Thompson, Bruce

Abstract Technological advancements have increased the number of human spaceflights, including the advent of space tourism and deep space travel. The structure and function of the pulmonary system are gravitationally dependent, highlighting the importance of understanding functional changes within the pulmonary system during transient and sustained microgravity exposure. This systematic review and meta-analysis provide an overview of effects of microgravity (0G) on various functional outcome measures of the human lungs relative to Earth gravity (1G). Twenty-eight studies comprising parabolic flights (~20 seconds), short- (≤30 days) and long-duration spaceflight (>30 days) were assessed. Outcome measures reported in 1G (before flight) and 0G (in-flight) were extracted. Fixed effects models showed microgravity caused a reduction in elastic work and carbon dioxide production, and increases in pulmonary diffusion capacity, compliance, and pulmonary capillary blood volume. Despite this, the effect sizes were small and likely have little clinical significance in healthy individuals. However, they could impact space tourists who have lower health requirements for space travel, and those with underlying obstructive respiratory disorders. The results demonstrate how traditional functional pulmonary testing provides essential physiological benchmarks that complement high-throughput data collection methods, enabling an integrated understanding of how molecular changes translate into functional respiratory outcomes in microgravity.

AbstractHow to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

AbstractClinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

e14640 Background: MicroRNAs (miRNAs) are non-coding RNAs that act as negative regulators of gene expression. They have been described to play roles in solid tumors and hematologic malignancies. However the role of miRNAs in multiple myeloma (MM) has not been yet fully described. Methods: We performed miRNA-profiling of primary bone marrow-derived CD138+ MM cells, compared to their normal cellular counterparts and validated data by qRT-PCR. In vitro and in vivo functional studies were performed on miRNA-15a- and -16–1-precursors-transfected MM cells. Effect of miRNA-15a and -16–1 on signaling cascades have been evaluated by western blot and immunofluorescence. NF-kB activity has been studied using the Active Motif TransAM kit. In vivo MM cell growth has been evaluated by either using an in vivo imaging model or bioluminescence. Angiogenesis has been studied both in vitro and in vivo using the chorioallantoic membrane model. Results: We identified a MM-specific miRNA signature characterized by down-expression of miRNA-15a, -16–1 and over-expression of miRNA-222/-221/-382/-181a/-181b (P<0.01). Data were confirmed by qRT-PCR on matched samples. Predicted targets for the decreased miRNAs in MM patients included pro-angiogenic cytokines, oncogenes, cell cycle regulators, NFkB activators. Conversely, predicted targets for the increased miRNAs included cell cycle inhibitors, suppressors of cytokine signaling, and pro-apoptotic factors. We demonstrated that miRNA-15a and - 16–1 regulate proliferation and growth of MM cells. Indeed, transfected cells showed decreased DNA synthesis; decreased cyclinD1/cyclinD3/CDC25a/pRb protein expression; phase G1 cell cycle arrest. Moreover, transfected cells showed inhibition of NFkB pathway as shown by reduced p65-/p50-/p52-NFkB activities; downregulation of p-p65/p50/p52 nuclear protein level; upregulation of cttosolic phospho-IkB; and inhibited translocation of p-p65 from the cytolplasm to the nucleus. Similarly, inhibition of MM cell growth was confirmed in vivo; and anti-angiogenic properties of miRNA-15a and -16–1 were demonstrated both in vitro and in vivo. Conclusions: These data indicate that miRNAs play a pivotal role in the biology of MM; providing the basis for the development of new miRNA-based targeted therapies in this disease. No significant financial relationships to disclose.

Objectives: To longitudinally measure LV diastolic function in HIV-exposed but uninfected (HEU) children perinatally exposed to ART. Design: HEU children who were perinatally exposed to antiretroviral therapy (ART) may be at risk for adverse cardiac effects. We have previously reported that those children have decreased left ventricular (LV) mass, dimension, and septal thickness with increased contractility. Methods: Serial echocardiograms were obtained at specific times from birth to 48 months from two groups of HIV-uninfected children: 148 HIV-negative children who were perinatally exposed to ART and 130 non-ART-exposed HIV-unexposed healthy controls. The following LV diastolic indices were obtained: mitral valve early and late diastolic velocity (E and A), tissue Doppler-derived LV-free wall and septal early diastolic velocity (LV e′ and sep e′). Results: All echocardiographic indices were significantly different in ART-exposed children compared with ART-unexposed healthy controls. Both E and A were overall lower at all ages by 8.28 cm/s (P = 0.0002) and 13.46 cm/s (P < 0.0001) respectively. E/A ratio was higher by 0.27, 0.46, and 0.28 units at birth, 1 year and 2 years of age, respectively (all P ≤ 0.01). Moreover, LV e′ and sep e′ were overall lower at all ages by 0.84 cm/s (P = 0.01) and 0.47 cm/s (P = 0.02), respectively. Conclusion: Children who were exposed to ART in utero have subclinical yet significant differences in specific LV diastolic indices. Follow-up with serial echocardiograms are recommended in this population to further assess the potential cardiac toxicity of perinatal exposure to ART.

Abstract Despite significant advances in our understanding and management of patients with acute respiratory distress syndrome (ARDS), the morbidity and mortality from ARDS remains high. Given the limited number of effective treatments for established ARDS, the strategic focus of ARDS research has shifted toward identifying patients with or at high risk of ARDS early in the course of the underlying illness, when strategies to reduce the development and progression of ARDS and associated organ failures can be systematically evaluated. In this review, we summarize the rationale, current evidence, and future directions in ARDS prevention.

Abstract Rationale Noninvasive ventilation (NIV) is increasingly used in patients with acute respiratory distress syndrome (ARDS). The evidence supporting NIV use in patients with ARDS remains relatively sparse. Objectives To determine whether, during NIV, the categorization of ARDS severity based on the PaO2/FiO2 Berlin criteria is useful. Methods The LUNG SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) study described the management of patients with ARDS. This substudy examines the current practice of NIV use in ARDS, the utility of the PaO2/FiO2 ratio in classifying patients receiving NIV, and the impact of NIV on outcome. Measurements and Main Results Of 2,813 patients with ARDS, 436 (15.5%) were managed with NIV on Days 1 and 2 following fulfillment of diagnostic criteria. Classification of ARDS severity based on PaO2/FiO2 ratio was associated with an increase in intensity of ventilatory support, NIV failure, and intensive care unit (ICU) mortality. NIV failure occurred in 22.2% of mild, 42.3% of moderate, and 47.1% of patients with severe ARDS. Hospital mortality in patients with NIV success and failure was 16.1% and 45.4%, respectively. NIV use was independently associated with increased ICU (hazard ratio, 1.446 [95% confidence interval, 1.159–1.805]), but not hospital, mortality. In a propensity matched analysis, ICU mortality was higher in NIV than invasively ventilated patients with a PaO2/FiO2 lower than 150 mm Hg. Conclusions NIV was used in 15% of patients with ARDS, irrespective of severity category. NIV seems to be associated with higher ICU mortality in patients with a PaO2/FiO2 lower than 150 mm Hg. Clinical trial registered with www.clinicaltrials.gov (NCT 02010073).

Abstract Rationale Disability guidelines are often based on pulmonary function testing, but factors other than lung function influence how an individual experiences physiologic impairment. Age may impact the perception of impairment in adults with chronic lung disease. Objectives To determine if self-report of physical functional impairment differs between older adults with chronic lung disease compared with younger adults with similar degrees of lung function impairment. Methods The Lung Tissue Research Consortium provided data on 981 participants with chronic obstructive pulmonary disease and interstitial lung disease who were well characterized with clinical, radiological, and pathological diagnoses. We used multiple logistic regression to determine if responses to health status questions (from the Short Form-12 and St. George’s Respiratory Questionnaire) related to perception of impairment differed in older adults (age ≥ 65 yr, n = 427) compared with younger adults (age &lt; 65 yr, n = 393). Measurements and Main Results Pulmonary function was higher in older adults (median FEV1 %, 70) compared with younger adults (median FEV1 %, 62) (P &lt; 0.001), whereas the median 6-minute-walk distance was similar between groups (372 m vs. 388 m, P = 0.21). After adjusting for potential confounders, older adults were less likely to report that their health limited them significantly in performing moderate activities (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.22–0.58) or climbing several flights of stairs (OR, 0.51; 95% CI, 0.34–0.77). The odds of reporting that their physical health limited the kinds of activities they performed were reduced by 63% in older adults (OR, 0.37; 95% CI, 0.24–0.58), and, similarly, the odds of reporting that their health caused them to accomplish less than they would like were also lower in older adults (OR, 0.39; 95% CI, 0.25–0.60). The OR for reporting that their breathing problem stops them from doing most things or everything was 0.35 (95% CI, 0.22–0.55) in older adults versus younger adults. Conclusions Older adults with chronic lung disease were less likely to report significant impairment in their activities compared with younger adults, suggesting they may perceive less limitation.

Abstract Mortality in National Heart, Lung and Blood Institute–sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials.