The characteristics of long-term survivors with idiopathic pulmonary fibrosis (IPF) have never been fully elucidated. We sought to illustrate the attenuated mortality and describe the characteristics ...of patients with IPF who survived at least 5 years beyond their initial presentation.
Patients with IPF evaluated between 1997 and 2006 were identified through the clinic database. Patients who survived beyond 5 years from the time of their evaluation were compared with those who died or underwent lung transplantation within 5 years. Survival analyses were performed from the time of initial evaluation and contingent on annualized survival thereafter.
Eighty-seven patients who survived at least 5 years formed the comparator group to whom other patients were contrasted. These patients had a higher BMI, FVC % predicted, FEV1 % predicted, total lung capacity % predicted, and diffusing capacity of lung for carbon monoxide % predicted, but a lower FEV1/FVC ratio and lower mean pulmonary artery pressures. More than one-half of these patients had moderate or severe disease at the time of presentation. Our annualized contingent survival analyses revealed a progressively increasing median survival dependent on the duration of the disease.
Although we were able to demonstrate differences in our 5-year survivors, rather than being a distinct group, these patients appear to exist within a continuum of improving survival dependent on prior disease duration. This progressively improving time-dependent prognosis mandates the serial reevaluation of an individual patient’s projected outcomes. The implementation of dynamic counseling is an important concept in more accurately predicting life expectancy for patients with IPF who are frequently haunted by the prospects of a dismal survival.
Chemoproteomic profiling is a powerful approach to define the selectivity of small molecules and endogenous metabolites with the human proteome. In addition to mechanistic studies, proteome ...specificity profiling also has the potential to identify new scaffolds for biomolecular sensing. Here, we report a chemoproteomics-inspired strategy for selective sensing of acetyl-CoA. First, we use chemoproteomic capture experiments to validate the N-terminal acetyltransferase NAA50 as a protein capable of differentiating acetyl-CoA and CoA. A Nanoluc-NAA50 fusion protein retains this specificity and can be used to generate a bioluminescence resonance energy transfer (BRET) signal in the presence of a CoA-linked fluorophore. This enables the development of a ligand displacement assay in which CoA metabolites are detected via their ability to bind the Nanoluc-NAA50 protein “host” and compete binding of the CoA-linked fluorophore “guest”. We demonstrate that the specificity of ligand displacement reflects the molecular recognition of the NAA50 host, while the window of dynamic sensing can be controlled by tuning the binding affinity of the CoA-linked fluorophore guest. Finally, we show that the method’s specificity for acetyl-CoA can be harnessed for gain-of-signal optical detection of enzyme activity and quantification of acetyl-CoA from cellular samples. Overall, our studies demonstrate the potential of harnessing insights from chemoproteomics for molecular sensing and provide a foundation for future applications in target engagement and selective metabolite detection.
OBJECTIVE The outcomes of patients with idiopathic pulmonary fibrosis (IPF) who undergo hospitalization have not been well characterized. We sought to determine the frequency of all-cause and ...respiratory-related hospitalizations and to evaluate their impact on the subsequent course and survival of patients with IPF. METHODS The records of patients with IPF evaluated at a tertiary center were examined for the cause and duration of hospitalization. Data on subsequent patient outcomes were collated. RESULTS The IPF cohort consisted of 592 patients, 25.3% of whom were hospitalized subsequent to their IPF diagnosis. A respiratory-related cause accounted for 77.3% of these hospitalizations. The median transplant-free survival for all patients was 23.3 months (interquartile range IQR, 7.6-63.6 months) from the time of consultation. Transplant-free survival after hospital admission was much lower for patients with a respiratory hospitalization compared with those with a nonrespiratory hospitalization (median survival, 2.8 months IQR, 0.63-16.2 months vs 27.7 months IQR, 7.4-59.6 months; P = .0004). Multivariate analyses demonstrated that both all-cause and respiratory-related hospitalizations were strongly associated with mortality after adjusting for baseline demographics. Among patients with a respiratory hospitalization, 22.4% died while in the hospital, whereas 16.4% eventually went on to lung transplantation. CONCLUSIONS Hospitalizations are common events in patients with IPF. Most hospitalizations are respiratory-related and are associated with high in-hospital mortality and limited survival beyond discharge. Both all-cause and respiratory hospitalizations are associated with mortality, and therefore, either could be used as an end point in IPF clinical trials.
Purpose: The need for community-viable, evidence-based intervention strategies for toddlers with autism spectrum disorder (ASD) is a national priority. The purpose of this research forum article is ...to identify gaps in intervention research and needs in community practice for toddlers with ASD, incorporate published findings from a randomized controlled trial (RCT) of the Early Social Interaction (ESI) model (Wetherby et al., 2014) to illustrate community-based intervention, report new findings on child active engagement from the ESI RCT, and offer solutions to bridge the research-to-community practice gap. Method: Research findings were reviewed to identify gaps in the evidence base for toddlers with ASD. Published and new findings from the multisite ESI RCT compared the effects of two different ESI conditions for 82 toddlers with ASD to teach parents how to support active engagement in natural environments. Results: The RCT of the ESI model was the only parent-implemented intervention that reported differential treatment effects on standardized measures of child outcomes, including social communication, developmental level, and adaptive behavior. A new measure of active engagement in the natural environment was found to be sensitive to change in 3 months for young toddlers with ASD and to predict outcomes on the standardized measures of child outcomes. Strategies for utilizing the Autism Navigator collection of web-based courses and tools using extensive video footage for families and professional development are offered for scaling up in community settings to change developmental trajectories of toddlers with ASD. Conclusions: Current health care and education systems are challenged to provide intervention of adequate intensity for toddlers with ASD. The use of innovative technology can increase acceleration of access to evidence-based early intervention for toddlers with ASD that addresses health disparities, enables immediate response as soon as ASD is suspected, and rapidly bridges the research-to-practice gap.
Widespread field-evolved resistance of bollworm Helicoverpa zea (Boddie) to Cry1 and Cry2 Bt proteins has threatened the utility of Bt cotton for managing bollworm. Consequently, foliar insecticide ...applications have been widely adopted to provide necessary additional control. Field experiments were conducted across the Mid-South and inTexas to devise economic thresholds for foliar insecticide applications targeting bollworm in cotton. Bt cotton technologies including TwinLink (TL; Cry1Ab+Cry2Ae), TwinLink Plus (TLP; Cry1Ab+Cry2Ae+Vip3Aa), Bollgard II (BG2; Cry1Ac+Cry2Ab), Bollgard 3 (BG3; Cry1Ac+Cry2Ab+Vip3Aa), WideStrike (WS; Cry1Ac+Cry1F), WideStrike 3 (WS3; Cry1Ac+Cry1F+Vip3Aa), and a non-Bt (NBT) variety were evaluated. Gain threshold, economic injury level, and economic thresholds were determined. A 6% fruiting form injury threshold was selected and compared with preventive treatments utilizing chlorantraniliprole. Additionally, the differences in yield from spraying bollworms was compared among Bt cotton technologies. The 6% fruiting form injury threshold resulted in a 25 and 75% reduction in insecticide applications relative to preventive sprays for WS and BG2, respectively. All Bt technologies tested in the current study exhibited a positive increase in yield from insecticide application. The frequency of yield increase from spraying WS was comparable to that of NBT. Significant yield increases due to insecticide application occurred less frequently in triple-gene Bt cotton. However, their frequencies were close to the dual-gene Bt cotton, except for WS. The results of our study suggest that 6% fruiting form injury is a viable threshold, and incorporating a vetted economic threshold into an Integrated Pest Management program targeting bollworm should improve the sustainability of cotton production.
The hypoxia-inducible factor (HIF) pathway, regulated by prolyl hydroxylase, is central to tissue adaptation to ischemia. The authors tested whether the prolyl hydroxylase inhibitor ...dimethyloxalylglycine reduces skin flap necrosis.
Dorsal skin flaps were raised on hairless rats, with dimethyloxalylglycine delivered intraperitoneally and/or topically for 7 days before and after surgery. After 14 treatment days, percentage of flap necrosis was compared grossly and tissue perfusion compared with an in vivo imaging system. Angiogenesis was compared using immunohistochemical CD31 staining and enzyme-linked immunosorbent assay for tissue vascular endothelial growth factor. Expression levels of HIF-1α and terminal deoxynucleotidyl transferase-mediated dUDP end-labeling were compared using immunohistochemical staining. Complete blood counts and gross necropsy specimens were obtained to assess systemic toxicity.
Dimethyloxalylglycine administration significantly improved postoperative flap viability, with combined topical and intraperitoneal dimethyloxalylglycine administration leading to reduced necrosis on postsurgical day 7 at 6 mg/kg/day, 12 mg/kg/day, 24 mg/kg/day, and 48 mg/kg/day versus controls (all p < 0.05). Compared with controls (unperfused, 39.9 ± 3.8 percent), dimethyloxalylglycine treatment led to a dose-dependent decrease in unperfused tissue at 6 mg/kg/day (11.4 ± 1.7 percent), 12 mg/kg/day (9.4 ± 4.2 percent), 24 mg/kg/day (4.7 ± 2.6 percent), and 48 mg/kg/day (1.4 ± 0.9 percent) (all p < 0.001). Topical dimethyloxalylglycine application alone administered at 48 mg/kg/day was sufficient to improve flap viability (p = 0.005). Dimethyloxalylglycine-treated flaps exhibited higher CD31 staining (p = 0.004), tissue vascular endothelial growth factor (p = 0.007), HIF-1α staining (p < 0.001), and reduced terminal deoxynucleotidyl transferase-mediated dUDP end-labeling staining (p = 0.045). There were no differences in hematocrit or macroscopic organ changes on gross necropsy.
Topical and systemic targeting of the HIF-1 pathway may be a promising therapeutic approach to improve flap resistance to ischemia.
Foliar-applied insecticide treatments may be necessary to manage thrips in cotton (Gossypium hirsutum L.) under severe infestations or when at-planting insecticide seed treatments do not provide ...satisfactory protection. The most common foliar-applied insecticide is acephate. Field observations in Tennessee suggest that the performance of acephate has declined. Thus, the first objective was to perform leaf-dip bioassays to assess if tobacco thrips, Frankliniella fusca (Hinds) (Thysanoptera: Thripidae), in cotton production regions have evolved resistance to foliar-applied insecticides. A second objective was to assess the performance of commonly applied foliar insecticides for managing thrips in standardized field trials in Arkansas, Tennessee, Mississippi, and Texas. For both objectives, several insecticides were evaluated including acephate, dicrotophos, dimethoate, lambda-cyhalothrin, imidacloprid, and spinetoram. Field trials and bioassays were completed from 2018 to 2021. Dose-response bioassays with acephate were performed on tobacco thrips field populations and a susceptible laboratory population. Bioassay results suggest that tobacco thrips have developed resistance to acephate and other organophosphate insecticides; however, this resistance seems to be most severe in Arkansas, Tennessee, and the Delta region of Mississippi. Resistance to other classes of insecticides were perhaps even more evident in these bioassays. The performance of these insecticides in field trials was variable, with tobacco thrips only showing consistent signs of resistance to lambda-cyhalothrin. However, it is evident that many populations of tobacco thrips are resistant to multiple classes of insecticides. Further research is needed to determine heritability and resistance mechanism(s).
Background: Hemothorax after lung transplantation may result in increased post-operative morbidity and mortality. Risk factors for developing hemothorax and the outcomes of patients who develop ...hemothorax have not been well studied. Methods: A retrospective chart review was performed on all patients who underwent lung transplantation at a single center between March 2009 and July 2014. Comparison was made between patients with and without hemothorax post-transplant. Results: There were 132 lung transplantations performed during the study period. Hemothorax was a complication in 17 (12.9 %) patients, occurring an average of 9 days after transplant. No difference was found between the hemothorax and non-hemothorax groups with respect to age, preoperative anticoagulation, lung allocation score, prior thoracotomy, coagulation profile, use of cardiopulmonary bypass, ischemic time, or postoperative P/F ratio. There was a trend towards a higher incidence of hemothorax in patients with underlying sarcoidosis and re-transplantation (p = 0.13 and 0.17, respectively). Hemothorax developed early (<48 h post-operatively) in 5 patients and presented in a delayed manner (≥48 h post-operatively) in 12 patients. Delayed hemothorax occurred primarily in the setting of anticoagulation (10 out of 12 patients). The hemothorax group had decreased ventilator-free days (p = 0.006), increased ICU length of stay (p = 0.01) and increased hospital length of stay (p = 0.005). Hemothorax was also associated with reduced 90-day survival (p = 0.001), but similar 1, 3, and 5-year survival (p = 0.63, p = 0.30, and p = 0.25), respectively). Conclusion: The development of hemothorax is associated with increased morbidity and decreased short-term survival. Hemothorax may present either within the first 48 h after surgery or in a delayed fashion, most commonly in the setting of anticoagulation.
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