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Amy L Olson, Kevin K Brown, Jeffrey J SwigrisDepartment of Medicine Division of Pulmonary Medicine, Interstitial Lung Disease Program and Autoimmune Lung Center, National Jewish Health, Denver, CO, USA Abstract: Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive pulmonary disease characterized by the insidious onset of shortness of breath due to parenchymal scarring. As IPF progresses, breathlessness worsens, physical functional capacity declines, and health-related quality of life (HRQL) – the impact of health or disease on a person’s satisfaction with their overall station in life – deteriorates. These two inextricably linked variables – breathlessness and physical functional capacity – are strong drivers of HRQL. With the emergence of new and prospective therapies for IPF, it is more important than ever to be able to accurately and reliably assess how IPF patients feel and function. Doing so will promote the development of novel interventions to target impairments in these areas and ensure that the field is capable of assessing the effect of therapeutics interventions on these critically important patient-centered outcomes. Keywords: idiopathic pulmonary fibrosis, health-related quality of life, functional status

One of the early events in the development of Type 2 diabetes appears to be an inhibition of insulin-mediated GLUT4 redistribution to the cell surface in tissues that express GLUT4. Understanding this process, and how it begins to breakdown in the development of insulin resistance is quite important as we face treatment and prevention of metabolic diseases. Over the past few years, and increasing number of laboratories have produced compelling data to demonstrate a role for both the actin and microtubule networks in the regulation of insulin-mediated GLUT4 redistribution to the cell surface. In this review, we explore this process from insulin-signal transduction to fusion of GLUT4 membrane vesicles, focusing on studies that have implicated a role for the cytoskeleton. We see from this body of work that both the actin network and the microtubule cytoskeleton play roles as targets of insulin action and effectors of insulin signaling leading to changes in GLUT4 redistribution to the cell surface and insulin-mediated glucose uptake. [ABSTRACT FROM AUTHOR]

Background: It is now recognized that a significant portion of patients with idiopathic pulmonary fibrosis (IPF) can have sudden and rapid deteriorations in disease course that cannot be explained by infection, heart failure, or thromboembolic disease. These events are often fatal and have been termed acute exacerbations (AEs) of underlying disease. While best described in patients with IPF, they have also been reported in patients with other forms of interstitial lung disease. We sought to determine if this same phenomenon occurs in patients with hypersensitivity pneumonitis (HP).Methods: We retrospectively reviewed our clinical experience at National Jewish Medical and Research Center for patients with surgical lung biopsy-proven fibrotic HP who had an acute decline in respiratory status and met criteria similar to those proposed for the diagnosis of an AE of IPF.Results: Over a 2-year period, we identified four patients with an AE of fibrotic HP. All patients had a clinical course similar to that most frequently described in AEs of IPF: respiratory failure requiring assisted ventilation, lack of clinical response to high-dose corticosteroid therapy, and a poor prognosis (all cases resulted in death or emergent lung transplantation). Lung biopsy at the time of the AE, explant, or autopsy revealed organizing diffuse alveolar damage superimposed on fibrotic lung disease.Conclusions: Fibrotic HP, like other forms of fibrotic lung disease, can be associated with AEs of disease. Further investigation into similarities and pathways common in AEs of various fibrotic lung diseases may yield additional insight into this recently recognized syndrome. [ABSTRACT FROM AUTHOR]

Congenital central hypoventilation syndrome (CCHS) typically presents in the newborn period. A case series of five adults is presented, each heterozygous for a documented polyalanine expansion mutation in the PHOX2B gene and evidence of nocturnal alveolar hypoventilation. All cases had symptoms in childhood, but survived to adulthood without ventilatory support. After identification of physiologic compromise, artificial ventilation was initiated. These adults have the mildest of the CCHS-related PHOX2B polyalanine expansion mutations, coding for only five extra alanines; three of the adults have affected offspring. Report of these cases should lead to a more rapid identification of CCHS presenting in adulthood. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) frequently complicates connective tissue diseases (CTDs). Glucocorticoids and immunomodulatory agents are regarded as mainstays of therapy for CTD-related ILD; however, apart from those studies that have evaluated certain medications for patients with scleroderma, few studies have been performed. In this study, our objectives were to examine the safety and tolerability of mycophenolate mofetil (MMF) and to determine its impact on lung function in patients with CTD-ILD.Methods: In this retrospective observational study, we analyzed patients at our center who ever received MMF for CTD-ILD. We examined the frequency and severity of side effects associated with MMF and used longitudinal data analytic methods to determine the ability of MMF to maintain lung function over time.Results: Twenty-eight patients were treated with MMF over 35.9 patient-years. The most common underlying CTD diagnosis was scleroderma (n = 9). The most common reason for initiating MMF was an adverse effect of a prior immunomodulatory agent. Six patients had clinically significant side effects related to MMF; all resolved with dose reduction. Compared to before MMF, the mean daily prednisone dose while patients were receiving MMF was lower (10 mg/d vs 15 mg/d, p = 0.09). In addition, since starting MMF, the average percentage of predicted forced vital capacity (FVC), average percentage of predicted total lung capacity, and average percentage of predicted diffusing capacity of the lung for carbon monoxide for the cohort increased by 2.3%, 4.0%, and 2.6%, respectively.Conclusion: MMF appears to be safe and well tolerated in patients with CTD-ILD. Larger-scale studies are needed to further evaluate the efficacy of MMF in this patient population. [ABSTRACT FROM AUTHOR]

This study examined the relationship among the recovery grip strength, functional outcomes; and work performance following occupational therapy intervention for hand trauma. This study had a sample size of 15 participants whose recovery grip strength was measured using a Jamar dynamometer, whose satisfaction with outcomes was measured by the Michigan Hand Outcomes Questionnaire (MHQ), and whose compliance with the home therapy program was measured by a visual analog scale (VAS). A Pearson r correlation demonstrated a significant relationship between recovery grip strength and two MHQ subset scores: overall hand function (r = 0.59, p = 0.019) and activities of daily living (ADL) performance (r = 0.61, p = 0.016). The participants' self-rating of compliance did not predict or influence either recovery grip strength or MHQ scores. A moderate positive correlation approaching significance (r = 0.51. p = 0.052) was found between grip strength and overall MHQ scores. The researchers concluded that a recovery grip strength measure should be used along with functional measures to appropriately assess overall hand function following hand trauma. [ABSTRACT FROM AUTHOR]

OBJECTIVE. To determine the incidence of depressive symptoms in mothers of toddlers in community pediatric practice. The interaction of employment and work role satisfaction with depressive symptoms was also investigated. SUBJECTS AND METHODS. Depression screening measures were completed by 233 mothers of toddlers (aged 12 to 24 months) at health supervision visits in two community pediatric practices in New Hampshire. Depression was evaluated with a depressive symptom screening inventory modified by Barrett, Oxman, and Gerber from the Hopkins Symptom Checklist for use in primary care population. Data were obtained on parents' socioeconomic variables, hours worked, and whether the mother was satisfied with her current role of being employed or not employed. RESULTS. Depressive symptoms were present in 42% of mothers. Rates of depressive symptoms were similar in employment groups but varied significantly with work role satisfaction. When both employment and satisfaction were considered, mothers who were dissatisfied were 3.7 times more likely to be depressed. After controlling for work role satisfaction, mothers working part time were half as likely to be depressed as mothers working full time and not employed. CONCLUSION. Depressive symptoms are a major problem for mothers of toddlers in middle class pediatric practice. Work role satisfaction and employment status together are related to depressive symptoms. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Rising rates of skin cancer associated with early-life sun exposure make it important to improve adolescent sun-protection practices. Our study objective was to determine if a multicomponent community-wide intervention could alter the decline in sun protection that begins in early adolescence. METHODS: A randomized, controlled trial was conducted in 10 communities to assess the impact of the SunSafe in the Middle School Years program. The intervention sought to (1) educate and activate adults and peers to role model and actively promote sun-protection practices and (2) create a pro-sun protection community environment. It targeted school personnel, athletic coaches, lifeguards, and clinicians and enlisted teens as peer advocates. Annual observations of cross-sectional samples of teens at community beach/pool sites were used to assess the impact of 1 and 2 years of intervention exposure compared to grade-matched controls. The outcome was percent of body surface protected by sunscreen, clothing, or shade. RESULTS: Observers determined the sun protection level of 1927 adolescents entering 6th to 8th grades. After 2 years of intervention exposure, adolescents at the beach/pool in intervention communities were significantly better protected than those in control communities. Over 2 years, the percent of body surface area protected declined by 23% in the control arm but only 8% in intervention arm. After intervention, the average percent of body surface protected at intervention sites (66.1%) was significantly greater than control sites (56.8%). Teens in intervention communities reported sun-protection advice from more adult sources, were more likely to use sunscreen, and applied it more thoroughly than control-site teens. CONCLUSIONS: Our multicomponent model addressing adolescent sun protection shows the power of engaging teens and adults from across the community as role models and educators. This new ecological approach shows promise in changing adolescent sun protection behaviors and reducing skin cancer risks. [ABSTRACT FROM AUTHOR]

Age-dependent changes in adipose tissue are thought to play a role in development of insulin resistance. A major age-dependent change in adipose tissue is the downregulation of key proteins involved in carbohydrate metabolism. In the current study, we investigate the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) a key governor of the rate of glycolysis in adipocytes via the synthesis of fructose-2,6-bisphosphate that was significantly downregulated in aged mice. We employed an adipocyte-specific PFKFB3 mouse line to investigate the role of PFKFB3 on adipocyte function. In both aged mice and PFKFB3-knockout mice, we observed an increase in O-glcNAcylated proteins consistent with a shift in glucose metabolism toward the hexosamine biosynthetic pathway. Under chow-fed conditions, PFKFB3 knockout resulted in significantly smaller adipocyte area, but no difference in total fat mass. While glucose tolerance was unchanged under chow conditions, when mice were challenged with a 4 weeks high-fat feeding, PFKFB3 deletion led to a greater decrease in glucose tolerance as well as a significant increase in macrophage infiltration. These results indicate that perturbation of the glycolytic pathway in adipose tissue has multiple effects of adipocyte biology and may play a significant role in metabolic changes associated with aging. Results of this student support the notion that changes in glucose metabolism in adipose tissue impact whole-body metabolism., (© 2024 Federation of American Societies for Experimental Biology.)

Rationale: While exposure to air pollution is a known risk factor for adverse pulmonary outcomes, its impact in individuals with idiopathic pulmonary fibrosis (IPF) is less well understood., Objective: To investigate the effects of long-term exposure to air pollution on disease severity and progression in patients with IPF and to determine whether genomic factors, such as MUC5B promoter polymorphism or telomere length, modify these associations., Methods: We performed analyses at enrollment and after one year of follow-up in the IPF-PRO Registry, a prospective observational registry that enrolled individuals with IPF at 46 US sites from June 2014 to October 2018. Five-year average pollution exposures (PM 2.5 , NO 2 , O 3 ) prior to enrollment date were estimated at participants' residential addresses with validated national spatio-temporal models. Multivariable regression models estimated associations between pollution exposure and physiologic measurements (FVC, DL CO , supplemental oxygen use at rest) and quality of life measurements (St. George's Respiratory Questionnaire [SGRQ], EuroQoL, Cough and Sputum Assessment Questionnaire) at enrollment. Cox proportional hazard models estimated associations between pollutants and a composite outcome of death, lung transplant, or >10% absolute decline in FVC % predicted in the year after enrollment. Models were adjusted for individual-level and spatial confounders, including proxies for disease onset. Gene-environment interactions with MUC5B and telomere length were assessed., Results: Of 835 participants, 94% were non-Hispanic Whites, 76% were male, mean (SD) age was 70 (7.7) years. In fully adjusted analyses, higher PM 2.5 exposure was associated with worse quality of life per SGRQ activity score (3.48 [95% confidence interval (CI) 0.64, 6.32] per 2µg/m 3 PM 2.5 ) and EuroQoL scores (-0.04 [95%CI -0.06, -0.01] per 2µg/m 3 PM 2.5 ), and lower FVC % predicted and lower DL CO % predicted at enrollment. Each 3 parts per billion difference in O 3 exposure was associated with a 1.57% [95% CI 0.15, 2.98] higher FVC % predicted at enrollment, although this effect was attenuated in multi-pollutant models. There was no association between NO 2 and enrollment measures, between pollution exposure and one-year outcomes, or evidence for gene-environment interactions., Conclusion: In the IPF-PRO Registry, long-term exposure to PM 2.5 was associated with worse quality of life and lung function at enrollment, but not with short-term disease progression or mortality. There was no evidence of effect modification by interaction of genomic factors with pollution. The reason for the unexpected relationship between O 3 exposure and higher FVC is unclear.

Background: The Myositis Interstitial Lung Disease Nintedanib Trial (MINT) is a hybrid trial, which is enrolling patients both at local sites and remotely via a decentralised site. The trial will investigate the efficacy and safety of nintedanib in patients with progressive myositis-associated interstitial lung disease (MA-ILD)., Methods/design: MINT is an exploratory, prospective randomised placebo-controlled trial. Eligible patients will have myositis and evidence of fibrosing ILD on high-resolution computed tomography (HRCT), be taking standard of care medications for myositis, and meet criteria for ILD progression within the prior 24 months based on decline in FVC, worsened fibrosis on HRCT, and/or worsened dyspnoea. Patients will be randomised 1:1 to receive nintedanib 150 mg twice daily or placebo for 12 weeks then open-label nintedanib for 12 weeks. Patients will be enrolled at local sites and a decentralised site. Most study visits will be completed remotely using telemedicine or digital health technologies. The primary endpoint is the change in Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnoea domain score at week 12. Other endpoints include changes in other L-PF questionnaire domains, lung function, imaging, and physical activity, and assessment of adverse events. Data collected using remote versus clinic enrolment, and using home versus clinic spirometry, will be compared., Discussion: MINT is an innovative, hybrid trial that will evaluate the effects of nintedanib on symptoms, quality of life, and ILD progression in patients with progressive MA-ILD and provide valuable information on the utility of decentralised recruitment and remote data collection in clinical trials., Trial Registration: Clinicaltrials.gov NCT05799755 (date of registration: 05/04/2023)., (© 2024. The Author(s).)

Background: To assess the characteristics of patients enrolled in the ILD-PRO Registry., Methods: The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months. Patient characteristics were analysed based on the number of patients with available data., Results: Of the first 491 patients enrolled, the majority were white (75.4%) and female (60.6%); 47.4% had a history of smoking. Reported ILDs were autoimmune disease-associated ILDs (47.2%), hypersensitivity pneumonitis (17.5%), idiopathic non-specific interstitial pneumonia (9.1%), interstitial pneumonia with autoimmune features (8.9%), unclassifiable ILD (7.6%), other ILDs (9.7%). At enrolment, median (Q1, Q3) FVC % predicted was 62.2 (49.4, 72.4) and DLco % predicted was 39.2 (30.2, 49.2). Median (Q1, Q3) total score on the St. George's Respiratory Questionnaire was 50.8 (35.9, 64.7). The most common comorbidities were gastroesophageal reflux disease (61.1%) and sleep apnoea (29.6%). Overall, 64.5% of patients were receiving immunosuppressive or cytotoxic therapy, 61.1% proton-pump inhibitors, 53.2% oral steroids, 19.8% nintedanib and 3.6% pirfenidone., Conclusions: Patients enrolled into the ILD-PRO Registry have a variety of ILD diagnoses, marked impairment in lung function and health-related quality of life, and high medication use. Longitudinal data from this registry will further our knowledge of the course of progressive pulmonary fibrosis., Trial Registration: ClinicalTrials.gov, NCT01915511; registered August 5, 2013., (© 2024. The Author(s).)

Introduction: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention., Methods: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry., Results: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification., Discussion: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology., Highlights: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Rationale: The proportion of patients who develop progressive pulmonary fibrosis (PPF), along with risk factors for progression remain poorly understood., Objectives: To examine factors associated with an increased risk of developing PPF among patients at a referral center., Methods: We identified patients with a diagnosis of interstitial lung disease (ILD) seen within the Cleveland Clinic Health System. Utilizing a retrospective observational approach we estimated the risk of developing progression by diagnosis group and identified key clinical predictors using the FVC component of both the original progressive fibrotic interstitial lung disease (PFILD) and the proposed PPF (ATS) criteria., Results: We identified 5934 patients with a diagnosis of ILD. The cumulative incidence of progression over the 24 months was similar when assessed with the PFILD and PPF criteria (33.1 % and 37.9 % respectively). Of those who met the ATS criteria, 9.5 % did not meet the PFILD criteria. Conversely, 4.3 % of patients who met PFILD thresholds did not achieve the 5 % absolute FVC decline criteria. Significant differences in the rate of progression were seen based on underlying diagnosis. Steroid therapy (HR 1.46, CI 1.31-1.62) was associated with an increased risk of progressive fibrosis by both PFILD and PPF criteria., Conclusion: Regardless of the definition used, the cumulative incidence of progressive disease is high in patients with ILD in the 24 months following diagnosis. Some differences are seen in the risk of progression when assessed by PFILD and PPF criteria. Further work is needed to identify modifiable risk factors for the development of progressive fibrosis., Competing Interests: Declaration of competing interest The study is funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Maeve Macmurdo, Xinge Ji, Alex Milinovich, Blaine Martyn-Dow, Aman Pande, Alex Zajichek, Janine Bauman, David Sugano, Michael W. Kattan and Daniel A. Culver are employed by the Cleveland Clinic which received research support from BIPI to collaborate on this project. Pratik Pimple, Amy L. Olson, Shaun Bender, and Craig Conoscenti are employees of BIPI. Daniel Culver received honoraria from BIPI for his participation in a Steering Committee, from Pliant for his participation in an Adjudication Committee and coverage for travel costs from Roche. All other members of the Cleveland Clinic study team cited no other disclosures., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m 2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m 2 and two at dose of 1.2 mg/m 2 . None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m 2 . One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT., (© 2024 Wiley Periodicals LLC.)

We employ amplitude- and phase-resolved second harmonic generation experiments to probe interactions of fused silica:aqueous interfaces with Al 3+ , Mg 2+ , and Na + cations at pH 4 and as a function of metal cation concentration. We quantify the second-order nonlinear susceptibility and the total interfacial potential in the presence and absence of a 10 mM screening electrolyte to understand the influence of charge screening on cation adsorption. Strong cation:surface interactions are observed in the absence of the screening electrolyte. The total potential is then employed to estimate the total number of absorbed cations cm -2 . The contributions to the total potential from the bound and mobile charges were separated using Gouy-Chapman-Stern model estimates. All three cations bind fully reversibly, indicating physisorption as the mode of interaction. Of the isotherm models tested, the K d adsorption model fits the data with binding constants of 3-30 and ∼300 mol -1 for the low (<0.1 mM) and high (0.1-3 mM) concentration regimes, corresponding to adsorption free energies of -13 to -18 and -24 kJ mol -1 at room temperature, respectively. The maximum surface coverages are around 10 13 cations cm -2 , matching the number of deprotonated silanol groups on silica at pH 4. Clear signs of decoupled Stern and diffuse layer nonlinear optical responses are observed and found to be cation-specific.

Background: Fibrosing interstitial lung disease (ILD) encompasses more than 200 diverse pulmonary disorders, of which up to 40% become progressive. The 4 underlying ILD types most likely to result in progression are unclassified ILD/idiopathic interstitial pneumonia (IIP), autoimmune ILDs, exposure-related ILD/hypersensitivity pneumonitis, and sarcoidosis., Objective: To compare health care resource utilization (HCRU) and costs among patients with fibrosing ILD that has progressed ("progressive" fibrosing cohort) vs patients whose fibrosis did not meet criteria set for progression ("not yet progressed" cohort)., Methods: This was a noninterventional study of commercial enrollees and Medicare Advantage with Part D beneficiaries, which used administrative claims data for the period from October 1, 2015, through May 31, 2021. Adult patients (aged ≥18 years) with fibrosing ILD and 12 months of continuous health plan enrollment were included. Patients with idiopathic pulmonary fibrosis, baseline ILD diagnoses, or missing demographic data were excluded. Patients were first classified according to the underlying type of fibrosing ILD. For statistical analyses of outcomes, 2 cohorts were compared within each subtype: progressive fibrosing ILD vs not yet progressed ILD. The final study population included propensity score-matched (PSM) patients (1:1) based on pre-ILD baseline demographic and clinical characteristics. HCRU categories included inpatient hospitalization counts and the number of inpatient days and total costs (in 2021 US dollars), analyzed descriptively and weighted by the per-patient-per-month cost. Lin's regression was used to predict 12-month total cost estimates for comparison by cohort., Results: The distribution by underlying conditions was as follows: autoimmune ILD (n = 4,156), HP (n = 8,181), sarcoidosis (n = 775), and unclassified ILD/IIP (n = 18,635). After PSM, pre-ILD baseline variables were generally well balanced between the progressive and not yet progressed fibrosing ILD cohorts. For all underlying subtypes of ILD, patients in the progressive cohort had significantly more utilization and higher costs compared with patients in the not yet progressed cohort. Progressive cohorts had significantly higher adjusted rates of inpatient days among patients with at least 1 inpatient stay compared with the not yet progressed cohorts (all P < 0.01). In addition, the progressive cohorts had significantly higher adjusted 12-month total costs, with the differences ranging from $24,493 to $55,072 (all comparisons P < 0.001)., Conclusions: Irrespective of underlying ILD type, patients with progressive fibrosing ILD had significantly increased HCRU and cost relative to those whose fibrosing ILD had not yet progressed.

Outcomes of myelofibrosis (MF) with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade, related in part to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplantation outcomes. However, most studies lack homogeneity in conditioning regimens used, limiting their ability to assess prognostic factors on transplantation outcomes. We aimed to identify the risk factors that predict transplantation outcomes in patients with MF who underwent matched or mismatched allo-SCT using a uniform myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis. This single-center study included patients with MF who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) and received busulfan and fludarabine conditioning with methotrexate/tacrolimus-based GVHD prophylaxis. Sixty-five patients with MF met the study criteria and were included in our analysis. At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (hazard ratio [HR], .33; 95% confidence interval [CI], .11 to .99; P = .048). For NRM, Hematopoietic Cell Transplantation Comorbidity Index (≥3 versus <3; HR, 10.09; 95% CI, 2.09 to 48.76; P = .004) and donor type (MUD versus MRD: HR, 5.38; 95% CI, 1.14 to 25.30; P = .033; MMUD versus MRD: HR, 10.73; 95% CI, 1.05 to 109.4; P = .045) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (≥3 versus <3; HR, 3.31; 95% CI, 1.22 to 8.99; P = .019) and donor type (MMUD versus MRD: HR, 5.20; 95% CI, 1.35 to 19.98; P = .016) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival, but the difference did not reach statistical significance (>12 months versus ≤12 months: NRM: HR, 7.20; 95% CI, .96 to 53.94; P = .055; OS: HR, 2.60; 95% CI, .95 to 7.14; P = .06). In a homogenous cohort of MF patients uniformly treated with busulfan/fludarabine myeloablative conditioning and methotrexate-based GVHD prophylaxis, we show that donor choice and HCT-CI are the 2 strongest predictors for improved survival after allo-SCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Dual expression of MYC and BCL2 proteins (double-expressor lymphoma [DEL]) as well as cell of origin (COO) are important prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) after conventional chemotherapy. We studied the prognostic impact of DEL and COO in patients with relapsed DLBCL treated with autologous stem cell transplant (ASCT). Three-hundred and three patients with stored tissue samples were identified. Classification was successful in 267 patients: 161 (60%) were DEL/non-double hit (DHL), 98 (37%) were non-DEL/non-DHL, and 8 (3%) were DEL/DHL. Compared to non-DEL/non-DHL, DEL/DHL had worse overall survival while DEL/non-DHL did not significantly differ in overall survival. On multivariable analysis, DEL/DHL, age >60 years, and >2 prior therapies, but not COO, were important prognostic factors for overall survival. When we explored the interaction of COO and BCL2 expression, patients with germinal center B-cell (GCB)/BCL2 (+) had inferior progression-free survival (PFS) compared to GCB/BCL2 (-) patients (HR, 4.97; P = 0.027). We conclude that the DEL/non-DHL and non-DEL/non-DHL subtypes of DLBCL have similar survival after ASCT. The negative impact of GCB/BCL2 (+) on PFS warrants future trials targeting BCL2 after ASCT. The inferior outcomes in DEL/DHL need to be verified in a larger number of patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Mild cognitive impairment (MCI) is a prodromal stage to dementia, affecting up to 20% of the aging population worldwide. Patients with MCI have an annual conversion rate to dementia of 15-20%. Thus, conditions that increase the conversion from MCI to dementia are of the utmost public health concern. The COVID-19 pandemic poses a significant impact on our aging population with cognitive decline as one of the leading complications following recovery from acute infection. Recent findings suggest that COVID-19 increases the conversion rate from MCI to dementia in older adults. Hence, we aim to uncover a mechanism for COVID-19 induced cognitive impairment and progression to dementia to pave the way for future therapeutic targets that may mitigate COVID-19 induced cognitive decline., Methodology: A prospective longitudinal study is conducted at the University of Oklahoma Health Sciences Center. Patients are screened in the Department of Neurology and must have a formal diagnosis of MCI, and MRI imaging prior to study enrollment. Patients who meet the inclusion criteria are enrolled and followed-up at 18-months after their first visit. Visit one and 18-month follow-up will include an integrated and cohesive battery of vascular and cognitive measurements, including peripheral endothelial function (flow-mediated dilation, laser speckle contrast imaging), retinal and cerebrovascular hemodynamics (dynamic vessel retinal analysis, functional near-infrared spectroscopy), and fluid and crystalized intelligence (NIH-Toolbox, n-back). Multiple logistic regression will be used for primary longitudinal data analysis to determine whether COVID-19 related impairment in neurovascular coupling and increases in white matter hyperintensity burden contribute to progression to dementia., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Owens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Older adults have unique risk factors for poor outcomes after hematopoietic stem-cell transplant (HSCT). We sought to determine the impact of our multidisciplinary supportive care program, Enhanced Recovery after stem-cell transplant (ER-SCT), on survival outcomes in patients age 65 years and older who underwent HSCT., Patients and Methods: In this retrospective study, clinicodemographic data, nonrelapse mortality (NRM), overall survival (OS), and relapse were compared between 64 patients age 65 years and older who underwent allogeneic stem-cell transplant during ER-SCT program's first year, October 2017 through September 2018, and 140 historical controls age 65 years and older who underwent allogeneic HSCT, January 2015 through September 2017., Results: In the ER-SCT cohort, 41% (26 of 64) of patients were women, and the median (range) age was 68 (65-74) years; in the control cohort, 38% (53 of 140) of patients were women, and the median (range) age was 67 (65-79) years. Hematopoietic cell transplant comorbidity index and donor type/cell source were similar between cohorts. The ER-SCT cohort had a lower 1-year NRM rate (13% v 26%, P = .03) and higher 1-year OS rate (74% v 53%, P = .007). Relapse rate did not differ significantly between cohorts. In multivariate analyses, ER-SCT was associated with improved 1-year NRM (hazard ratio, 0.4; 95% CI, 0.2 to 0.9; P = .02) and improved 1-year OS (hazard ratio, 0.5; 95% CI, 0.3 to 0.9; P = .03)., Conclusion: A multidisciplinary supportive care program may improve NRM and OS in older patients undergoing allogeneic HSCT. Randomized studies are warranted to confirm this benefit and explore which program components most contribute to the improved outcomes.

Due to renewable fuel mandates worldwide, the increase in biodiesel production has caused an oversupply of low-cost glycerol on the markets, which can negatively affect the sustainability of the biodiesel industry as a whole. In order to avoid that scenario, the transformation of glycerol into value-added products has been investigated, and the production of additives for internal combustion engine fuels is one good example of glycerol valorization. The present work presents a summary of the literature describing the most important chemical pathways through which glycerol can be converted into fuel additives, to be subsequently mixed with either gasoline, biodiesel, or diesel fuel. The focus is on the three major categories, namely glycerol acetals/ketals, ethers, and esters (acetates). Moreover, the effectiveness of the different glycerol-derived compounds is illustrated through several examples from the literature. Finally, a few research gaps on the topic are identified and suggestions for future work are described., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Suboptimal adolescent human papillomavirus (HPV) vaccination rates have been attributed to parental perceptions of the HPV vaccine. The internet has been cited as a setting where misinformation and controversy about HPV vaccination have been amplified., Objective: We aimed to test message effectiveness in changing parents' attitudes and behavioral intentions toward HPV vaccination., Methods: We conducted a web-based message-testing experiment with 6 control messages and 25 experimental messages and 5 from each of the 5 salient themes about HPV vaccination (theme 1: safety, side effects, risk, and ingredient concerns and long-term or major adverse events; theme 2: distrust of the health care system; theme 3: HPV vaccine effectiveness concerns; theme 4: connection to sexual activity; and theme 5: misinformation about HPV or HPV vaccine). Themes were identified from previous web-based focus group research with parents, and specific messages were developed by the study team using content from credible scientific sources. Through an iterative process of message development, the messages were crafted to be appropriate for presentation on a social media platform. Among the 1713 participants recruited via social media and crowdsourcing sites, 1043 eligible parents completed a pretest survey questionnaire. Participants were then randomly assigned to 1 of the 31 messages and asked to complete a posttest survey questionnaire that assessed attitudes toward the vaccine and perceived effectiveness of the viewed message. A subgroup of participants (189/995, 19%) with unvaccinated children aged 9 to 14 years was also assessed for their behavioral intention to vaccinate their children against HPV., Results: Parents in the experimental group had increased positive attitudes toward HPV vaccination compared with those in the control group (t 969 =3.03, P=.003), which was associated with increased intention to vaccinate among parents of unvaccinated children aged 9 to 14 years (r=1.14, P=.05). At the thematic level, we identified 4 themes (themes 2-5) that were relatively effective in increasing behavioral intentions by positively influencing attitudes toward the HPV vaccine (χ 2 5 =5.97, P=.31, root mean square error of approximation [RMSEA]=0.014, comparative fit index [CFI]=0.91, standardized root mean square residual [SRMR]=0.031). On the message level, messages that provided scientific evidence from government-related sources (eg, the Centers for Disease Control and Prevention) and corrected misinformation (eg, "vaccines like the HPV vaccine are simply a way for pharmaceutical companies to make money. That isn't true") were effective in forming positive perceptions toward the HPV vaccination messages., Conclusions: Evidence-based messages directly countering misinformation and promoting HPV vaccination in social media environments can positively influence parents' attitudes and behavioral intentions to vaccinate their children against HPV., (©Sunny Jung Kim, Jenna E Schiffelbein, Inger Imset, Ardis L Olson. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 24.11.2022.)

Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and several subtypes of B-cell non-Hodgkin lymphoma (NHL). However, its use remains limited to highly specialized centers, given the complexity of its administration and its associated toxicities. We previously reported our experience in using a novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy in the peri-transplant setting, where it exhibited an excellent safety profile with encouraging survival outcomes. We have since modified the SB CD19 CAR construct to improve its efficacy and shorten its manufacturing time. We report here the phase 1 clinical trial safety results. Fourteen heavily treated patients with relapsed/refractory ALL and NHL were infused. Overall, no serious adverse events were directly attributed to the study treatment. Three patients developed grades 1-2 cytokine release syndrome and none of the study patients experienced neurotoxicity. All dose levels were well tolerated and no dose-limiting toxicities were reported. For efficacy, 3 of 8 (38%) patients with ALL achieved CR/CRi (complete remission with incomplete count recovery) and 1 (13%) patient had sustained molecular disease positivity. Of the 4 patients with DLBCL, 2 (50%) achieved CR. The SB-based CAR constructs allow manufacturing of targeted CAR T-cell therapies that are safe, cost-effective and with encouraging antitumor activity., Competing Interests: The technology was advanced through research conducted at MD Anderson by LC. In January 2015, the technology was licensed by The University of Texas MD Anderson Cancer Center for commercial application to Alaunos Therapeutics formerly Ziopharm Oncology, Inc., and Precigen formerly Intrexon Corporation, in exchange for equity interests in each of these companies. LC and some co-authors received equity because of the licensing of this technology. From 2015 to 2021 LC was Chief Executive Officer at ZIOPHARM. The information being reported in this publication is research in which The University of Texas MD Anderson Cancer Center has an institutional financial conflict of interest. Because The University of Texas MD Anderson Cancer Center is committed to the protection of human subjects and the effective management of its financial conflicts of interest in relation to its research activities, The University of Texas MD Anderson Cancer Center has implemented an Institutional Conflict of Interest Management and Monitoring Plan to manage and monitor the conflict of interest with respect to The University of Texas MD Anderson Cancer Center’s conduct of this research. EG and LC were formerly employed by Alaunos Therapeutics and have equity ownership in the company. KR and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical and Affimed GmbH. KR participates on the Scientific Advisory Board for GemoAb, AvengeBio, Virogin Biotech, GSK, Bayer, Navan Technologies, and Caribou Biosciences. ES participates on Scientific Advisory Boards for Adaptimmune, Axio, Navan, Fibroblasts and Fibrobiologics, and the NY Blood Center; has licensing or patents with Takeda and Affimed; and honorarium from Bayer Healthcare Pharmaceuticals. PK has served on advisory boards for Kite and Pfizer; received research support from Amgen and Alaunos; and has been a consultant for Jazz. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Singh, Srour, Milton, McCarty, Dai, Gaballa, Ammari, Olivares, Huls, De Groot, Marin, Petropoulos, Olson, Anderlini, Im, Khouri, Hosing, Rezvani, Champlin, Shpall, Cooper and Kebriaei.)

Long term field studies are required to bridge gaps between research and practical application of arsenic phytoextraction with the arsenic-hyperaccumulating fern Pteris vittata. In a 4-year field study, we investigated the effects of nutrient application (compost, inorganic or organic nitrogen, inorganic or organic phosphorus) and soil texture (13 % and 35 % clay) on arsenic phytoextraction with P. vittata in moderately contaminated soils (74-79 mg As/kg in the 0-15 cm depth interval). We found the highest phytoextraction rates, 5 ± 1 kg As/ha/y, in a coarse-textured compost-amended soil after 2 years of phytoextraction. Phytoextraction rates decreased over time, likely due to decreased root growth in mature stands, indicating plants should be replaced every 2-3 years to maintain phytoextraction efficiency. Across soil textures, nitrogen or phosphorus application led to a 60 % decrease in mean frond arsenic concentrations, leading to mean phytoextraction rates 54 % lower than in control ferns. In the fine-textured soil, frond arsenic concentrations were 54 % lower than in the coarse-textured soil, and fewer ferns survived from year 3 to 4. Across soil textures, compost application increased fern survival. We show that phytoextraction with P. vittata is limited to specific soil and climate conditions, narrower than those under which P. vittata grows in the wild., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1 ) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2 ) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results: 1 ) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2 ) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.

Introduction: We aimed to describe healthcare resource utilization (HCRU) patterns and costs in patients with fibrosing interstitial lung disease (ILD) and those with a progressive phenotype of fibrosing ILD in a US claims database., Methods: Data from the IBM ® MarketScan ® databases (1 October 2011-30 September 2015) were used. Diagnosis codes documented on medical claims on two occasions (without any claims during the 12 months prior) identified patients with incident fibrosing ILD. Patients with chronic fibrosing ILD with a progressive phenotype were identified by proxies for progression. Patients aged ≥ 18 years with 365 days of continuous coverage before the index date were eligible for inclusion. Data were analyzed for 12 months prior to identification of fibrosing ILD/progressive phenotype (baseline) and 12 months after (follow-up). Outcomes included treatment patterns, outpatient and inpatient claims, and costs., Results: We identified 23,577 patients with incident fibrosing ILD and 14,722 with the progressive phenotype. Follow-up data were available for 9986 and 5840 patients, respectively. The most frequent ILD-related medications during baseline were corticosteroids (49.4% and 56.6%). Mean (± standard deviation [SD]) annualized number of outpatient claims was 30.0 (± 26.4) and 34.1 (± 27.7) in the baseline period and 36.2 (± 28.6) and 41.9 (± 30.2) in the follow-up in fibrosing ILD and with a progressive phenotype, respectively. Mean (SD) number of all-cause hospitalizations was 0.5 (± 1.1) and 0.7 (± 1.2) during baseline and 0.6 (± 1.1) and 0.7 (± 1.2) during follow-up. Mean (SD) total costs were $40,907 (± 92,496) and $49,561 (± 98,647) during baseline and $46,157 (± 102,858) and $54,215 (± 116,833) during follow-up. Inpatient mortality during follow-up was 53.50 and 77.44 per 1000 patient-years., Conclusion: HCRU and costs were high in patients with chronic fibrosing ILD with a progressive phenotype, likely reflecting the disease severity and the need for close monitoring and acute care. Outpatient claims accounted for a substantial proportion of the total costs., (© 2022. The Author(s).)

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematological malignancy; however, some patients achieve durable remission with allogeneic hematopoietic cell transplantation (allo-HCT). We report on all 17 patients with BPDCN who underwent allo-HCT at our center between 2000 and 2020. The median age was 39 (18-67) years. All (n = 16, 94%), except one patient, had systemic disease involving bone marrow and/or other organs. Ten patients (59%) were in first complete remission (CR1) at allo-HCT. The donor source was matched related or unrelated in ten (59%) and alternate donor in seven (41%) patients. Five (31%) patients developed acute graft-versus-host disease (GVHD), all grade I-II. The cumulative incidence (CI) of chronic GVHD at five-year was 34%. The CI of non-relapse mortality at one-year was 29%. Progression-free survival (PFS) rates at two-year and five-year were 49% (95% CI = 22-71%) and 39% (95% CI = 14-64%), respectively. The two-year and five-year overall survival (OS) rates were 65% (95% CI = 38-82%) and 40% (95% CI = 12-68%), respectively. The five-year rate for both PFS and OS was 80% in CR1 patients versus 0% in patients not in CR1. In conclusion, allo-HCT provides long-lasting remissions in BPDCN patients, particularly when performed in CR1., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: To compare outcomes between patients with relapsed follicular lymphoma who received a nonmyeloablative allogeneic stem cell transplant (alloSCT) and those who received an autologous transplant (autoSCT)., Patients and Methods: We evaluated 194 patients with follicular lymphoma who received an alloSCT ( n = 98) or autoSCT ( n = 96) at MD Anderson Cancer Center (Houston, TX). The transplant type used was based on donor availability and by Medicare reimbursement guidelines. Patients who received an alloSCT were enrolled in four consecutive trials in which they received fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning. autoSCT patients received R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan)., Results: The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for patients who received an alloSCT compared with those who received an autoSCT (62% vs. 46%; P = 0.048). Similarly, progression-free survival rates were 52% in patients who received an alloSCT and 31% in those who received an autoSCT ( P < 0.001), and the 8-year relapse rates were 11% and 43%, respectively ( P < 0.0001). Only three patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 to 4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Nonrelapse mortality was similar between the two groups (15% vs. 11% at 8 years; P = 0.27)., Conclusions: This study shows that alloSCT is curative and confers superior survival compared with autoSCT in patients with follicular lymphoma., (©2021 American Association for Cancer Research.)

Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.6, p = 0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Proliferation and differentiation of preadipocytes, and other cell types, is accompanied by an increase in glucose uptake. Previous work showed that a pulse of high glucose was required during the first 3 days of differentiation in vitro, but was not required after that. The specific glucose metabolism pathways required for adipocyte differentiation are unknown. Herein, we used 3T3-L1 adipocytes as a model system to study glucose metabolism and expansion of the adipocyte metabolome during the first 3 days of differentiation. Our primary outcome measures were GLUT4 and adiponectin, key proteins associated with healthy adipocytes. Using complete media with 0 or 5 mM glucose, we distinguished between developmental features that were dependent on the differentiation cocktail of dexamethasone, insulin, and isobutylmethylxanthine alone or the cocktail plus glucose. Cocktail alone was sufficient to activate the capacity for 2-deoxglucose uptake and glycolysis, but was unable to support the expression of GLUT4 and adiponectin in mature adipocytes. In contrast, 5 mM glucose in the media promoted a transient increase in glucose uptake and glycolysis as well as a significant expansion of the adipocyte metabolome and proteome. Using genetic and pharmacologic approaches, we found that the positive effects of 5 mM glucose on adipocyte differentiation were specifically due to increased expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key regulator of glycolysis and the ancillary glucose metabolic pathways. Our data reveal a critical role for PFKFB3 activity in regulating the cellular metabolic remodeling required for adipocyte differentiation and maturation., (© 2021 Federation of American Societies for Experimental Biology.)

Introduction: Many fibrosing interstitial lung diseases (ILDs) develop a chronic progressive phenotype. While idiopathic pulmonary fibrosis, which is always progressive, is well characterized with established treatment options, the epidemiology of other chronic fibrosing ILDs with a progressive phenotype has not been widely investigated. Treatment options are limited, with a high unmet need. This claims database study estimates the incidence and prevalence of these diseases in the USA., Methods: Diagnosis, procedure and resource utilization codes from insurance claims were used to identify patients with fibrosing ILD and those with a chronic progressive phenotype among 37,565,644 adult patients in the IBM ® MarketScan ® Research Database 2012-2015. Two eligible ILD claims were required for a fibrosing ILD diagnosis. Progression was defined using a novel algorithm constituted by criteria considered proxies for progression. Patients were defined as having incident (new) or existing diagnoses based on claims during a 365-day period before study entry., Results: The estimated age- and sex-adjusted prevalence per 100,000 persons of fibrosing ILD (95% confidence interval) was 117.82 (116.56, 119.08) and of chronic fibrosing ILDs with a progressive phenotype was 70.30 (69.32, 71.27). The estimated adjusted incidence per 100,000 patient-years of fibrosing ILD was 51.56 (50.88, 52.24) and of chronic fibrosing ILDs with a progressive phenotype was 32.55 (32.01, 33.09). Among incident fibrosing ILD patients, 57.3% experienced progression over a median of 117 days (interquartile range 63-224), with largely comparable rates of progression among different diseases., Conclusions: Chronic fibrosing ILDs with a progressive phenotype comprise a relatively new disease construct requiring varied approaches to obtain reliable estimates of prevalence and incidence. This is the first large claims database study using real-world data to provide estimates of the prevalence and incidence of these diseases among a very large segment of the US population and could form the groundwork for future studies., (© 2021. The Author(s).)

Background: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown., Methods: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m 2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival., Results: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01)., Conclusions: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome., (© 2021 American Cancer Society.)

Age of ILD onset is similar in patients with RA-UIP and RA-NSIP but duration of RA before ILD onset differs https://bit.ly/3lgjfDJ., Competing Interests: Conflict of interest: M.P. Mohning has nothing to disclose. Conflict of interest: I. Amigues has nothing to disclose. Conflict of interest: M.K. Demoruelle has nothing to disclose. Conflict of interest: E.R. Fernández Pérez has nothing to disclose. Conflict of interest: T.J. Huie has nothing to disclose. Conflict of interest: R.K. Keith has nothing to disclose. Conflict of interest: A.L. Olson has nothing to disclose. Conflict of interest: Z.X. Yunt has nothing to disclose. Conflict of interest: J.H. Chung has nothing to disclose. Conflict of interest: S. Hobbs has nothing to disclose. Conflict of interest: J.J. Swigris has nothing to disclose. Conflict of interest: J.J. Solomon has nothing to disclose., (Copyright ©ERS 2021.)

Digital therapeutics can overcome many of the barriers to translation of evidence-based treatment for substance use, mental health, and other behavioral health conditions. Delivered via nearly ubiquitous platforms such as the web, smartphone applications, text messaging, and videoconferencing, digital therapeutics can transcend the time and geographic boundaries of traditional clinical settings so that individuals can access care when and where they need it. There is strong empirical support for digital therapeutic approaches for behavioral health, yet implementation science with regard to scaling use of digital therapeutics for behavioral health is still in its early stages. In this paper, we summarize the proceedings of a day-long workshop, "Implementation Science and Digital Therapeutics," sponsored and hosted by the Center for Technology and Behavioral Health at Dartmouth College. The Center for Technology and Behavioral Health is an interdisciplinary P30 Center of Excellence funded by the National Institute on Drug Abuse, with the mission of promoting state-of-the-technology and state-of-the-science for the development, evaluation, and sustainable implementation of digital therapeutic approaches for substance use and related conditions. Workshop presentations were grounded in current models of implementation science. Directions and opportunities for collaborative implementation science research to promote broad adoption of digital therapeutics for behavioral health are offered., (©Sarah E Lord, Aimee N C Campbell, Mary F Brunette, Leonardo Cubillos, Sophia M Bartels, William C Torrey, Ardis L Olson, Steven H Chapman, John A Batsis, Daniel Polsky, Edward V Nunes, Katherine M Seavey, Lisa A Marsch. Originally published in JMIR Mental Health (http://mental.jmir.org), 28.01.2021.)

Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT., (© 2020 S. Karger AG, Basel.)

Over 43 million U.S. residents rely on private unregulated wells for their drinking water, raising public health concerns, particularly in regions like northern New England where widespread groundwater arsenic contamination is now recognized. Children are particularly vulnerable to adverse health effects from arsenic exposure. Despite AAP Guidelines, approaches to engage pediatric clinicians in promoting private well testing have not been previously described. We sought to determine the most effective practice approaches to achieve successful well water testing in routine pediatric care. 12 primary care clinics were block randomized to one of four study arms. Two intervention variables were assessed: (1) test results access (parent only vs. parent and clinic) and (2) follow up approaches (yes/no). Parents of children under 12 months using a private well were eligible. Prepaid water tests were provided. Primary outcome was parental water test completion. Eleven clinics successfully implemented processes identifying well users. 240 testing kits were dispensed. Completion rates averaged 29% (range 10 to 61%). The study arm with both clinic results access and staff follow up system was 2.3 times more likely to achieve test completion than other arms (95% CI 1.12-4.86, p = .03). Kit distribution by clinicians versus nursing staff, irrespective of study arm, had 2.4 times greater completion (95% CI 1.13-5.11, p = .02). Systematic drinking water source screening can be improved in pediatric care. Higher testing completion was found in practices randomized to reminders and structured follow up versus single visit discussion, but clinician involvement was the most predictive factor., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)