A dedicated high-quality service for the management of patients with an inherited risk of colorectal cancer.

AIM: To demonstrate the quality improvement associated with the implementation of a specialist family history of bowel cancer service in secondary care. METHOD: The following outcomes were assessed: (1) adherence to the British Society of Gastroenterology (BSG) guidelines for colonoscopic surveillance of individuals with a family history of colorectal cancer (CRC); (2) adherence to the revised Bethesda criteria for the identification of CRC patients with suspected Lynch syndrome; (3) identification of inherited syndromes with increased CRC risk; and (4) colonoscopic adenoma detection rate. Data were collected for a 21-month period before and after the establishment of this service for all patients who underwent colonoscopic surveillance for a family history of CRC and all patients newly diagnosed with CRC. Analyses compared the number of colonoscopies performed that were not indicated by BSG guidelines, the average number of years early that patients were screened, the adenoma detection rate and the rate of tumour testing for mismatch repair genes before and after the implementation of the service. RESULTS: Following the establishment of the service there was a reduction in the number of colonoscopies not indicated by BSG guidelines (39.6% before and 5.8% after, P < 0.001, chi-square test) and surveillance colonoscopy took place at a more appropriate age (10.6 years too early before and 5.9 years early after, P = 0.01, t-test). There was an increased adenoma detection rate (17% before and 31.9% after, P < 0.01, chi-square test) and increased tumour MMR testing (3.4% before and 91.8% after, P < 0.01, chi-square test). CONCLUSION: The introduction of a family history of bowel cancer service results in improved patient care through improved adherence to guidelines for colonoscopic surveillance and increased cancer detection rates.

Experience of the implementation and outcomes of universal testing for Lynch syndrome in the United Kingdom.

AIM: Colorectal cancer (CRC) is diagnosed in approximately 45 000 people annually in the UK, and it is estimated that Lynch syndrome (LS) accounts for 3.1% of these cases. In February 2017, National Institute for Health and Care Excellence (NICE guideline DG27 recommended universal testing of new cases of CRC for mismatch repair (MMR) status. The aim of this study was to implement universal testing for LS in CRC patients in a secondary care setting. METHOD: We prospectively collected data on consecutive newly diagnosed CRC patients at our centre from November 2016 to August 2018, including evidence of MMR status determined by immunohistochemistry. We recorded clinicopathological data including age at diagnosis, stage, tumour site, reported histological findings and MMR tumour status. Statistical analysis was performed using the chi-square test and the two-tailed t-test for binary and continuous variables, respectively. RESULTS: A cohort of 203 consecutive patients were diagnosed with CRC during this period. Universal MMR testing was performed for the 198 CRC patients in whom a diagnosis of adenocarcinoma was confirmed, with colonoscopic biopsy used as the source material in 68.6% of cases. Twenty-three CRCs (11.6%) were MMR deficient (dMMR). Most dMMR CRCs (21/23) were early stage tumours (Dukes A or B, P = 0.002). In 39 Dukes B CRCs in patients under 70 years of age, the result of MMR testing influenced decision-making about personalized treatment with 5-fluorouracil based chemotherapy. CONCLUSION: Our results demonstrate that universal testing of all new cases of CRC for features suggestive of LS is feasible and effective in the UK. Our data also indicate the importance of genetic testing and personalized oncological care.

Upper gastrointestinal complications following ablation therapy for atrial fibrillation.

BACKGROUND: Following ablation therapy for cardiac arrhythmias, patients may develop upper gastrointestinal (UGI) symptoms. The vagus nerve is close to the atria and may be affected by ablating energy. AIM: To identify structural or functional complications in UGI tract following ablation for atrial fibrillation (AF) and clinical outcomes and association with vagal dysfunction. METHODS: Using natural language processing of electronic medical records and an AF ablation database of 5380 patients treated during 17 years, we identified 40 patients with UGI complications. We evaluated vagal dysfunction by electrocardiogram (ECG) showing lack of sinus arrhythmia (variation in R-R interval by ≥120 milliseconds, in presence of normal sinus P waves and constant P-R interval). KEY RESULTS: Among 40 patients: (A) eight had structural GI complications confirmed by diagnostic tests: seven with esophageal ulcer/erosions and no signs of UGI bleeding and one developed esophagopericardial fistula (and survived with treatment); (B) 15 had functional UGI complications confirmed by objective motility tests. Nine had newly developed symptoms and six had aggravated symptoms; and (C) the remaining 17 had GI symptoms without relevant diagnostic results. Most UGI issues resolved spontaneously or with conservative treatment. However, 2 died several weeks after ablation procedure; cause of death was suspected atrioesophageal fistula or esophageal rupture. Vagal dysfunction persisted for 3 months in 13 and was transient in 8. CONCLUSIONS/INFERENCES: Although most GI issues resolved spontaneously, there should be a high index of clinical suspicion in patients with persistent symptoms. Vagal dysfunction may serve as a marker of more extensive tissue damage.

Decipher correlation patterns post prostatectomy: initial experience from 2 342 prospective patients.

BACKGROUND: Currently, there are multiple commercially available RNA-based biomarkers that are Medicare approved and suggested for use by the National Comprehensive Cancer Network guidelines. There is uncertainty as to which patients benefit from genomic testing and for whom these tests should be ordered. Here, we examined the correlation patterns of Decipher assay to understand the relationship between the Decipher and patient tumor characteristics. METHODS: De-identified Decipher test results (including Decipher risk scores and clinicopathologic data) from 2 342 consecutive radical prostatectomy (RP) patients tested between January and September 2015 were analyzed. For clinical testing, tumor specimen from the highest Gleason grade was sampled using a 1.5 mm tissue punch. Decipher scores were calculated based on a previously locked model. Correlations between Decipher score and clinicopathologic variables were computed using Spearman's rank correlation. Mixed-effect linear models were used to study the association of practice type and Decipher score. The significance level was 0.05 for all tests. RESULTS: Decipher score had a positive correlation with pathologic Gleason score (PGS; r=0.37, 95% confidence interval (CI) 0.34-0.41), pathologic T-stage (r=0.31, 95% CI 0.28-0.35), CAPRA-S (r=0.32, 95% CI 0.28-0.37) and patient age (r=0.09, 95% CI 0.05-0.13). Decipher reclassified 52%, 76% and 40% of patients in CAPRA-S low-, intermediate- and high-risk groups, respectively. We detected a 28% incidence of high-risk disease through the Decipher score in pT2 patients and 7% low risk in pT3b/pT4, PGS 8-10 patients. There was no significant difference in the Decipher score between patients from community centers and those from academic centers (P=0.82). CONCLUSIONS: Although Decipher correlated with baseline tumor characteristics for over 2 000 patients, there was significant reclassification of tumor aggressiveness as compared to clinical parameters alone. Utilization of the Decipher genomic classifier can have major implications in assessment of postoperative risk that may impact physician-patient decision making and ultimately patient management.

123s and ABCs: developmental shifts in logarithmic-to-linear responding reflect fluency with sequence values.

When placing numbers along a number line with endpoints 0 and 1000, children generally space numbers logarithmically until around the age of 7, when they shift to a predominantly linear pattern of responding. This developmental shift of responding on the number placement task has been argued to be indicative of a shift in the format of the underlying representation of number (Siegler & Opfer, ). In the current study, we provide evidence from both child and adult participants to suggest that performance on the number placement task may not reflect the structure of the mental number line, but instead is a function of the fluency (i.e. ease) with which the individual can work with the values in the sequence. In Experiment 1, adult participants respond logarithmically when placing numbers on a line with less familiar anchors (1639 to 2897), despite linear responding on control tasks with standard anchors involving a similar range (0 to 1287) and a similar numerical magnitude (2000 to 3000). In Experiment 2, we show a similar developmental shift in childhood from logarithmic to linear responding for a non-numerical sequence with no inherent magnitude (the alphabet). In conclusion, we argue that the developmental trend towards linear behavior on the number line task is a product of successful strategy use and mental fluency with the values of the sequence, resulting from familiarity with endpoints and increased knowledge about general ordering principles of the sequence.A video abstract of this article can be viewed at:http://www.youtube.com/watch?v=zg5Q2LIFk3M.

Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis.

BACKGROUND AND OBJECTIVES: Mucinous cystic neoplasms and intraductal papillary mucinous tumours have greater malignant potential than serous cystic neoplasms. EUS alone is inadequate for characterising these lesions but the addition of FNA may significantly improve diagnostic accuracy. The performance of EUS-FNA is highly variable in published studies. AIM: To determine the diagnostic accuracy of EUS-FNA to differentiate mucinous versus non-mucinous cystic lesions with cyst fluid analysis for cytology and carcinoembryonic antigen (CEA) by performing a meta-analysis of published studies. METHODS: Relevant studies were identified via structured database search and included if they used a reference standard of definitive surgical histology or clinical follow-up of at least 6 months. Data from selected studies were pooled to give summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and Receiver Operating Characteristic (ROC) curve. Pre-defined subgroup analysis was performed. RESULTS: Eighteen studies (published 2002-2011) were included, with a total of 1438 patients. For cytology, pooled sensitivity was 54(95%CI 49-59)% and specificity 93(90-95)%. The diagnostic odds ratio (DOR) was 13.3 (4.37-49.43), with I(2) of 77.1%. For CEA sensitivity was 63(59-67)% and specificity 88(83-91)%. The DOR was 10.76(6.29-18.41) with an I(2) of 25.4%. The diagnostic accuracy of EUS-FNA was enhanced in prospective studies and studies of <36 months duration. No impact of publication bias on our results was demonstrated. CONCLUSIONS: Fine-needle aspiration has moderate sensitivity but high specificity for mucinous lesions. EUS-FNA, when used in conjunction with cross sectional imaging, is a useful diagnostic tool for the correct identification of mucinous cysts.

Age- and limb-related differences in the vasoconstrictor response to limb dependency are not mediated by a sympathetic mechanism in humans.

AIMS: We tested the hypotheses that vasoconstrictor responses to limb dependency are: (i) greater in the leg than the arm, (ii) impaired with age and (iii) not sympathetically mediated. METHODS: Vascular responses to limb dependency (i.e. lowering the limb from heart level to 30 cm below heart level) were determined in 17 young and 17 older adults. Indices of blood flow were obtained in the brachial and popliteal arteries (Doppler ultrasound) as well as in the cutaneous circulation (forearm and calf using laser-Doppler flowmetry). Vasoconstriction was quantified by calculating the indices of vascular resistance as height corrected mean arterial pressure/limb blood velocity or skin flux. A second group of subjects repeated the limb dependency trials after acute systemic sympathetic blockade. RESULTS: Limb dependency increased vascular resistance index in the brachial artery (∆59 ± 8%; P<0.05) and popliteal artery (∆99 ± 10%; P<0.05 for change in heart level and brachial vs. popliteal) of young and older adults (∆60 + 9% brachial and ∆61 ± 7% popliteal arteries; P<0.05 for change in heart level and response in popliteal young vs. older adults). In contrast, cutaneous vasoconstrictor responses to limb dependency were similar in the forearm (∆218 ± 29% and ∆200 ± 29% for young and older adults, respectively) and calf (∆257 ± 32% and ∆236 ± 29%; all P<0.05 from heart level) of young and older adults. Vasoconstrictor responses to limb dependency were not affected by sympathetic blockade in young or older adults. CONCLUSION: These findings indicate that age-, limb-, and tissue-related differences may exist in the vasoconstrictor response to limb dependency in healthy humans, which are not sympathetically mediated.

Primary carnitine deficiency and sudden death: in vivo evidence of myocardial lipid peroxidation and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2.

OBJECTIVES: Primary carnitine deficiency is an autosomal recessive disorder caused by mutations in the SLC22A5 gene which results in impaired carnitine transport, cytosolic fatty acid accumulation and impaired beta oxidation. The disease is associated with cardiomyopathy and arrhythmias, but the mechanism is unknown. We hypothesized that carnitine deficiency results in increased myocardial oxidative stress. METHODS: We evaluated a 22-year-old woman with primary carnitine deficiency and ventricular fibrillation, as well as her first-degree relatives. RESULTS: Sequencing of SLC22A5 identified two deleterious mutations (A142S and R488H) and a novel mutation predicted to be a splice variant. Histology demonstrated increased myocardial lipid deposition and swollen mitochondria. Immunohistochemistry demonstrated accumulation of the reactive aldehyde 4-hydroxy-2-nonenal, indicative of increased lipid peroxidation, and sulfonylation of sarcoendoplasmic reticulum calcium ATPase 2 at cysteine 674. CONCLUSIONS: These findings suggest that increased oxidant stress may contribute to myocardial dysfunction and arrhythmogenesis in this disorder.

Somatic p16(INK4a) loss accelerates melanomagenesis.

Loss of p16(INK4a)-RB and ARF-p53 tumor suppressor pathways, as well as activation of RAS-RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16(INK4a) are associated with familial melanoma, most melanomas result from somatic genetic events: often p16(INK4a) loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16(INK4a)-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16(INK4a) and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16(INK4a) and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.

Warfarin induction at 5 mg daily is safe with a low risk of anticoagulant overdose: results of an audit of patients with deep vein thrombosis commencing warfarin.

BACKGROUND: Conventionally warfarin therapy is initiated using a loading dose given over several days. Daily international normalised ratio (INR) monitoring is recommended to prevent overdose; however, with a large proportion of patients with deep vein thrombosis now receiving treatment out of hospital daily blood tests are inconvenient. We introduced a low-dose protocol for starting anticoagulant therapy that only required INR testing on days 4 and 6 and audited the results to assess safety and efficacy. METHODS: Two-hundred and forty-eight patients with confirmed deep vein thrombosis were started on warfarin therapy at 5 mg daily for 3 days. INR measurements were taken at day 4 and day 6. RESULTS: Of these patients, 21% had an INR within the therapeutic range on day 4 and 52% had a therapeutic INR on day 6. The risk of overdose was small with only one case with an INR above 4.0 on day 4 and nine cases on day 6. There were no reported cases of bleeding. CONCLUSION: The low-dose protocol with infrequent testing is safe and convenient for outpatient management. However, our results suggest that patients on this protocol take between 6-10 days to achieve a stable INR.

Prevention principles for practitioners: a solution or an illusion?

The social work profession has sought to eliminate, or at the very least, ameliorate those social ills that were believed to contribute to severe social and personal dysfunction. Prevention programs have been a primary factor in this endeavor. Prevention programs have addressed a vast array of difficulties including adolescent suicide, youth violence, teenage pregnancy, home visiting programs for families at high-risk for neglect and abuse as well as out-of-home placement. This paper addresses the concept of prevention and incorporates the notion of resilience in eight (8) prevention practice principles. Case examples are provided as well as a discussion for future directions for prevention in the field of social work.

Central arterial compliance is associated with age- and habitual exercise-related differences in cardiovagal baroreflex sensitivity.

Background- Cardiovagal baroreflex sensitivity (BRS) declines with age but is favorably modulated by habitual aerobic exercise. We tested the hypothesis that compliance (transducing capacity) of an elastic artery in which baroreceptors are located is associated with these age-exercise interactions. Methods and Results- Nine young (28+/-1 years old) and 9 older (65+/-1) sedentary and 10 young (27+/-1) and 9 older (63+/-2) endurance-trained healthy men were studied. Cardiovagal BRS was assessed conventionally (R-R interval-systolic blood pressure [SBP] relation) by the Oxford technique. Because of age-associated increases in central arterial stiffness, cardiovagal BRS was expressed with both peripheral (Finapres) and central (applanation tonometry) SBP values. The change in carotid artery end-systolic lumen diameter (ultrasonography) per unit increase in SBP and the slope of the R-R interval-carotid artery diameter relation also were determined. Cardiovagal BRS declined with age in both sedentary ( approximately 65%) and endurance-trained ( approximately 40%) men but was higher in endurance-trained than sedentary older men regardless of the SBP values used (all P<0.05). Changes in carotid artery lumen diameter per unit increase in SBP mirrored these differences in cardiovagal BRS (all P<0.05). Thus, R-R interval prolongation per unit increase in carotid artery diameter was not different among the groups (P>0.70). Conclusions- These results demonstrate that age- and habitual exercise-related differences in cardiovagal BRS are associated with corresponding differences in carotid artery compliance among healthy men.

Comparison and clinical application of frequency domain methods in analysis of neonatal heart rate time series.

The frequency content of the heart rate (HR) series contains information regarding the state of the autonomic nervous system. Of particular importance is respiratory sinus arrhythmia (RSA), the high-frequency fluctuation in HR attributable to respiration. The unevenly sampled nature of heart rate data, however, presents a problem for the discrete Fourier transform. Interpolation of the HR series allows even sampling, but filters high-frequency content. The Lomb periodogram (LP) is a regression-based method that addresses these issues. To evaluate the efficacy of the LP and Fourier techniques in detecting RSA, we compared the spectrum of intervals, the spectrum of HR samples, and the LP of simulated and clinical neonatal time series. We found the LP was superior to the spectrum of intervals and the spectrum of HR samples in analysis near the critical frequency of one half the average sampling rate. Applying the LP to clinical data, we found (1) evidence of stochastic resonance, an enhancement of periodicity with the addition of small amounts of noise, and (2) reduced power at all frequencies prior to clinical diagnosis of neonatal sepsis.

Blood pressure reductions with exercise and sodium restriction in postmenopausal women with elevated systolic pressure: role of arterial stiffness.

OBJECTIVES: This study determined the relative efficacy of aerobic exercise (daily walking) and moderate dietary sodium restriction (sodium intake <100 mmol/day) for reducing systolic blood pressure (SBP) and pulse pressure (PP) in postmenopausal women with elevated initial levels, and the potential role of reductions in large artery stiffness in these changes. BACKGROUND: Lifestyle behaviors are recommended for lowering blood pressure (BP) in adults with elevated baseline levels, but there is little information as to the relative efficacy of different interventions or the mechanisms underlying their potential beneficial effects. METHODS: After baseline measurements and random assignment, 35 nonmedicated healthy postmenopausal women with SBP between 130 and 159 mm Hg completed three months of either aerobic (walking) exercise (n = 18; 62 +/- 9 years, mean +/- SD) or moderate dietary sodium restriction (SR) (n = 17; 65 +/- 10 years, mean +/- SD). RESULTS: Body mass and composition, plasma volume, and fasting concentrations of metabolic coronary risk factors did not differ between the groups at baseline or change with intervention. Systolic BP and PP at rest decreased with both exercise and SR (p < 0.05); however, the reductions were three- to fourfold greater with SR (p < 0.05). Sodium restriction, but not exercise, also reduced 24-h SBP and PP (p < 0.05). Aortic pulse wave velocity (PWV) and carotid augmentation index were reduced only with SR (p < 0.05). Changes in SBP and PP at rest and over 24 h correlated with the corresponding changes in aortic PWV (r = 0.53 to 0.61, p < 0.01). CONCLUSIONS: Moderate SR lowers SBP and PP in postmenopausal women with elevated baseline levels more than does daily walking. The greater blood pressure reductions with SR may be mediated in part by a decrease in the stiffness of the large elastic arteries.

Smaller age-associated reductions in leg venous compliance in endurance exercise-trained men.

We determined the independent and interactive influences of aging and habitual endurance exercise on calf venous compliance in humans. We tested the hypotheses that calf venous compliance is 1) reduced with age in sedentary and endurance-trained men, and 2) elevated in young and older endurance-trained compared with age-matched sedentary men. We studied 8 young (28 +/- 1 yr) and 8 older (65 +/- 1) sedentary, and 8 young (27 +/- 1) and 8 older (63 +/- 2) endurance-trained men. Calf venous compliance was measured in supine subjects by inflating a venous collecting cuff, placed above the knee, to 60 mmHg for 8 min and then decreasing cuff pressure at 1 mmHg/s to 0 mmHg. Calf venous compliance was determined using the first derivative of the pressure-volume relation during cuff pressure reduction (compliance = beta(1) + 2. beta(2). cuff pressure). Calf venous compliance was reduced with age in sedentary (approximately 40%) and endurance-trained men (approximately 20%) (both P < 0.01). Furthermore, calf venous compliance was approximately 70-120% greater in endurance-trained compared with age-matched sedentary men and approximately 30% greater in older endurance-trained compared with young sedentary men (both P < 0.01). These data indicate that calf venous compliance is reduced with age in sedentary and endurance-trained men, but compliance is better preserved in endurance-trained men.

Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men.

1. In experimental animals chronic elevations in arterial blood flow increase the lumen diameter and reduce the intima-media thickness (IMT) of the arterial segment involved. We determined whether intermittent elevations in active muscle blood flow associated with regular aerobic leg exercise induced such expansive arterial remodelling in the common femoral artery of humans. 2. In the cross-sectional study 53 sedentary (47 +/- 2 years) and 55 endurance exercise-trained (47 +/- 2 years) men were studied. Common femoral artery lumen diameter (B-mode ultrasound) was 7 % greater (9.62 +/- 0.12 vs. 9.03 +/- 0.13 mm), and femoral IMT (0.46 +/- 0.02 vs. 0.55 +/- 0.02 mm) and IMT/lumen ratio were 16-21 % smaller in the endurance-trained men (all P < 0.001). Basal femoral artery blood flow (duplex ultrasound) was not different, shear stress tended to be lower (P = 0.08), and mean femoral tangential wall stress was 30 % higher in the endurance-trained men (P < 0.001). 3. In the intervention study 22 men (51 +/- 2 years) were studied before and after 3 months of regular aerobic leg exercise (primarily walking). After training, the femoral diameter increased by 9 % (8.82 +/- 0.18 vs. 9.60 +/- 0.20 mm), and IMT (0.65 +/- 0.05 vs. 0.56 +/- 0.05 mm) and the IMT/lumen ratio were approximately 15-20 % smaller (all P < 0.001). Basal femoral blood flow and shear stress were not different after training, whereas the mean femoral tangential wall stress increased by 31 %. The changes in arterial structure were not related to changes in risk factors for atherosclerosis. 4. Our results are consistent with the concept that regular aerobic leg exercise induces expansive arterial remodelling in the femoral artery of healthy men. This adaptive process is produced by even a moderate training stimulus, is not obviously dependent on corresponding improvements in risk factors for atherosclerosis, and is robust, occurring in healthy men of different ages.

Age-associated changes in cardiovagal baroreflex sensitivity are related to central arterial compliance.

Cardiovagal baroreflex sensitivity (BRS) declines with advancing age in humans, but the underlying mechanism has not been established. Using two different approaches, we determined the relation between age-associated decline in cardiovagal BRS and the compliance of an artery in which arterial baroreceptors are located. First, we measured carotid artery compliance (via the simultaneous application of ultrasonography and arterial applanation tonometry) and cardiovagal BRS (phase IV of the Valsalva maneuver) in 47 healthy sedentary men that varied widely in age (19--76 yr). Cardiovagal BRS declined progressively with age (r = -0.69; P < or = 0.001) and was positively related to carotid artery compliance (r = 0.71; P < or = 0.001). Stepwise multiple-regression analysis revealed that carotid artery compliance was the strongest independent physiological correlate of cardiovagal BRS and that it explained 51% of the total variance. Second, we studied 13 middle-aged and older previously sedentary men (age 56 +/- 2 yr) before and after 13 wk of aerobic exercise intervention. Regular exercise increased both cardiovagal BRS and carotid artery compliance (P < 0.05) and the two events were strongly and positively related (r = 0.72; P < 0.01). We conclude that reduced carotid artery compliance may play an important mechanistic role in age-associated decrease in cardiovagal BRS in healthy sedentary humans.