Alveolar hypoxia, alveolar macrophages, and systemic inflammation

Diseases featuring abnormally low alveolar PO2 are frequently accompanied by systemic effects. The common presence of an underlying inflammatory component suggests that inflammation may contribute to the pathogenesis of the systemic effects of alveolar hypoxia. While the role of alveolar macrophages in the immune and defense functions of the lung has been long known, recent evidence indicates that activation of alveolar macrophages causes inflammatory disturbances in the systemic microcirculation. The purpose of this review is to describe observations in experimental animals showing that alveolar macrophages initiate a systemic inflammatory response to alveolar hypoxia. Evidence obtained in intact animals and in primary cell cultures indicate that alveolar macrophages activated by hypoxia release a mediator(s) into the circulation. This mediator activates perivascular mast cells and initiates a widespread systemic inflammation. The inflammatory cascade includes activation of the local renin-angiotensin system and results in increased leukocyte-endothelial interactions in post-capillary venules, increased microvascular levels of reactive O2 species; and extravasation of albumin. Given the known extrapulmonary responses elicited by activation of alveolar macrophages, this novel phenomenon could contribute to some of the systemic effects of conditions featuring low alveolar PO2

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Guided tissue regeneration for periodontal infra-bony defects (Cochrane Review)

BACKGROUND: Conventional treatment of destructive periodontal (gum) disease arrests the disease but does not usually regain the bone support or connective tissue lost in the disease process. Guided tissue regeneration (GTR) is a surgical procedure that specifically aims to regenerate the periodontal tissues when the disease is advanced and could overcome some of the limitations of conventional therapy. OBJECTIVES: To assess the efficacy of GTR in the treatment of periodontal infra-bony defects measured against conventional surgery (open flap debridement (OFD)) and factors affecting outcomes. SEARCH STRATEGY: We conducted an electronic search of the Cochrane Oral Health Group Trials Register, MEDLINE and EMBASE up to April 2004. Handsearching included Journal of Periodontology, Journal of Clinical Periodontology, Journal of Periodontal Research and bibliographies of all relevant papers and review articles up to April 2004. In addition, we contacted experts/groups/companies involved in surgical research to find other trials or unpublished material or to clarify ambiguous or missing data and posted requests for data on two periodontal electronic discussion groups. SELECTION CRITERIA: Randomised, controlled trials (RCTs) of at least 12 months duration comparing guided tissue regeneration (with or without graft materials) with open flap debridement for the treatment of periodontal infra-bony defects. Furcation involvements and studies specifically treating aggressive periodontitis were excluded. DATA COLLECTION AND ANALYSIS: Screening of possible studies and data extraction was conducted independently. The methodological quality of studies was assessed in duplicate using individual components and agreement determined by Kappa scores. Methodological quality was used in sensitivity analyses to test the robustness of the conclusions. The Cochrane Oral Health Group statistical guidelines were followed and the results expressed as mean differences (MD and 95% CI) for continuous outcomes and risk ratios (RR and 95% CI) for dichotomous outcomes calculated using random-effects models. Any heterogeneity was investigated. The primary outcome measure was change in clinical attachment. MAIN RESULTS: The search produced 626 titles, of these 596 were clearly not relevant to the review. The full text of 32 studies of possible relevance was obtained and 15 studies were excluded. Therefore 17 RCTs were included in this review, 16 studies testing GTR alone and two testing GTR+bone substitutes (one study had both test treatment arms).No tooth loss was reported in any study although these data are incomplete where patient follow up was not complete. For attachment level change, the mean difference between GTR and OFD was 1.22 mm (95% CI Random Effects: 0.80 to 1.64, chi squared for heterogeneity 69.1 (df = 15), P < 0.001, I(2) = 78%) and for GTR + bone substitutes was 1.25 mm (95% CI 0.89 to 1.61, chi squared for heterogeneity 0.01 (df = 1), P = 0.91). GTR showed a significant benefit when comparing the numbers of sites failing to gain 2 mm attachment with risk ratio 0.54 (95% CI Random Effects: 0.31 to 0.96, chi squared for heterogeneity 8.9 (df = 5), P = 0.11). The number needed to treat (NNT) for GTR to achieve one extra site gaining 2 mm or more attachment over open flap debridement was therefore 8 (95% CI 5 to 33), based on an incidence of 28% of sites in the control group failing to gain 2 mm or more of attachment. For baseline incidences in the range of the control groups of 3% and 55% the NNTs are 71 and 4. Probing depth reduction was greater for GTR than OFD: 1.21 mm (95% CI 0.53 to 1.88, chi squared for heterogeneity 62.9 (df = 10), P < 0.001, I(2) = 84%) or GTR + bone substitutes, weighted mean difference 1.24 mm (95% CI 0.89 to 1.59, chi squared for heterogeneity 0.03 (df = 1), P = 0.85). For gingival recession, a statistically significant difference between GTR and open flap debridement controls was evident (mean difference 0.26 mm (95% CI Random Effects: 0.08, 0.43, chi squared for heterogeneity 2.7 (df = 8), P = 0.95), with a greater change in recession from baseline for the control group. Regarding hard tissue probing at surgical re-entry, a statistically significant greater gain was found for GTR compared with open flap debridement. This amounted to a weighted mean difference of 1.39 mm (95% CI 1.08 to 1.71, chi squared for heterogeneity 0.85 (df = 2), P = 0.65). For GTR + bone substitutes the difference was greater, with mean difference 3.37 mm (95% CI 3.14 to 3.61). Adverse effects were generally minor although with an increased treatment time for GTR. Exposure of the barrier membrane was frequently reported with a lack of evidence of an effect on healing. AUTHORS' CONCLUSIONS: GTR has a greater effect on probing measures of periodontal treatment than open flap debridement, including improved attachment gain, reduced pocket depth, less increase in gingival recession and more gain in hard tissue probing at re-entry surgery. However there is marked variability between studies and the clinical relevance of these changes is unknown. As a result, it is difficult to draw general conclusions about the clinical benefit of GTR. Whilst there is evidence that GTR can demonstrate a significant improvement over conventional open flap surgery, the factors affecting outcomes are unclear from the literature and these might include study conduct issues such as bias. Therefore, patients and health professionals need to consider the predictability of the technique compared with other methods of treatment before making final decisions on use. Since trial reports were often incomplete, we recommend that future trials should follow the CONSORT statement both in their conduct and reporting. There is therefore little value in future research repeating simple, small efficacy studies. The priority should be to identify factors associated with improved outcomes as well as investigating outcomes relevant to patients. Types of research might include large observational studies to generate hypotheses for testing in clinical trials, qualitative studies on patient-centred outcomes and trials exploring innovative analytic methods such as multilevel modelling. Open flap surgery should remain the control comparison in these studies

Practical implications of motion correction with motion insensitive radial k-space acquisitions in MRI

Objective: To highlight specific instances when radial k-space acquisitions in MRI result in image artifacts and how to ameliorate such artifacts. Methods: We acquired axial T₂ weighted MR images on (1) the American College of Radiology (ACR) phantom and (2) a sedated sheep with rectilinear and multiblade radial k-space filling acquisitions. Images were acquired on four (2 × 1.5T and 2 × 3T) different MRI scanners. For the radial k-space acquisitions, we acquired images with and without motion correction. All images were visually inspected for the presence of artifact. Results: Images collected via the conventional rectilinear method were of diagnostic quality and free of artifact. Both ACR and sheep images acquired with radial k-space acquisitions and motion correction suffered significant artifact at different slice locations, scan sessions and across all the four scanners. Severity of the artifact was associated with echo train length. However, the artifact was eliminated when motion correction was not employed. Conclusion: When little to no motion is present, the use of motion correction with radial k-space acquisitions can compromise image quality. However, image quality is quickly improved, and the artifact eliminated, by repeating the scan without motion correction or by using a conventional rectilinear alternative. Advances in Knowledge: By improving awareness and understanding of this artifact, MRI users will be able to adjust MRI protocols, resulting in more successful scanning sessions, better image quality, fewer call backs and increased diagnostic confidence