Coronavirus disease 2019 (COVID‐19) continues to impact older adults disproportionately with respect to serious consequences ranging from severe illness and hospitalization to increased mortality ...risk. Concurrently, concerns about potential shortages of healthcare professionals and health supplies to address these issues have focused attention on how these resources are ultimately allocated and used. Some strategies, for example, misguidedly use age as an arbitrary criterion that disfavors older adults in resource allocation decisions. This is a companion article to the American Geriatrics Society (AGS) position statement, “Resource Allocation Strategies and Age‐Related Considerations in the COVID‐19 Era and Beyond.” It is intended to inform stakeholders including hospitals, health systems, and policymakers about ethical considerations that should be considered when developing strategies for allocation of scarce resources during an emergency involving older adults. This review presents the legal and ethical background for the position statement and discusses these issues that informed the development of the AGS positions: (1) age as a determining factor, (2) age as a tiebreaker, (3) criteria with a differential impact on older adults, (4) individual choices and advance directives, (5) racial/ethnic disparities and resource allocation, and (6) scoring systems and their impact on older adults. It also considers the role of advance directives as expressions of individual preferences in pandemics. J Am Geriatr Soc 68:1143–1149, 2020.
See related paper by Farrell et al.
Older adults suffering from chronic pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung disease, and critical illnesses, such as sepsis and acute respiratory ...failure, are more vulnerable to adverse outcomes like disability and greater side effects from treatments. In this update, we discuss recent practice-changing clinical trials and observational studies in Pulmonary & Critical Care Medicine that have advanced our understanding of the diagnosis or management of older adults with chronic lung diseases or critical illnesses.
Antisynthetase syndrome is an autoimmune condition, characterized by antibodies directed against an aminoacycl transfer RNA synthetase along with clinical features that can include interstitial lung ...disease (ILD), myositis, Raynaud’s phenomenon, and arthritis. There is a higher prevalence and increased severity of ILD in patients with antisynthetase syndrome, as compared with dermatomyositis and polymyositis, inflammatory myopathies with which it may overlap phenotypically. The diagnosis is made by a multidisciplinary approach, synthesizing rheumatology and pulmonary evaluations, along with serologic, radiographic, and occasionally muscle and/or lung biopsy results. Patients with antisynthetase syndrome often require multimodality immunosuppressive therapy to control the muscle and/or pulmonary manifestations of their disease. The long-term care of these patients mandates careful attention to the adverse effects and complications of chronic immunosuppressive therapy, and disease-related sequelae that can include progressive ILD necessitating lung transplantation, pulmonary hypertension, malignancy, and a decreased survival. It is expected that a greater awareness of the clinical features of this syndrome will allow for an earlier diagnosis and appropriate treatment to improve outcomes in patients with antisynthetase syndrome.
Coronavirus disease 2019 (COVID‐19) continues to impact older adults disproportionately, from severe illness and hospitalization to increased mortality risk. Concurrently, concerns about potential ...shortages of healthcare professionals and health supplies to address these needs have focused attention on how resources are ultimately allocated and used. Some strategies misguidedly use age as an arbitrary criterion, inappropriately disfavoring older adults. This statement represents the official policy position of the American Geriatrics Society (AGS). It is intended to inform stakeholders including hospitals, health systems, and policymakers about ethical considerations to consider when developing strategies for allocating scarce resources during an emergency involving older adults. Members of the AGS Ethics Committee collaborated with interprofessional experts in ethics, law, nursing, and medicine (including geriatrics, palliative care, emergency medicine, and pulmonology/critical care) to conduct a structured literature review and examine relevant reports. The resulting recommendations defend a particular view of distributive justice that maximizes relevant clinical factors and deemphasizes or eliminates factors placing arbitrary, disproportionate weight on advanced age. The AGS positions include (1) avoiding age per se as a means for excluding anyone from care; (2) assessing comorbidities and considering the disparate impact of social determinants of health; (3) encouraging decision makers to focus primarily on potential short‐term (not long‐term) outcomes; (4) avoiding ancillary criteria such as “life‐years saved” and “long‐term predicted life expectancy” that might disadvantage older people; (5) forming and staffing triage committees tasked with allocating scarce resources; (6) developing institutional resource allocation strategies that are transparent and applied uniformly; and (7) facilitating appropriate advance care planning. The statement includes recommendations that should be immediately implemented to address resource allocation strategies during COVID‐19, aligning with AGS positions. The statement also includes recommendations for post‐pandemic review. Such review would support revised strategies to ensure that governments and institutions have equitable emergency resource allocation strategies, avoid future discriminatory language and practice, and have appropriate guidance to develop national frameworks for emergent resource allocation decisions. J Am Geriatr Soc 68:1136–1142, 2020.
See related paper by Farrell et al.
Idiopathic pulmonary fibrosis (IPF) is characterized by the transforming growth factor (TGF)-β-dependent differentiation of lung fibroblasts into myofibroblasts, leading to excessive deposition of ...extracellular matrix proteins, which distort lung architecture and function. Metabolic reprogramming in myofibroblasts is emerging as an important mechanism in the pathogenesis of IPF, and recent evidence suggests that glutamine metabolism is required in myofibroblasts, although the exact role of glutamine in myofibroblasts is unclear. In the present study, we demonstrate that glutamine and its conversion to glutamate by glutaminase are required for TGF-β-induced collagen protein production in lung fibroblasts. We found that metabolism of glutamate to α-ketoglutarate by glutamate dehydrogenase or the glutamate-pyruvate or glutamate-oxaloacetate transaminases is not required for collagen protein production. Instead, we discovered that the glutamate-consuming enzymes phosphoserine aminotransferase 1 (PSAT1) and aldehyde dehydrogenase 18A1 (ALDH18A1)/Δ
-pyrroline-5-carboxylate synthetase (P5CS) are required for collagen protein production by lung fibroblasts. PSAT1 is required for
glycine production, whereas ALDH18A1/P5CS is required for
proline production. Consistent with this, we found that TGF-β treatment increased cellular concentrations of glycine and proline in lung fibroblasts. Our results suggest that glutamine metabolism is required to promote amino acid biosynthesis and not to provide intermediates such as α-ketoglutarate for oxidation in mitochondria. In support of this, we found that inhibition of glutaminolysis has no effect on cellular oxygen consumption and that knockdown of oxoglutarate dehydrogenase has no effect on the ability of fibroblasts to produce collagen protein. Our results suggest that amino acid biosynthesis pathways may represent novel therapeutic targets for treatment of fibrotic diseases, including IPF.
Case studies are presented that relate to the possibility that diaphragmatic atrophy may limit the progression of idiopathic pulmonary fibrosis (IPF). One case study involves a 78-year-old man, with ...gastroesophageal reflux, premature hair graying, and a family history of pulmonary fibrosis, who developed cough and dyspnea. At age 61 years, he was ejected off a forklift and landed on his back and left shoulder, requiring arthroscopic surgery. Usual interstitial penumonia pattern was demonstrated through chest computed tomography. On the other hand, a 74-year-old man with quiescent multiple sclerosis was presented with cough and dyspnea. Lung function was severely restricted, with reduced diffusion capacity. Chest CT demonstrated a probable usual interstitial pneumonia pattern. The case studies support the hypothesis that IPF results from gene-environment interactions.
TGF-β promotes excessive collagen deposition in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). The amino acid composition of collagen is unique due to its high (33%) glycine content. ...Here, we report that TGF-β induces expression of glycolytic genes and increases glycolytic flux. TGF-β also induces the expression of the enzymes of the de novo serine synthesis pathway (phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH)) and de novo glycine synthesis (serine hydroxymethyltransferase 2 (SHMT2)). Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for TGF-β-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF.
Abstract Background Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was ...recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown Methods A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. Results Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.013 and 0.015 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49–3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21–3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement Conclusions A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function.
The current interstitial lung disease (ILD) classification has overlapping clinical presentations and outcomes. Cluster analysis modeling is a valuable tool in identifying distinct clinical ...phenotypes in heterogeneous diseases. However, this approach has yet to be implemented in ILD.
Using cluster analysis, novel ILD phenotypes were identified among subjects from a longitudinal ILD cohort, and outcomes were stratified according to phenotypic clusters compared with subgroups according to current American Thoracic Society/European Respiratory Society ILD classification criteria.
Among subjects with complete data for baseline variables (N = 770), four clusters were identified. Cluster 1 (ie, younger white obese female subjects) had the highest baseline FVC and diffusion capacity of the lung for carbon monoxide (Dlco). Cluster 2 (ie, younger African-American female subjects with elevated antinuclear antibody titers) had the lowest baseline FVC. Cluster 3 (ie, elderly white male smokers with coexistent emphysema) had intermediate FVC and Dlco. Cluster 4 (ie, elderly white male smokers with severe honeycombing) had the lowest baseline Dlco. Compared with classification according to ILD subgroup, stratification according to phenotypic clusters was associated with significant differences in monthly FVC decline (Cluster 4, –0.30% vs Cluster 2, 0.01%; P < .0001). Stratification by using clusters also independently predicted progression-free survival (P < .001) and transplant-free survival (P < .001).
Among adults with diverse chronic ILDs, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might better predict meaningful clinical outcomes than current ILD diagnostic criteria.
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