Derivation of Mortal Injury Metric for Studies of Rapid Decompression of Depth-Acclimated Physostomous Fish

In 2005 the U.S. Army Corps of Engineers (USACE) began a study to investigate the response of hatchery and run-of-the-river (ROR) juvenile Chinook salmon to the effects of rapid decompression during passage through mainstem Federal Columbia River Power System (FCRPS) Kaplan turbines. In laboratory studies conducted by Pacific Northwest National Laboratory (PNNL) for USACE since 2005, juvenile fish have been exposed to rapid decompression in a barometric pressure chamber. An initial study considered the response of juvenile Chinook salmon bearing radio transmitters to rapid decompression resulting from exposure to a pressure time history simulating the worst case condition that might be experienced during passage through an operating turbine. The study in 2005 found that acclimation depth was a very important treatment factor that greatly influenced the significantly higher incidence of injury and mortality of rapidly decompressed Chinook salmon bearing radio telemetry devices. In 2006 we initiated a statistical investigation using data in hand into derivation of a new end-point measure for assessment of the physiological response of juvenile Chinook salmon to rapid decompression. Our goal was a measure that would more fully utilize both mortality and injury data while providing a better assessment of the most likely survival outcome for juvenile physostomous fish exposed to rapid decompression. The conclusion of the analysis process was to classify fish as mortally injured when any of the 8 injuries are present, regardless of whether the fish was last observed alive or not. The mortally injured classification has replaced mortality as the end point metric for our rapid decompression studies. The process described in this report is an example of how a data set may be analyzed to identify decision criterion for objective classification of test fish to a specific end-point. The resulting list of 8 mortal injuries is applicable to assess injuries from rapid decompression and is currently being applied to ongoing studies. We intend to update this analysis as more data becomes available and to extend it to ROR Chinook salmon smolt. The method itself is applicable to other injury and mortality data for juvenile salmonids from laboratory and field studies related to all dam passage routes and for collision, strike, and shear injuries in addition to decompression

Chromium Toxicity Test for Fall Chinook Salmon (Oncorhynchus tshawytscha) Using Hanford Site Groundwater: Onsite Early Life-Stage Toxicity Evaluation

The objective of this study was to evaluate site-specific effects for early life-stage (eyed eggs to free swimming juveniles) fall chinook salmon that might be exposed to hexavalent chromium from Hanford groundwater sources. Our exposure conditions included hexavalent chromium obtained from Hanford groundwater wells near the Columbia River, Columbia River water as the diluent, and locally adapted populations of fall chinook salmon. This report describes both a 96-hr pretest using rainbow trout eggs and an early life-stage test beginning with chinook salmon eggs

Low Probability Tail Event Analysis and Mitigation in the BPA Control Area

This report investigated the uncertainties with the operations of the power system and their contributions to tail events, especially under high penetration of wind. A Bayesian network model is established to quantify the impact of these uncertainties on system imbalance. The framework is presented for a decision support tool, which can help system operators better estimate the need for balancing reserves and prepare for tail events

Implementing telephone triage in general practice: a process evaluation of a cluster randomised controlled trial

Background: Telephone triage represents one strategy to manage demand for face-to-face GP appointments in primary care. However, limited evidence exists of the challenges GP practices face in implementing telephone triage. We conducted a qualitative process evaluation alongside a UK-based cluster randomised trial (ESTEEM) which compared the impact of GP-led and nurse-led telephone triage with usual care on primary care workload, cost, patient experience, and safety for patients requesting a same-day GP consultation. The aim of the process study was to provide insights into the observed effects of the ESTEEM trial from the perspectives of staff and patients, and to specify the circumstances under which triage is likely to be successfully implemented. Here we report perspectives of staff. Methods: The intervention comprised implementation of either GP-led or nurse-led telephone triage for a period of 2-3 months. A qualitative evaluation was conducted using staff interviews recruited from eight general practices (4 GP triage, 4 Nurse triage) in the UK, implementing triage as part of the ESTEEM trial. Qualitative interviews were undertaken with 44 staff members in GP triage and nurse triage practices (16 GPs, 8 nurses, 7 practice managers, 13 administrative staff). Results: Staff reported diverse experiences and perceptions regarding the implementation of telephone triage, its effects on workload, and on the benefits of triage. Such diversity were explained by the different ways triage was organised, the staffing models used to support triage, how the introduction of triage was communicated across practice staff, and by how staff roles were reconfigured as a result of implementing triage. Conclusion: The findings from the process evaluation offer insight into the range of ways GP practices participating in ESTEEM implemented telephone triage, and the circumstances under which telephone triage can be successfully implemented beyond the context of a clinical trial. Staff experiences and perceptions of telephone triage are shaped by the way practices communicate with staff, prepare for and sustain the changes required to implement triage effectively, as well as by existing practice culture, and staff and patient behaviour arising in response to the changes made. Trial registration: Current Controlled Trials ISRCTN20687662. Registered 28 May 2009

Assessment of Barotrauma Resulting from Rapid Decompression of Depth Acclimated Juvenile Chinook Salmon Bearing Radio Telemetry Transmitters

A multifactor study was conducted by Battelle for the US Army Corps of Engineers to assess the significance of the presence of a radio telemetry transmitter on the effects of rapid decompression from simulated hydro turbine passage on depth acclimated juvenile run-of-the-river Chinook salmon. Study factors were: (1) juvenile chinook salmon age;, subyearling or yearling, (2) radio transmitter present or absent, (3) three transmitter implantation factors: gastric, surgical, and no transmitter, and (4) four acclimation depth factors: 1, 10, 20, and 40 foot submergence equivalent absolute pressure, for a total of 48 unique treatments. Exposed fish were examined for changes in behavior, presence or absence of barotrauma injuries, and immediate or delayed mortality. Logistic models were used to test hypotheses that addressed study objectives. The presence of a radio transmitter was found to significantly increase the risk of barotrauma injury and mortality at exposure to rapid decompression. Gastric implantation was found to present a higher risk than surgical implantation. Fish were exposed within 48 hours of transmitter implantation so surgical incisions were not completely healed. The difference in results obtained for gastric and surgical implantation methods may be the result of study design and the results may have been different if tested fish had completely healed surgical wounds. However, the test did simulate the typical surgical-release time frame for in-river telemetry studies of fish survival so the results are probably representative for fish passing through a turbine shortly following release into the river. The finding of a significant difference in response to rapid decompression between fish bearing radio transmitters and those not implies a bias may exist in estimates of turbine passage survival obtained using radio telemetry. However, the rapid decompression (simulated turbine passage) conditions used for the study represented near worst case exposure for fish passing through turbines. At this time, insufficient data exist about the distribution of river-run fish entering turbines, and particularly, the distribution of fish passing through turbine runners, to extrapolate study findings to the population of fish passing through FCRPS turbines. This study is the first study examining rapid decompression study to include acclimation depth as an experimental factor for physostomous fish. We found that fish acclimated to deeper depth were significantly more vulnerable to barotrauma injury and death. Insufficient information about the distribution of fish entering turbines and their depth acclimation currently exists to extrapolate these findings to the population of fish passing through turbines. However, the risk of barotrauma for turbine-passed fish could be particularly high for subyearling Chinook salmon that migrate downstream at deeper depths late in the early summer portion of the outmigration. Barotrauma injuries led to immediate mortality delayed mortality and potential mortality due to increased susceptibility to predation resulting from loss of equilibrium or swim bladder rupture

Daily and Nondaily Oral Preexposure Prophylaxis in Men and Transgender Women Who Have Sex With Men: The Human Immunodeficiency Virus Prevention Trials Network 067/ADAPT Study

Background: Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. Methods: At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time-driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self-report, drug concentrations, and electronic drug monitoring. Results: From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of ≥2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time-driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. Conclusions: Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment

Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066)

Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4+ TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/106 PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes

Copper binding to the Alzheimer’s disease amyloid precursor protein

Alzheimer’s disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called Aβ by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce Aβ levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in Aβ production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer’s disease

Can We Systematically Review Studies That Evaluate Complex Interventions?

In three Viewpoints, Sasha Shepperd and colleagues, Geoff Wong, and Aziz Sheikh explore various approaches to help systematic reviewers who wish to review complex health interventions

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability