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The math book
Applying the Big Ideas Simply Explained series' trademark combination of authoritative, accessible text and bold graphics to chart the development of math through history, The Math Book explores and explains subjects ranging from ancient mathematical ideas and inventions, such as prehistoric tally bones and Sumerian multiplication tables, through the developments in mathematics during medieval and Renaissance Europe, to the more recent rise of game and group theory. Tracing math through the scientific revolution to its 21st-century use in computers, the internet, and AI, The Math Book uses an innovative graphic-led approach to make the subject accessible to everyone.
BOOK
Primary cervical screening with high risk human papillomavirus testing: observational study
To provide the first report on the main outcomes from the prevalence and incidence rounds of a large pilot of routine primary high risk human papillomavirus (hrHPV) testing in England, compared with contemporaneous primary liquid based cytology screening.
Observational study.
The English Cervical Screening Programme.
578 547 women undergoing cervical screening in primary care between May 2013 and December 2014, with follow-up until May 2017; 183 970 (32%) were screened with hrHPV testing.
Routine cervical screening with hrHPV testing with liquid based cytology triage and two early recalls for women who were hrHPV positive and cytology negative, following the national screening age and interval recommendations.
Frequency of referral for a colposcopy; adherence to early recall; and relative detection of cervical intraepithelial neoplasia grade 2 or worse from hrHPV testing compared with liquid based cytology in two consecutive screening rounds.
Baseline hrHPV testing and early recall required approximately 80% more colposcopies, (adjusted odds ratio 1.77, 95% confidence interval 1.73 to 1.82), but detected substantially more cervical intraepithelial neoplasia than liquid based cytology (1.49 for cervical intraepithelial neoplasia grade 2 or worse, 1.43 to 1.55; 1.44 for cervical intraepithelial neoplasia grade 3 or worse, 1.36 to 1.51) and for cervical cancer (1.27, 0.99 to 1.63). Attendance at early recall and colposcopy referral were 80% and 95%, respectively. At the incidence screen, the 33 506 women screened with hrHPV testing had substantially less cervical intraepithelial neoplasia grade 3 or worse than the 77 017 women screened with liquid based cytology (0.14, 0.09 to 0.23).
In England, routine primary hrHPV screening increased the detection of cervical intraepithelial neoplasia grade 3 or worse and cervical cancer by approximately 40% and 30%, respectively, compared with liquid based cytology. The very low incidence of cervical intraepithelial neoplasia grade 3 or worse after three years supports extending the screening interval.
Journal Article
Extension of cervical screening intervals with primary human papillomavirus testing: observational study of English screening pilot data
AbstractObjectivesTo provide updated evidence about the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cervical cancer after a negative human papillomavirus (HPV) test in primary cervical screening, by age group and test assay.DesignObservational study.SettingReal world data from the English HPV screening pilot’s first and second rounds (2013-16, follow-up to end of 2019).Participants1 341 584 women.InterventionsCervical screening with HPV testing or liquid based cytological testing (cytology or smear tests). Women screened with cytology were referred to colposcopy after high grade cytological abnormalities or after borderline or low grade abnormalities combined with a positive HPV triage test. Women screened with HPV testing who were positive were referred at baseline if their cytology triage test showed at least borderline abnormalities or after a retest (early recall) at 12 and 24 months if they had persistent abnormalities.Main outcome measuresDetection of CIN3+ and cervical cancer after a negative HPV test.ResultsFor women younger than 50 years, second round detection of CIN3+ in this study was significantly lower after a negative HPV screen in the first round than after cytology testing (1.21/1000 v 4.52/1000 women screened, adjusted odds ratio 0.26, 95% confidence interval 0.23 to 0.30), as was the risk of interval cervical cancer (1.31/100 000 v 2.90/100 000 woman years, adjusted hazard ratio 0.44, 0.23 to 0.84). Risk of an incident CIN3+ detected at the second screening round in the pilot five years after a negative HPV test was even lower in women older than 50 years, than in three years in women younger than 50 years (0.57/1000 v 1.21/1000 women screened, adjusted odds ratio 0.46, 0.27 to 0.79). Women with negative HPV tests at early recall after a positive HPV screening test without cytological abnormalities had a higher detection rate of CIN3+ at the second routine recall than women who initially tested HPV negative (5.39/1000 v 1.21/1000 women screened, adjusted odds ratio 3.27, 95% confidence interval 2.21 to 4.84). Detection after a negative result on a clinically validated APTIMA mRNA HPV test was similar to that after clinically validated cobas and RealTime DNA tests (for CIN3+ at the second round 1.32/1000 v 1.14/1000 women screened, adjusted odds ratio 1.05, 0.73 to 1.50).ConclusionsThese data support an extension of the screening intervals, regardless of the test assay used: to five years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older. The screening interval for HPV positive women who have negative HPV tests at early recall should be kept at three years.
Journal Article
16/18 genotyping in triage of persistent human papillomavirus infections with negative cytology in the English cervical screening pilot
Background
In the English pilot of primary cervical screening with high-risk human papillomavirus (HR-HPV), we exploited natural viral clearance over 24 months to minimise unnecessary referral of HR-HPV+ women with negative cytology. Three laboratories were permitted to use 16/18 genotyping to select women for referral at 12-month recall. We estimated the clinical impact of this early genotyping referral.
Methods
The observed numbers of women referred to colposcopy and with detected high-grade cervical intraepithelial neoplasia (CIN2+), and of women who did not attend early recall in the three laboratories were compared with those estimated to represent a situation without an early genotyping referral. The 95% confidence intervals (CI) for the differences between the protocols were calculated by using a parametric bootstrap.
Results
Amongst 127,238 screened women, 16,097 (13%) had HR-HPV infections. The genotyping protocol required 5.9% (95% CI: 4.4–7.7) additional colposcopies and led to a detection of 1.2% additional CIN2+ (95% CI: 0.6–2.0), while 2.3% (95% CI: 2.1–2.5) fewer HR-HPV+/cytology− women did not attend the early recall compared with the non-genotyping protocol.
Conclusions
In a screening programme with high quality of triage cytology and high adherence to early recall,16/18 genotyping of persistent HPV infections does not substantially increase CIN2+ detection.
Journal Article
Transcription Factor Ets-1 Regulates Fibroblast Growth Factor-1-Mediated Angiogenesis in vivo: Role of Ets-1 in the Regulation of the PI3K/AKT/MMP-1 Pathway
We previously demonstrated that a modified secreted form of fibroblast growth factor 1 (FGF-1), a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis, the so-called chick chorioallantoic membrane assay or CAM. We recently defined the importance of the phosphatidylinositol 3-kinase/AKT pathway in FGF-1-mediated angiogenesis in this model using specific pharmacological inhibitors. In our continuing efforts to define the molecular signaling pathway regulating FGF-1-induced angiogenesis in vivo, we utilized a transcription factor activity assay and identified transcription factor Ets-1 as a critical effector of FGF-1-induced angiogenesis. Both activity and mRNA expression levels of the Ets-1 molecule were increased in response to FGF-1 overexpression in CAMs, as documented by electrophoretic mobility shift assay (gel shift) and reverse transcription real-time PCR techniques, respectively. Furthermore, the delivery of Ets-1 antisense (AS) into CAM tissues effectively reduced angiogenesis in the CAM assay. In addition, both Ets-1 AS-treated chicken CAMs and cultured endothelial cells exhibited a reduction in matrix metalloproteinase 1 gene expression levels. The Ets-1 AS-treated endothelial cells also demonstrated a reduction in migration. These data suggest that Ets-1 activation is a requisite for FGF-1-mediated angiogenesis in vivo. Therefore, Ets-1 might be a potential target for the generation of inhibitor drugs for the treatment of FGF-dependent pathological angiogenesis such as metastatic tumors, rheumatoid arthritis and diabetic retinopathy.
Journal Article
Neuropilin-1 Is Essential for Enhanced VEGF165-Mediated Vasodilatation in Collateral-Dependent Coronary Arterioles of Exercise-Trained Pigs
Background/Aims: Exercise training enhances vasodilatation to vascular endothelial growth factor (VEGF 165 ) in collateral-dependent coronary arterioles. Interaction of VEGF receptor 2 (VEGFR-2) and the non-tyrosine-kinase receptor, neuropilin-1 has been reported to potentiate VEGF 165 -mediated signaling. In the current study, we tested the hypotheses that neuropilin-1 mediates the exercise-enhanced VEGF 165 -mediated vasodilatation in collateral-dependent arterioles and that neuropilin-1 and/or VEGFR-2 protein levels are increased in these arterioles. Methods: Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of miniature swine. Eight weeks after surgery, the animals were randomized into sedentary or exercise training (treadmill run; 5 days/week; 14 weeks) protocols. Coronary arterioles (∼100 μm diameter) were isolated from both collateral-dependent and control (left anterior descending) myocardial regions and studied by in vitro videomicroscopy or frozen for immunoblot analysis. Results: Exercise-enhanced VEGF 165 -mediated vasodilatation in collateral-dependent arterioles was reversed by inhibition of the VEGF 165 -neuropilin-1 interaction. VEGF 121 , which does not interact with neuropilin-1, induced similar vasodilatation in arterioles from all treatment groups. Immunoblot revealed significantly elevated VEGFR-1, VEGFR-2 and neuropilin-1 protein levels in collateral-dependent arterioles of exercise-trained pigs. Conclusions: Neuropilin-1 plays a vital role in the exercise-enhanced VEGF 165 -mediated vasodilatation of collateral-dependent coronary arterioles and is associated with increased neuropilin-1 receptor protein levels.
Journal Article
Neuropilin-1 is essential for enhanced VEGF(165)-mediated vasodilatation in collateral-dependent coronary arterioles of exercise-trained pigs
Exercise training enhances vasodilatation to vascular endothelial growth factor (VEGF(165)) in collateral-dependent coronary arterioles. Interaction of VEGF receptor 2 (VEGFR-2) and the non-tyrosine-kinase receptor, neuropilin-1 has been reported to potentiate VEGF(165)-mediated signaling. In the current study, we tested the hypotheses that neuropilin-1 mediates the exercise-enhanced VEGF(165)-mediated vasodilatation in collateral-dependent arterioles and that neuropilin-1 and/or VEGFR-2 protein levels are increased in these arterioles.
Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of miniature swine. Eight weeks after surgery, the animals were randomized into sedentary or exercise training (treadmill run; 5 days/week; 14 weeks) protocols. Coronary arterioles (approximately 100 microm diameter) were isolated from both collateral-dependent and control (left anterior descending) myocardial regions and studied by in vitro videomicroscopy or frozen for immunoblot analysis.
Exercise-enhanced VEGF(165)-mediated vasodilatation in collateral-dependent arterioles was reversed by inhibition of the VEGF(165)-neuropilin-1 interaction. VEGF(121), which does not interact with neuropilin-1, induced similar vasodilatation in arterioles from all treatment groups. Immunoblot revealed significantly elevated VEGFR-1, VEGFR-2 and neuropilin-1 protein levels in collateral-dependent arterioles of exercise-trained pigs.
Neuropilin-1 plays a vital role in the exercise-enhanced VEGF(165)-mediated vasodilatation of collateral-dependent coronary arterioles and is associated with increased neuropilin-1 receptor protein levels.
Journal Article
Effects of gradual coronary artery occlusion and exercise training on gene expression in swine heart
Gradual occlusion (O) of the swine left circumflex coronary artery (LCX) with an ameroid occluder results in complete O within 3 weeks, collateral vessel development, and compensatory hypertrophy. The purpose of this investigation was to determine the independent and combined effects of O and exercise training (E) on gene expression in the swine heart. Adult Yucatan miniature swine were assigned to one of the following groups (n = 6-9/group): sedentary control (S), exercise-trained (E), sedentary swine subjected to LCX occlusion (SO), and exercise-trained swine with LCX occlusion (EO). Exercise consisted of progressive treadmill running conducted 5 d/wk for 16 weeks. Gene expression was studied in myocardium isolated from the collateral-dependent left ventricle free wall (LV) and the collateral-independent septum (SEP) by RNA blotting. E and O each stimulated cardiac hypertrophy independently (p < 0.001) with no interaction. O but not E increased atrial natriuretic factor expression in the LV, but not in the SEP. E decreased the expression of β-myosin heavy chain in the LV, but not in the SEP. E retarded the expression of collagen III mRNA in SEP; but not in the LV. Exercise training and coronary artery occlusion each stimulate cardiac hypertrophy independently and induce different patterns of gene expression.
Journal Article