The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy ± chemotherapy

BACKGROUND: Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC) treated by radiotherapy ± chemotherapy. METHODS: We used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67), immunohistochemistry for carbonic anhydrase IX (CA IX) and glucose transporter-1 (GLUT-1) was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34), enzyme linked immunosorbent assay (ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated. RESULTS: For CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02) and disease-free survival (p = 0.04) with a trend for regional control (p = 0.06). In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009), disease-free survival (p = 0.02) and overall survival (p = 0.005). CONCLUSION: To our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be the most important parameter to judge radiotherapy responses. Furthermore, the combined assessment of CA IX and GLUT-1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

BACKGROUND: A 24-year-old man presented with previously diagnosed Marfan\u27s syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment. INVESTIGATIONS: CT scans, arteriogram, genetic mutation screening of transforming growth factor beta receptors 1 and 2. DIAGNOSIS: Diffuse and rapidly progressing vascular disease in a patient who met the diagnostic criteria for Marfan\u27s syndrome, but was later rediagnosed with Loeys-Dietz syndrome. Genetic testing also revealed a de novo mutation in transforming growth factor beta receptor 2. MANAGEMENT: Regular cardiovascular surveillance for aneurysms and dissections, and aggressive surgical treatment of vascular disease

Treatment of uterine prolapse stage 2 or higher: a randomized multicenter trial comparing sacrospinous fixation with vaginal hysterectomy (SAVE U trial)

Contains fulltext : 97471.pdf (publisher's version ) (Open Access)BACKGROUND: Pelvic organ prolapse is a common health problem, affecting up to 40% of parous women over 50 years old, with significant negative influence on quality of life. Vaginal hysterectomy is currently the leading treatment method for patients with symptomatic uterine prolapse. Several studies have shown that sacrospinous fixation in case of uterine prolapse is a safe and effective alternative to vaginal hysterectomy. However, no large randomized trials with long-term follow-up have been performed to compare efficacy and quality of life between both techniques.The SAVE U trial is designed to compare sacrospinous fixation with vaginal hysterectomy in the treatment of uterine prolapse stage 2 or higher in terms of prolapse recurrence, quality of life, complications, hospital stay, post-operative recovery and sexual functioning. METHODS/DESIGN: The SAVE U trial is a randomized controlled multi-center non-inferiority trial. The study compares sacrospinous fixation with vaginal hysterectomy in women with uterine prolapse stage 2 or higher. The primary outcome measure is recurrence of uterine prolapse defined as: uterine descent stage 2 or more assessed by pelvic organ prolapse quantification examination and prolapse complaints and/or redo surgery at 12 months follow-up. Secondary outcomes are subjective improvement in quality of life measured by generic (Short Form 36 and Euroqol 5D) and disease-specific (Urogenital Distress Inventory, Defecatory Distress Inventory and Incontinence Impact Questionnaire) quality of life instruments, complications following surgery, hospital stay, post-operative recovery and sexual functioning (Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire). Analysis will be performed according to the intention to treat principle. Based on comparable recurrence rates of 3% and considering an upper-limit of 7% to be non-inferior (beta 0.2 and one sided alpha 0.025), 104 patients are needed per group. DISCUSSION: The SAVE U trial is a randomized multicenter trial that will provide evidence whether the efficacy of sacrospinous fixation is similar to vaginal hysterectomy in women with uterine prolapse stage 2 or higher. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1866

Anthropometric factors and breast cancer risk among urban and rural women in South India: a multicentric case–control study

Breast cancer (BC) incidence in India is approximately twice as high in urban women than in rural women, among whom we investigated the role of anthropometric factors and body size. The study was conducted at the Regional Cancer Centre, Trivandrum, and in three cancer hospitals in Chennai during 2002–2005. Histologically confirmed cases (n=1866) and age-matched controls (n=1873) were selected. Anthropometric factors were measured in standard ways. Information on body size at different periods of life was obtained using pictograms. Odds ratios (OR) of BC were estimated through logistic regression modelling. Proportion of women with body mass index (BMI)>25.0 kg/m2, waist size >85 cm and hip size >100 cm was significantly higher among urban than rural women. Risk was increased for waist size >85 cm (pre-menopausal: OR=1.24, 95% CI: 0.96–1.62; post-menopausal: 1.61, 95% CI: 1.22–2.12) and hip size >100 cm (pre-menopausal: OR=1.47, 95% CI: 1.05–2.06; post-menopausal 2.42, 95% CI: 1.72–3.41). Large body size at age 10 (OR=1.75, 95% CI: 1.01–3.03) and increased BMI (OR=1.33, 95% CI: 1.05–1.69 for 25.0–29.9 kg/m2 and OR=1.56, 95% CI: 1.03–2.35 for 30+ kg/m2) were associated with pre-menopausal BC risk. Our data support the hypotheses that increased anthropometric factors are risk factors of BC in India

Priority for the Worse Off and the Social Cost of Carbon

The social cost of carbon (SCC) is a monetary measure of the harms from carbon emission. Specifically, it is the reduction in current consumption that produces a loss in social welfare equivalent to that caused by the emission of a ton of CO2. The standard approach is to calculate the SCC using a discounted-utilitarian social welfare function (SWF)—one that simply adds up the well-being numbers (utilities) of individuals, as discounted by a weighting factor that decreases with time. The discounted-utilitarian SWF has been criticized both for ignoring the distribution of well-being, and for including an arbitrary preference for earlier generations. Here, we use a prioritarian SWF, with no time-discount factor, to calculate the SCC in the integrated assessment model RICE. Prioritarianism is a well-developed concept in ethics and theoretical welfare economics, but has been, thus far, little used in climate scholarship. The core idea is to give greater weight to well-being changes affecting worse off individuals. We find substantial differences between the discounted-utilitarian and non-discounted prioritarian SCC

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page

Program Spending to Increase Adherence: South African Cervical Cancer Screening

Background: Adherence is crucial for public health program effectiveness, though the benefits of increasing adherence must ultimately be weighed against the associated costs. We sought to determine the relationship between investment in community health worker (CHW) home visits and increased attendance at cervical cancer screening appointments in Cape Town, South Africa. Methodology/Principal Findings: We conducted an observational study of 5,258 CHW home visits made in 2003–4 as part of a community-based screening program. We estimated the functional relationship between spending on these visits and increased appointment attendance (adherence). Increased adherence was noted after each subsequent CHW visit. The costs of making the CHW visits was based on resource use including both personnel time and vehicle-related expenses valued in 2004 Rand. The CHW program cost R194,018, with 1,576 additional appointments attended. Adherence increased from 74% to 90%; 55% to 87%; 48% to 77%; and 56% to 80% for 6-, 12-, 24-, and 36-month appointments. Average per-woman costs increased by R14–R47. The majority of this increase occurred with the first 2 CHW visits (90%, 83%, 74%, and 77%; additional cost: R12–R26). Conclusions/Significance: We found that study data can be used for program planning, identifying spending levels that achieve adherence targets given budgetary constraints. The results, derived from a single disease program, are retrospective, and should be prospectively replicated

What is the easier and more reliable dose calculation for iv Phenytoin in children at risk of developing convulsive status epilepticus, 18 mg/kg or 20 mg/kg?

Background: With the Convulsive Status Guidelines due for renewal, we wondered if a phenytoin dose of ‘20 mg/kg’ would be easier to calculate correctly and therefore safer than the current ‘18 mg/kg’. An educational exercise in dose calculation was therefore undertaken to assess ease of calculation. Method: A standard question paper was prepared, comprising five clinical scenarios with children of varying ages and estimated body weights. Medical students, trainee doctors at registrar and senior house officer level, and consultant paediatricians were asked to complete the exercise, in private, by one of two medical students (SD, PS). Calculations were done with and without a calculator, for 18 mg/kg and for 20 mg/kg in randomised order. Speed and errors (greater than 10%) were determined. The data analysis was performed using SPSS version 18. Results: All answered all 20 scenarios, giving a total of 300 answers per doctor/student group, and 300 answers per type of calculation. When comparing the 2 doses, the numbers of errors more than 10% were significantly less in 20 mg/kg dose (0.33%) as compared to the 18 mg/kg dose (9.3%) (p<0.0001). Speed off calculation was significantly decreased in 20 mg/kg dose when compared with 18 mg/kg dose, with (p<0.001) or without (p<0.0001) the calculator. Speed was more than halved and errors were much less frequent by using a calculator, for the 18 mg/kg dose but no difference with or without the calculator for 20 mg/kg dose. Conclusion: We recommend that the future guidelines should suggest iv Phenytoin at 20 mg/kg rather than 18 mg/kg. This will make the calculation easier and reduce the risk of significant errors

Building a Social Mandate for Climate Action: Lessons from COVID-19

The COVID-19 imposed lockdown has led to a number of temporary environmental side effects (reduced global emissions, cleaner air, less noise), that the climate community has aspired to achieve over a number of decades. However, these benefits have been achieved at a massive cost to welfare and the economy. This commentary draws lessons from the COVID-19 crisis for climate change. It discusses whether there are more sustainable ways of achieving these benefits, as part of a more desirable, low carbon resilient future, in a more planned, inclusive and less disruptive way. In order to achieve this, we argue for a clearer social contract between citizens and the state. We discuss how COVID-19 has demonstrated that behaviours can change abruptly, that these changes come at a cost, that we need a ‘social mandate’ to ensure these changes remain in the long-term, and that science plays an important role in informing this process. We suggest that deliberative engagement mechanisms, such as citizens’ assemblies and juries, could be a powerful way to build a social mandate for climate action post-COVID-19. This would enable behaviour changes to become more accepted, embedded and bearable in the long-term and provide the basis for future climate action