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Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

STUDY OBJECTIVES: Although subjective-objective sleep discrepancy has long been observed in patients with insomnia, the profiles of this discrepancy are poorly understood. Further, sleep discrepancy in insomnia with sleep comorbidities remains underexplored. We sought to better characterize sleep discrepancy among patient groups with and without insomnia and comorbid conditions such as obstructive sleep apnea (OSA). METHODS: Using data from the Sleep Heart Health Study, we conducted a secondary analysis describing (1) the profile of self-reported and objective sleep measures in patients with insomnia (IS group; n = 73) and comorbid OSA (IS + OSA group; n = 143), compared with individuals with OSA only (OSA group; n = 296) and normal sleep control patients (NSC group; n = 126); (2) the comparative magnitude of sleep misperception between these 4 groups; and (3) the self-reported quality of life (QOL) in the 4 groups. RESULTS: Subjective-objective sleep discrepancy existed in all 4 groups, including the NSC group. Controlling for age, sex, mental health conditions, sleep apnea severity, and objectively measured sleep time, the presence of self-reported insomnia had the strongest association with sleep discrepancy. In patients with insomnia, sleep onset latency was overestimated (7.8 ± 36.8 min in the IS group; P < .001 when compared to the NSC and OSA groups), with the largest differences seen in the comorbid IS + OSA group (15.0 ± 56.8 min). Insomnia conferred the most negative impact on QOL, with the combined IS + OSA group reporting the lowest QOL. CONCLUSIONS: Self-reported insomnia is associated with sleep discrepancy and negative QOL. Those with comorbid OSA reported the greatest sleep discrepancy and the lowest QOL. Future research is warranted to further understand individual profiles of misperception and insomnia phenotypes. CITATION: Ma Y, Goldstein MR, Davis RB, Yeh GY. Profile of subjective-objective sleep discrepancy in patients with insomnia and sleep apnea. J Clin Sleep Med. 2021;17(11):2155–2163.

Objective Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19). We conducted this study to determine if there is a correlation between hemoglobin A1C (HbA1C) level and poor outcomes in hospitalized patients with diabetes and COVID-19. Methods This is a retrospective, single-center, observational study of patients with diabetes (defined by an HbA1C level of ≥6.5% or known medical history of diabetes) who had a confirmed case of COVID-19 and required hospitalization. All patients were admitted to our institution between March 3, 2020, and May 5, 2020. HbA1C results for each patient were divided into quartiles: 5.1% to 6.7% (32-50 mmol/mol), 6.8% to 7.5% (51-58 mmol/mol), 7.6% to 8.9% (60-74 mmol/mol), and >9% (>75 mmol/mol). The primary outcome was in-hospital mortality. Secondary outcomes included admission to an intensive care unit, invasive mechanical ventilation, acute kidney injury, acute thrombosis, and length of hospital stay. Results A total of 506 patients were included. The number of deaths within quartiles 1 through 4 were 30 (25%), 37 (27%), 34 (27%), and 24 (19%), respectively. There was no statistical difference in the primary or secondary outcomes among the quartiles, except that acute kidney injury was less frequent in quartile 4. Conclusion There was no significant association between HbA1C level and adverse clinical outcomes in patients with diabetes who are hospitalized with COVID-19. HbA1C levels should not be used for risk stratification in these patients.

STUDY OBJECTIVES: Prior studies have suggested a benefit of yoga for alleviating sleep disturbance; however, many studies have had methodological limitations. This trial study aimed to extend that literature by including an active sleep hygiene comparison. METHODS: Participants aged 25–59 years with a primary complaint of sleep onset insomnia lasting at least 6 months were block randomized to an 8-week Kundalini yoga or sleep hygiene intervention, both consisting of initial 60-minute instruction and weekly check-ins. Daily sleep diaries and questionnaires were collected at baseline, throughout the intervention, and at 6-month follow-up. Data were analyzed using linear mixed models (n = 20 in each group). RESULTS: Participant ratings of the interventions did not significantly differ. Sleep hygiene improved several diary and questionnaire outcomes, however, yoga resulted in even greater improvements corresponding to medium-to-large between-group effect sizes. Total sleep time increased progressively across yoga treatment (d = 0.95, P = .002), concurrent with increased sleep efficiency (d = 1.36, P < .001) and decreased sleep onset latency (d = −1.16, P < .001), but without changes in pre-sleep arousal (d =−0.30, P = .59). Remission rates were also higher for yoga compared to sleep hygiene, with ≥ 80% of yoga participants reporting average sleep onset latency < 30 minutes and sleep efficiency > 80% at 6-month follow-up. For over 50% of yoga participants, the insomnia severity index decreased by at least 8 points at end of treatment and follow-up. CONCLUSIONS: Yoga, taught in a self-care framework with minimal instructor burden, was associated with self-reported improvements above and beyond an active sleep hygiene comparison, sustained at 6-month follow-up. Follow-up studies are needed to assess actigraphy and polysomnography outcomes, as well as possible mechanisms of change. Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Yoga as a Treatment for Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT00033865; Identifier: NCT00033865. CITATION: Khalsa SBS, Goldstein MR. Treatment of chronic primary sleep onset insomnia with Kundalini yoga: a randomized controlled trial with active sleep hygiene comparison. J Clin Sleep Med. 2021;17(9):1841–1852.

The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FcεR)–mediated activation of mast cells and basophils, IgG (FcγR)–mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dose-dependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.

The autonomic system plays an important role in regulating blood pressure (BP). BP is elevated at night when individuals remain awake and continues to be elevated during either the night or the day if wakefulness persists. There is a close relationship between the high frequency (HF) of the variability of the RR interval (RRI), an index of parasympathetic predominance, and delta power during slow-wave sleep bouts. In addition, there is an HF rebound once sleep is permitted following sleep deprivation. Furthermore, this is the case for acute total sleep deprivation, as well as for models of chronic sleep restriction. Evidence indicates that sleep is important for autonomic homeostasis. It has long been recognized that physiological stress induces sympathetic activation. However, the simple fact that humans can voluntarily, and sometimes even with great pleasure, deprive themselves of sleep, has led us to overlook the role that deficient sleep plays as a physiological stressor. Physiological and epidemiological data have shown that short sleep is a risk factor for a broad range of morbidity and all-cause mortality. Understanding the role sleep plays in autonomic regulation can open new opportunities for the development of sleep interventions to improve cardiovascular health.

In power systems modelling, optimization methods based on certain objective function(s) are widely used to provide solutions for decision makers. For complex high-dimensional problems, such as network hosting capacity evaluation of intermittent renewables, simplifications are often used which can lead to the ‘optimal’ solution being suboptimal or nonoptimal. Even where the optimization problem is resolved, it would still be valuable to introduce some diversity to the solution for long-term planning purposes. This paper introduces a general framework for solving optimization for power systems that treats an optimization problem as a history match problem which is resolved via statistical emulation and uncertainty quantification. Emulation constructs fast statistical approximations to the complex computer simulation model in order to identify appropriate choices of candidate solutions for given objective function(s). Uncertainty quantification is adopted to capture multiple sources of uncertainty attached to each candidate solution and is conducted via Bayes linear analysis. It is demonstrated through a hosting capacity case study involving variable wind generation and active network management. The proposed method effectively identified not only the maximum connectable capacities but also a diverse set of near-optimal solutions, and so provided flexible guides for using the existing network to maximize the benefits of renewable generation.

Persistent HPV infection is causative for the majority of cervical cancer cases; however, current guidelines do not require HPV testing for newly diagnosed cervical cancer. Using an institutional cohort of 88 patients with cervical cancer treated uniformly with standard-of-care chemoradiation treatment (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared with patients with HPV 16+ tumors, consistent with previously published studies. Using RNA sequencing analysis, we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I in cervical tumors with HPV genotypes other than HPV 16. These findings were validated using whole transcriptome data from The Cancer Genome Atlas (n = 304). For the first time to our knowledge, transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional data set (n = 88) and within the HPV 16+ subset (n = 36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct mechanisms dependent upon p53-p21. Our findings suggest that high expression of E6*I and E6 may represent novel biomarkers of CRT efficacy, and these patients may benefit from alternative treatment strategies.

Objective Mindfulness-based interventions (MBI) have been shown to reduce subjective symptoms of insomnia but the effects on objective measures remain unclear. The purpose of this study was to examine sleep EEG microarchitecture patterns from a randomized controlled trial of Mindfulness-Based Stress Reduction (MBSR) and Mindfulness-Based Therapy for Insomnia (MBTI). Methods Sleep EEG spectral analysis was conducted on 36 participants with chronic insomnia (>6 months) randomized to 8-week MBSR, MBTI, or self-monitoring control (SM). Overnight polysomnography with 6-channel EEG was conducted at baseline, post-treatment, and 6-month follow-up. Spectral power averaged from channels C3/C4 across NREM epochs (excluding N1) was examined for within-group changes and relationships with self-report measures. Results Increases in absolute NREM beta (16–25 Hz) power were observed from baseline to post-treatment (p = .02, d = 0.53) and maintained at 6-month follow-up (p = .01, d = 0.57) in the combined MBI groups, and additionally in the gamma (25–40 Hz) range at follow-up for the MBTI group only. No significant changes in these frequency bands were observed for SM. Following mindfulness intervention, NREM beta was positively associated with Five-Facet Mindfulness (FFM) score (rho = 0.37, p = .091) and negatively associated with Insomnia Severity Index (rho = −0.43, p = .047). Conclusion These results in people with insomnia corroborate prior reports of increased high-frequency sleep EEG power associated with mindfulness training. This change in beta EEG pattern merits further evaluation as a potential marker of the effects of mindfulness meditation on sleep, especially given the paradoxical findings in the context of insomnia. Clinical Trial Registration clinicaltrials.gov , NCT00768781 .

BACKGROUND & AIMS We evaluated treatment withdrawal, long-term outcomes, and safety of budesonide oral suspension (BOS) 2.0 mg twice daily in patients with eosinophilic esophagitis who completed a 12-week induction study. METHODS Induction full responders (≤6 eosinophils per high-power field [eos/hpf] and ≥30% reduction in the Dysphagia Symptom Questionnaire score) to BOS 2.0 mg twice daily (ORBIT1/SHP621-301/NCT02605837) were randomized to continue BOS (BOS-BOS) or withdraw to placebo (BOS-PBO) for 36 weeks (ORBIT2/SHP621-302/NCT02736409). Induction partial responders and nonresponders, and patients who received induction placebo, received BOS for 36 weeks. The primary end point was the proportion of BOS-BOS and BOS-PBO patients who relapsed (≥15 eos/hpf and ≥4 days of dysphagia [Dysphagia Symptom Questionnaire] over 2 weeks) by week 36. The key secondary end point was the proportion of induction partial responders and nonresponders who fully responded after 52 weeks of total BOS therapy. Other secondary end points included the proportion of induction full responders with histologic responses (≤1, ≤6

Meningiomas are among the most common tumors of the adult central nervous system (CNS). They are classified by the World Health Organization into three pathologic grades with increasing severity: grade I are benign with favorable treatment outcomes and low recurrence rates while grade III display malignant behavior and poor progression-free survival. Previous studies have shown that inactivation of NF-2 is the most common genetic event in high-grade meningioma; however, there is dearth of molecular data to distinguish grade II (AM-II) from the even more aggressive grade III (AM-III). As part of a routine diagnostic workup, 19 AM-II and 5 AM-III were submitted for targeted sequencing on a panel of twenty-four genes relevant to CNS tumors. The data generated during the course of clinical care was collected and re-analyzed with the aim of identifying molecular features to distinguish AM-II and AM-III. Our cases contained several well-characterized, potentially actionable mutations, but we did not find any novel, recurrent sequence variants. Copy number variations were common in both AM-II and AM-III; chr22q loss was the most prevalent followed in decreasing frequency by losses of chr1p, chr14q, and chr10. In particular, chr10 loss was noted in 4 of 5 AM-III cases but none of the AM-II cases. This suggests that chr10 loss may serve as a diagnostic and perhaps a prognostic marker to differentiate AM-II from AM-III. If confirmed in larger studies, our finding could further aid the classification of meningioma.

Objective: Compare two distinct psychosocial stress-management workshops.Participants: Undergraduate and graduate students (n = 69 for analysis, completed April 2017).Methods: Participants were ran...

Objective: Paragangliomas (PGLs) are one of the many neoplasms associated with von Hippel-Lindau (VHL) disease. VHL disease type 2C is a unique subtype characterized by the presence of a PGL or pheochromocytoma without other VHL-associated neoplasms. This report describes a rare germline mutation in the VHL gene in a patient with isolated PGL. Methods: The clinical presentation, urinary metanephrines and normetanephrines, computed tomography scan, meta-iodobenzylguanidine scintiscan, surgical pathology, and genetic testing of a patient with PGL and a rare VHL gene mutation are described. A literature review is also presented. Results: A 23-year-old, Indian woman was incidentally found to have an indeterminate 4.2 × 3.6 × 3.2-cm mass adjacent to the liver. A 36-year-old first cousin was recently diagnosed with a PGL. Her 24-hour urinary metanephrines were 6,886 μg/g creatinine (reference range is 81 to 330 μg/g creatinine) and normetanephrines were 6,810 μg/g creatinine (reference range is 20 to 158 μg/g creatinine). Surgical pathology revealed a PGL adjacent to a normal adrenal gland. Genetic testing revealed a mutation in VHL p.L163F. Surveillance for other tumors associated with VHL disease has been negative thus far. Her cousin has not undergone genetic testing despite recommendations to do so. Conclusion: We present the first reported case of PGL in a patient with VHL disease caused by a missense mutation in VHL p.L163F. To date, reports of this rare mutation have only involved patients with pheochromocytoma and without other tumors associated with VHL disease, suggesting that VHL p.L163F mutation may cause a VHL disease type 2C phenotype.

Contains fulltext : 229013.pdf (Publisher’s version ) (Closed access) OBJECTIVES: The Kidney Disease: Improving Global Outcomes urine output criteria for acute kidney injury lack specificity for identifying patients at risk of adverse renal outcomes. The objective was to develop a model that analyses hourly urine output values in real time to identify those at risk of developing severe oliguria. DESIGN: This was a retrospective cohort study utilizing prospectively collected data. SETTING: A cardiac ICU in the United Kingdom. PATIENTS: Patients undergoing cardiac surgery between January 2013 and November 2017. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Patients were randomly assigned to development (n = 981) and validation (n = 2,389) datasets. A patient-specific, dynamic Bayesian model was developed to predict future urine output on an hourly basis. Model discrimination and calibration for predicting severe oliguria (< 0.3 mL/kg/hr for 6 hr) occurring within the next 12 hours were tested in the validation dataset at multiple time points. Patients with a high risk of severe oliguria (p > 0.8) were identified and their outcomes were compared with those for low-risk patients and for patients who met the Kidney Disease: Improving Global Outcomes urine output criterion for acute kidney injury. Model discrimination was excellent at all time points (area under the curve > 0.9 for all). Calibration of the model's predictions was also excellent. After adjustment using multivariable logistic regression, patients in the high-risk group were more likely to require renal replacement therapy (odds ratio, 10.4; 95% CI, 5.9-18.1), suffer prolonged hospital stay (odds ratio, 4.4; 95% CI, 3.0-6.4), and die in hospital (odds ratio, 6.4; 95% CI, 2.8-14.0) (p < 0.001 for all). Outcomes for those identified as high risk by the model were significantly worse than for patients who met the Kidney Disease: Improving Global Outcomes urine output criterion. CONCLUSIONS: This novel, patient-specific model identifies patients at increased risk of severe oliguria. Classification according to model predictions outperformed the Kidney Disease: Improving Global Outcomes urine output criterion. As the new model identifies patients at risk before severe oliguria develops it could potentially facilitate intervention to improve patient outcomes.

Background We aimed to evaluate the clinical outcomes of molecular glioblastoma (mGBM) as compared to histological GBM (hGBM) and to determine the prognostic impact of TERT mutation, EGFR amplification, and CDKN2A/B deletion on isocitrate dehydrogenase (IDH)-wildtype GBM. Methods IDH-wildtype GBM patients treated with radiation therapy (RT) between 2012 and 2019 were retrospectively analyzed. mGBM was defined as grade II-III IDH-wildtype astrocytoma without histological features of GBM but with one of the following molecular alterations: TERT mutation, EGFR amplification, or combination of whole chromosome 7 gain and whole chromosome 10 loss. Overall survival (OS) and progression-free survival (PFS) were calculated from RT and analyzed using the Kaplan–Meier method. Multivariable analysis (MVA) was performed using Cox regression to identify independent predictors of OS and PFS. Results Of the 367 eligible patients, the median follow-up was 11.7 months. mGBM and hGBM did not have significantly different OS (median: 16.6 vs 13.5 months, respectively, P = .16), nor PFS (median: 11.7 vs 7.3 months, respectively, P = .08). However, mGBM was associated with better OS (hazard ratio [HR] 0.50, 95% CI 0.29–0.88) and PFS (HR 0.43, 95% CI 0.26–0.72) than hGBM after adjusting for known prognostic factors on MVA. CDKN2A/B deletion was associated with worse OS (HR 1.57, 95% CI 1.003–2.46) and PFS (HR 1.57, 95% CI 1.04–2.36) on MVA, but TERT mutation and EGFR amplification were not. Conclusion Criteria for mGBM may require further refinement and validation. CDKN2A/B deletion, but not TERT mutation or EGFR amplification, may be an independent prognostic biomarker for IDH-wildtype GBM patients.

Background: There are limited treatment options available for patients with advanced pancreatic ductal adenocarcinoma (PDAC). We conducted a phase II study evaluating the efficacy and safety of capecitabine/oxaliplatin (CAPOX) in patients with locally advanced and metastatic PDAC treated in the first and second lines. Methods: Forty subjects with advanced PDAC and ECOG performance status ≥2 were enrolled. Treatment consisted of capecitabine 2,000 mg/m 2 orally in two divided doses daily for 14 days and oxaliplatin 130 mg/m 2 intravenously day 1 every 21 days. The primary endpoint was response rate (RR); secondary endpoints included safety analysis, progression free survival (PFS) and overall survival (OS). Results: The overall RR was 12.5% (N=3); the disease control rate was 67% (N=16). Due to the protocol definition for eligibility of response evaluation, only 60% (N=24) were evaluable for the primary endpoint. Median progression free survival (mPFS) was 3.8 months (95% CI: 1.3, 6.2); median OS (mOS) was 7.4 months (95% CI: 4.8, 12.2). The most common grade 3/4 toxicities included: fatigue (19%), nausea (17%), and diarrhea (14%). Conclusions: CAPOX is an active regimen in patients with advanced PDAC and is associated with acceptable toxicity. Careful consideration should be given to response endpoints and outcome measures when studying this characteristically ill population.

Introduction Current diagnostic classifications define insomnia based on self-reported sleep difficulties. However, differences between self-reported and objectively measured sleep parameters (subjective-objective sleep discrepancy or sleep misperception) are very common. Insomnia and sleep apnea cause common impairments that overlap and have negative impacts on overall health. Previous studies have encouraged an in-depth understanding of subjective-objective sleep discrepancy to inform a role for behavioral, mind-body approaches to insomnia. In this study, utilizing patients with insomnia and comorbid sleep apnea, we aimed to understand associations between self-reported insomnia, sleep difficulties, sleep misperception and quality-of-life. Methods We conducted a secondary analysis using data from the Sleep Heart Health Study (a multi-site nationally representative sample) to examine the profile of subjective and objective sleep measures in people with insomnia (IS, n=73) and comorbid sleep apnea (IS+SA, n=143), compared to individuals with sleep apnea only (SA, n=296) and normal sleep controls (NSC, n=126). We also compared the magnitude of sleep misperception between these four groups and examined the corresponding impact of subjective insomnia complaints on quality-of-life. Results Sleep discrepancy was found in all four groups. After controlling for age, sex, mental health conditions, sleep apnea severity, and objectively measured sleep time, the presence of self-reported insomnia had the strongest association with sleep discrepancy on total sleep time (TST, β=-34.4, p Conclusion Sleep discrepancy exists in normal controls, insomnia, and sleep apnea. Subjects with self-reported insomnia have a higher degree of sleep misperception. Both sleep apnea and self-reported insomnia are associated with negative QOL. Those with comorbid sleep apnea report the greatest sleep discrepancy and lowest QOL. Further research is needed to better understand individual profiles of misperception and insomnia phenotypes, apnea comorbidity and quality-of-life. Behavioral, mind-body interventions may offer strategies to address mental stress, sleep misperception, and insomnia. Support (if any) NCCIH T32AT000051 and NHLBI 5T32HL007901-22

Purpose/Objective(s) Medulloblastoma has been categorized into four subgroups based on genetic and epigenetic profiling. However, molecular pathways determining radiotherapy response in this tumor remain unknown. Here, we investigated the role of the EZH2-dependent histone H3K27 tri-methylation in radiation response in medulloblastoma. Materials/Methods We analyzed the H3K27me3 expression medulloblastoma tumor samples and determined the correlation between the H3K27me3 status and PFS and OS in 36 non-WNT/SHH medulloblastoma patients. We used an ex vivo mouse model of group 3 medulloblastoma to elucidate the molecular mechanism of radiation resistance in H3K27me3-deficient tumors and develop an approach to target radiotherapy resistance. Results We demonstrate that 47.2% of group 3 and 4 medulloblastoma patients have H3K27me3-deficient tumors. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates and poor overall survival. We show that an epigenetic switch from H3K27me3 to H3K27ac occurs at certain genomic loci in H3K27me3-deficient medulloblastoma cells altering the transcriptional profile. The resulting up-regulation of EPHA2 (ephrin type-A receptor 2) stimulates an over-activation of the pro-survival AKT signaling pathway leading to radiotherapy resistance. We show that BET inhibitors target radiation resistance in H3K27me3-deficient medulloblastoma by suppressing H3K27ac levels, blunting EPHA2 overexpression and mitigating the excessive AKT signaling. Additionally, BET inhibition sensitizes medulloblastoma cells to radiation by enhancing apoptotic response through suppression of Bcl-XL and up-regulation of Bim expression. Conclusion Our work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. Based on these findings we propose an epigenetically guided personalized treatment approach to target radiotherapy resistance in medulloblastoma patients.

Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic and transcriptional profiling. However, molecular pathways determining radiotherapy response in this tumor remain elusive. Here, we investigated the role of the EZH2-dependent histone H3K27 tri-methylation in radiotherapy response in medulloblastoma. We demonstrate that 47.2% of group 3 and 4 medulloblastoma patients have H3K27me3-deficient tumors. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates and poor overall survival. We show that an epigenetic switch from H3K27me3 to H3K27ac occurs at specific genomic loci in H3K27me3-deficient medulloblastoma cells altering the transcriptional profile. The resulting up-regulation of EPHA2 (ephrin type-A receptor 2) stimulates an excessive activation of the pro-survival AKT signaling pathway leading to radiotherapy resistance. We show that BET inhibition targets radiation resistance in H3K27me3-deficient medulloblastoma by suppressing H3K27ac levels, blunting EPHA2 overexpression and mitigating the excessive AKT signaling. Additionally, BET inhibition sensitizes medulloblastoma cells to radiation by enhancing apoptotic response through suppression of Bcl-XL and up-regulation of Bim expression. Our work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. Based on these findings we propose an epigenetically guided treatment approach targeting radiotherapy resistance in medulloblastoma patients.

Insomnia is the most prevalent sleep disorder, particularly among middle and older aged adults, and is associated with a variety of negative health consequences, including higher risk for cardiovascular disease. Unfortunately, the mechanisms linking insomnia with cardiovascular risk remain largely unknown, thus limiting targeted therapeutic interventions. The hyperarousal hypothesis has attracted the most support, positing that insomnia is a result of multisystem over-activation, including sympathetic hyperactivity, which promotes wakefulness and blocks the occurrence of sleep at the desired time. The results from literature in support of this hypothesis are inconclusive and mainly relay on studies that used methods to assess sympathetic activity lacking in specificity and reproducibility. The present review aims at summarizing the primary findings on autonomic nervous system regulation in insomnia while highlighting the advantages and limitations of the methods mainly used to support the increase in sympathetic function in insomnia. Collectively, this review aims to provide novel perspectives on conceptualizing insomnia and suggest innovative approaches to help elucidate the relationship between insomnia and autonomic nervous system activity.

Study objectives To clarify whether hypersomnolence disorder is associated with a specific sleep phenotype and altered neurophysiological function in persons with and without hypersomnolence disorder and major depressive disorder (MDD). Methods Eighty-three unmedicated persons with and without hypersomnolence disorder and/or MDD underwent ad libitum high-density EEG polysomnography. Clinical and sleep architecture variables were compared between groups. Topographic patterns of slow-wave activity (SWA) relative to healthy controls were compared, with correlations between topographic SWA and daytime sleepiness assessed. Reductions in SWA in hypersomnolence disorder were mapped to specific cortical areas using source localization. Results Regardless of the presence or absence of comorbid MDD, persons with hypersomnolence disorder had increased sleep duration relative to both controls and persons with MDD without hypersomnolence. Participants with hypersomnolence disorder also demonstrated reduced bilateral centroparietal low-frequency activity during nonrapid eye movement sleep relative to controls, a pattern not observed in persons with MDD but without hypersomnolence. SWA in these regions was negatively correlated with subjective measures of daytime sleepiness. Source localization demonstrated reductions in SWA in the supramarginal gyrus, somatosensory, and transverse temporal cortex in participants with hypersomnolence disorder. Conclusions Hypersomnolence disorder is characterized by increased sleep duration with normal sleep continuity, regardless of the presence or absence of comorbid depression. Reduced local SWA may be a specific neurophysiological finding in hypersomnolence disorder. Further research is warranted to elucidate the mechanisms through which these cortical changes are related to clinical complaints of daytime sleepiness.

Effective transmission expansion planning is necessary to ensure a power system can satisfy all demand both reliably and economically. However, at the time reinforcement decisions are made many elements of the future system background are uncertain, such as demand level, type and location of installed generators, and plant availability statistics. Making decisions which account for such uncertainties is presently usually done by considering a small set of plausible scenarios, and the resulting limited coverage of parameter space limits confidence that the resulting decision will be a good one with respect to the real world. This paper presents a methodology which uses statistical emulators to quantify uncertainty in mathematical model outputs for all points at which it has not been evaluated, and hence to control properly uncertainties in the decision process arising from the finite size set of scenarios. The result is a generally applicable approach to network planning under uncertainty, including decision makers’ risk preferences, which scales well with problem size. The approach is demonstrated on a Great Britain test problem, which replicates key features of the model the Transmission Owners use for practical strategic planning studies.

Trimodality therapy (chemoradiation and surgery) is the standard of care for stage II/III rectal cancer but nearly one third of patients do not receive radiation therapy (RT). We examined the relationship between the density of radiation oncologists and the travel distance to receipt of RT.A retrospective study based on the National Cancer Data Base identified 26,845 patients aged 18 to 80 years with stage II/III rectal cancer diagnosed from 2007 to 2010. Radiation oncologists were identified through the Physician Compare dataset. Generalized estimating equations clustering by hospital service area was used to examine the association between geographic access and receipt of RT, controlling for patient sociodemographic and clinical characteristics.Of the 26,845 patients, 70% received RT within 180 days of diagnosis or within 90 days of surgery. Compared with a travel distance of12.5 miles, patients diagnosed at a reporting facility who traveled ≥50 miles had a decreased likelihood of receipt of RT (50-249 miles, adjusted odds ratio 0.75, P.001; ≥250 miles, adjusted odds ratio 0.46; P=.002), all else being equal. The density level of radiation oncologists was not significantly associated with the receipt of RT. Patients who were female, nonwhite, and aged ≥50 years and had comorbidities were less likely to receive RT (P.05). Patients who were uninsured but self-paid for their medical services, initially diagnosed elsewhere but treated at a reporting facility, and resided in Midwest had an increased the likelihood of receipt of RT (P.05).An increased travel burden was associated with a decreased likelihood of receiving RT for patients with stage II/III rectal cancer, all else being equal; however, radiation oncologist density was not. Further research of geographic access and establishing transportation assistance programs or lodging services for patients with an unmet need might help decrease geographic barriers and improve the quality of rectal cancer care.

Background: While efficacy of Sudarshan Kriya Yoga (SKY) has been demonstrated in a number of prior studies, little is known about the effects of SKY taught as part of the Your Enlightened Side (YES+) workshop designed for college students and other young adults. Aims: This study aimed to assess the effects of YES+, a yogic breathing-based life skills workshop, on multiple measures of well-being and physiological stress response. Materials and Methods: Two nonrandomized open-trial pilot studies were conducted with a total of 74 young adults (age 25.4 ± 6.6 years; 55% female). Study 1 collected a variety of self-report questionnaires at baseline, postworkshop, and 1-month follow-up. Study 2 collected self-report questionnaires in addition to electrocardiography with a stationary cycling challenge at baseline and 1-month follow-up. Results: Study 1: Improvements in self-reported depression (P's ≤ 0.010), perceived stress (P's ≤ 0.002), life satisfaction (P's ≤ 0.002), social connectedness (P's ≤ 0.004), and gratitude (P's ≤ 0.090) were observed at postworkshop and 1-month after workshop relative to baseline. Study 2: Improvements in self-reported emotion regulation were observed at 1-month follow-up relative to baseline (P = 0.019). Positive and Negative Affect Schedule-Expanded Form positive affect increased (P = 0.021), while fatigue and sadness decreased (P's ≤ 0.005). During the stationary cycling challenge, rate to recovery of electrocardiography inter-beat interval also increased from baseline to 1-month follow-up (P = 0.077). Conclusions: These findings suggest that a life skills workshop integrating yogic breathing techniques may provide self-empowering tools for enhancing well-being in young adults. Future research is indicated to further explore these effects, particularly in regards to vagal tone and other aspects of stress physiology.

Introduction Fatigue and pain are prominent features of functional impairment in insomnia. This study aimed to better understand behavioral and physiological mechanisms of these complex relationships. Methods 22 participants with insomnia disorder (DSM-5 criteria, 18 female, age 18-49yrs) and 22 good-sleeper controls (19 female, age 18-47yrs) completed two-weeks sleep logs and actigraphy recordings prior to coming to the laboratory for overnight polysomnography and subsequent daytime testing that included questionnaires, three trials of cold pressor test (CPT), and pain testing with blood draws collected throughout. Insomnia diagnosis was determined by a board-certified sleep specialist, and exclusion criteria included psychiatric history within past 6 months, other sleep disorder, significant medical conditions, and any medications within past two weeks with significant effects on inflammation, autonomic function, or other psychotropic effects. For CPT, participants were instructed to immerse hand in ice cold water for at least one minute and rate pain intensity throughout the immersion and 3-minute recovery. Data were analyzed with linear mixed models. Results Per inclusion criteria, PSQI scores were differed between groups (insomnia: 10.2±2.7, range 7–16; control: 1.9±1.3, range 0–5; p Conclusion These data indicate that habituation to and acute recovery from pain is deteriorated in chronic insomnia, which may be a key contributor to maintained pathophysiology over time and mechanism to target with comprehensive treatment. Support Merck Inc. MISP# 51971 (investigator-initiated), NIH/National Center for Research Resources UL1-RR02758 and M01-RR01032 to the Harvard Clinical and Translational Science Center.

Introduction Sleep disturbances are more common in women than in men, as are many chronic pain disorders characterized by inflammation and fatigue. This study investigated sex differences in fatigue and pain responses to sleep disruption and whether such responses recover with uninterrupted sleep. Methods 24 healthy young individuals (12 women; ages 18–42 yrs) participated in a study consisting of two counterbalanced 19-day experimental in-hospital stays, separated by two months. Following 3 baseline nights, participants were exposed to 3 nights of sleep disruption (SD) involving delayed sleep onset, hourly awakenings, and early-morning awakenings without return to sleep, followed by 1 night of recovery sleep. This 4-day cycle was repeated three times and finished with 3 additional nights of recovery sleep. Total sleep opportunity on SD nights was 4 hrs, and on recovery/sleep control (SC) nights was 8 hrs. Light exposure, ambient temperature, food and fluid intake, and physical activity were controlled. Self-reported fatigue and pain, pain sensitivity, and habituation were collected throughout. Data were analyzed with linear mixed models. Results For women but not men, fatigue in response to SD recovered incompletely starting after the 2nd sleep disruption-recovery cycle and remained elevated after the final 3 recovery nights in women (p Conclusion These results indicate that incomplete recovery in both fatigue and pressure pain, alongside a lack of habituation to cold pain, in response to sleep disruption may explain the common co-occurrence of insomnia, fatigue, and pain observed as more prevalent in women. Support NIH/NINDS R01-NS091177; NIH/National Center for Research Resources UL1-RR02758 and M01-RR01032 to the Harvard Clinical and Translational Science Center.

Radiofrequency ablation (RFA) of cavotricuspid isthmus (CTI) is the first line treatment of typical atrial flutter as it is very effective with a low risk of complications. Despite close anatomic proximity of RCA with cavotricuspid isthmus, right coronary artery (RCA) occlusion is a rarely reported

This chapter presents a brief review of the Bayesian graphical models (BGM) approach to software testing, which the authors developed in close collaboration with industrial software testers. It provides discussion of a range of topics for practical implementation of the BGM approach, including modeling for test–retest scenarios, the expected duration of the retest cycle, incorporation of multiple failure modes, and diagnostic methods. The chapter addresses model maintenance and evolution, including consideration of novel system functionality. It discusses end‐to‐end testing of complex systems, and presents methods to assess the viability of the BGM approach for individual applications. These are all important aspects of high‐complexity testing which software testers have to deal with in practice, and for which Bayesian statistical methods can provide useful tools. The chapter also provides the basic approaches to these important issues. These should enable software testers, with support from statisticians, to develop implementations for specific test scenarios.

Approximate Bayesian Computation (ABC) and other simulation-based\ud inference methods are becoming increasingly used for inference in\ud complex systems, due to their relative ease-of-implementation. We briefly\ud review some of the more popular variants of ABC and their application\ud in epidemiology, before using a real-world model of HIV transmission to\ud illustrate some of challenges when applying ABC methods to high dimensional,\ud computationally intensive models. We then discuss an alternative\ud approach—history matching—that aims to address some of these issues,\ud and conclude with a comparison between these different methodologies.

Background Several cardiac surgery risk prediction models based on postoperative data have been developed. However, unlike preoperative cardiac surgery risk prediction models, postoperative models are rarely externally validated or utilized by clinicians. The objective of this study was to externally validate three postoperative risk prediction models for intensive care unit (ICU) mortality after cardiac surgery. Methods The logistic Cardiac Surgery Scores (logCASUS), Rapid Clinical Evaluation (RACE), and Sequential Organ Failure Assessment (SOFA) scores were calculated over the first 7 postoperative days for consecutive adult cardiac surgery patients between January 2013 and May 2015. Model discrimination was assessed using receiver operating characteristic curve analyses. Calibration was assessed using the Hosmer–Lemeshow (HL) test, calibration plots, and observed to expected ratios. Recalibration of the models was performed. Results A total of 2255 patients were included with an ICU mortality rate of 1.8%. Discrimination for all three models on each postoperative day was good with areas under the receiver operating characteristic curve of >0.8. Generally, RACE and logCASUS had better discrimination than SOFA. Calibration of the RACE score was better than logCASUS, but ratios of observed to expected mortality for both were generally Conclusion All three models demonstrated good discrimination for the first 7 days after cardiac surgery. After recalibration, logCASUS and RACE scores appear to be most useful for daily risk prediction after cardiac surgery. If appropriately calibrated, postoperative cardiac surgery risk prediction models have the potential to be useful tools after cardiac surgery.

Purpose Geographic access to care may be associated with receipt of chemotherapy but has not been fully examined. This study sought to evaluate the association between density of oncologists and travel distance and receipt of adjuvant chemotherapy for colon cancer within 90 days of colectomy. Patients and Methods Patients in the National Cancer Data Base with stage III colon cancer, diagnosed between 2007 and 2010, and age 18 to 80 years were selected. Generalized estimating equation clustering by hospital service area was conducted to examine the association between geographic access and receipt of oncology services, controlling for patient sociodemographic and clinical characteristics. Results Of 34,694 patients in the study cohort, 75.7% received adjuvant chemotherapy within 90 days of colectomy. Compared with travel distance less than 12.5 miles, patients who traveled 50 to 249 miles (odds ratio [OR], 0.87; P = .009) or ≥ 250 miles (OR, 0.36; P < .001) had decreased likelihood of receiving adjuvant chemotherapy. Density level of oncologists was not statistically associated with receipt of adjuvant chemotherapy (low v high density: OR, 0.98; P = .77). When stratifying analyses by insurance status, non–privately insured patients who resided in areas with low density of oncologists were less likely to receive adjuvant chemotherapy (OR, 0.85; P = .03). Conclusion Increased travel burden was associated with a decreased likelihood of receiving adjuvant chemotherapy, regardless of insurance status. Patients with nonprivate insurance who resided in low-density oncologist areas were less likely to receive adjuvant chemotherapy. If these findings are validated prospectively, interventions to decrease geographic barriers may improve the timeliness and quality of colon cancer treatment.

Introduction: UNAIDS calls for fewer than 500,000 new HIV infections/year by 2020, with treatment-as-prevention being a key part of their strategy for achieving the target. A better understanding of the contribution to transmission of people at different stages of the care pathway can help focus intervention services at populations where they may have the greatest effect. We investigate this using Uganda as a case study.\ud Methods: An individual-based HIV/ART model was fitted using history matching. 100 model fits were generated to account for uncertainties in sexual behaviour, HIV epidemiology, and ART coverage up to 2015 in Uganda. A number of different ART scale-up intervention scenarios were simulated between 2016-2030. The incidence and proportion of transmission over time from people with primary infection, post-primary ART-naïve infection, and people currently or previously on ART was calculated.\ud Results: In all scenarios, the proportion of transmission by ART-naïve people decreases, from 70% (61%-79%) in 2015 to between 23% (15%-40%) and 47% (35%-61%) in 2030. The proportion of transmission by people on ART increases from 7.8% (3.5%-13%) to between 14% (7.0%-24%) and 38% (21%-55%). The proportion of transmission by ART dropouts increases from 22% (15%-33%) to between 31% (23%-43%) and 56% (43%-70%).\ud Conclusions: People who are currently or previously on ART are likely to play an increasingly large role in transmission as ART coverage increases in Uganda. Improving retention on ART, and ensuring that people on ART remain virally suppressed, will be key in reducing HIV incidence in Uganda.\ud

Summary Complex stochastic models are commonplace in epidemiology, but their utility depends on their calibration to empirical data. History matching is a (pre)calibration method that has been applied successfully to complex deterministic models. In this work, we adapt history matching to stochastic models, by emulating the variance in the model outputs, and therefore accounting for its dependence on the model's input values. The method proposed is applied to a real complex epidemiological model of human immunodeficiency virus in Uganda with 22 inputs and 18 outputs, and is found to increase the efficiency of history matching, requiring 70% of the time and 43% fewer simulator evaluations compared with a previous variant of the method. The insight gained into the structure of the human immunodeficiency virus model, and the constraints placed on it, are then discussed.

Background With ambitious new UNAIDS targets to end AIDS by 2030, and new WHO treatment guidelines, there is increased interest in the best way to scale-up ART coverage. We investigate the cost-effectiveness of various ART scale-up options in Uganda. Methods Individual-based HIV/ART model of Uganda, calibrated using history matching. 22 ART scale-up strategies were simulated from 2016 to 2030, comprising different combinations of six single interventions (1. increased HIV testing rates, 2. no CD4 threshold for ART initiation, 3. improved ART retention, 4. increased ART restart rates, 5. improved linkage to care, 6. improved pre-ART care). The incremental net monetary benefit (NMB) of each intervention was calculated, for a wide range of different willingness/ability to pay (WTP) per DALY averted (health-service perspective, 3% discount rate). Results For all WTP thresholds above $210, interventions including removing the CD4 threshold were likely to be most cost-effective. At a WTP of $715 (1 × per-capita-GDP) interventions to improve linkage to and retention/re-enrolment in HIV care were highly likely to be more cost-effective than interventions to increase rates of HIV testing. At higher WTP (> ~ $1690), the most cost-effective option was ‘Universal Test, Treat, and Keep’ (UTTK), which combines interventions 1–5 detailed above. Conclusions Our results support new WHO guidelines to remove the CD4 threshold for ART initiation in Uganda. With additional resources, this could be supplemented with interventions aimed at improving linkage to and/or retention in HIV care. To achieve the greatest reductions in HIV incidence, a UTTK policy should be implemented. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2420-y) contains supplementary material, which is available to authorized users.

We provide a statistical interpretation of current practice in climate modeling. In this review, we define weather and climate, clarify the relationship between simulator output and simulator climate, distinguish between a climate simulator and a statistical climate model, provide a statistical interpretation of the ubiquitous practice of anomaly correction along with a substantial generalization (the best-parameter approach), and interpret simulator/data comparisons as posterior predictive checking, including a simple adjustment to allow for double counting. We also discuss statistical approaches to simulator tuning, assessing parametric uncertainty, and responding to unrealistic outputs. We finish with a more general discussion of larger themes.

Anticipated oncologist shortages are largely consistent with the ASCO 2007 workforce study but somewhat more delayed. The ACA may exacerbate the shortage.

The challenge of understanding complex systems often gives rise to a multiplicity of models. It is natural to consider whether the outputs of these models can be combined to produce a system prediction that is more informative than the output of any one of the models taken in isolation. And, in particular, to consider the relationship between the spread of model outputs and system uncertainty. We describe a statistical framework for such a combination, based on the exchangeability of the models, and their coexchangeability with the system. We demonstrate the simplest implementation of our framework in the context of climate prediction. Throughout we work entirely in means and variances to avoid the necessity of specifying higher-order quantities for which we often lack well-founded judgments.

Modelling of inspection data for large scale physical systems is critical to assessment of their integrity. We present a general method for inference about system state and associated model variance structure from spatially distributed time series that are typically short, irregular, incomplete and not directly observable. Bayes linear analysis simplifies parameter estimation and avoids often-unrealistic distributional assumptions. Second-order exchangeability judgements facilitate variance learning for sparse inspection time-series. The model is applied to inspection data for minimum wall thickness from corroding pipe-work networks on a full-scale offshore platform, and shown to give materially different forecasts of remnant life compared with an equivalent model neglecting variance learning.

How may we develop methods of analysis which address the consequences of the mismatch between the formal structural requirements of Bayesian analysis and the actual assessments that are carried out in practice? A paper by Watson and Holmes provides an overview of methods developed to address such issues and makes suggestions as to how such analyses might be carried out. This article adds commentary on the principles and practices which should guide us in such problems.

Despite remarkable advances in design, implantable cardioverter-defibrillator (ICD) leads remain the component most susceptible to failure, which often leads to substantial adverse clinical outcomes. This article focuses on management strategies when ICD lead systems fail. Two cases involving management decisions for ICD lead failures are presented and discussed. One involves a common mode of presentation, inappropriate shocks. The second involves an alert in a patient with a complex system and multiple comorbidities. Although a systematic approach is outlined, management decisions must be balanced by a risk-and-benefit assessment of the individual patient.

Bayesian statistics plays a crucial role in the quantification of uncertainty for complex industrial problems. We discuss practical issues with the implementation of this approach, and explain the role of Bayes linear methodology in addressing such problems. We then discuss ways in which the Bayes linear approach has been implemented in industrial practice. We choose three areas of research and application to describe this impact. In each case, we review the underpinning technical research and then discuss the application. The chosen areas of impact are asset management, with reference to work by London Underground Ltd., chemical sensitisation analysis, with reference to methodology applied by Unilever and FERA, and reservoir engineering, with reference to software for history maching for reservoir simulators.

In this paper, we discuss combining expert knowledge and computer simulators in order to provide decision support for policy makers managing complex physical systems. We allow future states of the complex system to be viewed after initial policy is made, and for those states to influence revision of policy. The potential for future observations and intervention impacts heavily on optimal policy for today and this is handled within our approach. We show how deriving policy dependent system uncertainty using computer models leads to an intractable backwards induction problem for the resulting decision tree. We introduce an algorithm for emulating an upper bound on our expected loss surface for all possible policies and discuss how this might be used in policy support. To illustrate our methodology, we look at choosing an optimal CO2 abatement strategy, combining an intermediate complexity climate model and an economic utility model with climate data.

Prostate cancer is the most common cancer in men, both in the USA and Europe. Although incurable, metastatic disease can often be controlled for years with anti-androgen therapy. Once the disease becomes castrate resistant, the median survival is 18 months. There is growing evidence that the immune system, and in particular cytokines, play an important role in prostate cancer immunosurveillance and progression. Here, we have undertaken a clinical investigation of the role of two closely related cytokines, IL-4 and IL-13 in prostate cancer. In the largest series studied to date, we show that serum IL-4, but not IL-13 is significantly elevated in castrate resistant, compared to androgen sensitive disease. Notably however, serum IL-4 levels are also raised in patients with benign prostatic disease. Analysis of benign and malignant prostate tissue demonstrates that the source of IL-4 is epithelial cells rather than infiltrating leukocytes. Together, our data are consistent with a dual role for IL-4 in prostate cancer development. In benign disease, our data add to the evidence that IL-4 serves a protective role. By contrast, the data support a direct role for IL-4 in the progression of prostate cancer from androgen responsive, to advanced castrate-resistant disease.

Purpose Stereotactic body radiotherapy (SBRT) has been used successfully to treat patients with locally advanced pancreas cancer. However, many patients develop metastatic disease soon after diagnosis and may receive little benefit from such therapy. We therefore retrospectively analyzed a planned strategy of initial chemotherapy with restaging and then treatment for those patients with no evidence of metastatic progression with SBRT. Methods and Materials Forty-seven patients received gemcitabine (1,000 mg/m2 per week for 3 weeks then 1 week off) until tolerance, at least six cycles, or progression. Patients without metastases after two cycles were treated with SBRT (tolerance-based dose of 24–36 Gy in 3 fractions) between the third and fourth cycles without interrupting the chemotherapy cycles. Results Eight of the 47 patients (17%) were found to have metastatic disease after two cycles of gemcitabine; the remaining 39 patients received SBRT. The median follow-up for survivors was 21 months (range, 6–36 months). The median overall survival for all patients who received SBRT was 20 months, and the median progression-free survival was 15 months. The local control rate was 85% (33 of 39 patients); and 54% of patients (21 of 39) developed metastases. Late Grade III toxicities such as GI bleeding and obstruction were observed in 9% (3/39) of patients. Conclusion For patients with locally advanced pancreas cancer, this strategy uses local therapy for those who are most likely to benefit from it and spares those patients with early metastatic progression from treatment. SBRT delivers such local therapy safely with minimal interruption to systemic chemotherapy, thereby potentially improving the outcome in these patients.

The purpose of this study was to explore Meals on Wheels' (MOW) organizational potential for integrating depression screening, referral, and treatment for homebound older adults. In a survey of 164 MOW administrators, MOW's current practice of depression services was examined, and the administrators' perception of MOW's organizational potential was measured focusing on external environment, financial resources, staffing/skills, and values and goals. Only 20 out of 164 MOWs provide depression screening, and 19 provide in-home counseling for their clients, while 86 provide referral services. About 64-72% of MOWs that are not current providers of screening and/or referrals want to provide the services, and 21% of those that are not current providers of in-home counseling want to provide it.

Purpose Patients with nonmetastatic locally advanced unresectable pancreatic cancer have a dismal prognosis. Conventional concurrent chemoradiotherapy requires 6 weeks of daily treatment and can be arduous. We explored the safety and effectiveness of a 3-day course of hypofractionated stereotactic body radiotherapy (SBRT) followed by gemcitabine in this population. Patients and Methods A total of 36 patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with ≥12 months of follow-up were included. They received three fractions of 8, 10, or 12 Gy (total dose, 24–36 Gy) of SBRT according to the tumor location in relation to the stomach and duodenum, using fiducial-based respiratory motion tracking on a robotic radiosurgery system. The patients were then offered gemcitabine for 6 months or until tolerance or disease progression. Results With an overall median follow-up of 24 months (range, 12–33), the local control rate was 78%, the median overall survival time was 14.3 months, the median carbohydrate antigen 19-9–determined progression-free survival time was 7.9 months, and the median computed tomography-determined progression-free survival time was 9.6 months. Of the 36 patients, 28 (78%) eventually developed distant metastases. Six patients (17%) were free of progression at the last follow-up visit (range, 13–30 months) as determined by normalized tumor markers with stable computed tomography findings. Nine Grade 2 (25%) and five Grade 3 (14%) toxicities attributable to SBRT occurred. Conclusion Hypofractionated SBRT can be delivered quickly and effectively in patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with acceptable side effects and minimal interference with gemcitabine chemotherapy.

Modelling of complex corroding industrial systems is critical to effective inspection and maintenance for assurance of system integrity. Wall thickness and corrosion rate are modelled for multiple dependent corroding components, given observations of minimum wall thickness per component. At each inspection, partial observations of the system are considered. A Bayes linear approach is adopted simplifying parameter estimation and avoiding often unrealistic distributional assumptions. Key system variances are modelled, making exchangeability assumptions to facilitate analysis for sparse inspection time series. A utility-based criterion is used to assess quality of inspection design and aid decision making. The model is applied to inspection data from pipework networks on a full-scale offshore platform.