated management of the initial rhythms was assessed using information captured by the AEDs. RESULTS: There were 84 cardiac arrests in the AED period and 82 in the pre-AED period. Patient and event characteristics were similar in each period. The initial rhythm was shockable in 16% of cases. Return of spontaneous circulation was higher in the AED period (54% vs. 35%, P=0.02) but the proportion of hospital survivors in each period was similar (22% vs. 19%, P=0.56). The adjusted odds ratio for hospital survival when an AED was available was 1.22 (95% CI 0.53-2.84, P=0.64). An AED was applied in 77/84 (92%) possible cases. Median interruption to chest compressions was 12s (inter-quartile range 12-13). An automated shock was delivered in 8/13 (62%) possible cases. CONCLUSIONS: Availability of AEDs was not independently associated with hospital survival. Shockable presenting rhythms were not common and, in keeping with the manufacturer's specifications, the AEDs did not shock all potentially shockable rhythms. The hands-off time associated with automated rhythm management was considerable.

Fluid therapy using a balanced crystalloid solution and acid-base stability after cardiac surgery.

OBJECTIVE: To evaluate the effect of fluid therapy using Accusol (Baxter Healthcare, McGaw Park, Ill, USA), a crystalloid solution containing sodium bicarbonate and other electrolytes and having a strong ion difference of 35 mEq/L, on acid-base stability after cardiac surgery. DESIGN: Retrospective per-protocol comparison. SETTING: Intensive care unit of St Vincent's Hospital, a teaching hospital in Melbourne, Australia. PARTICIPANTS: Consecutive adult patients admitted in daytime hours after elective on-pump coronary artery bypass graft surgery between May and October 2008 constituted the "pre-Accusol group" (n=40), and those admitted between May and October 2009 and who were treated with Accusol constituted the "Accusol group" (n=51). MAIN OUTCOME MEASURES: The fluids and their component electrolytes administered; change in standard base excess (SBE) between the time of intensive care admission and 04:00 h the next day. RESULTS: The Accusol group received a median Accusol dose of 1.86 mL/kg/h (interquartile range, 1.51-2.20 mL/ kg/h), which accounted for 38% (SD, 10%) of the total volume of fluid administered. The change in SBE was +0.03mmol/L (95% CI, -0.57 to 0.64 mmol/L; P = 0.91) in the Accusol group compared with -2.05mmol/L (95% CI, -2.64 to -1.45; P < 0.01) in the pre-Accusol group. The strong ion difference of the electrolytes administered as components of fluid therapies was higher in the Accusol group by 55.5mEq (95% CI, 40.0 to 71.0mEq; P < 0.01). Only 8% of the Accusol group received albumin compared with 48% of the pre-Accusol group (P < 0.01). CONCLUSIONS: SBE was more stable in patients treated with Accusol. Further studies are needed to determine whether use of solutions such as Accusol influences important patient outcomes.

Automated external defibrillators and survival after in-hospital cardiac arrest: early experience at an Australian teaching hospital.

OBJECTIVE: To evaluate the effect of the introduction of automated external defibrillators (AEDs) on survival after inhospital cardiac arrest. DESIGN, SETTING AND PARTICIPANTS: Before-and-after study that compared patients during the 2 years before (8 November 2005 to 7 November 2007) and the year after (8 November 2007 to 7 November 2008) the deployment of AEDs to the non-critical care areas of a university teaching hospital. MAIN OUTCOME MEASURES: Return of spontaneous circulation (ROSC) and survival to hospital discharge. RESULTS: 55 in-hospital cardiac arrests occurred in the 2-year pre-AED period and 31 in the 1-year AED period. Patients had similar baseline characteristics in the pre-AED and AED periods including witnessed arrest (53% v 48%), arrest in an acute inpatient ward (78% v 90%), and initial arrest rhythm of pulseless ventricular tachycardia or ventricular fibrillation (18% v 16%). The proportions of patients with ROSC were similar in the pre-AED and AED periods (42% v 55%), as were the proportions who survived to hospital discharge (22% v 29%). In the AED period, the relative risk of ROSC was 1.31 (95% CI, 0.84- 2.04) and the relative risk of survival to hospital discharge was 1.33 (95% CI, 0.63-2.80). CONCLUSIONS: ROSC and survival to hospital discharge did not change significantly after deployment of AEDs. The existence of a timely and robust resuscitation response with relatively good baseline outcomes, and the low proportion of initial shockable arrest rhythms may have limited the capacity of AEDs to improve survival.

Nonperturbative measurement of the local magnetic field using pulsed polarimetry for fusion reactor conditions (invited).

A novel diagnostic technique for the remote and nonperturbative sensing of the local magnetic field in reactor relevant plasmas is presented. Pulsed polarimetry [Patent No. 12/150,169 (pending)] combines optical scattering with the Faraday effect. The polarimetric light detection and ranging (LIDAR)-like diagnostic has the potential to be a local B(pol) diagnostic on ITER and can achieve spatial resolutions of millimeters on high energy density (HED) plasmas using existing lasers. The pulsed polarimetry method is based on nonlocal measurements and subtle effects are introduced that are not present in either cw polarimetry or Thomson scattering LIDAR. Important features include the capability of simultaneously measuring local T(e), n(e), and B(parallel) along the line of sight, a resiliency to refractive effects, a short measurement duration providing near instantaneous data in time, and location for real-time feedback and control of magnetohydrodynamic (MHD) instabilities and the realization of a widely applicable internal magnetic field diagnostic for the magnetic fusion energy program. The technique improves for higher n(e)B(parallel) product and higher n(e) and is well suited for diagnosing the transient plasmas in the HED program. Larger devices such as ITER and DEMO are also better suited to the technique, allowing longer pulse lengths and thereby relaxing key technology constraints making pulsed polarimetry a valuable asset for next step devices. The pulsed polarimetry technique is clarified by way of illustration on the ITER tokamak and plasmas within the magnetized target fusion program within present technological means.

Quantitative gene expression analysis in a nonhuman primate model of antibiotic-induced nephrotoxicity.

Gene expression patterns using microarrays have been described for rodent models of nephrotoxicity. To determine if significant gene expression changes previously identified have application across multiple species, we studied quantitative gene expression changes in the kidneys of female cynomolgus monkeys after exposure to two nephrotoxicants. Animals were dosed with the aminoglycoside gentamicin (10 mg/kg), the experimental oligosaccharide antibiotic everninomicin (30 or 60 mg/kg), or a combination of gentamicin (10 mg/kg) and everninomicin (30 mg/kg) for 7 days. Monkeys receiving these drugs in combination developed renal lesions as early as Day 1. By Day 7, monkeys dosed with 60 mg/kg everninomicin alone also developed renal lesions, while the group exposed to both compounds had more extensive renal damage. The modulation of several genes previously reported to be associated with nephrotoxicity in rodent models was confirmed using quantitative real-time PCR. Among these, waf-1, matrix metalloproteinase-9, and vimentin exhibited changes consistent with the definition of a genomic indicator of toxicity. In addition, we identified three early gene biomarkers that may be predictive of drug-induced nephrotoxicity: clusterin, osteopontin, and hepatitis A virus cellular receptor-1. Logistic regression demonstrated a high degree of correlation between changes in gene expression and the probability of the development of histopathologic lesions. These results are the first confirming rodent gene expression changes associated with nephrotoxicity in a nonhuman primate model and provide preliminary evidence for identifying early gene expression changes predicting the onset of drug-induced renal tubular damage in cynomolgus monkeys.