Objective
Physical activity and exercise are key components in the management of cystic fibrosis (CF). Completing exercise programs online may minimize the risk of cross‐infection and increase access ...for people with CF. This study aimed to understand the perspectives of people with CF regarding intervention content for a telehealth exercise program.
Methods
Individual semistructured qualitative interviews were conducted in adults with CF purposefully sampled for age, disease severity, and social demographics. Interviews were recorded, transcribed verbatim, and analyzed thematically by two researchers independently.
Results
Participants were 23 adults with CF (14 females) aged from 21 to 60 years. Three major themes (subthemes) were generated: “Personalizing components to an exercise program” (customizing an exercise program to the individual person and their unique health and exercise needs, enjoyment and variety of exercise activities, accessibility and exercise fitting around competing demands or commitments), “The importance of maintaining connections” (challenges regarding face‐to‐face interactions for people with CF, accountability of scheduled exercise sessions with others, shared experiences between people with CF and specialist support from the CF care team), and “Monitoring health and exercise” (perception of health status and monitoring and recording exercise participation and health).
Conclusion
This study provides important information regarding the preferences of adults with CF for telehealth exercise interventions. Interventions should be tailored to the individual person with CF, include an opportunity to maintain connections with peers and the CF multidisciplinary team, and provide a method to monitor progress over time.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
ABSTRACT
Background
Frailty is prevalent in lung transplant (LTx) candidates, but the impact and subsequent frailty trajectory is unclear. This study aimed to investigate frailty over the first year ...after LTx.
Method
Post‐LTx recipients completed a thrice weekly 12‐week directly supervised exercise rehabilitation program. Edmonton Frail Scale (EFS) was used to assess frailty. Primary outcome was 6‐Minute Walk Distance (6MWD) measured at pre‐LTx, prerehabilitation, postrehabilitation, and 1 year post‐LTx.
Results
106 of 139 recruited participants underwent LTx: mean age 58 years, 48% male, 52% with chronic obstructive pulmonary disease. Mean (± SD) frailty scores pre‐LTx and 1 year post‐LTx were 5.54 ± 2.4 and 3.28 ±1.5. Mean 6MWD improved significantly for all: prerehabilitation 326 m (SD 116), versus postrehabilitation 523 m (SD 101) (p < 0.001) versus 1 year 512 m (SD 120) (p < 0.001). There were significant differences between an EFS > 7 (frail) and EFS ≤ 7 (not frail) for 6MWD, grip strength (GS), anxiety, and depression. Postrehabilitation, there were no significant differences in 6MWD, GS, anxiety, or depression while comparing EFS > 7 versus ≤ 7. At 1 year, there was a significant difference in depression but not 6MWD, GS, or anxiety between those EFS ≤ 7 and > 7 (p = 0.017).
Conclusion
Participants in a structured post‐LTx rehabilitation program improved in functional exercise capacity (6MWD), GS, depression, and anxiety. For frail participants exercise capacity, depression, anxiety, and GS were well managed in rehabilitation with no significant differences between those who were not frail. Pre‐LTx frailty may be reversible post‐LTx and should not be an absolute contraindication to LTx.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Objective
Measurement of physical function is important to guide physical therapy for patients post-lung transplantation (LTx). The Sit-to-Stand (STS) test has proven utility in chronic ...disease, but psychometric properties post-LTx are unknown. The study aimed to assess reliability, validity, responsiveness, and feasibility of the 60-second STS post-LTx.
Methods
This was a measurement study in 62 inpatients post-LTx (31 acute postoperative; 31 medical readmissions). Interrater reliability was assessed with 2 STS tests undertaken by different assessors at baseline. Known group validity was assessed by comparing STS repetitions in postoperative and medical groups. Content validity was assessed using comparisons to knee extensor and grip strength, measured with hand-held dynamometry. Criterion validity was assessed by comparison of STS repetitions and 6-minute walk distance postoperatively. Responsiveness was assessed using effect sizes over inpatient admission.
Results
Median (interquartile range) age was 62 (56–67) years; time post-LTx was 5 (5–7) days postoperative and 696 (244–1849) days for medical readmissions. Interrater reliability was excellent (intraclass correlation coefficient type 2,1 = 0.96), with a mean learning effect of 2 repetitions. Repetitions were greater for medical at baseline (mean 18 vs 8). More STS repetitions were associated with greater knee extensor strength (postoperative r = 0.57; medical r = 0.47) and 6-minute walk distance (postoperative r = 0.68). Effect sizes were 0.94 and 0.09, with a floor effect of 23% and 3% at baseline (postoperative/medical) improving to 10% at discharge. Patients incapable of attempting a STS test were excluded, reducing generalizability to critical care. Physical rehabilitation was not standardized, possibly reducing responsiveness.
Conclusions
The 60-second STS demonstrated excellent interrater reliability and moderate validity and was responsive to change postoperatively.
Impact
The 60-second STS represents a safe, feasible functional performance tool for inpatients post-LTx. Two tests should be completed at each time point.
Postoperative rehabilitation is crucial following lung transplantation (LTx); however, it is unclear whether intensive rehabilitation is feasible to deliver in the acute setting. We aimed to ...establish the feasibility and safety of intensive acute physiotherapy post-LTx.
This feasibility trial randomized 40 adults following bilateral sequential LTx to either standard (once-daily) or intensive (twice-daily) physiotherapy. Primary outcomes were feasibility (recruitment and delivery of intensive intervention) and safety. Secondary outcomes included six-minute walk test; 60-second sit-to-stand; grip strength; physical activity; pain; EQ-5D-5L; length of stay; and readmissions. Data were collected at baseline, week 3, and week 10 post-LTx. ClinicalTrials.gov #NCT03095859.
Of 83 LTx completed during the trial, 49% were eligible and 48% provided consent. Median age was 61 years {range 18-70}; waitlist time 85 days IQR 35-187. Median time to first mobilization was 2 days 2-3. Both groups received a median of 10 7-14 standard interventions post-randomization. A median of 9 6-18 individual intensive interventions were attempted (86% successful), the most common barrier being medical procedures/investigations (67%). No intervention-related adverse events or between-group differences in secondary outcomes were observed.
Acute, intensive physiotherapy was feasible and safe post-LTx. This trial provides data to underpin definitive trials to establish efficacy.
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DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Postoperative rehabilitation is crucial following lung transplantation (LTx); however, it is unclear whether intensive rehabilitation is feasible to deliver in the acute setting. We aimed to ...establish the feasibility and safety of intensive acute physiotherapy post-LTx.
This feasibility trial randomized 40 adults following bilateral sequential LTx to either standard (once-daily) or intensive (twice-daily) physiotherapy. Primary outcomes were feasibility (recruitment and delivery of intensive intervention) and safety. Secondary outcomes included six-minute walk test; 60-second sit-to-stand; grip strength; physical activity; pain; EQ-5D-5L; length of stay; and readmissions. Data were collected at baseline, week 3, and week 10 post-LTx. ClinicalTrials.gov #NCT03095859.
Of 83 LTx completed during the trial, 49% were eligible and 48% provided consent. Median age was 61 years {range 18-70}; waitlist time 85 days IQR 35-187. Median time to first mobilization was 2 days 2-3. Both groups received a median of 10 7-14 standard interventions post-randomization. A median of 9 6-18 individual intensive interventions were attempted (86% successful), the most common barrier being medical procedures/investigations (67%). No intervention-related adverse events or between-group differences in secondary outcomes were observed.
Acute, intensive physiotherapy was feasible and safe post-LTx. This trial provides data to underpin definitive trials to establish efficacy.
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DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement ...component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J wild type (WT), C1q-deficient ( C1qa
, lacking classical pathway activation), complement protein 4-deficient ( C4
, lacking classical and lectin pathway activation), complement factor D-deficient ( FD
, lacking alternative pathway activation), and C1qa/FD
(lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa
, C4
, or C1qa/FD
mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD
mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b/iC3b/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD
mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD
mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol. NEW & NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing/recovery during alcoholic liver disease.
Autophagy maintains cellular homeostasis and plays a critical role in the development of non-alcoholic fatty liver and steatohepatitis. The pseudokinase mixed lineage kinase domain-like (MLKL) is a ...key downstream effector of receptor interacting protein kinase 3 (RIP3) in the necroptotic pathway of programmed cell death. However, recent data reveal that MLKL also regulates autophagy. Herein, we tested the hypothesis that MLKL contributes to the progression of Western diet-induced liver injury in mice by regulating autophagy.
Rip3+/+, Rip3−/−, Mlkl+/+ and Mlkl−/− mice were fed a Western diet (FFC diet, high in fat, fructose and cholesterol) or chow for 12 weeks. AML12 and primary mouse hepatocytes were exposed to palmitic acid (PA).
The FFC diet increased expression, phosphorylation and oligomerization of MLKL in the liver. Mlkl, but not Rip3, deficiency protected mice from FFC diet-induced liver injury. The FFC diet also induced accumulation of p62 and LC3-II, as well as markers of endoplasmic reticulum stress, in Mlkl+/+ but not Mlkl−/− mice. Mlkl deficiency in mice also prevented the inhibition of autophagy by a protease inhibitor, leupeptin. Using an mRFP-GFP-LC3 reporter in cultured hepatocytes revealed that PA blocked the fusion of autophagosomes with lysosomes. PA triggered MLKL expression and translocation, first to autophagosomes and then to the plasma membrane, independently of Rip3. Mlkl, but not Rip3, deficiency prevented inhibition of autophagy in PA-treated hepatocytes. Overexpression of Mlkl blocked autophagy independently of PA. Additionally, pharmacologic inhibition of autophagy induced MLKL expression and translocation to the plasma membrane in hepatocytes.
Taken together, these data indicate that MLKL-dependent, but RIP3-independent, signaling contributes to FFC diet-induced liver injury by inhibiting autophagy.
Autophagy is a regulated process that maintains cellular homeostasis. Impaired autophagy contributes to cell injury and death, thus playing a critical role in the pathogenesis of a number of diseases, including non-alcohol-associated fatty liver and steatohepatitis. Herein, we show that Mlkl-dependent, but Rip3-independent, signaling contributed to diet-induced liver injury and inflammatory responses by inhibiting autophagy. These data identify a novel co-regulatory mechanism between necroptotic and autophagic signaling pathways in non-alcoholic fatty liver disease.
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•MLKL-mediated signaling contributes to FFC diet-induced liver injury.•FFC diet or palmitic acid treatment induces MLKL expression in hepatocytes.•Palmitic acid drives MLKL translocation to autophagosomes independently of Rip3.•Mlkl, but not Rip3, regulates autophagic flux in a murine model of NAFL/NASH.•Pharmacologic inhibition of autophagy induces MLKL expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Macrophage migration inhibitory factor (MIF), a pluripotent immune regulator, is an emerging mediator in alcohol‐related liver disease (ALD). MIF is associated with ALD progression through ...its chemokine‐ and cytokine‐like activities.
Methods
Mechanistic studies into the role of MIF in ethanol (EtOH)‐induced liver injury were performed in Mif−/− mice and in C57BL/6J mice treated with a small‐molecule MIF antagonist, MIF098, after Gao‐Binge (acute‐on‐chronic) EtOH feeding, an EtOH feeding protocol associated with hepatic neutrophilia and induction of the unfolded protein response (UPR).
Results
The MIF axis, for example, MIF and MIF receptors invariant polypeptide of major histocompatibility complex, class II antigen‐associated (CD74), CXCR2, CXCR4, and CXCR7, was enhanced in the livers of alcoholic hepatitis (AH) patients as compared to healthy controls. Mif−/− mice were protected from hepatocellular injury after Gao‐Binge feeding, independent of neutrophilia and inflammation, but were associated with the UPR. Interestingly, the UPR signature in AH patients and in mice following Gao‐Binge feeding was biased toward cell death with increased expression of pro‐cell death CCAAT–enhancer‐binding protein homologous protein (CHOP) and decreased prosurvival GRP78. The UPR and liver injury 6 hours after binge were prevented both in Mif−/− mice and in MIF098‐treated mice. However, both MIF interventions led to increased liver injury and exacerbated the hepatic UPR 9 hours after binge. Induction of upstream UPR signaling and expression of CHOP protein by thapsigargin in alpha mouse liver 12 hepatocytes were blunted by coexposure to MIF098, directly connecting MIF to UPR in hepatocytes.
Conclusions
The current study revealed that, in addition to its cytokine/chemokine functions, MIF is an upstream regulator of UPR in response to EtOH feeding in mice. Importantly, both MIF and UPR can either protect or contribute to liver injury, dependent upon the stage or severity of EtOH‐induced liver injury.
MIF is a pivotal regulator of innate immunity in alcohol‐related liver disease and in models of ethanol feeding in mice. In the current study, MIF was discovered to control aspects of the UPR following Gao‐Binge ethanol feeding in mice independent of inflammation. Global Mif deletion (A, B) and a MIF inhibitor, MIF098 (C, D), prevented ethanol‐induced eIF2α phosphorylation and expression of CHOP protein in livers of mice. MIF098 also decreased UPR activation in thapsigargin‐challenged hepatocytes (E–F) linking MIF directly to the UPR.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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•Interferon regulatory factor 3 (IRF3) has both transcriptional and non-transcriptional activity.•Gao-binge ethanol exposure increases both the phosphorylation and ubiquitination of ...IRF3.•Irf3−/− are protected from ethanol-induced liver injury but mice expressing non-transcriptional IRF3 activity are not.•The non-transcriptional activity of IRF3 modulates the innate immune environment of the liver.
Interferon regulatory factor 3 (IRF3) is a transcription factor mediating antiviral responses, yet recent evidence indicates that IRF3 also has critical non-transcriptional functions, including activating RIG-I-like receptors-induced IRF-3-mediated pathway of apoptosis (RIPA) and restricting activity of NF-κB. Using a novel murine model expressing only non-transcriptional IRF3 activity (Irf3S1/S1), we tested the hypothesis that non-transcriptional functions of IRF3 modulate innate immune responses in the Gao-binge (acute-on-chronic) model of alcohol-related liver disease.
IRF3 and IRF3-mediated signals were analysed in liver samples from 5 patients transplanted for alcoholic hepatitis and 5 healthy controls. C57BL/6, Irf3−/− and Irf3S1/S1 mice were exposed to Gao-binge ethanol-induced liver injury. IRF3-mediated RIPA was investigated in cultured macrophages.
Phospho-IRF3 and IRF3-mediated signals were elevated in livers of patients with alcoholic hepatitis. In C57BL/6 mice, Gao-binge ethanol exposure activated IRF3 signaling and resulted in hepatocellular injury. Indicators of liver injury were differentially impacted by Irf3 genotype. Irf3−/−, but not Irf3S1/S1, mice were protected from steatosis, elevated alanine/aspartate aminotransferase levels and inflammatory cytokine expression. In contrast, neutrophil accumulation and endoplasmic reticulum stress were independent of genotype. Protection from Gao-binge injury in Irf3−/− mice was associated with an increased ratio of Ly6Clow (restorative) to Ly6Chigh (inflammatory) cells compared to C57BL/6 and Irf3S1/S1 mice. Reduced ratios of Ly6Clow/Ly6Chigh in C57BL/6 and Irf3S1/S1 mice were associated with increased apoptosis in the Ly6Clow population in response to Gao-binge. Activation of primary macrophage cultures with Poly (I:C) induced translocation of IRF3 to the mitochondria, where it associated with Bax and activated caspases 3 and 9, processes indicative of activation of the RIPA pathway.
Taken together, these data identify that the non-transcriptional function of IRF3 plays an important role in modulating the innate immune environment in response to Gao-binge ethanol exposure, via regulation of immune cell apoptosis.
Activation of the innate immune system contributes to inflammation in the progression of alcohol-related liver disease, as well as to the resolution of injury. Here we show that the protein IRF3 modulates the innate immune environment of the liver in a mouse model of alcoholic hepatitis. It does this by increasing the apoptotic cell death of immune cells that promote the resolution of injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•We review data on urban agriculture and food security in low-income countries.•Producing food for household consumption drives participation in urban agriculture.•Urban agriculture can positively ...impact food availability and dietary diversity.•It may provide household income, but not always enough to ensure food security.•Urban agriculture can create distinct benefits for women, financially and socially.
With increasing global urbanization and environmental threats, ensuring food security for poor city residents is a critical challenge. An ongoing debate is whether urban agriculture (UA) may serve as a pathway to food security for poor urban households. To assess this potential within low-income countries, we used standard systematic review procedures to synthesize findings from 35 peer-reviewed journal articles from 1980 to 2013 that presented data on UA and food security indicators. Though data quality was often lacking, several key findings emerged. Many of the reviewed studies found subsistence to be the primary motivation for practicing UA, followed by financial benefit, with UA substantially contributing to farming households’ food availability in some settings. Results regarding UA’s impact on dietary diversity reveal that in some farming systems UA may provide households with greater access to specific foods. Evidence also indicates that UA can be a key source of household income, though actual returns were low. Furthermore, results show that UA can facilitate women’s contribution to household food availability amid other household responsibilities, and can provide distinct benefits such as economic and social advancement. Although UA participation does not appear to fully eliminate pressure urban households face in obtaining food, a lack of supportive policies may constrain its potential. Municipal planning and agricultural policies that more effectively incorporate UA—and that integrate gender—may diminish barriers to productive UA practice. More rigorous research on UA’s contribution to food security in settings where supportive policies have been enacted would more clearly elucidate these linkages.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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