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Pancreatic ductal adenocarcinoma (PDAC) is the most common neoplastic disease of the pancreas, accounting for more than 90% of all pancreatic malignancies. As a highly lethal malignancy, PDAC is the fourth leading cause of cancer‐related deaths worldwide with a 5‐year overall survival of less than 8%. The efficacy and outcome of PDAC treatment largely depend on the stage of disease at the time of diagnosis. Surgical resection followed by adjuvant chemotherapy remains the only possibly curative therapy, yet 80%–90% of PDAC patients present with nonresectable PDAC stages at the time of clinical presentation. Despite our advancing knowledge of PDAC, the prognosis remains strikingly poor, which is primarily due to the difficulty of diagnosing PDAC at the early stages. Recent advances in glycoproteomics and glycomics based on mass spectrometry have shown that aberrations in protein glycosylation plays a critical role in carcinogenesis, tumor progression, metastasis, chemoresistance, and immuno‐response of PDAC and other types of cancers. A growing interest has thus been placed upon protein glycosylation as a potential early detection biomarker for PDAC. We herein take stock of the advancements in the early detection of PDAC that were carried out with mass spectrometry, with special focus on protein glycosylation. [ABSTRACT FROM AUTHOR]

And because Teresa I only i removes Adam's liability with respect to Dan, Adam remains liable to be harmed by Teresa. Given this difference in comparative responsibility between Adam and Dan, Adam has a duty to assume the costs of Dan's attack. Given Contraction, Dan would wrong Teresa in this same way by disregarding her demand that he not protect her: Dan would treat Teresa as lacking powers she has to mitigate some of her own rights-based protections. Absent her refusal, Adam is liable to be harmed by Dan and there is sufficient reason to impose such harm (since harming Adam will greatly benefit Teresa). Thus, when Teresa refuses protection, she makes it so that the reasons condition on defensive harm is no longer satisfied for Dan: Dan now lacks sufficient reason to harm Adam. [Extracted from the article]

Background: Guidelines recommend early coronary angiography (CA) in patients with non‐ST‐elevation myocardial infarction (NSTEMI) irrespective of age. However, elderly patients are less likely to be treated according to these guidelines due to their perceived high risk and medical comorbidities. Whether an invasive strategy is associated with improved survival in patients aged ≥85 years remains uncertain due to their exclusion from randomised trials. Aims: Patients were stratified based on whether they underwent invasive management with CA with a view to revascularisation versus conservative management. The primary outcome was long‐term mortality. Methods: Consecutive patients aged ≥85 years presenting to a tertiary centre with NSTEMI between 2008 and 2018 were included in this retrospective cohort study. Results: Of 7591 patients with NSTEMI, 1052 patients aged ≥85 years were included. Ninety‐nine (9.4%) patients underwent CA. Those undergoing CA were more likely to be younger, male, live independently, without mobility or cognitive issues (all P < 0.01). Overall, 495 (47%) patients died during a mean follow up of 1.3 ± 1 year. On Cox regression, after adjusting for age, pre‐morbid functional status, cognition and cardiovascular risk factors, invasive management was the strongest predictor for survival (hazard ratio 0.47; 95% confidence interval 0.26–0.85; P = 0.01). Invasive management was associated with a trend to increased risk of in‐hospital bleeding (6.1% vs 2.6%; P = 0.054) with no significant difference in stroke (2.0% vs 3.8%; P = 0.37). Conclusion: In patients aged ≥85 years who presented with NSTEMI, invasive management was associated with improved survival without significant differences in bleeding or stroke. A randomised controlled study assessing the efficacy and safety of invasive management in very elderly patients with NSTEMI is warranted. [ABSTRACT FROM AUTHOR]

Background: Optimal secondary prevention pharmacotherapy is the cornerstone of post‐acute coronary syndrome (ACS) management. The prognostic impact of not receiving five guideline‐recommended therapies is poorly described. Aim: To ascertain the prognostic significance of suboptimal pharmacotherapy in ACS survivors. Methods: Consecutive patients with ACS from the Melbourne Interventional Group registry who were alive at 30 days following their index percutaneous coronary intervention were included. Patients were divided into three categories based on the number of secondary prevention medications prescribed. The optimal medical therapy (OMT), near‐optimal medical therapy (NMT), suboptimal medical therapy (SMT) groups were prescribed 5, 4 and ≤ 3 medications, respectively. Primary endpoint was long‐term mortality. Cox‐proportional hazard modelling was undertaken to assess independent predictors of survival. Results: Of the 9375 patients included, 5678 (60.6%) received OMT, 2903 (31.0%) received NMT and 794 (8.5%) received SMT. Patients receiving SMT were older, more likely to be female and had higher burden of comorbidities (renal impairment, congestive heart failure, diabetes, peripheral vascular disease; P < 0.01 for all). SMT was associated with higher long‐term mortality at 3.9 ± 2.2 years when compared to NMT and OMT (16.8% vs 10.5% vs 8.2%, P < 0.001). Compared to OMT, SMT was an independent predictor of long‐term mortality (hazard ratio, HR 1.62, 95% confidence interval, CI 1.30–2.02, P < 0.01) while NMT was associated with a clinically significant 14% mortality hazard (HR 1.14, 95% CI 0.97–1.34, P = 0.11). Conclusions: There is a graded long‐term hazard associated with not receiving OMT after an ACS. Improvements in secondary prevention pharmacotherapy models of care are warranted to further decrease the long‐term mortality. [ABSTRACT FROM AUTHOR]

Introduction: Coronary angiogram, while a powerful diagnostic tool in coronary artery disease, is not without an associated risk from ionising radiation. There are a number of factors that influence the amount of radiation the patient receives during the procedure, some of which are under the control of the operator. One of these is an adjustment of the fluoroscopic pulse rate. This study aims to assess the feasibility of using ultra‐low pulse rate (3 pulses per second(pps)) fluoroscopy during routine diagnostic coronary angiogram procedures and the effect it has on fluoroscopy time, diagnostic clarity and radiation dose. Methods: A retrospective study of three operators each undertaking 50 coronary angiogram procedures was performed. One of the operators used a pulse rate of 3 pps and 6 pps for fluoroscopic screening while the control groups used the standard 10 pps mode utilised at this centre. Results: Results demonstrated no reduction of diagnostic clarity, up to a 58% reduction in Dose Area Product and no increase in fluoroscopy time with the 3 pps setting. Conclusions: Findings from this pilot study suggest that utilisation of ultra‐low pulse rate fluoroscopy in routine transfemoral diagnostic coronary angiography in the catheterisation laboratory is feasible. This project assessed the feasibility of utilising pulse rates as low as 3 pulses per second (pps) in coronary angiograms. The findings show that by working with application specialists, systems could allow for imaging at 3 pps without adversely affecting the patient. There was a significant reduction in radiation dose when 3 pps was utilised. [ABSTRACT FROM AUTHOR]

The role of the histone chaperone SPT6 in mammalian cells is not fully understood. Here, we investigated the involvement of SPT6 in type I interferon (IFN)‐induced transcription in murine fibroblasts. In RNA‐seq analysis, Spt6 siRNA attenuates about half of ~ 200 IFN‐stimulated genes (ISGs), while not affecting housekeeping genes. ISGs with high mRNA induction are more susceptible to Spt6 siRNA than those with lower levels of induction. ChIP analysis shows that SPT6 is recruited to highly inducible, Spt6 siRNA‐sensitive ISGs, but not to other siRNA‐insensitive ISGs. Furthermore, SPT6 recruitment is abrogated in cells lacking the histone methyltransferase NSD2. In co‐IP experiments, SPT6 interacts with NSD2. In summary, SPT6 facilitates IFN‐induced transcription, highlighting its critical role in gene activation. [ABSTRACT FROM AUTHOR]

As the number of older adults continues to rise worldwide, the prevention of physical disability among seniors is an increasingly important public health priority. Physical exercise is among the best known methods of preventing disability, but accumulating evidence indicates that considerable variability exists in the responsiveness of older adults to standard training regimens. Accordingly, a need exists to develop tailored interventions to optimize the beneficial effects of exercise on the physical function of older adults at risk for becoming disabled. The present review summarizes the available literature related to the use of adjuvant or alternative strategies intended to enhance the efficacy of exercise in improving the physical function of older adults. Within this work, we also discuss potential future research directions in this area. [Copyright &y& Elsevier]

The article discusses a study that evaluated percutaneous coronary intervention (PCI) practice trends and 12-month outcomes from April 1, 2004 to March 31, 2008 at seven public hospitals in Victoria. It reports on the decline in the use of drug-eluting stents (DES) despite the increase in patient risk profile and lesion complexity. The study reveals that 12-month adverse outcomes remained low, while procedural success remained high, with the use of prolonged dual anti-platelet therapy.

Aims The presence of heart failure (HF) is an established risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention (PCI). The aim of this study was to determine the prevalence and impact of concomitant HF on major outcomes in contemporary PCI practice. Methods and results We analysed 5006 consecutive PCIs (2004–2006) enrolled in the Melbourne Interventional Group registry. Baseline characteristics, in-hospital, 30-day, and 12-month outcomes of patients with a history of HF (n= 189, 3.8%) were compared with patients without HF (n= 4817, 96.2%). Patients with a history of HF were older (mean age 72.9 ± 9.8 vs. 64.3 ± 12 years, P< 0.01) and had higher rates of diabetes (37.0 vs. 23.5%, P< 0.01), renal dysfunction (Cr >200 μmol/L; 16.5 vs. 3.9%, P< 0.01), multi-vessel disease (79.8 vs. 58.7%, P< 0.01), and presentation with cardiogenic shock (4.8 vs. 2.1%, P= 0.02). At 12 months, patients with HF had higher overall mortality (13.7 vs. 3.5%, P< 0.01) and rates of HF admission (10.4 vs. 2.0%, P< 0.01). Independent predictors of recurrent HF admission included history of HF [odds ratio (OR) 2.2, 95% confidence interval (CI) 1.2–4.2, P< 0.01] and renal dysfunction (OR 2.5, 95% CI 1.4–4.4, P< 0.01). At 12 months, patients with HF had lower rates of statin (73.9 vs. 89.2%, P< 0.01) and beta-blocker use (55.6 vs. 59.0%, P< 0.01). Angiotensin-converting enzyme-inhibitor/angiotensin receptor blocker use was also relatively low in HF patients (79.6%). Conclusion While the overall incidence of HF in patients undergoing PCI is low, underutilization of HF therapies may contribute to an increased likelihood of subsequent re-admission and increased mortality. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia, a syndrome resembling complex regional pain syndrome (CRPS). Previous studies suggest that the pathogenesis of some of these changes involves an exaggerated regional inflammatory response to injury and we postulated that inflammatory cytokines contribute to the development of CRPS-like changes after fracture. Methods: The distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were given drinking water with or without the cytokine inhibitor pentoxifylline (PTX) starting the day before fracture and continuing for 4 weeks, after which time the cast was removed and multiple assays were performed in the hindpaw. PCR and immunoassays were used to evaluate changes in cytokine expression. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured by microcomputed tomography (μCT). Results: Tibia fracture chronically up-regulated TNFα, IL-1β and IL-6 mRNA and protein levels in hindpaw skin and PTX treatment significantly reduced the mRNA expression and cytokine protein levels for all these cytokines. PTX inhibited the nociceptive sensitization and some vascular changes, but had insignificant effects on most of the bone-related parameters measured in these studies. Immunostaining of hindpaw skin was negative for immunocyte infiltration at 4 weeks post-fracture. Conclusions: These results suggest that pro-inflammatory cytokines contribute to the nociceptive and vascular sequelae of fracture and that PTX treatment can reverse these CRPS-like changes. [Copyright &y& Elsevier]

Objective: To examine short- and medium-term outcomes of percutaneous coronary interventions (PCIs), with a focus on comparing drug-eluting stents (DESs) with bare-metal stents (BMSs).Design, Setting and Participants: Retrospective analysis of data from the Melbourne Interventional Group (MIG) registry, a large multicentre Australian registry. The study cohort consisted of 6364 consecutive patients undergoing 7167 PCIs between April 2004 and August 2007.Main Outcome Measures: Clinical events including death, myocardial infarction (MI), target lesion revascularisation (TLR), target vessel revascularisation (TVR) and major adverse cardiac events (MACE) (a composite of death, MI and TVR), at 30 days and at 12 months.Results: The cohort was predominantly male (74%), with a mean age of 64.7 years (SD, 12.0 years). DESs were used in 3482 (51.4%) of PCIs. In the overall cohort, rates of clinical events were low at 30 days: mortality (1.9%), MI (2.4%), TLR (2.0%), TVR (2.4%) and MACE (5.7%). At 12 months, event rates were: mortality (5.2%), MI (6.0%), TLR (5.8%), TVR (8.2%) and MACE (16.2%). Patients receiving DESs had similar mortality rates to those receiving BMSs (4.0% v 6.0%; P = 0.62 [propensity score-adjusted]); late thrombosis rates were also similar in the two groups (0.8% v 1.1%; P = 0.38). The proportion of patients receiving DESs fell significantly over time, from 54.9% in the first 24 months to 44.7% in the last 15 months of the study period (P < 0.01). Independent predictors of 12-month mortality included diabetes, renal failure, ST-segment-elevation MI and cardiogenic shock.Conclusion: Our clinical event rates were comparable with international registry outcomes. Rates of mortality and stent thrombosis were no higher in patients with DESs than those with BMSs. Although DESs were used in about half the procedures (preferentially for higher-risk lesions), recent trends suggest their use is in decline. [ABSTRACT FROM AUTHOR]

This study investigated the effect of varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in 24 adult smokers and compared these findings with data generated using human in vitro systems. Subjects were randomized to receive varenicline 1 mg twice a day or placebo for 13 days and then switched to the alternative treatment after a 1-week washout period. A single dose of warfarin 25 mg was given on day 8 of each treatment period, and serial blood samples were collected over 144 hours postdose. Pharmacokinetic parameters for both (R)- and (S)-warfarin and international normalized ratio (INR) values were determined. Varenicline was assessed as an inhibitor and inducer of human cytochrome P450 activities using liver microsomes and hepatocytes, respectively. Consistent with the in vitro data, no alteration in human pharmacokinetics of warfarin enantiomers was observed with varenicline treatment. The 90% confidence intervals for the ratios of area under the concentration— time curve from zero hours to infinity and peak plasma concentrations were completely contained within 80% to 125%. Warfarin pharmacodynamic parameters, maximum INR, and the area under the prothrombin (INR)—time curve, were also unaffected by steady-state varenicline. Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment. [ABSTRACT FROM PUBLISHER]

Varenicline is a novel and selective α4β2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double-blind, placebo-controlled, dose-escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose-proportional increases in maximum observed plasma concentrations and area under the plasma concentration-time curve from time zero to the end of the dosing interval values were observed between the 1-mg and 2-mg daily doses of varenicline. Once- and twice-daily dosing resulted, on average, in an approximate 2- and 3-fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration- or time-dependent changes in the pharmacokinetics of varenicline upon repeat dosing. [ABSTRACT FROM PUBLISHER]

Varenicline is a novel selectiveα4β2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly (≥65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance≥70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone. [ABSTRACT FROM PUBLISHER]

Varenicline is a novel and selective α4β2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of varenicline. [ABSTRACT FROM PUBLISHER]

The diagnoses of cracked teeth and incomplete coronal fracture have historically been symptom based. The dental operating microscope at 16x magnification can fundamentally change a clinician's ability to diagnose such conditions. Clinicians have been observing cracks under extreme magnification for nearly a decade. Patterns have become clear that can lead to appropriate treatment prior to symptoms or to devastation to tooth structure. Conversely, many cracks are not structural and can lead to misdiagnosis and overtreatment. Methodic microscopic examination, an understanding of crack progression, and an appreciation of the types of cracks will guide a doctor to make appropriate decisions. Teeth can have structural cracks in various stages. To date, diagnosis and treatment are very often at end stage of crack development. CLINICAL SIGNIFICANCE. This article gives new guidelines for recognition, visualization, classification, and treatment of cracked teeth based on the routine use of 16x magnification. The significance of enamel cracks as they relate to dentinal cracks is detailed. [ABSTRACT FROM AUTHOR]

Rationale. Depression is reported as a serious adverse event of antiviral therapy used to treat patients with hepatitis C (HCV); therefore, there is a need to identify a reliable and valid measure of depressive symptoms for this population. Aims. To determine reliability, construct validity and predictive validity of the Center for Epidemiological Studies Depression Scale (CES-D) in a hepatitis C (HCV) population. Ethical issues. Study reviewed/approved by the University Institutional Review Board and informed consent obtained. Methods. Longitudinal design testing psychometric properties of the CES-D prior to treatment and 4 and 24 weeks postinitiation of treatment. Reliability was tested using Cronbach's coefficient α . Construct validity was tested, prior to therapy, using principal components factoring with varimax rotation. Predictive validity was tested using repeated measures analysis of variance (anova) of CES-D scores at 4 and 24 weeks postinitiation of treatment. Results. Non-probability sample, 116 adult HCV patients [62 (53%) males and 54 (47%) females]. Reliability (Cronbach's α) = 0·88 pretreatment, 0·89 week 4 and 0·90 week 24. Construct validity testing revealed four factors: negative affect; positive affect; somatic; and depressed affect/somatic. Exception for two items, ‘felt sad’ and ‘couldn’t get going', all items loaded distinctly with correlation coefficients in the range of 0·51–0·84. Predictive validity testing revealed a statistically significant effect over time (P < 0·001) in the direction predicted (pretreatment x = 13·97; post 4 weeks x = 19·54 and 24 weeks x = 19·97). Conclusions. The CES-D is a reliable and valid instrument to screen for depressive symptoms in HCV patients. The instrument detected the predicted increase in depression associated with HCV. Examination of the sensitivity and specificity is needed to determine the most accurate cut-off score. [ABSTRACT FROM AUTHOR]

The oral pharmacokinetics of cilomilast (Ariflo®) were investigated in five separate studies in healthy volunteers. Cilomilast was rapidly absorbed, and pharmacokinetics were dose proportional after single and repeat dosing. The elimination half-life was 7 to 8 hours; accordingly, steady state was reached on the 3rd day of dosing. The degree of accumulation following repeat twice-daily dosing was predictable from the data following a single dose. Although systemic exposure (AUC) was, on average, 21% higher in elderly (65-84 years) compared with young subjects, values for Cmax and t1/2 were similar, and no difference in tolerability was noted. Single and repeat doses of cilomilast up to and including 15 mg (dosed before or taken between meals) were well tolerated. Dosing with food reduced the rate of absorption without affecting total bioavailability. Hence, tolerability was optimal in the fed state; repeat doses up to and including 30 mg twice daily after meals were well tolerated following dose titration. [ABSTRACT FROM PUBLISHER]

A study of the complexes formed between short linear DNA and three H1 variants, a typical somatic H1, and the extreme variants H5, from chicken erythrocytes, and spill from sea urchin sperm, has revealed differences between H1, H5 and spill that have implications for chromatin structure and folding. 1. All three histones bind cooperatively to DNA in 35 mM NaCl forming similar, but not identical, rod-like complexes. With sufficiently long DNA the complexes may be circular, circles forming more easily with H5 and spill than with H1. 2. The binding of H5 and spill to DNA is cooperative even in 5 mM NaCl, resulting in well-defined thin filaments that appear to contain two DNA molecules bridged by histone molecules. In contrast, HI binds distributively over all the DNA molecules in 5 mM NaCl, but forms short stretches similar in appearance to the thin filaments formed with H5 and spill. Rods appear to arise from the intertwining of regular thin filaments containing cooperatively bound histone molecules on raising the NaCl concentration to 35 mM. 3. The compositions of the rods correspond to one histone molecule for about every 47 bp (HI), 81 bp (HS) and 112 bp (spH1), suggesting average spacings of 24 bp (H1), 41 bp (H5) and 56 bp (spH1) in the component thin (double) filaments. Strikingly, these values are proportional to the linker lengths of the chromatins in which the particular H1 variant is the main or sole H1. [ABSTRACT FROM AUTHOR]

This paper proposes the use of ‘dreamwork’ to evoke historical patterns or transgenerational themes. A new variant of dreamwork is described. This work is systemic as well as symbolic, combining aspects of both Gestalt and Family System therapies. Two examples present this experiential exploration of recursive historical themes. The integration of these approaches is demonstrated. Implications of this therapeutic dramatization for couple therapy are suggested. [ABSTRACT FROM AUTHOR]