In Vitro Antimicrobial Properties and Their Mechanisms in Relation to Reactive Oxygen Species of Canine Platelet-Rich Fibrin.

Platelet-rich fibrin (PRF), which has been shown to promote wound and bone regeneration, has demonstrated antimicrobial properties against periodontal pathogens. However, in veterinary medicine, no study has determined the antimicrobial effects of canine platelet-rich fibrin (cPRF). Therefore, this study aimed to determine the antimicrobial effect of cPRF against E. coli and S. pseudintermedius found in dogs' wounds and against the standard strain S. aureus. Additionally, the mechanism of the existing antibacterial activity of cPRF, which involves the formation of reactive oxygen species (ROS), was tested. Blood samples from six dogs were processed for cPRF. The antimicrobial properties of three groups (growth control, cPRF, and drug control) were evaluated at 0.5, 4, 8, and 24 h using a time-kill assay. The killing mechanisms involving ROS were evaluated using horseradish peroxidase (HRP) to suppress ROS production in PRF (PRF-SR). Subsequently, tests for antimicrobial properties and ROS generation were compared to those of the growth control and cPRF groups. The results showed that cPRF had significant antimicrobial properties against E. coli but no antimicrobial properties against S. pseudintermedius. After the ROS suppression, PRF-SR did not show an antimicrobial property against E. coli. Moreover, cPRF-treated bacteria exhibited significantly greater intracellular ROS than PRF-SR. In conclusion, canine PRF showed an antimicrobial effect against E. coli, and its antibacterial mechanism was related to releasing ROS.

Proximity of Water Wells to Public Water Testing Facilities in Alberta Using Drive Times.

Approximately 10% of Albertans rely on well water for domestic purposes. The responsibility of water testing and stewardship is left to private well owners. Few well water owners conduct routine testing of their well water supplies. Drive times to public water testing facilities may be an important factor limiting a well owner's ability to conduct routine water testing. The objective of this study is to describe the proximity of water wells, using drive times, to public water testing facilities and describe the availability of facilities based on hours of operation. Using network analysis, we determined the proportion of a sample of wells within 3 estimated drive times of public water testing facilities. 5872 wells were included in the sample. One hundred and seven water testing facilities were mapped within the province. Of the 5872 wells mapped, 89% were located within 30 minutes of a water testing facility, 15% were located within 0 to 10 minutes of a water testing facility, 48% were located between 10 and 20 minutes of a water testing facility and 37% were located within 20 to 30 minutes of a water testing facility. Further analysis revealed that access to water testing facilities may be influenced by the hours of operation of the facilities.

Economic premiums associated with Mycobacterium avium ssp. paratuberculosis-negative replacement purchases in major dairy-producing regions.

Johne's disease, or paratuberculosis, is an infectious disorder of the intestines that can affect domestic and wild ruminants that is caused by an infection with Mycobacterium avium ssp. paratuberculosis (MAP). Although the economic losses due to Johne's disease in dairy cattle herds and the benefits and costs of various potential control practices have been estimated before, little is known about the economic value of purchasing MAP-negative dairy replacements in major dairy-producing regions. This study used Markov Chain Monte Carlo simulation techniques to compare 2 sets of MAP-negative and MAP-positive herds across a comprehensive selection of regions: herds purchasing MAP-negative replacement animals and herds purchasing replacement animals with unknown MAP infection status. The economic benefits per MAP-negative replacement purchased were then estimated over a 10-yr horizon, and the additional value of MAP-negative replacements when compared with unknown status replacements were calculated as a percentage premium of the average aggregated dairy replacement price in each region. An average benefit of US$76 per MAP-negative replacement purchase was estimated in major dairy-producing regions, equivalent to a premium of 13%, with higher premiums in regions characterized by below-average replacement prices and on-average farm-gate prices. It was also estimated that the greatest benefits from MAP-negative replacement purchases are associated with MAP-negative herds that successfully remain uninfected.

The Impact of Experiences and Perceptions of Highly Pathogenic Avian Influenza (HPAI) on Water-Related Biosecurity Behaviour in Rural Vietnam.

BACKGROUND: In Southeast Asia from 2004 to 2006, highly pathogenic avian influenza (HPAI) resulted in culling 45 million birds and jeopardizing sustainable agricultural production. HPAI is highly virulent; small-scale farms present a high-risk environment for disease transmission between animals and humans. We investigated how attitudes toward HPAI influence water-related biosecurity mitigation behaviors on small-scale farms in Vietnam using the conceptual framework Social Cognitive Theory. METHOD: We analyzed a secondary cross-sectional data set from northern (Thai Binh) and southern (An Giang) provinces in Vietnam, describing a stratified randomized selection of 600 small-scale farmers who were interviewed using questionnaires and in-person interviews. Logistic regression analysis and odds ratios were used to examine relationships between factors influencing HPAI attitudes, social norms, perceived importance, and behaviors (α = 0.10) RESULTS: Concern about the severity of HPAI was significantly associated with increased perceived importance for all water management biosecurity methods (p < 0.01). Media and/or peer influence had negative effects on perceived importance to practice water-related biosecurity (p < 0.10). High importance of practice water-related biosecurity resulted in high uptake (p < 0.05). Past experiences with HPAI were significant in predicting perceived importance; none were significant in describing behavior uptake. DISCUSSION: Biosecurity guidelines may not be consistent with management styles of Vietnamese small-scale farms; perceived importance of a behavior may be an important mediating variable. Gaps exist in uptake of water management practices as biosecurity for HPAI, potentially negatively affected by peer and media influence. Our results should be of interest to public health and policy authorities addressing HPAI mitigation.

Corrigendum: Effectiveness and Economic Viability of Johne's Disease (Paratuberculosis) Control Practices in Dairy Herds.

[This corrects the article DOI: 10.3389/fvets.2020.614727.].

Estimation of the value of Johne's disease (paratuberculosis) control to Canadian dairy producers.

Johne's disease (JD), or paratuberculosis, is an infectious disorder primarily associated with cattle and sheep and resulting in significant economic losses for dairy producers. The dairy cattle herd-level prevalence in Canada has recently been estimated to be greater than 40%, but the willingness to pay for JD control practices such as testing-and-culling and vaccination among Canadian dairy producers is unknown. This study used confidential cost-of-production data from the Canadian Dairy Commission to develop a Canadian dairy production model incorporating feed, land, labor, and machinery. A second dataset from a nationally distributed questionnaire (closed in March 2020) was used to estimate individual dairy producer valuations of the reduced per-cow cost of milk production that would result from JD control. This is a novel application of compensating variation and equivalent variation (CV and EV), with dairy producers framed as consumers of production inputs and milk output as a proxy for utility. Assuming a within-herd prevalence of 12.5% and a 50% reduction of that prevalence over 10 years, it was estimated JD control has an annual value of CA$28 per cow for the average Canadian dairy producer. Within-herd prevalence, the effectiveness of control at reducing within-herd prevalence, and the time required to achieve that reduction were identified as important factors. With the same assumption of 12.5% within-herd prevalence but with 100% reductions in that prevalence, estimated values ranged from over CA$55 to over CA$90 per cow per year depending on the timeframe of the control program. When assuming a 10-year period required to achieve control, the estimated values exceeded CA$90 per cow per year in various scenarios for herds with higher within-herd prevalence (greater than 20%).

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. PATIENTS AND METHODS: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. RESULTS: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%-34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. CONCLUSIONS: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.See related commentary by Schulte and Eggert, p. 3507.

Economic losses due to Johne's disease (paratuberculosis) in dairy cattle.

Johne's disease (JD), or paratuberculosis, is an infectious inflammatory disorder of the intestines primarily associated with domestic and wild ruminants including dairy cattle. The disease, caused by an infection with Mycobacterium avium subspecies paratuberculosis (MAP) bacteria, burdens both animals and producers through reduced milk production, premature culling, and reduced salvage values among MAP-infected animals. The economic losses associated with these burdens have been measured before, but not across a comprehensive selection of major dairy-producing regions within a single methodological framework. This study uses a Markov chain Monte Carlo approach to estimate the annual losses per cow within MAP-infected herds and the total regional losses due to JD by simulating the spread and economic impact of the disease with region-specific economic variables. It was estimated that approximately 1% of gross milk revenue, equivalent to US$33 per cow, is lost annually in MAP-infected dairy herds, with those losses primarily driven by reduced production and being higher in regions characterized by above-average farm-gate milk prices and production per cow. An estimated US$198 million is lost due to JD in dairy cattle in the United States annually, US$75 million in Germany, US$56 million in France, US$54 million in New Zealand, and between US$17 million and US$28 million in Canada, one of the smallest dairy-producing regions modeled.

Variations in the profitability of dairy farms in Victoria, Australia by different levels of engagement in bovine Johne's disease control.

Paratuberculosis or Johne's disease (JD) prevalence in Australia is low at the cow-level with varying herd-level prevalence. Control strategies incorporating vaccination are limited, suggesting opportunities for changes in regulatory oversight. In order to study this further, we examined the economic benefits of participation in JD control programmes in Australia with and without vaccination as well as knowledge, attitudes, and practices (KAP) relating to JD. We used an online questionnaire to gather information describing demographics and KAP from 71 Australian dairy farms. Data from fully completed questionnaires from 32 farms in Victoria, Australia combined with cost and revenue data averaged from several years of the Dairy Farm Monitor Project were used to then simulate a larger robust dataset. These production data informed the simulation model to establish farm profitability. A partial farm budget was then developed to estimate the benefits of engaging in JD control activities. Respondents who stated they participated in JD control programmes gained an additional $43.80/cow/year net income (profit) compared to non-participants. Respondents also using a JD vaccine gained an additional $35.84/cow/year over non-users; this represents $10.56/cow/year over and above the average producer in the industry. However, we also noted that there clearly exists a barrier between farmers stated intentions to participate and actual participation in JD control activities. These significant differences in net income realized by farms using different approaches to JD control (in this case, adoption of vaccination) offer a starting point from which to explore questions of how much farmers would be willing to pay for control activities, why they are willing to pay, and the likelihood of participating. Communication of the benefits of participation needs to improve to bridge this gap between farmers stated intentions and their actions. Simulation modelling suggests increased profitability from participation in JD control programs and vaccination in Australia. The JD regulatory policies of other countries may benefit from the Australian experience with JD control.

Perspectives on the model-based approach to proton therapy trials: A retrospective study of a lung cancer randomized trial.

PURPOSE: The goal of this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. METHODS AND MATERIALS: A model-based approach, based on three widely used normal tissue complication probability (NTCP) models for radiation pneumonitis (RP), was applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected ΔNTCP value was above a threshold of 5%. The endpoint chosen matched that of the original trial, the first occurrence of severe (grade ≥3) RP. RESULTS: Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for lung cancer using RP as the normal tissue endpoint. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. This result does show limitations in NTCP models which would affect the success of a model-based trial approach. No conclusion regarding the development of RP in patients randomized by the model-based approach could statistically be made. CONCLUSIONS: Uncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. The impact of these uncertainties on enrollment in model-based trials depends on the predicted difference between the two treatment arms and on the set threshold for patient stratification. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint.

Exploring Well Water Testing Behaviour Through the Health Belief Model.

Health problems can arise from consuming contaminated well water. Well water testing can help prevent negative health outcomes associated with consuming contaminated water. The aim of this study was to understand the factors influencing well owner decisions to conduct water testing through the theoretical lens of the Health Belief Model. We conducted semi-structured interviews with 20 well owners and used framework analysis to sort and analyse the data. The results demonstrated that well owners' perceived susceptibility to well water contamination was low, while the perceived severity of contamination, benefits of testing, and self-efficacy towards testing were high. Cues to action to promote testing focused on increasing well owner education and awareness through well stewardship programmes and reminders to test. Participants faced some barriers to water testing. Increasing education and awareness about well water contamination and water testing, while reducing logistical barriers to testing, may improve compliance with water testing.

Effectiveness and Economic Viability of Johne's Disease (Paratuberculosis) Control Practices in Dairy Herds.

Johne's disease (JD or paratuberculosis) control programs have been established in many dairy-producing regions. However, the effectiveness (reduction of within-herd prevalence) and the relative economic impact as measured by, for example, the ratio of benefits to costs (BCR) across a comprehensive selection of regions and potential control practices require further investigation. Within a Markovian framework using region-specific economic variables, it was estimated that vaccination was the most promising type of JD control practice modeled, with dual-effect vaccines (reducing shedding and providing protective immunity) having BCRs between 1.48 and 2.13 in Canada, with a break-even period of between 6.17 and 7.61 years. Dual-effect vaccines were also estimated to yield BCRs greater than one in almost all major dairy-producing regions, with greater ratios in regions characterized by above-average farm-gate prices and annual production per cow. Testing and culling was comparably effective to a dual-effect vaccine at test sensitivities >70% but would remain economically unviable in almost all regions modeled.

Factors influencing perceptions of private water quality in North America: a systematic review.

BACKGROUND: An estimated four million and 43 million people in Canada and the USA use private water supplies. Private water supplies are vulnerable to waterborne disease outbreaks. Private water supplies in Canada and the USA are often unregulated and private water management is often a choice left to the owner. Perceptions of water quality become important in influencing the adoption of private water stewardship practices, therefore safeguarding public health. METHODS: We conducted a systematic literature review to understand factors that shape perceptions of water quality among private water users. We searched six computer databases (Web of science, Medline, Scopus, EBSCO, PubMed and Agricola). The search was limited to primary peer-reviewed publications, grey literature and excluded conference proceedings, review articles, and non-peer review articles. We restricted the search to papers published in English and to articles which published data on surveys of private water users within Canada and the USA. The search was also restricted to publications from 1986 to 2017. The literature search generated 36,478 records. Two hundred and four full text were reviewed. RESULTS: Fifty-two articles were included in the final review. Several factors were found to influence perceptions of water quality including organoleptic preferences, chemical and microbiological contaminants, perceived risks, water well infrastructure, past experience with water quality, external information, demographics, in addition to the values, attitudes, and beliefs held by well owners. CONCLUSIONS: Understanding the factors that shape perceptions of water quality among private water users is an important step in developing private water management policies to increase compliance towards water testing and treatment in Canada and the USA. As many jurisdictions in Canada and the USA do not have mandatory private water testing or treatment guidelines, delineating these factors is an important step in informing future research and guiding policy on the public health of private water systems.

Factors Influencing Mitigation of Risk of Waterborne Disease in Vietnam Among Small Scale Integrated Livestock Farmers.

The integrated livestock, crops, and fish (VAC) model of integrated small scale agriculture has been important to economic and ecological sustainability in Vietnam for many centuries. Recently, emerging waterborne diseases including avian influenza as well as the potential for zoonotic disease arising from small scale farms have jeopardized the VAC model. In order to promote mitigation of the risk of waterborne and other diseases in the VAC system, there needs to be recognition of the significant predictors of such behavior, particularly with respect to water sources including well and rain water. We report primarily quantitative results of research generated from 300 farms in each of North and South Vietnam that indicate the small scale farmers who are more likely to engage in mitigation of waterborne disease are those who raise pigs, perceive themselves to be more at risk of HPAI infection from well water, report they are good livestock managers, value the advice of health care workers, and where a female household member is the decision maker for family health. These results bear importance to water and health policy formulators in rural Vietnam. (JEL I130, I180, O130, Q180, Q570). JEL CLASSIFICATIONS: I130: Health and economic developmentI180: Public healthO130: Economic Development: Agriculture; EnvironmentQ180: Agricultural policy; Food policyQ570: Ecological economics: biodiversity conservation.

Use of Bayesian networks in predicting contamination of drinking water with E. coli in rural Vietnam.

Background: More than 70 million Vietnamese rely on small-scale farming for some form of household income. Water on many of those farms is contaminated with waste, including animal manure, partly due to non-sustainable waste management. This increases the risk of water-related zoonotic disease transmission. The purpose of this research was to examine the impact of various demographic and management factors on the likelihood of finding Escherichia coli in drinking water sourced from wells and rainwater on farms in Vietnam. Methods: A Bayesian Belief Network (BBN) was designed to describe association between various deterministic and probabilistic variables gathered from 600 small-scale integrated (SSI) farmers in Vietnam. The variables relate to E. coli content of their drinking water sourced on-farm from wells and rainwater, and stored in on-farm large vessels, including concrete water tanks. The BBN was developed using the Netica software tool; the model was calibrated and goodness of fit examined using concordance of predictability. Results: Sensitivity analysis of the model revealed that choice variables, including engagement in mitigation of water contamination and livestock management activities, were particularly likely to influence endpoint values, reflecting the highly variable and impactful nature of preferences, attitudes and beliefs relating to mitigation strategies. Quantitative variables including numbers of livestock (particularly chickens) and income also had a high impact. The highest concordance (62%) was achieved with the BBN reported in this paper. Conclusions: This BBN model of SSI farming in Vietnam is helpful in understanding the complexity of small-scale agriculture and how various factors work in concert to influence contamination of on-farm drinking water as indicated by the presence of E. coli. The model will also be useful for identifying and estimating the impact of policy options such as improved delivery of clean water management training for rural areas, particularly where such analysis is combined with other analytical and policy tools. With appropriate knowledge translation, the model results will be particularly useful in helping SSI farmers understand their options for engaging in public health mitigation strategies addressing clean water that do not significantly disrupt their agriculture-based livelihoods.

Predicting Patient-specific Dosimetric Benefits of Proton Therapy for Skull-base Tumors Using a Geometric Knowledge-based Method.

PURPOSE: To predict the organ at risk (OAR) dose levels achievable with proton beam therapy (PBT), solely based on the geometric arrangement of the target volume in relation to the OARs. A comparison with an alternative therapy yields a prediction of the patient-specific benefits offered by PBT. This could enable physicians at hospitals without proton capabilities to make a better-informed referral decision or aid patient selection in model-based clinical trials. METHODS AND MATERIALS: Skull-base tumors were chosen to test the method, owing to their geometric complexity and multitude of nearby OARs. By exploiting the correlations between the dose and distance-to-target in existing PBT plans, the models were independently trained for 6 types of OARs: brainstem, cochlea, optic chiasm, optic nerve, parotid gland, and spinal cord. Once trained, the models could estimate the feasible dose-volume histogram and generalized equivalent uniform dose (gEUD) for OAR structures of new patients. The models were trained using 20 patients and validated using an additional 21 patients. Validation was achieved by comparing the predicted gEUD to that of the actual PBT plan. RESULTS: The predicted and planned gEUD were in good agreement. Considering all OARs, the prediction error was +1.4 ± 5.1 Gy (mean ± standard deviation), and Pearson's correlation coefficient was 93%. By comparing with an intensity modulated photon treatment plan, the model could classify whether an OAR structure would experience a gain, with a sensitivity of 93% (95% confidence interval: 87%-97%) and specificity of 63% (95% confidence interval: 38%-84%). CONCLUSIONS: We trained and validated models that could quickly and accurately predict the patient-specific benefits of PBT for skull-base tumors. Similar models could be developed for other tumor sites. Such models will be useful when an estimation of the feasible benefits of PBT is desired but the experience and/or resources required for treatment planning are unavailable.

Validation of nuclear models in Geant4 using the dose distribution of a 177 MeV proton pencil beam.

A proton pencil beam is associated with a surrounding low-dose envelope, originating from nuclear interactions. It is important for treatment planning systems to accurately model this envelope when performing dose calculations for pencil beam scanning treatments, and Monte Carlo (MC) codes are commonly used for this purpose. This work aims to validate the nuclear models employed by the Geant4 MC code, by comparing the simulated absolute dose distribution to a recent experiment of a 177 MeV proton pencil beam stopping in water. Striking agreement is observed over five orders of magnitude, with both the shape and normalisation well modelled. The normalisations of two depth dose curves are lower than experiment, though this could be explained by an experimental positioning error. The Geant4 neutron production model is also verified in the distal region. The entrance dose is poorly modelled, suggesting an unaccounted upstream source of low-energy protons. Recommendations are given for a follow-up experiment which could resolve these issues.

A basic strategy to manage global health with reference to livestock production in Asia.

Newly emerging infectious diseases (nEIDs) have increased rapidly presenting alarming challenges to global health. We argue that for effective management of global health a basic strategy should include at least three essential tactical forms: actions of a directly focused nature, institutional coordination, and disciplinary integration in approaches to health management. Each level of action is illustrated with examples from the livestock sector in Asia. No clear example of all three tactical forms in place can be found from developing countries where food security is a significant threat although Vietnam is developing a comprehensive strategy. Finally, an ecosystem health approach to global health management is advocated; such an approach moves away from the traditional single disciplinary approach. Stronger guidance is needed to direct ecohealth research and application in the management of global health.

Glioblastoma with signet-ring morphology: a case report and review of the literature.

Primary central nervous system tumors with signet-ring morphology are exceedingly rare. We report an unusual case of glioblastoma with signet-ring cell features in an 81-year-old woman. Microscopic examination revealed a highly anaplastic tumor, with a prominent proportion of tumor cells exhibiting signet-ring appearance characterized by classic round cytoplasmic inclusions and eccentrically positioned nuclei. The tumor cells were immunoreactive for glial fibrillary acidic protein and S100, and negative for cytokeratins, confirming their glial origin. Ultrastructurally, the tumor cells were noted to contain intermediate filaments, and by fluorescence in-situ hybridization analysis, they demonstrated intact 1p/19q. The presence of signet-ring cells in the central nervous system should immediately raise the suspicion of metastatic carcinoma, particularly from the upper gastrointestinal tract. In the present case, however, the morphological and immunohistochemical features were diagnostic of a malignant primary glial neoplasm (glioblastoma). This case highlights the diagnostic difficulties that can arise in such instances, given the rarity of signet-ring morphology in primary central nervous system tumors.

Early inhaled nitric oxide therapy in premature newborns with respiratory failure.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).