Frailty in Pulmonary and Critical Care Medicine Singer, Jonathan P; Lederer, David J; Baldwin, Matthew R
Annals of the American Thoracic Society,
08/2016, Letnik:
13, Številka:
8
Journal Article
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Odprti dostop
Conceptualized first in the field of geriatrics, frailty is a syndrome characterized by a generalized vulnerability to stressors resulting from an accumulation of physiologic deficits across multiple ...interrelated systems. This accumulation of deficits results in poorer functional status and disability. Frailty is a "state of risk" for subsequent disproportionate declines in health status following new exposure to a physiologic stressor. Two predominant models have emerged to operationalize the measurement of frailty. The phenotype model defines frailty as a distinct clinical syndrome that includes conceptual domains such as strength, activity, wasting, and mobility. The cumulative deficit model defines frailty by enumerating the number of age-related things wrong with a person. The biological pathways driving frailty include chronic systemic inflammation, sarcopenia, and neuroendocrine dysregulation, among others. In adults with chronic lung disease, frailty is independently associated with more frequent exacerbations of lung disease, all-cause hospitalization, declines in functional status, and all-cause mortality. In addition, frail adults who become critically ill are more likely develop chronic critical illness or severe disability and have higher in-hospital and long-term mortality rates. The evaluation of frailty appears to provide important prognostic information above and beyond routinely collected measures in adults with chronic lung disease and the critically ill. The study of frailty in these populations, however, requires multipronged efforts aimed at refining clinical assessments, understanding the mechanisms, and developing therapeutic interventions.
CT measurement of body composition may improve lung transplant candidate selection. We assessed whether skeletal muscle adipose deposition on abdominal and thigh CT scans was associated with 6 min ...walk distance (6MWD) and wait-list survival in lung transplant candidates. Each ½-SD decrease in abdominal muscle attenuation (indicating greater lipid content) was associated with 14 m decrease in 6MWD (95% CI -20 to -8) and 20% increased risk of death or delisting (95% CI 10% to 40%). Each ½-standard deviation decrease in thigh muscle attenuation was associated with 15 m decrease in 6MWD (95% CI -21 to -10). CT imaging may improve candidate risk stratification.
HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75. These small molecules act as molecular glues promoting ...hyper-multimerization of HIV-1 IN protein to severely perturb maturation of viral particles. Herein, we describe a new series of INLAIs based on a benzene scaffold that display antiviral activity in the single digit nanomolar range. Akin to other compounds of this class, the INLAIs predominantly inhibit the late stages of HIV-1 replication. A series of high-resolution crystal structures revealed how these small molecules engage the catalytic core and the C-terminal domains of HIV-1 IN. No antagonism was observed between our lead INLAI compound BDM-2 and a panel of 16 clinical antiretrovirals. Moreover, we show that compounds retained high antiviral activity against HIV-1 variants resistant to IN strand transfer inhibitors and other classes of antiretroviral drugs. The virologic profile of BDM-2 and the recently completed single ascending dose phase I trial (ClinicalTrials.gov identifier: NCT03634085) warrant further clinical investigation for use in combination with other antiretroviral drugs. Moreover, our results suggest routes for further improvement of this emerging drug class.
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal ...structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD). Projecting from their principal binding pocket on the IN CCD dimer, the compounds act as molecular glue by engaging a triad of invariant HIV-1 IN CTD residues, namely, Tyr226, Trp235, and Lys266, to nucleate the CTD-CCD interaction. The drug-induced interface involves the CTD SH3-like fold and extends to the beginning of the IN carboxyl-terminal tail region. We show that mutations of HIV-1 IN CTD residues that participate in the interface with the CCD greatly reduce the IN-aggregation properties of Pirmitegravir. Our results explain the mechanism of the ALLINI-induced condensation of HIV-1 IN and provide a reliable template for the rational development of this series of antiretrovirals through the optimization of their key contacts with the viral target.
Despite the remarkable success of combination antiretroviral therapy, HIV-1 remains among the major causes of human suffering and loss of life in poor and developing nations. To prevail in this drawn-out battle with the pandemic, it is essential to continue developing advanced antiviral agents to fight drug resistant HIV-1 variants. Allosteric integrase inhibitors (ALLINIs) are an emerging class of HIV-1 antagonists that are orthogonal to the current antiretroviral drugs. These small molecules act as highly specific molecular glue, which triggers the aggregation of HIV-1 integrase. In this work, we present high-resolution crystal structures that reveal the crucial interactions made by two potent ALLINIs, namely, BI-D and Pirmitegravir, with HIV-1 integrase. Our results explain the mechanism of drug action and will inform the development of this promising class of small molecules for future use in antiretroviral regimens.
Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long‐term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a ...paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush‐derived transcriptomic signatures in CLAD (n = 24) versus non‐CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type‐1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO‐1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type‐1 profile with detection of IFN‐γ, TNF‐α, and IL‐1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.
This cross‐sectional analysis of transbronchial brush samples from lung transplant recipients identifies a transcriptomic signature marked by type‐1 immunity in recipients with chronic lung allograft dysfunction compared to stable controls.
The COVID-19 pandemic has highlighted and amplified family caregiving obligations for many clinical investigators and other biomedical researchers. Unpredictable access to daycare, schools, assisted ...living facilities, informal networks, and other sources of care of children, older adults, or those with special needs has been harrowing. The National Academies of Science, Engineering, and Medicine emphasized such challenges will impair the vitality of the scientific workforce, calling for research and action to bolster resources for those facing family caregiving responsibilities as they pursue careers in fields that include academic medicine. In the US, where social policies addressing needs of workers with families are less robust than elsewhere in the world, engagement in demanding professional pursuits was challenging before the pandemic. Lack of family-friendly policies has a disparate impact on single parents and women, who are more likely to shoulder family caregiving responsibilities due to persistent gendered societal norms and expectations; the result is limited access of professions like medicine to the full talent pool.
The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and in critical illness survivors. Because respiratory disease and chronic illness can ...greatly limit physical activity, the measurement of participation in traditional leisure time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients.
To test and validate substituting the Duke Activity Status Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Physical Activity (MLTA) questionnaire, a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype (FFP) instrument.
In separate multicenter prospective cohort studies of adults with advanced lung disease who were candidates for lung transplant and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated content validity by testing floor effects and construct validity through comparisons with conceptually related factors. We tested the predictive validity of substituting the DASI for the MLTA in the FFP assessment using Cox models to estimate associations between the FFP and delisting/death before transplant in those with advanced lung disease and 6-month mortality in older intensive care unit (ICU) survivors.
Among 618 adults with advanced lung disease and 130 older ICU survivors, the MLTA had a substantially greater floor effect than the DASI (42% vs. 1%, and 49% vs. 12%, respectively). The DASI correlated more strongly with strength and function measures than did the MLTA in both cohorts. In models adjusting for age, sex, comorbidities, and illness severity, substitution of the DASI for the MLTA led to stronger associations of the FFP with delisting/death in lung transplant candidates (FFP-MLTA hazard ratio HR, 1.42; 95% confidence interval CI, 0.55-3.65; FFP-DASI HR, 2.99; 95% CI, 1.03-8.65) and with mortality in older ICU survivors (FFP-MLTA HR, 2.68; 95% CI, 0.62-11.6; FFP-DASI HR, 5.71; 95% CI, 1.34-24.3).
The DASI improves the construct and predictive validity of frailty assessment in adults with advanced lung disease or recent critical illness. This simple questionnaire should replace the more complex MLTA in assessing the frailty phenotype in these populations.
Frail lung transplant candidates are more likely to be delisted or die without receiving a transplant. Further knowledge of what frailty represents in this population will assist in developing ...interventions to prevent frailty from developing. We set out to determine whether frail lung transplant candidates have reduced exercise capacity independent of disease severity and diagnosis.
Sixty-eight adult lung transplant candidates underwent cardiopulmonary exercise testing (CPET) and a frailty assessment (Fried's Frailty Phenotype (FFP)). Primary outcomes were peak workload and peak aerobic capacity (V˙O2). We used linear regression to adjust for age, gender, diagnosis, and lung allocation score (LAS).
The mean ± SD age was 57 ± 11 years, 51% were women, 57% had interstitial lung disease, 32% had chronic obstructive pulmonary disease, 11% had cystic fibrosis, and the mean LAS was 40.2 (range 19.2–94.5). In adjusted models, peak workload decreased by 10 W (95% CI 4.7 to 14.6) and peak V˙O2 decreased by 1.8 mL/kg/min (95% CI 0.6 to 2.9) per 1 unit increment in FFP score. After adjustment, exercise tolerance was 38 W lower (95% CI 18.4 to 58.1) and peak V˙O2 was 8.5 mL/kg/min lower (95% CI 3.3 to 13.7) among frail participants compared to non-frail participants. Frailty accounted for 16% of the variance (R2) of watts and 19% of the variance of V˙O2 in adjusted models.
Frailty contributes to reduced exercise capacity among lung transplant candidates independent of disease severity.
•Frail lung transplant candidates have reduced exercise capacity out of proportion to the severity of their lung disease.•Frail lung transplant candidates have an average VO2 peak of less than 10 mL/kg/min.•In lung transplant candidates, reduced aerobic muscle strength demonstrated the strongest correlation with frailty.
IntroductionHyperkalaemia is common, life-threatening and often requires emergency department (ED) management; however, no standardised ED treatment protocol exists. Common treatments transiently ...reducing serum potassium (K+) (including albuterol, glucose and insulin) may cause hypoglycaemia. We outline the design and rationale of the Patiromer Utility as an Adjunct Treatment in Patients Needing Urgent Hyperkalaemia Management (PLATINUM) study, which will be the largest ED randomised controlled hyperkalaemia trial ever performed, enabling assessment of a standardised approach to hyperkalaemia management, as well as establishing a new evaluation parameter (net clinical benefit) for acute hyperkalaemia treatment investigations.Methods and analysisPLATINUM is a Phase 4, multicentre, randomised, double-blind, placebo-controlled study in participants who present to the ED at approximately 30 US sites. Approximately 300 adult participants with hyperkalaemia (K+ ≥5.8 mEq/L) will be enrolled. Participants will be randomised 1:1 to receive glucose (25 g intravenously <15 min before insulin), insulin (5 units intravenous bolus) and aerosolised albuterol (10 mg over 30 min), followed by a single oral dose of either 25.2 g patiromer or placebo, with a second dose of patiromer (8.4 g) or placebo after 24 hours. The primary endpoint is net clinical benefit, defined as the mean change in the number of additional interventions less the mean change in serum K+, at hour 6. Secondary endpoints are net clinical benefit at hour 4, proportion of participants without additional K+-related medical interventions, number of additional K+-related interventions and proportion of participants with sustained K+ reduction (K+ ≤5.5 mEq/L). Safety endpoints are the incidence of adverse events, and severity of changes in serum K+ and magnesium.Ethics and disseminationA central Institutional Review Board (IRB) and Ethics Committee provided protocol approval (#20201569), with subsequent approval by local IRBs at each site, and participants will provide written consent. Primary results will be published in peer-reviewed manuscripts promptly following study completion.Trial registration numberNCT04443608.
Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury-related mortality. The effect of these medications on post-traumatic brain injury (TBI) ...inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI.
An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mg/kg of TXA, 400 mg/kg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIU/kg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation.
One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS.
Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI.
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