What factors empower general practitioners for early cancer diagnosis? A 20-country European Delphi Study.

BACKGROUND: Some symptoms are recognised as red flags for cancer, causing the General Practitioner (GP) to refer the patient for investigation without delay. However, many early symptoms of cancer are vague and unspecific, and in these cases, a delay in referral risks a diagnosis of cancer that is too late. Empowering GPs in their management of patients that may have cancer is likely to lead to more timely cancer diagnoses. AIM: To identify the factors that affect European GPs' empowerment in making an early diagnosis of cancer. METHODS: This was a Delphi study involving GPs in 20 European countries. We presented GPs with 52 statements representing factors that could empower GPs to increase the number of early cancer diagnoses. Over three Delphi rounds, we asked GPs to indicate the clinical relevance of each statement on a Likert scale.The final list of statements indicated those that were considered by consensus to be the most relevant. RESULTS: In total, 53 GPs from 20 European countries completed the Delphi process, out of the 68 GPs who completed round one. Twelve statements satisfied the pre-defined criteria for relevance. Five of the statements related to screening and four to the primary/secondary care interface. The other selected statements concerned information technology (IT) and GPs' working conditions. Statements relating to training, skills and working efficiency were not considered priority areas. CONCLUSION: GPs consider that system factors relating to screening, the primary-secondary care interface, IT and their working conditions are key to enhancing their empowerment in patients that could have cancer. These findings provide the basis for seeking actions and policies that will support GPs in their efforts to achieve timely cancer diagnosis.

A comparative study of ambulatory central hemodynamics and arterial stiffness parameters in peritoneal dialysis and hemodialysis patients.

BACKGROUND: Ambulatory pulse-wave velocity (PWV), augmentation pressure, and augmentation index (AIx) are associated with increased cardiovascular events and death in hemodialysis. The intermittent nature of hemodialysis generates a distinct ambulatory pattern, with a progressive increase of augmentation pressure and AIx during the interdialytic interval. No study so far has compared the ambulatory course of central hemodynamics and PWV between peritoneal dialysis and hemodialysis patients. METHODS: Thirty-eight patients under peritoneal dialysis and 76 patients under hemodialysis matched in a 1 : 2 ratio for age, sex and dialysis vintage underwent 48-h ambulatory blood pressure (BP) monitoring with the oscillometric Mobil-O-Graph device. Parameters of central hemodynamics [central SBP, DBP and pulse pressure (PP)], wave reflection [AIx, heart rate-adjusted AIx; AIx(75) and augmentation pressure] and PWV were estimated from the 48-h recordings. RESULTS: Over the total 48-h period, no significant differences were observed between peritoneal dialysis and hemodialysis patients in mean levels of central SBP, DBP, PP, augmentation pressure, AIx, AIx(75) and PWV. However, patients under peritoneal dialysis and hemodialysis displayed different trajectories in all the above parameters over the course of the recording: in peritoneal dialysis patients no differences were noted in central SBP (125.0 ±â€Š19.2 vs. 126.0 ±â€Š17.8 mmHg, P = 0.25), DBP, PP, augmentation pressure (13.0 ±â€Š6.8 vs. 13.7 ±â€Š7. mmHg, P = 0.15), AIx(75) (25.9 ±â€Š6.9 vs. 26.3 ±â€Š7.8%, P = 0.54) and PWV (9.5 ±â€Š2.1 vs. 9.6 ±â€Š2.1 m/s, P = 0.27) from the first to the second 24-h period of the recording. In contrast, hemodialysis patients showed significant increases in all these parameters from the first to second 24 h (SBP: 119.5 ±â€Š14.4 vs. 124.6 ±â€Š15.0 mmHg, P < 0.001; augmentation pressure: 10.9 ±â€Š5.3 vs. 13.1 ±â€Š6.3 mmHg, P < 0.001; AIx(75): 24.7 ±â€Š7.6 vs. 27.4 ±â€Š7.9%, P < 0.001; PWV: 9.1 ±â€Š1.8 vs. 9.3 ±â€Š1.8 m/s, P < 0.001). Peritoneal dialysis patients had numerically higher levels than hemodialysis patients in all the above parameters during all periods studied and especially during the first 24-h. CONCLUSION: Central BP, wave reflection indices and PWV during a 48-h recording are steady in peritoneal dialysis but gradually increase in hemodialysis patients. During all studied periods, peritoneal dialysis patients have numerically higher levels of all studied parameters, a fact that could relate to higher cardiovascular risk.

An RCT of Fecal Immunochemical Test Colorectal Cancer Screening in Veterans Without Recent Primary Care.

INTRODUCTION: The use of screening can prevent death from colorectal cancer, yet people without regular healthcare visits may not realize the benefits of this preventive intervention. The objective of this study was to determine the effectiveness of a mailed screening invitation or mailed fecal immunochemical test in increasing colorectal cancer screening uptake in veterans without recent primary care encounters. STUDY DESIGN: Three-arm pragmatic randomized trial. SETTING/PARTICIPANTS: Participants were screening-eligible veterans aged 50-75 years, without a recent primary care visit who accessed medical services at the Corporal Michael J. Crescenz Veteran Affairs Medical Center between January 1, 2017, and July 31, 2017. All data were analyzed from March 1, 2018, to July 31, 2018. INTERVENTION: Participants were randomized to (1) usual opportunistic screening during a healthcare visit (n=260), (2) mailed invitation to screen and reminder phone calls (n=261), or (3) mailed fecal immunochemical test outreach plus reminder calls (n=61). MAIN OUTCOME MEASURES: The main outcome under investigation was the completion of colorectal cancer screening within 6 months after randomization. RESULTS: Of 782 participants in the trial, 53.9% were aged 60-75 years and 59.7% were African American. The screening rate was higher in the mailed fecal immunochemical test group (26.1%) compared with usual care (5.8%) (rate difference=20.3%, 95% CI=14.3%, 26.3%; RR=4.52, 95% CI=2.7, 7.7) or screening invitation (7.7%) (rate difference=18.4%, 95% CI=12.2%, 24.6%; RR=3.4, 95% CI=2.1, 5.4). Screening completion rates were similar between invitation and usual care (rate difference=1.9%, 95% CI= -2.4%, 6.2%; RR=1.3, 95% CI=0.7, 2.5). CONCLUSIONS: Mailed fecal immunochemical test screening promotes colorectal cancer screening participation among veterans without a recent primary care encounter. Despite the addition of reminder calls, an invitation letter was no more effective in screening participation than screening during outpatient appointments. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov NCT02584998.

Ambulatory Blood Pressure Trajectories and Blood Pressure Variability in Diabetic and Non-Diabetic Chronic Kidney Disease.

BACKGROUND: Diabetic kidney disease is the leading cause of end-stage renal disease worldwide. Whether diabetes mellitus (DM) is an additional factor leading to elevated blood pressure (BP) levels and BP variability (BPV) in patients with chronic kidney disease (CKD) is unknown. This study aimed to compare ambulatory BP levels, BP trends and BPV in diabetic and non-diabetic patients with CKD. METHODS: This study included 48 diabetic and 48 non-diabetic adult patients (>18 years) with CKD (estimated glomerular filtration rate [eGFR] <90 and ≥15 mL/min/1.73 m2), matched in a 1:1 ratio for age, sex and eGFR within each CKD stage (2, 3a, 3b and 4). All patients underwent 24-h ambulatory BP measurement with the Mobil-O-graph device. To evaluate the effect of DM and time on the trajectories of 24-h BP levels, we performed two-way mixed ANOVA analysis for repeated measurements using hourly means. BPV was calculated with validated formulas. RESULTS: In total, patients with DM had significantly higher 24-h systolic BP (SBP; 132.13 ± 10.71 vs. 124.16 ± 11.45; p = 0.001) and pulse pressure (PP; 57.1 ± 9.6 vs. 49.5 ± 10.9; p < 0.001), but similar 24-h diastolic BP (DBP; 75.00 ± 8.43 vs. 74.62 ± 6.86 mm Hg; p = 0.809) compared to patients without DM. A similar trend was evident across all CKD stages. The effect of DM on BP trajectories during the recording period was significant for SBP (F = 18.766, p < 0.001, partial η2 = 0.261) and marginally significant for DBP (F = 3.782, p = 0.057, partial η2 = 0.067). Twenty-four hour SBP SD, weighted SD (wSD) and average real variability (ARV; 10.94 ± 2.75 vs. 9.46 ± 2.10; p = 0.004), as well as 24 h DBP SD, wSD, coefficient of variation (CV) and ARV (8.23 ± 2.10 vs. 7.10 ± 1.33; p = 0.002) were significantly higher in diabetic compared to non-diabetic CKD patients. CONCLUSIONS: Ambulatory SBP and PP levels are higher and SBP-profile is different in patients with diabetic compared to those with non-diabetic CKD. Systolic and diastolic BPV are also higher in diabetics. These findings may signify a higher cardiovascular risk for patients with both DM and CKD compared to patients with CKD alone, through higher BP levels and BPV.

Anaphylaxis-induced atrial fibrillation and anesthesia: Pathophysiologic and therapeutic considerations.

Atrial fibrillation is the most common cardiac arrhythmia in western society affecting more than 35 million individuals worldwide annually. It is a common postoperative complication and may also occur spontaneously during general and local anesthesia administration. Aging, diabetes mellitus, hypertension, and cardiovascular diseases including cardiomyopathies, congenital cardiac anomalies, heart failure, myocardial ischemia, pericarditis, previous cardiac surgery, vascular disease, and valvular heart disease are some correlated factors. Beyond age, increased incidence of atrial fibrillation has been correlated to autoimmune system activation as it is the underlying mechanism of persistent atrial fibrillation development. Current research supports an association between the complement system activation and lymphocyte-pro-inflammatory cytokines release with the cardiac conduction system and atrial fibrosis. The loss of CD28 antigen from CD4+ CD28+ T lymphocytes seems to play a major role in atrial fibrillation development and prognosis. Except atrial fibrillation, a variety of additional electrocardiographic changes, resembling those with digitalis intoxication may accompany anaphylaxis and particularly Kounis syndrome. Histamine is one well-known mediator in allergic and inflammatory conditions as physiologically regulates several cardiovascular and endothelial functions with arrhythmogenic potential. The increased oxidative stress, measured by the redox potentials of glutathione, has been correlated with atrial fibrillation incidence and prevalence. The use of antazoline, a first-generation antihistamine agent used for rapid conversion of recent-onset atrial fibrillation in patients with preserved left ventricular function and for rapid atrial fibrillation termination during accessory pathway ablation denotes that anaphylaxis-induced histamine production could be the cause of atrial fibrillation at least in some instances. The anaphylaxis diagnosis in anesthesia can be challenging owing to the absence of cutaneous manifestetions such as flushing, urticaria, or angioedema. Anticoagulation for stroke prevention, rate and rhythm control medications, invasive methods such as radiofrequency ablation or cryoablation of pulmonary veins as well surgical ablation constitute the treatment basis of atrial fibrillation. Understanding the underlying mechanisms of atrial fibrillation by cardiologists, anesthesiologists and surgeons, as well as potential treatments, to optimize care is of paramount importance.

Kounis Syndrome­not a Single-organ Arterial Disorder but a Multisystem and Multidisciplinary Disease

Coronary symptoms associated with conditions related to mast cell activation and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, further inducing allergic, hypersensitivity, anaphylactic, or anaphylactic insults, are currently referred to as the Kounis syndrome. Kounis syndrome is caused by inflammatory mediators released during allergic insults, post-inflammatory cell activation, and interactions via multidirectional stimuli. A platelet subset of 20% with high- and low-affinity IgE surface receptors is also involved in this process. Kounis syndrome is not just a single-organ but also a complex multisystem and multi-organ arterial clinical condition; it affects the coronary, mesenteric, and cerebral arteries and is accompanied by allergy­hypersensitivity­anaphylaxis involving the skin, respiratory, and vascular systems in the context of anesthesia, surgery, radiology, oncology, or even dental and psychiatric medicine; further, it has significantly influences both morbidity and mortality. Kounis syndrome might be caused by numerous and continuously increasing causes, with broad clinical symptoms and signs, via multi-organ arterial system involvement, in patients of any age, thereby demonstrating predominant anaphylactic features in terms of a wide spectrum of mast cell-association disorders. Cardiac symptoms, such as chest pain, coronary vasospasm, angina pectoris, myocardial infarction, stent thrombosis, acute cardiac failure, and sudden cardiac death associated with subclinical, clinical, acute, or chronic allergic reactions, constitute the clinical manifestations of this syndrome. Since its first description, a common pathway between allergic and non-allergic coronary events has been demonstrated. The hypothesis is based on the existence of a much higher degree of mast cell degranulation at plaque erosion or rupture sites compared with at the adjacent areas or even more distant segments in post-acute myocardial infarction of non-allergic etiology. Although mast cell activation, differentiation, and mediator release takes days or weeks, the mast cell degranulation may occur just before any acute coronary event, further resulting in coronary artery vasoconstriction and atheromatous plaque rupture. It seems that medications and natural molecules stabilizing the mast cell membrane as well as monoclonal antibodies protecting the mast cell surface can emerge as novel therapeutic modalities for acute coronary and cerebrovascular event prevention.

Association Between High-Dose Spironolactone and Decongestion in Patients with Acute Heart Failure: An Observational Retrospective Study.

BACKGROUND: Acute congestive heart failure (ACHF) is a state of severe, secondary hyperaldosteronism. Relief of congestion has prognostic implications. Our aim was to assess associations between high-dose spironolactone and (1) decongestion and (2) safety in patients with ACHF. METHODS: The charts of 20 patients who were hospitalized with ACHF and received high doses of spironolactone (75-300 mg daily, group A) on top of standard of care (SOC) treatment were retrospectively studied and compared with the ones of 20 matched patients who received SOC treatment alone (group B). RESULTS: The two groups were similar as per their baseline characteristics. Mean daily spironolactone dose was 143 ± 56 in group A vs. 25 ± 25 mg in group B (P < 0.001). Patients of group A demonstrated significantly greater daily urine output (median [25th, 75th percentile] 2.9 [2.3, 3.9] vs. 2.2 [1.9, 2.5] L/day, P = 0.009), daily weight loss (1.1 [0.9, 1.7] vs. 0.4 [0.2, 1.2] kg/day, P = 0.005) and total body weight loss (10.5 [7.3, 13.8] vs. 3.8 [3.0, 6.0] kg, P < 0.001) compared with patients of group B. There were no differences in incidence of renal dysfunction, hypokalemia and hyperkalemia. CONCLUSION: In patients with ACHF, administration of high doses of spironolactone on top of SOC treatment appears safe and is associated with greater decongestion than SOC alone.

Financial incentives for completion of fecal occult blood tests among veterans: a 2-stage, pragmatic, cluster, randomized, controlled trial.

BACKGROUND: Rates of patient completion of fecal occult blood tests (FOBTs) are often low. OBJECTIVE: To examine whether financial incentives increase rates of FOBT completion. DESIGN: A 2-stage, parallel-design, pragmatic, cluster, randomized, controlled trial with clustering by clinic day (ClinicalTrials.gov: NCT01516489). SETTING: Primary care clinic of the Philadelphia Veterans Affairs Medical Center. PATIENTS: 1549 patients who were prescribed an FOBT (unique samples of 713 patients for stage 1 and 836 patients for stage 2). INTERVENTION: In stage 1, patients were assigned to usual care or receipt of $5, $10, or $20 for FOBT completion. In stage 2, different patients were assigned to usual care or receipt of $5, a 1 in 10 chance of $50, or entry into a $500 raffle for FOBT completion. MEASUREMENTS: Primary outcome was FOBT completion within 30 days. Preplanned subgroup analyses examined 30-day FOBT completion by previous nonadherence to a prescribed FOBT. RESULTS: In stage 1, none of the incentives increased rates of FOBT completion. In stage 2, a 1 in 10 chance of $50 increased FOBT completion compared with usual care (between-group difference, 19.6% [95% CI, 10.7% to 28.6%]; P < 0.001) but a $5 fixed payment and entry into a raffle for $500 did not. None of the incentives were more effective among patients who had previously been nonadherent to an FOBT than among patients who had previously completed an FOBT. LIMITATIONS: Single Veterans Affairs medical center setting, short follow-up, use of 3-sample rather than 1-sample immunochemical FOBTs, limited power to detect small effects of incentives, inability to evaluate cost-effectiveness. CONCLUSION: A 1 in 10 chance of receiving $50 was effective at increasing rates of FOBT completion, but 5 other tested incentives were not. PRIMARY FUNDING SOURCE: Veterans Affairs Center for Health Equity Research and Promotion.

Polyadenylation site prediction using PolyA-iEP method.

This chapter presents a method called PolyA-iEP that has been developed for the prediction of polyadenylation sites. More precisely, PolyA-iEP is a method that recognizes mRNA 3'ends which contain polyadenylation sites. It is a modular system which consists of two main components. The first exploits the advantages of emerging patterns and the second is a distance-based scoring method. The outputs of the two components are finally combined by a classifier. The final results reach very high scores of sensitivity and specificity.

StackTIS: a stacked generalization approach for effective prediction of translation initiation sites.

The prediction of the translation initiation site in an mRNA or cDNA sequence is an essential step in gene prediction and an open research problem in bioinformatics. Although recent approaches perform well, more effective and reliable methodologies are solicited. We developed an adaptable data mining method, called StackTIS, which is modular and consists of three prediction components that are combined into a meta-classification system, using stacked generalization, in a highly effective framework. We performed extensive experiments on sequences of two diverse eukaryotic organisms (Homo sapiens and Oryza sativa), indicating that StackTIS achieves statistically significant improvement in performance.

The incidence of deep vein thrombosis detected by routine surveillance ultrasound in neurosurgery patients receiving dual modality prophylaxis.

The optimal method of thromboprophylaxis and the value of screening ultrasonography for detection of deep venous thrombosis (DVT) in neurosurgery patients remains unclear. The goal of this study was to determine the incidence of DVT in neurosurgical patients who, by hospital protocol, receive surveillance ultrasonography of the lower extremities twice weekly, in addition to prophylaxis with unfractionated heparin and external pneumatic compression sleeves. A retrospective review of 7,298 ultrasound studies carried out on 2,593 patients over 4 years at a university neurosurgical hospital was conducted. There was a 7.4% incidence of proximal lower extremity DVT and a 9.7% total incidence including distal DVT. A greater number of distal DVTs were detected with the implementation of whole-leg ultrasonography in the last 2 years of observation. Chart review of 237 patients diagnosed with DVT demonstrated an admitting diagnosis of subarachnoid hemorrhage in nearly half of the patients. The median hospital length of stay for DVT patients was 18 days. Institutional control data demonstrated non-ruptured aneurysm and cerebrovascular anomalies to be the leading reason for admission, followed closely by subarachnoid hemorrhage. The hospital protocol of biweekly screening ultrasound and dual modality prophylaxis for neurosurgery patients resulted in a proximal DVT incidence consistent with that demonstrated by previous studies of standardized dual modality prophylaxis, and higher than that demonstrated in previous studies that employed ultrasound screening protocols.

Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio?

Warfarin is a commonly used oral anticoagulant, and has well-established clinical efficacy. However, it has a narrow therapeutic window, and a mode-of-action affected by inter-individual differences and environmental factors. The effectiveness and safety of warfarin are closely related to maintenance of the international normalized ratio (INR) within therapeutic range. A supra-therapeutic INR puts patients at risk of bleeding, whereas a sub-therapeutic INR may not protect against thromboembolic complications. Research suggests a lack of anticoagulation control during warfarin therapy in different settings. Careful monitoring of the INR is essential, especially in geriatric or cancer populations who are at an increased risk of major hemorrhage. Warfarin is an effective treatment but optimization of the risk-benefit ratio is crucial in order to maximize efficacy and safety. Here, we will assess the extent to which INRs are an issue in the management of warfarin therapy, and the effect INRs may have on clinical outcomes.

MANTIS: a data mining methodology for effective translation initiation site prediction.

The prediction of the translation initiation site in a genomic sequence with the highest possible accuracy is an important problem that still has to be investigated by the research community. Current approaches perform quite well, however there is still room for a more general framework for the researchers who want to follow an effective and reliable methodology. We developed a prediction methodology that combines ad hoc as well as discovered knowledge in order to significantly increase the achieved accuracy reliably. Our methodology is modular and consists of three major decision components: a consensus component, a coding region classification component and a novel ATG location-based component that allows for the utilization of the advantages of the popular Ribosome Scanning Model while overcoming its limitations. All three of them are combined into a meta-classification system, using stacked generalization, in a highly effective prediction framework. We performed extensive comparative experiments on four different datasets, showing that the increase in terms of accuracy and adjusted accuracy is not only statistically significant, but also the highest reported.