Persistence Of Treatment Effects Research Articles

Chemotherapy-Induced Peripheral Neuropathy and Falls in Cancer Survivors Relate to Digital Balance and Gait Impairments.

Chemotherapy-induced peripheral neuropathy (CIPN) and falls can be persistent side effects of cancer treatment. Standing postural sway and gait tests with body-worn, inertial sensors provide objective digital balance and gait measures that represent several different domains controlling mobility. Specific domains of balance and gait that related to neuropathy and falls are unknown. The aim of this study was to determine which domains of balance and gait differed between cancer survivors who report (1) CIPN symptoms versus no symptoms, (2) a history of falls in the past 6 months versus no falls, and (3) prospective falls over 12 months versus no falls. Postural sway during 30 seconds of quiet standing and gait characteristics from a 7-m timed up and go test were recorded with six synchronized inertial sensors (Opals by APDM Wearable Technologies, a Clario Company) in 425 older, female cancer survivors (age: 62 ± 6 years). A principal component analysis (PCA) approach was used to identify independent domains of mobility from 15 balance and gait measures. PCA analysis revealed five independent domains (PC1 = sway amplitude, PC2 = gait pace, PC3 = sway frequency, PC4 = gait spatial-temporal, and PC5 = turning) that accounted for 81% of the variance of performance. Cancer survivors who reported CIPN symptoms had significantly higher sway frequency (PC3) than asymptomatic survivors. Past fallers had significantly larger sway area (PC1) and slower gait pace (PC2) than nonfallers. Prospective fallers showed a significantly smaller stride length (PC4) than nonfallers. Digital balance and gait measures using wearable sensors during brief standing and walking tests provide objective metrics of CIPN-related mobility impairment and fall risk that could be useful for oncology clinical trials.

Social benefits for European Union immigrants? A survey experiment on misperceptions

Using new experimental panel data for Germany, I investigate the role of income misperceptions for welfare restrictive preferences toward European Union immigrants. A majority of respondents misperceive their relative income position in Germany and the European Union and demand that European Union immigrants work and pay taxes before obtaining equal rights to social benefits. Randomized treatments inform subjects about their position in the national and European Union income distribution. My results provide evidence that welfare restrictive preferences are formed in the context of misperceived own income positions: Respondents become more welfare restrictive when they learn about a higher national or lower European Union income position. Information about European Union misperceptions has a persistent treatment effect after 3 months, driven by respondents with larger initial misperceptions, but becomes insignificant after one year.

Measuring and predicting the effect of remyelinating therapy in multiple sclerosis: a randomised controlled trial protocol (RESTORE)

IntroductionRemyelination failure hampers symptomatic recovery in multiple sclerosis (MS), underlining the importance of developing remyelinating therapies. Optic neuritis is currently the most established method of measuring remyelination in MS trials....

Persistent effects of intramammary ceftiofur treatment on the gut microbiome and antibiotic resistance in dairy cattle

BackgroundIntramammary (IMM) ceftiofur treatment is commonly used in dairy farms to prevent mastitis, though its impact on the cattle gut microbiome and selection of antibiotic-resistant bacteria has not been elucidated. Herein, we enrolled 40 dairy (Holstein) cows at the end of the lactation phase for dry-cow therapy: 20 were treated with IMM ceftiofur (Spectramast®DC) and a non-antibiotic internal teat sealant (bismuth subnitrate) and 20 (controls) received only bismuth subnitrate. Fecal grab samples were collected before and after treatment (weeks 1, 2, 3, 5, 7, and 9) for bacterial quantification and metagenomic next-generation sequencing.ResultsOverall, 90% and 24% of the 278 samples had Gram-negative bacteria with resistance to ampicillin and ceftiofur, respectively. Most of the cows treated with ceftiofur did not have an increase in the number of resistant bacteria; however, a subset (25%) shed higher levels of ceftiofur-resistant bacteria for up to 2 weeks post-treatment. At week 5, the antibiotic-treated cows had lower microbiota abundance and richness, whereas a greater abundance of genes encoding extended-spectrum β-lactamases (ESBLs), CfxA, ACI-1, and CMY, was observed at weeks 1, 5 and 9. Moreover, the contig and network analyses detected associations between β-lactam resistance genes and phages, mobile genetic elements, and specific genera. Commensal bacterial populations belonging to Bacteroidetes most commonly possessed ESBL genes followed by members of Enterobacteriaceae.ConclusionThis study highlights variable, persistent effects of IMM ceftiofur treatment on the gut microbiome and resistome in dairy cattle. Antibiotic-treated cattle had an increased abundance of specific taxa and genes encoding ESBL production that persisted for 9 weeks. Fecal shedding of ESBL-producing Enterobacteriaceae, which was classified as a serious public health threat, varied across animals. Together, these findings highlight the need for additional studies aimed at identifying factors associated with shedding levels and the dissemination and persistence of antibiotic resistance determinants on dairy farms across geographic locations.

Novel Findings of Early Cardiac Dysfunction in Patients With Childhood-Onset Inflammatory Bowel Disease Using Layer-Specific Strain Analysis.

Patients with inflammatory bowel disease (IBD) are at a higher risk of developing cardiovascular diseases than healthy individuals, owing to persistent chronic inflammation and treatment effects. This study aimed to assess left ventricular function in patients with childhood-onset IBD using layer-specific strain analysis and to identify early indicators of cardiac dysfunction in them. A total of 47 patients with childhood-onset ulcerative colitis (UC), 20 patients with Crohn's disease (CD), and 75 age- and sex-matched healthy control subjects were included in this study. Conventional echocardiographic measurements of layer-specific (ie, endocardium, midmyocardium, and epicardium) global longitudinal strain and global circumferential strain (GCS) were evaluated in these participants. Layer-specific strain analysis showed that global longitudinal strain was lower in all layers for the UC (P < .001) and CD (P < .001) groups, regardless of the age at onset, but that GCS was only lower in the midmyocardial (P = .032) and epicardial (P = .018) layers in the CD group than in the control group. Although the mean left ventricular wall thickness was not significantly different among the groups, it was significantly correlated with the GCS of the endocardial layer in the CD group (ρ= -0.615; P = .004), suggesting that thickening of the left ventricular wall occurred as a compensatory mechanism to maintain the endocardial strain in the CD group layer. Children and young adults with childhood-onset IBD displayed decreased midmyocardial deformation. Layer-specific strain could also be useful to identify indicators of cardiac dysfunction in patients with IBD.

Altered somatosensory functioning and mechanism-based classification in breast cancer patients with persistent pain.

Pain is one of the most frequent and persistent side effects of breast cancer treatment. Besides pain, breast cancer survivors (BCS) are prone to experience a myriad of other signs and symptoms related to altered somatosensory function, including for example, hypoesthesia, allodynia, and hyperalgesia, both at the local site of cancer and in remote body parts. Different breast cancer treatments can have a direct effect on somatosensory functioning, resulting in a wide range of these signs and symptoms. To our knowledge, currently no comprehensive overview exists on altered somatosensory functioning and resulting signs and symptoms in BCS with persistent pain. Investigating altered somatosensory functioning in this population could provide more insights in the underpinning pathophysiological mechanisms and consequently improve prevention and treatment in the future. Therefore, in this paper, first, normal somatosensory functioning is described. Second, quantitative sensory testing is presented as the recommend method to evaluate somatosensory functioning. Third, existing evidence on altered somatosensory functioning in BCS with persistent pain is summarized. Altered somatosensory functioning related to the most common cancer treatment modalities, including surgery and radiotherapy, hormone therapy, and chemotherapy are discussed. In addition, evidence on the presence of nociplastic pain as pain resulting from altered somatosensory functioning without evidence for nociception and/or neuropathy in BCS is summarized. At last, a discussion on this available evidence, limitations, and perspectives for clinical practice and for research are made.

Postinjury Treatment to Mitigate the Effects of Aeromedical Evacuation After Traumatic Brain Injury in a Porcine Model

IntroductionEarly aeromedical evacuation after traumatic brain injury (TBI) has been associated with worse neurologic outcomes in murine studies and military populations. The goal of this study was to determine if commonly utilized medications, including allopurinol, propranolol, or tranexamic acid (TXA), could mitigate the secondary traumatic brain injury experienced during the hypobaric and hypoxic environment of aeromedical evacuation. MethodsPorcine TBI was induced via controlled cortical injury. Twenty nonsurvival pigs were separated into four groups (n = 5 each): TBI+25 mL normal saline (NS), TBI+4 mg propranolol, TBI+100 mg allopurinol, and TBI+1g TXA. The pigs then underwent simulated AE to an altitude of 8000 ft for 4 h with an SpO2 of 82-85% and were sacrificed 4 h later. Hemodynamics, serum cytokines, and hippocampal p-tau accumulation were assessed. An additional survival cohort was partially completed with TBI/NS (n = 5), TBI/propranolol (n = 2) and TBI/allopurinol groups (n = 2) survived to postinjury day 7. ResultsThere were no significant differences in hemodynamics, tissue oxygenation, cerebral blood flow, or physiologic markers between treatment groups and saline controls. Transient differences in IL-1b and IL-6 were noted but did not persist. Neurological Severity Score (NSS) was significantly lower in the TBI + allopurinol group on POD one compared to NS and propranolol groups. P-tau accumulation was decreased in the nonsurvival animals treated with allopurinol and TXA compared to the TBI/NS group. ConclusionsAllopurinol, propranolol, and TXA, following TBI, do not induce adverse changes in systemic or cerebral hemodynamics during or after a simulated postinjury flight. While transient changes were noted in systemic cytokines and p-tau accumulation, further investigation will be needed to determine any persistent neurological effects of injury, flight, and pharmacologic treatment.

Patient Preferences for Treatment Outcomes in Oncology with a Focus on the Older Patient-A Systematic Review.

Simple SummaryIn oncology, treatment outcomes can be competing, which means that one treatment could benefit one outcome, like survival, and negatively influence another, like independence. The choice of treatment therefore depends on the patient’s preference for outcomes, which needs to be assessed explicitly. Especially in older patients, patient preferences are important. Our systematic review summarizes all studies that assessed patient preferences for various treatment outcome categories. A total of 28 studies with 4374 patients were included, of which only six studies included mostly older patients. Although quality of life was only included in half of the studies, overall quality of life (79%) was most frequently prioritized as highest or second highest, followed by overall survival (67%), progression- and disease-free survival (56%), absence of severe or persistent treatment side effects (54%), treatment response (50%), and absence of transient short-term side effects (16%). In shared decision-making, these results can be used by healthcare professionals to better tailor the information provision and treatment recommendations to the individual patient.For physicians, it is important to know which treatment outcomes are prioritized overall by older patients with cancer, since this will help them to tailor the amount of information and treatment recommendations. Older patients might prioritize other outcomes than younger patients. Our objective is to summarize which outcomes matter most to older patients with cancer. A systematic review was conducted, in which we searched Embase and Medline on 22 December 2020. Studies were eligible if they reported some form of prioritization of outcome categories relative to each other in patients with all types of cancer and if they included at least three outcome categories. Subsequently, for each study, the highest or second-highest outcome category was identified and presented in relation to the number of studies that included that outcome category. An adapted Newcastle–Ottawa Scale was used to assess the risk of bias. In total, 4374 patients were asked for their priorities in 28 studies that were included. Only six of these studies had a population with a median age above 70. Of all the studies, 79% identified quality of life as the highest or second-highest priority, followed by overall survival (67%), progression- and disease-free survival (56%), absence of severe or persistent treatment side effects (54%), and treatment response (50%). Absence of transient short-term side effects was prioritized in 16%. The studies were heterogeneous considering age, cancer type, and treatment settings. Overall, quality of life, overall survival, progression- and disease-free survival, and severe and persistent side effects of treatment are the outcomes that receive the highest priority on a group level when patients with cancer need to make trade-offs in oncologic treatment decisions.

Abstract TP19: Sex Differences In The Impact Of Stroke On Retrieval Of Remote Fear Memory And Mir20a-3p Treatment

Preamble: Stroke is the major cause of death and disability worldwide. In addition to the immediate disability, stroke also results in diffuse secondary damage to regions distal to the ischemic region. Here we used the contextual fear conditioning test to assess the integrated functioning of affective and cognitive circuits after stroke in males and females, as well as the impact of mir20a-3p on this long term behavior. Methodology: Middle-aged (acyclic) females and males were injected stereotaxically with endothelin-1 in the left middle cerebral artery (MCA) region to create an ischemic stroke. Mir20a-3p mimics or scrambled oligo was administered i.v. 4h and 24h after stroke. Tests of sensory motor function including adhesive tape removal (ART) were performed prior to and after stroke. Long term cognitive changes were assessed by contextual fear conditioning (CFC) and the novel object recognition test (NORT). Results: Sensory motor deficits induced by stroke were abrogated with mir20a-3p treatment in both sexes. Contextual fear conditioning was evaluated by percent freezing during acquisition, extinction and retrieval. Sex differences were noted in fear extinction even prior to stroke, with males displaying resistance to extinction. At 30 days post-stroke, % freezing was no different from the pre-stroke extinction in females, while males showed a significant decrease in freezing rates after stroke, irrespective of treatment. In females, remote fear memory retrieval was reduced in vehicle-treated stroke rats, while the mir20a-3p treated group did not differ significantly from their pre-stroke levels. In contrast, both vehicle and mir20a-3p treated males showed a significant decline in freezing in response to fear retrieval. In female vehicle treated rats, the retrieval of remote fear memory continued to be impaired even at 100d post stroke(p&lt;0.05), but preserved in miR20a-3p treatment group, indicating a persistent cognitive impairment and treatment effect. Conclusion: While mir20a-3p treatment improved sensory motor performance in both sexes, fear related memories were better preserved in females at 30 days, suggesting that neuroprotectants may have similar effects in the short term but may diverge in a sex specific manner in the chronic phase.

Are Your Tax Problems an Opportunity Not to Pay Taxes? Evidence From a Randomized Survey Experiment

Taxpayers often view tax rules and filing processes as complicated. In this paper I study whether the perceived tax uncertainty among peers leads to a reduction of voluntary tax compliance. I find strong supportive evidence for this hypothesis using a survey experiment for a large representative sample of the German population. Providing randomized information that others are uncertain about how to file their taxable income decreases individual tax morale. This suggests that subjects use negative peer signals as an excuse in order to opt-out of tax compliance. Studying related heterogeneous treatment effects, I find that both older and left-wing subjects are more responsive to tax uncertainty of others. I also show persistent treatment effects among very honest taxpayers in a follow-up survey.

Abstract S07-04: Impact of COVID-19-related psychosocial distress on health-related quality of life in rural cancer survivors

Abstract Purpose: Rural cancer survivors report poorer health-related quality of life (QOL) than those residing in urban areas and have been disproportionately impacted by COVID-19. This study explored associations between the perceived threat of COVID-19 and psychosocial distress due to COVID-19 on health-related QOL in rural cancer survivors residing in central Pennsylvania. Method: Previous participants (n=195) in the Partnering to Prevent and Control Cancer (PPCC) study who had a working email address were sent an email invitation to complete an online questionnaire. Of the 195 cancer survivors contacted, 90 (46.2%) have responded to the email invitation and completed the questionnaire to date. The questionnaire assessed sociodemographics, perceived threat of COVID-19, psychosocial distress related to COVID-19, and QOL (physical and social functioning, role limitations due to physical health and emotional problems, fatigue, emotional well-being, pain, and general health). Linear regression models were used to explore associations between COVID-19 perceived threat and psychosocial distress and QOL; all models were adjusted for age, body mass index (BMI), and education. Results: Rural cancer survivors who completed the online questionnaire were mostly women (70%), non-Hispanic white (97.8%), in their 60s (M age=60.4±13.9 years), with overweight (M BMI=29.0±7.6 kg/m2), and college graduates (67.8%). Most participants were breast (37.8%) or prostate (23.3%) cancer survivors, not currently receiving treatment (93.3%), and were more than 12 weeks but less than 5 years post-treatment (93.7%). Nearly half (41.1%) of participants rated their health as excellent or very good, and 17.8% rated their health as fair or poor. Generally, participants felt that COVID-19 was a threat to them, their city, school, community, or household (M score=17.2±3.4, scale: 5-20), but did not feel anxious, worried, or depressed due to the COVID-19 outbreak (M score=6.8±3.1, scale: 5-20). Although perceived threat was not associated with QOL, psychosocial distress related to COVID-19 was significantly associated with role limitations due to emotional problems (B=-3.958, SE=.993, p&amp;lt;.001), energy/fatigue (B=-2.730, SE=.606, p&amp;lt;.001), emotional well-being (B=-3.733, SE=.435, p&amp;lt;.001), and social functioning (B=-2.987, SE=.730, p&amp;lt;.001) in adjusted models. Conclusions: Although the perceived threat of COVID-19 was low among rural cancer survivors, participants reported elevated psychosocial distress related to COVID-19, which negatively impacted their mental but not physical health. These findings highlight the potential of the COVID-19 outbreak to exacerbate the persistent long-term adverse effects of cancer treatment on health-related QOL among rural cancer survivors. Psychosocial and behavioral interventions are critically needed to reduce COVID-19-related psychosocial distress among rural cancer survivors and to improve QOL and promote health equity among this vulnerable, underserved population. Citation Format: Scherezade K. Mama, Michelle Cardel, Kathryn H. Schmitz. Impact of COVID-19-related psychosocial distress on health-related quality of life in rural cancer survivors [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S07-04.

Long-term treatment of Japanese cedar pollinosis with Japanese cedar pollen SLIT drops and persistence of treatment effect: A post-marketing clinical trial

BackgroundThere have been no reports of treatment effect persistence after long-term sublingual immunotherapy (SLIT) in patients with Japanese cedar (JC) pollinosis. Therefore, we conducted a post-marketing clinical trial to investigate the efficacy, safety, and effect persistence of JC pollen SLIT drops after approximately 3 years of treatment. MethodsThis was an open-label trial of 233 patients with JC pollinosis who were treated with JC pollen SLIT drops for approximately 3 years (2015–2017) and followed-up for an additional 2 years (2018–2019). Efficacy and effect persistence were evaluated using nasal and ocular symptom scores, daily use of rescue medication, and Japanese Rhinoconjunctivitis Quality of Life Questionnaire scores recorded during the JC pollen dispersal season of each year. Safety was evaluated by monitoring adverse events and adverse drug reactions. ResultsThe mean combined total nasal symptom and medication score (range 0–18) during the peak symptom periods of 2015 through 2019 were 5.47 ± 3.38, 4.52 ± 3.13, 3.58 ± 2.63, 5.28 ± 4.01, and 6.83 ± 4.65, respectively. The percentage of patients who used no rescue medications during the same periods was 64.8%, 75.2%, 80.3%, 63.7%, and 50.3%, respectively. A total of 138 adverse drug reaction incidents were recorded in 73 of the 233 patients (31.3%), of which 134 incidents (97.1%) were mild in severity. ConclusionsJC pollen SLIT drops demonstrated treatment duration-dependent efficacy with effects that persisted for 2 years after cessation of treatment. The drug had a favorable safety profile over the 5-year study period.

Quality of Life, Toxicity and Unmet Needs in Nasopharyngeal Cancer Survivors.

Concerted research efforts over the last three decades have resulted in improved survival and outcomes for patients diagnosed with nasopharyngeal carcinoma (NPC). The evolution of radiotherapy techniques has facilitated improved dose delivery to target volumes while reducing dose to the surrounding normal tissue, improving both disease control and quality of life (QoL). In parallel, clinical trials focusing on determining the optimal systemic therapy to use in conjunction with radiotherapy have been largely successful, resulting in improved locoregional, and distant control. As a consequence, neoadjuvant chemotherapy (NACT) prior to definitive chemoradiotherapy has recently emerged as the preferred standard for patients with locally advanced NPC. Two of the major challenges in interpreting toxicity and QoL data from the published literature have been the reliance on: (1) clinician rather than patient reported outcomes; and (2) reporting statistical rather than clinical meaningful differences in measures. Despite the lower rates of toxicity that have been achieved with highly conformal radiotherapy techniques, survivors remain at moderate risk of persistent and long-lasting treatment effects, and the development of late radiation toxicities such as hearing loss, cranial neuropathies and cognitive impairment many years after successful treatment can herald a significant decline in QoL. Future approaches to reduce long-term toxicity will rely on: (1) identifying individual patients most likely to benefit from NACT; (2) development of response-adapted radiation strategies following NACT; and (3) anticipated further dose reductions to organs at risk with proton and particle therapy. With increasing numbers of survivors, many in the prime of their adult life, research to identify, and strategies to address the unmet needs of NPC survivors are required. This contemporary review will summarize our current knowledge of long-term toxicity, QoL and unmet needs of this survivorship group.

Persistent treatment effect of cerliponase alfa in children with CLN2 disease: A > 4 year update from an ongoing multicenter extension study

Persistent treatment effect of cerliponase alfa in children with CLN2 disease: A > 4 year update from an ongoing multicenter extension study

Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast acting opioid remifentanil

The orexin (hypocretin) system is multifaceted, and regulates sleep-wake cycles, nociception, endocrine function and reward-seeking behavior. We have established an important role for this system in motivation for drugs of abuse. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the short-acting μ‐opioid receptor agonistremifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24 h, but not on a third test at 48 h. When injected into ventral pallidum (VP) the effects of SB were more persistent, with reduced motivation observed for up to 48 h. We next made SB injections into VP 24 h prior to behavioral testing; this produced effects that persisted for at least 72 h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24 h earlier. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations have important ramifications for the future clinical use of orexin receptor antagonists for the treatment of addiction.

Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study

Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of -3·6% per year and in 6-min walking distance of -10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from -8·7% per year in weeks 0-28 to -0·9% per year in weeks 28-52, p<0·0001) and 6-min walking distance (from -54·9 m per year to -3·5 m per year, p=0·0224). Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF. Promedior.

Comparative Efficacy of Therapies for Treatment of Depression for Patients Undergoing Maintenance Hemodialysis: A Randomized Clinical Trial.

Although depression is common among patients receiving maintenance hemodialysis, data on their acceptance of treatment and on the comparative efficacy of various therapies are limited. To determine the effect of an engagement interview on treatment acceptance (phase 1) and to compare the efficacy of cognitive behavioral therapy (CBT) versus sertraline (phase 2) for treating depression in patients receiving hemodialysis. Multicenter, parallel-group, open-label, randomized controlled trial. (ClinicalTrials.gov: NCT02358343). 41 dialysis facilities in 3 U.S. metropolitan areas. Patients who had been receiving hemodialysis for at least 3 months and had a Beck Depression Inventory-II score of 15 or greater; 184 patients participated in phase 1, and 120 subsequently participated in phase 2. Engagement interview versus control visit (phase 1) and 12 weeks of CBT delivered in the dialysis facility versus sertraline treatment (phase 2). The primary outcome for phase 1 was the proportion of participants who started depression treatment within 28 days. For phase 2, the primary outcome was depressive symptoms measured by the Quick Inventory of Depressive Symptoms-Clinician-Rated (QIDS-C) at 12 weeks. The proportion of participants who initiated treatment after the engagement or control visit did not differ (66% vs. 64%, respectively; P= 0.77; estimated risk difference, 2.1 [95% CI, -12.1 to 16.4]). Compared with CBT, sertraline treatment resulted in lower QIDS-C depression scores at 12 weeks (effect estimate, -1.84 [CI, -3.54 to -0.13]; P= 0.035). Adverse events were more frequent in the sertraline than the CBT group. No randomized comparison was made with no treatment, and persistence of treatment effect was not assessed. An engagement interview with patients receiving maintenance hemodialysis had no effect on their acceptance of treatment for depression. After 12 weeks of treatment, depression scores were modestly better with sertraline treatment than with CBT. Patient-Centered Outcomes Research Institute, Dialysis Clinic, Kidney Research Institute, and National Institute of Diabetes and Digestive and Kidney Diseases.

The Abecedarian Approach to Social, Educational, and Health Disparities.

This paper places the Abecedarian Approach in theoretical and historical context and reviews the results from three randomized controlled trials that have tested an experimental protocol designed to prevent cognitive disabilities and their social consequences. Results affirm that cognitive disabilities can be prevented in early childhood and subsequent academic achievement enhanced via a multipronged comprehensive approach that contains individualized and responsive early childhood education starting in early infancy, coupled with pediatric health care, good nutrition, and family-oriented social services. Additional important findings reveal that the most vulnerable children benefited the most and that cognitive gains were not at the expense of children's socioemotional development or relationship to family. In general, mothers derived benefits in education and employment and teenage mothers especially benefited from their children participating in the early education treatment group. On the whole, the overall pattern of results supports a multidisciplinary, individualized, and long-term longitudinal perspective on human development and prevention science. Recent structural and functional brain imaging in the fifth decade of life shows persistent effects of intensive early educational treatment. Independent recent cost-benefit analysis in adulthood reveals a 7.3:1 return on investment with a 13.7% average annual rate of return. The paper concludes with a discussion of implications of the Abecedarian Approach to today's high-risk population in the USA.

Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness.

Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln+/- mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln+/- mice. We then studied how minoxidil, an ATP-sensitive K+ channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln+/- mice than in WT mice. Treatment of Eln+/- mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln+/- mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW & NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin ( Eln)+/- mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K+ channel opener increased Eln gene expression and altered 126 other matrix-associated genes.

Dietary modifications for bowel dysfunction in rectal cancer survivors: The Altering Intake, Managing Symptoms (AIMS) intervention study.

141 Background: Rectal cancer survivors often experience persistent long-term effects of treatment. Functional deficits, such as bowel dysfunction, are associated with poor quality of life (QOL). There is a lack of evidence-based interventions to address bowel dysfunction symptoms in rectal cancer survivors. The purpose of this abstract is to describe the development and design of the Altering Intake, Managing Symptoms (AIMS) intervention to manage bowel dysfunction in rectal cancer survivors. Methods: Survivors with stage I-III rectosigmoid colon or rectal cancer who are 6 months post-treatment, &gt; 21 years, and English-speaking are eligible to participate. The AIMS intervention is a ten (30-40 minute) session, 4 month, telephone-based intervention delivered by trained health coaches. Outcome measures are assessed at baseline, 4 and 6 months, and include the MSKCC Bowel Function Tool, the COH-QOL-CRC, and adherence to cancer survivorship diet guidelines. Results: Based on the Chronic Care Self-Management Model (CCM), the AIMS intervention applies social cognitive theory to improve self-efficacy and self-management of bowel symptoms by coaching survivors to modify their diets to attenuate symptoms and enhance diet quality. Motivational interviewing-based behavioral approaches are applied, such as goal setting, self-monitoring, identification of barriers, and problem-solving. Monitoring of diet health involves review of 24 hour dietary recalls in conjunction with food and symptom diaries to promote survivor-directed behavior change resulting in improved bowel health. Conclusions: The AIMS intervention is among the first and few to address diet behavior changes for symptom management in rectal cancer survivors. It has the potential to positively impact the quality of long-term rectal cancer survivorship by integrating classic behavior change theories for cancer symptom management. Findings from the study will inform the design and development of future multi-institutional Phase II and III randomized trials. Clinical trial information: NCT03063918.