Recombinant Mitochondrial Transcription Factor A with N-terminal Mitochondrial Transduction Domain Increases Respiration and Mitochondrial Gene Expression in G11778A Leber's Hereditary Optic Neuropathy Cybrid Cells

Diseases involving mitochondrial defects usually manifest themselves in high-energy, post-mitotic tissues such as brain, retina, skeletal and cardiac muscle and frequently cause deficiencies in mitochondrial bioenergetics. We have developed a scalable procedure to produce recombinant human mitochondrial transcription factor A (TFAM) modified with an N-terminal protein transduction domain (PTD) and mitochondrial localization signal (MLS) that allow it to cross membranes and enter mitochondria through its "mitochondrial transduction domain" (MTD,=PTD+MLS). _In vitro_ studies in a classic mitochondrial disease cell model demonstrated that Alexa488-labeled MTD-TFAM rapidly entered the mitochondrial compartment. MTD-TFAM treatment of these cell lines reversibly increased oxygen consumption (respiration) rates 3-fold, levels of respiratory proteins and mitochondrial gene expression. _In vivo_ results demonstrated that respiration increased to lesser degrees in mitochondria from tissues of mice injected with MTD-TFAM. MTD-TFAM can alter mitochondrial bioenergetics and holds promise for treatment of mitochondrial diseases involving deficiencies of energy production

Management control systems in not-for-profit organizations: a case study

Management control has been defined as "the process by which management assures that an organization carries out its strategies effectively and efficiently." Rapidly rising costs evidenced over the past decade have resulted in increased emphasis on these qualities in all organizations, particularly those in the public sector or similar nonprofit, service-oriented organizations where management controls have historically been lacking. This thesis investigates the requirement for and feasibility of developing a formal management control systems in these organizations. The key traits, characteristics and standards important to management control are developed from a literature survey and contrasted against procedures identified in a field study as existing in a nonprofit organization. The authors conclude that a requirement for a formal management control system exists and make recommendations for implementing such a system utilizing tailored output measures and a program budget structure.http://archive.org/details/managementcontro00beneCommander, United States NavyLieutenant Commander, United States NavyApproved for public release; distribution is unlimited

Quantifying injury to common bottlenose dolphins from the Deepwater Horizon oil spill using an age-, sex- and class-structured population model

Field studies documented increased mortality, adverse health effects, and reproductive failure in common bottlenose dolphins Tursiops truncatus following the Deepwater Horizon (DWH) oil spill. In order to determine the appropriate type and amount of restoration needed to compensate for losses, the overall extent of injuries to dolphins had to be quantified. Simply counting dead individuals does not consider long-term impacts to populations, such as the loss of future reproductive potential from mortality of females, or the chronic health effects that continue to compromise survival long after acute effects subside. Therefore, we constructed a sex- and agestructured model of population growth and included additional class structure to represent dolphins exposed and unexposed to DWH oil. The model was applied for multiple stocks to predict injured population trajectories using estimates of post-spill survival and reproductive rates. Injured trajectories were compared to baseline trajectories that were expected had the DWH incident not occurred. Two principal measures of injury were computed: (1) lost cetacean years (LCY); the difference between baseline and injured population size, summed over the modeled time period, and (2) time to recovery; the number of years for the stock to recover to within 95% of baseline. For the dolphin stock in Barataria Bay, Louisiana, the estimated LCY was substantial: 30 347 LCY (95% CI: 11 511 to 89 746). Estimated time to recovery was 39 yr (95% CI: 24 to 80). Similar recovery timelines were predicted for stocks in the Mississippi River Delta, Mississippi Sound, Mobile Bay and the Northern Coastal Stock.Publisher PDFPeer reviewe

Factors influencing COVID-19 testing among Native Americans and Latinos in two rural agricultural communities: a qualitative study

ObjectiveTo examine factors influencing decisions to test for COVID-19 among Native Americans on the Flathead Reservation in Montana and the Latino community in the Yakima Valley of Washington state.MethodsWe conducted 30 key informant interviews with community leaders and six focus groups with community members to examine factors impacting decisions to test for COVID-19 during the second year of the COVID-19 pandemic from May 2021 to June 2021.ResultsThree major themes that impacted testing for COVID-19 were identified: (1) Social factors, including the influence of families and friends and employment practices; (2) health factors, including testing procedures, home-based testing, and health communication; and (3) contextual factors, including distrust for government and medical communities and the impact on cultural practices and celebrations.ConclusionsSocial, health, and contextual factors influence the decision to test for COVID-19. Understanding the community's perception is critical for successful implementation of preventive strategies

Factors Associated with Physician Agreement on Verbal Autopsy of over 11500 Injury Deaths in India

Worldwide, injuries account for 9.8% of all deaths. The majority of these deaths occur in low- and middle-income countries where vital registration systems are often inadequate. Verbal autopsy (VA) is a tool used to ascertain cause of death in such settings. Validation studies for VA using hospital diagnosed causes of death as comparisons have shown that injury deaths can be reliably diagnosed by VA. However, no study has assessed the factors that may affect physicians' abilities to code specific causes of injury death using VA.This study used data from over 11 500 verbal autopsies of injury deaths from the Million Death Study (MDS) in which 6.3 million people in India were monitored from 2001–2003 for vital events. Deaths that occurred in the MDS were coded by two independent physicians. This study focused on whether physician agreement on the classification of injury deaths was affected by characteristics of the deceased and respondent. Agreement was analyzed using three primary methods: 1) kappa statistic; 2) sensitivity and specificity analysis using the final VA diagnosed category of injury death as gold standard; and 3) multivariate logistic regression using a conceptual hierarchical model. The overall agreement for all injury deaths was 77.9% with a kappa of 0.74 (99% CI 0.74–0.75). Deaths in the injury categories of “transport”, “falls”, “drowning” and “other unintentional injury” occurring outside the home were associated with greater physician agreement than those occurring at home. In contrast, self-inflicted injury deaths that occurred outside the home were associated with lower physician agreement.With few exceptions, most characteristics of the deceased and the respondent did not influence physician agreement on the classification of injury deaths. Physician training and continued adaptation of the VA tool should focus on the reasons these factors influenced physician agreement

'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

An expert-based system to predict population survival rate from health data

This work was supported by the Office of Naval Research Marine Mammal Biology Program [grant number N00014-17-1-2868].Timely detection and understanding of causes for population decline are essential for effective wildlife management and conservation. Assessing trends in population size has been the standard approach but we propose that monitoring population health could prove more effective. We collated data from seven bottlenose dolphin (Tursiops truncatus) populations in southeastern U.S. to develop the Veterinary Expert System for Outcome Prediction (VESOP), which estimates survival probability using a suite of health measures identified by experts as indices for inflammatory, metabolic, pulmonary, and neuroendocrine systems. VESOP was implemented using logistic regression within a Bayesian analysis framework, and parameters were fit using records from five of the sites that had a robust stranding network and frequent photographic identification (photo-ID) surveys to document definitive survival outcomes. We also conducted capture-mark-recapture (CMR) analyses of photo-ID data to obtain separate estimates of population survival rates for comparison with VESOP survival estimates. VESOP analyses found multiple measures of health, particularly markers of inflammation, were predictive of 1- and 2-year individual survival. The highest mortality risk one year following health assessment related to low alkaline phosphatase, with an odds ratio of 10.2 (95% CI 3.41-26.8), while 2-year mortality was most influenced by elevated globulin (9.60; 95% CI 3.88-22.4); both are markers of inflammation. The VESOP model predicted population-level survival rates that correlated with estimated survival rates from CMR analyses for the same populations (1-year Pearson's r = 0.99; p = 1.52e-05, 2-year r = 0.94; p = 0.001). While our proposed approach will not detect acute mortality threats that are largely independent of animal health, such as harmful algal blooms, it is applicable for detecting chronic health conditions that increase mortality risk. Random sampling of the population is important and advancement in remote sampling methods could facilitate more random selection of subjects, obtainment of larger sample sizes, and extension of the approach to other wildlife species.Publisher PDFPeer reviewe

Modeling population effects of the Deepwater Horizon oil spill on a long-lived species

This research was enabled partly by a grant from The Gulf of Mexico Research Initiative (GOMRI).The 2010 Deepwater Horizon (DWH) oil spill exposed common bottlenose dolphins (Tursiops truncatus) in Barataria Bay, Louisiana to heavy oiling that caused increased mortality and chronic disease and impaired reproduction in surviving dolphins. We conducted photographic surveys and veterinary assessments in the decade following the spill. We assigned a prognostic score (good, fair, guarded, poor, or grave) for each dolphin to provide a single integrated indicator of overall health, and we examined temporal trends in prognostic scores. We used expert elicitation to quantify the implications of trends for the proportion of the dolphins that would recover within their lifetime. We integrated expert elicitation, along with other new information, in a population dynamics model to predict the effects of observed health trends on demography. We compared the resulting population trajectory with that predicted under baseline (no spill) conditions. Disease conditions persisted and have recently worsened in dolphins that were presumably exposed to DWH oil: 78% of those assessed in 2018 had a guarded, poor, or grave prognosis. Dolphins born after the spill were in better health. We estimated that the population declined by 45% (95% CI 14–74) relative to baseline and will take 35 years (95% CI 18–67) to recover to 95% of baseline numbers. The sum of annual differences between baseline and injured population sizes (i.e., the lost cetacean years) was 30,993 (95% CI 6607–94,148). The population is currently at a minimum point in its recovery trajectory and is vulnerable to emerging threats, including planned ecosystem restoration efforts that are likely to be detrimental to the dolphins’ survival. Our modeling framework demonstrates an approach for integrating different sources and types of data, highlights the utility of expert elicitation for indeterminable input parameters, and emphasizes the importance of considering and monitoring long-term health of long-lived species subject to environmental disasters. Article impact statement: Oil spills can have long-term consequences for the health of long-lived species; thus, effective restoration and monitoring are needed.Publisher PDFPeer reviewe

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix