Cardiovascular Burden of the V142I Transthyretin Variant.

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

Navigating Post-Operative Outcomes: A Comprehensive Reframing of an Original Graded Prognostic Assessment in Patients with Brain Metastases.

BACKGROUND: Graded Prognostic Assessment (GPA) has been proposed for various brain metastases (BMs) tailored to the primary histology and molecular profiles. However, it does not consider whether patients have been operated on or not and does not include surgical outcomes as prognostic factors. The residual tumor burden (RTB) is a strong predictor of overall survival. We validated the GPA score and introduced "volumetric GPA" in the largest cohort of operated patients and further explored the role of RTB as an additional prognostic factor. METHODS: A total of 630 patients with BMs between 2007 and 2020 were included. The four GPA components were analyzed. The validity of the original score was assessed using Cox regression, and a modified index incorporating RTB was developed by comparing the accuracy, sensitivity, specificity, F1-score, and AUC parameters. RESULTS: GPA categories showed an association with survival: age (p < 0.001, hazard ratio (HR) 2.9, 95% confidence interval (CI) 2.5-3.3), Karnofsky performance status (KPS) (p < 0.001, HR 1.3, 95% CI 1.2-1.5), number of BMs (p = 0.019, HR 1.4, 95% CI 1.1-1.8), and the presence of extracranial manifestation (p < 0.001, HR 3, 95% CI 1.6-2.5). The median survival for GPA 0-1 was 4 months; for GPA 1.5-2, it was 12 months; for GPA 2.5-3, it was 21 months; and for GPA 3.5-4, it was 38 months (p < 0.001). RTB was identified as an independent prognostic factor. A cut-off of 2 cm3 was used for further analysis, which showed a median survival of 6 months (95% CI 4-8) vs. 13 months (95% CI 11-14, p < 0.001) for patients with RTB > 2 cm3 and <2 cm3, respectively. RTB was added as an additional component for a modified volumetric GPA score. The survival rates with the modified GPA score were: GPA 0-1: 4 months, GPA 1.5-2: 7 months, GPA 2.5-3: 18 months, and GPA 3.5-4: 34 months. Both scores showed good stratification, with the new score showed a trend towards better discrimination in patients with more favorable prognoses. CONCLUSION: The prognostic value of the original GPA was confirmed in our cohort of patients who underwent surgery for BM. The RTB was identified as a parameter of high prognostic significance and was incorporated into an updated "volumetric GPA". This score provides a novel tool for prognosis and clinical decision making in patients undergoing surgery. This method may be useful for stratification and patient selection for further treatment and in future clinical trials.

Safe Linkage of Cohort and Population-Based Register Data in a Genomewide Association Study on Health Care Expenditure.

There are research questions whose answers require record linkage of multiple databases that may be characterized by limited options for full data sharing. For this purpose, the Open Data Infrastructure for Social Science and Economic Innovations (ODISSEI) consortium has supported the development of the ODISSEI Secure Supercomputer (OSSC) platform that allows researchers to link cohort data to data from Statistics Netherlands and run large-scale analyses in a high-performance computing (HPC) environment. Here, we report a successful record linkage genomewide association (GWA) study on expenditure for total health, mental health, primary and hospital care, and medication. Record linkage for genotype data from 16,726 participants from the Netherlands Twin Register (NTR) with data from Statistics Netherlands was accomplished in the secure OSSC platform, followed by gene-based tests and estimation of total and single nucleotide polymorphism (SNP)-based heritability. The total heritability of expenditure ranged between 29.4% (SE 0.8) and 37.5% (SE 0.8), but GWA analyses did not identify SNPs or genes that were genomewide significantly associated with health care expenditure. SNP-based heritability was between 0.0% (SE 3.5) and 5.4% (SE 4.0) and was different from zero for mental health care and primary care expenditure. We conclude that successfully linking genotype data to administrative health care expenditure data from Statistics Netherlands is feasible and demonstrates a series of analyses on health care expenditure. The OSSC platform offers secure possibilities for analyzing linked data in large scale and realizing sample sizes required for GWA studies, providing invaluable opportunities to answer many new research questions.

Genetic correlates of socio-economic status influence the pattern of shared heritability across mental health traits.

Epidemiological studies show high comorbidity between different mental health problems, indicating that individuals with a diagnosis of one disorder are more likely to develop other mental health problems. Genetic studies reveal substantial sharing of genetic factors across mental health traits. However, mental health is also genetically correlated with socio-economic status (SES), and it is therefore important to investigate and disentangle the genetic relationship between mental health and SES. We used summary statistics from large genome-wide association studies (average N ~ 160,000) to estimate the genetic overlap across nine psychiatric disorders and seven substance use traits and explored the genetic influence of three different indicators of SES. Using genomic structural equation modelling, we show significant changes in patterns of genetic correlations after partialling out SES-associated genetic variation. Our approach allows the separation of disease-specific genetic variation and genetic variation shared with SES, thereby improving our understanding of the genetic architecture of mental health.

[Childhood cancer in part of France: Key issues and organization of care in Corsica island]. / État des lieux des maladies onco-hématologiques pédiatriques en Corse et organisation des soins.

INTRODUCTION: In France, the management of pediatric cancers is carried out in reference hospitals that can delegate care to local health centres (LHC), forming "care networks". There is no LHC in Corsica, forcing children and their families to leave the island for all care in the reference centre. The aim of this study was to describe the situation in Corsica and to consider this organisation. METHODS: This is a descriptive preliminary study based on databases from the National Childhood Cancer Registry, "RHeOP" network and a patient questionnaire. We included over a period of 10 years all children with onco-hematological disease who resided in Corsica. RESULTS: The incidence of pediatric cancers since 2005 ranged from 5 to 12 new cases per year. The hospital centre of Timone (Marseille) was the reference centre for 73% of patients, followed by Nice University Hospital for 14%. Almost all the parents interviewed (90%) were in favour of creating an LHC and all of them highlighted many difficulties that, according to them, could be improved by the presence of a LHC in Corsica (organisation of travel, delay and distance from home…). However, there currently appears to be a lack of training for medical and paramedical staff to provide quality second-line care. CONCLUSION: The rates of pediatric onco-hematological diseases in Corsica may warrant the creation of an LHC on the island. Additional cost studies on the feasibility of an LHC in Corsica are needed to optimise the care and quality of life of these children and their families.

Genetic correlates of social stratification in Great Britain.

Human DNA polymorphisms vary across geographic regions, with the most commonly observed variation reflecting distant ancestry differences. Here we investigate the geographic clustering of common genetic variants that influence complex traits in a sample of ~450,000 individuals from Great Britain. Of 33 traits analysed, 21 showed significant geographic clustering at the genetic level after controlling for ancestry, probably reflecting migration driven by socioeconomic status (SES). Alleles associated with educational attainment (EA) showed the most clustering, with EA-decreasing alleles clustering in lower SES areas such as coal mining areas. Individuals who leave coal mining areas carry more EA-increasing alleles on average than those in the rest of Great Britain. The level of geographic clustering is correlated with genetic associations between complex traits and regional measures of SES, health and cultural outcomes. Our results are consistent with the hypothesis that social stratification leaves visible marks in geographic arrangements of common allele frequencies and gene-environment correlations.

Vehicular Air Pollution in Houston, Texas: An Intra-Categorical Analysis of Environmental Injustice.

This article contributes to distributive environmental justice (EJ) research on air pollution by analyzing racial/ethnic and related intra-categorical disparities in health risk from exposure to on-road hazardous air pollutants (HAPs) in Harris County, Texas. Previous studies in this urban area have not examined intra-ethnic heterogeneity in EJ outcomes or disproportionate exposure to vehicular pollutants. Our goal was to determine how the EJ implications of cancer risk from exposure to on-road HAP sources differ across and within each major racial/ethnic group (Hispanics, non-Hispanic Blacks, and non-Hispanic Whites), based on data from the Environmental Protection Agency's National-Scale Air Toxics Assessment (2011) and American Community Survey (2009-2013). Statistical analyses are based on generalized estimating equations which account for clustering of analytic units. Results indicated that Hispanics and non-Hispanic Blacks are exposed to significantly higher cancer risk than non-Hispanic Whites. When each racial/ethnic group was disaggregated based on contextually relevant characteristics, individuals who are in poverty, foreign-born, renters, and have limited English proficiency are found to be disproportionately located in areas exposed to significantly higher cancer risk, regardless of their major racial/ethnic designation. Our findings underscore the need to conduct intra-categorical EJ analysis for uncovering inequalities that get concealed when broadly defined racial/ethnic categories are used.

18F- FDG PET/CT joint assessment of early therapeutic response in rheumatoid arthritis patients treated with rituximab.

BACKGROUND: 18F-FDG PET/CT has been proposed in the evaluation of the disease activity in rheumatoid arthritis (RA). The goals of this study were to evaluate the reproducibility of the technique, to compare metabolic parameters to clinical, biological and ultrasonographic parameters before and after treatment and to evaluate whether the early metabolic response was related to the outcome. 18F- FDG PET/CT of the hands, wrists and knees was obtained in 15 patients with anti-TNFα refractory RA, at baseline and 16 weeks after treatment with rituximab. The number of PET-positive joints (PET+ joints), the cumulative standard uptake value (cSUV) and the composite index (CI) were defined. The composite clinical index DAS28, CRP serum levels and the number of joints positive at ultrasonography (US+ joints) and the cumulative synovial thickness (CST) were also assessed at baseline and week 24. RESULTS: High interobserver agreement was observed, both at baseline and after treatment. The number of PET+ joints was not correlated with the number of joints tender or swollen. The 3 metabolic parameters were strongly correlated with US, CRP and DAS28 at baseline and with US and CRP (CSUV, CI) at week 16, but no longer with the DAS28 index. The metabolic response based on the change in the visual PET/CT joint analysis predicted the outcome with a high negative predictive value of 91%, with a 91% specificity, and an 86% accuracy. CONCLUSIONS: These preliminary data suggest that 18F- FDG PET/CT is a reproducible and accurate tool for evaluating disease activity in refractory rheumatoid arthritis and its non-response to rituximab. The correlation obtained with US joint assessment gives relevance to objective diseased joints through imaging techniques.

Association of a Competency-Based Assessment System With Identification of and Support for Medical Residents in Difficulty.

Importance: Competency-based medical education is now established in health professions training. However, critics stress that there is a lack of published outcomes for competency-based medical education or competency-based assessment tools. Objective: To determine whether competency-based assessment is associated with better identification of and support for residents in difficulty. Design, Setting, and Participants: This cohort study of secondary data from archived files on 458 family medicine residents (2006-2008 and 2010-2016) was conducted between July 5, 2016, and March 2, 2018, using a large, urban family medicine residency program in Canada. Exposures: Introduction of the Competency-Based Achievement System (CBAS). Main Outcomes and Measures: Proportion of residents (1) with at least 1 performance or professionalism flag, (2) receiving flags on multiple distinct rotations, (3) classified as in difficulty, and (4) with flags addressed by the residency program. Results: Files from 458 residents were reviewed (pre-CBAS: n = 163; 81 [49.7%] women; 90 [55.2%] aged >30 years; 105 [64.4%] Canadian medical graduates; post-CBAS: n = 295; 144 [48.8%] women; 128 [43.4%] aged >30 years; 243 [82.4%] Canadian medical graduates). A significant reduction in the proportion of residents receiving at least 1 flag during training after CBAS implementation was observed (0.38; 95% CI, 0.377-0.383), as well as a significant decrease in the numbers of distinct rotations during which residents received flags on summative assessments (0.24; 95% CI, 0.237-0.243). There was a decrease in the number of residents in difficulty after CBAS (from 0.13 [95% CI, 0.128-0.132] to 0.17 [95% CI, 0.168-0.172]) depending on the strictness of criteria defining a resident in difficulty. Furthermore, there was a significant increase in narrative documentation that a flag was discussed with the resident between the pre-CBAS and post-CBAS conditions (0.18; 95% CI, 0.178-0.183). Conclusions and Relevance: The CBAS approach to assessment appeared to be associated with better identification of residents in difficulty, facilitating the program's ability to address learners' deficiencies in competence. After implementation of CBAS, residents experiencing challenges were better supported and their deficiencies did not recur on later rotations. A key argument for shifting to competency-based medical education is to change assessment approaches; these findings suggest that competency-based assessment may be useful.

CRENAME, A Molecular Microbiology Method Enabling Multiparametric Assessment of Potable/Drinking Water.

The microbial assessment of potable/drinking water is done to ensure that the resource is free of fecal contamination indicators or waterborne pathogens. Culture-based methods for verifying the microbial safety are limited in the sense that a standard volume of water is generally tested for only one indicator (family) or pathogen.In this work, we describe a membrane filtration-based molecular microbiology method, CRENAME (Concentration Recovery Extraction of Nucleic Acids and Molecular Enrichment), exploiting molecular enrichment by whole genome amplification (WGA) to yield, in less than 4 h, a nucleic acid preparation which can be repetitively tested by real-time PCR for example, to provide multiparametric presence/absence tests (1 colony forming unit or microbial particle per standard volume of 100-1000 mL) for bacterial or protozoan parasite cells or particles susceptible to contaminate potable/drinking water.

Assessment of cardiac allograft systolic function by global longitudinal strain: From donor to recipient.

BACKGROUND: Cardiac allografts are routinely evaluated by left ventricular ejection fraction (LVEF) before and after transplantation. However, myocardial deformation analyses with LV global longitudinal strain (GLS) are more sensitive for detecting impaired LV myocardial systolic performance compared with LVEF. METHODS: We analyzed echocardiograms in 34 heart donor-recipient pairs transplanted at Duke University from 2000 to 2013. Assessments of allograft LV systolic function by LVEF and/or LV GLS were performed on echocardiograms obtained pre-explanation in donors and serially in corresponding recipients. RESULTS: Donors had a median LVEF of 55% (25th, 75th percentile, 54% to 60%). Median donor LV GLS was -14.6% (-13.7 to -17.3%); LV GLS was abnormal (ie, >-16%) in 68% of donors. Post-transplantation, LV GLS was further impaired at 6 weeks (median -11.8%; -11.0 to -13.4%) and 3 months (median -11.4%; -10.3 to -13.9%) before recovering to pretransplant levels in follow-up. Median LVEF remained ≥50% throughout follow-up. We found no association between donor LV GLS and post-transplant outcomes, including all-cause hospitalization and mortality. CONCLUSIONS: GLS demonstrates allograft LV systolic dysfunction in donors and recipients not detected by LVEF. The clinical implications of subclinical allograft dysfunction detected by LV GLS require further study.

[Suicide among the French National Police forces: Implication of life events and life trajectories]. / Suicide dans la Police nationale française : trajectoires de vie et facteurs associés.

OBJECTIVES: Research indicates that suicide rates are high among members of law enforcement. Our objectives were: (1) to determine life events implicated in suicide mortality among French law enforcement; and (2) to describe the different life trajectories of police officers who deceased by suicide. METHODS: All suicides of police officers which occurred during 2008 (n=49) were explored using the psychological autopsy method. Key informants were: a supervisor, a colleague and a member of the family or a close friend. Each of them were interviewed by trained psychologists using standardized questionnaires exploring: sociodemographic characteristics, life events, social integration and support, health service use, mental health with the Composite International Diagnostic Interview short form (CIDI-SF), occupational stress with the Spielberger Inventory, impulsiveness with the Barratt Impulsiveness Scale and aggressiveness with the Brown-Goodwin Lifetime Aggression Scale. Information was then summarized in a timetable life trajectory of all life areas. All cases were finally appraised by at least two experts in order to identify the determinants of the suicide and to determine psychiatric diagnoses. For each period of time, a burdensomeness score was determined, from 6 (no adversity) to 1 (adversities in each sphere of life). RESULTS: Of the 49 cases of suicide, two were excluded and 39 were investigated and appraised (response rate: 39/47=83%). Eighty-two percent of the suicide cases were men and the mean age at death was 35years. In more than half of the cases, police officers used their service weapon to commit suicide. All deceased police officers were suffering from mental health symptoms (primarily depression). Of them, two thirds had used healthcare for this distress. The main other cause of suicide was problems in the married life (70% of the cases). Four distinct types of life trajectories of adversities could be identified by a qualitative analysis. DISCUSSION: It is the first time such a study was performed in France, and results are concordant with those of the literature. This study showed that all deceased police officers were suffering from mental disorders and that there was not one single profile of life trajectory: screening and support of police officers in distress need to be prioritized. Moreover, results suggested that the availability of the service weapon during off-duty periods should be reconsidered. This study helped the Home ministry to elaborate and improve strategies to prevent suicide among police officers.

Cost-effectiveness analysis of antiviral treatment in the management of seasonal influenza A: point-of-care rapid test versus clinical judgment.

BACKGROUND: A point-of-care rapid test (POCRT) may help early and targeted use of antiviral drugs for the management of influenza A infection. OBJECTIVE: (i) To determine whether antiviral treatment based on a POCRT for influenza A is cost-effective and, (ii) to determine the thresholds of key test parameters (sensitivity, specificity and cost) at which a POCRT based-strategy appears to be cost effective. METHODS: An hybrid « susceptible, infected, recovered (SIR) ¼ compartmental transmission and Markov decision analytic model was used to simulate the cost-effectiveness of antiviral treatment based on a POCRT for influenza A in the social perspective. Data input parameters used were retrieved from peer-review published studies and government databases. The outcome considered was the incremental cost per life-year saved for one seasonal influenza season. RESULTS: In the base-case analysis, the antiviral treatment based on POCRT saves 2 lives/100,000 person-years and costs $7600 less than the empirical antiviral treatment based on clinical judgment alone, which demonstrates that the POCRT-based strategy is dominant. In one and two way-sensitivity analyses, results were sensitive to the POCRT accuracy and cost, to the vaccination coverage as well as to the prevalence of influenza A. In probabilistic sensitivity analyses, the POCRT strategy is cost-effective in 66% of cases, for a commonly accepted threshold of $50,000 per life-year saved. CONCLUSION: The influenza antiviral treatment based on POCRT could be cost-effective in specific conditions of performance, price and disease prevalence.

Multiparametric comparison of chromogenic-based culture methods used to assess the microbiological quality of drinking water and the mFC method combined with a molecular confirmation procedure.

MI agar and Colilert(®), as well as mFC agar combined with an Escherichia coli-specific molecular assay (mFC + E. coli rtPCR), were compared in terms of their sensitivity, ease of use, time to result and affordability. The three methods yielded a positive E. coli signal for 11.5, 10.8, and 11.5% of the 968 well water samples tested, respectively. One hundred and thirty-six (136) samples gave blue colonies on mFC agar and required confirmation. E. coli-specific rtPCR showed false-positive results in 23.5% (32/136) of cases. In terms of ease of use, Colilert was the simplest method to use while the MI method provided ease of use comparable to all membrane filtration methods. However, the mFC + E. coli rtPCR assay required highly trained employees for confirmation purposes. In terms of affordability, and considering contamination rate of well water samples tested, the Colilert method and the mFC + E. coli rtPCR assay were at least five times more costly than the MI agar method. Overall, compared with the other two methods tested, the MI agar method offers the most advantages to assess drinking water quality.

[Dynamic reconstruction of Achilles tendon by free composite perforator flap with functional assessment]. / Reconstruction dynamique de tendon d'Achille par lambeau perforant composite avec évaluation fonctionnelle.

INTRODUCTION, DEFECTS: Achilles tendon are common in patients after immobilization, therefore the reconstruction of a ruptured Achilles tendon with defects remains a surgical challenge. The ideal characteristics are a thin layer of skin, a strong tendon component, combined with a reliable blood supply and minimal morbidity at the donor site. We present a reconstructive technique using a composite anterolateral thigh perforator free flap, meeting these criteria, for the treatment of rupture of Achilles tendon with cutaneous and tendon defect. METHODS: A 34-year-old patient presenting a third rupture of his left Achilles tendon with 4cm composite defect was reconstructed with a contralateral anterolateral thigh perforator flap with part of the fasciae latae. The latter was raised by dissecting one intramuscular perforating artery from a descending branch of the lateral circumflex femoral artery. The postoperative observation period was one year. The functional outcome was determined by clinical scores (IKDC, OAK and Lysholm-Tegner). RESULTS: The healing time was 21 days. At six months, the aesthetic and functional result was satisfactory without delayed healing or secondary rupture. The aesthetic discomfort at the donor site was considered negligible by the patient. At one year, there is a continuing stability with no recurrence. The functional result was considered good with a clinical score of 75/100. CONCLUSION: Therefore, this method seems to be a good option for complex reconstruction of Achilles meeting the requirements of reconstruction with good stability at a distance.

Multi-model comparison of the economic and energy implications for China and India in an international climate regime.

This paper presents a modeling comparison on how stabilization of global climate change at about 2 °C above the pre-industrial level could affect economic and energy systems development in China and India. Seven General Equilibrium (CGE) and energy system models on either the global or national scale are soft-linked and harmonized with respect to population and economic assumptions. We simulate a climate regime, based on long-term convergence of per capita carbon dioxide (CO2) emissions, starting from the emission pledges presented in the Copenhagen Accord to the United Nations Framework Convention on Climate Change and allowing full emissions trading between countries. Under the climate regime, Indian emission allowances are allowed to grow more than the Chinese allowances, due to the per capita convergence rule and the higher population growth in India. Economic and energy implications not only differ among the two countries, but also across model types. Decreased energy intensity is the most important abatement approach in the CGE models, while decreased carbon intensity is most important in the energy system models. The reduction in carbon intensity is mostly achieved through deployment of carbon capture and storage, renewable energy sources and nuclear energy. The economic impacts are generally higher in China than in India, due to higher 2010-2050 cumulative abatement in China and the fact that India can offset more of its abatement cost though international emission trading.

Involving users in the refinement of the competency-based achievement system: an innovative approach to competency-based assessment.

BACKGROUND: Competency-based assessment innovations are being implemented to address concerns about the effectiveness of traditional approaches to medical training and the assessment of competence. AIM: Integrating intended users' perspectives during the piloting and refinement process of an innovation is necessary to ensure the innovation meets users' needs. Failure to do so results in no opportunity for users to influence the innovation, nor for developers to assess why an innovation works or does not work in different contexts. METHODS: A qualitative participatory action research approach was used. Sixteen first-year residents participated in three focus groups and two interviews during piloting. Verbatim transcripts were analyzed individually and then across all transcripts using a constant comparison approach. RESULTS: The analysis revealed three key characteristics related to the impact on the residents' acceptance of the innovation as being a worthwhile investment of time and effort: access to frequent, timely, and specific feedback from preceptors. Findings were used to refine the innovation further. CONCLUSION: This study highlights the necessary conditions for assessing the success of implementation of educational innovations. Reciprocal communication between users and developers is vital. This reflects the approaches recommended in the Ottawa Consensus Statement on research in assessment published in Medical Teacher in March 2011.

Follow-up care after childhood cancer: survivors' expectations and preferences for care.

AIMS: To describe (1) self-rated quality of life, late effects and perceived future vulnerability, (2) expectations before a follow-up appointment, subsequent satisfaction and preferences for different models of care and (3) differences between survivors in quality of life, perceived late effects, vulnerability, expectations regarding follow-up, information needs (topics they want to and did discuss) and preferences for different models of care depending on risk stratification among childhood cancer survivors. METHOD: One hundred and twelve of 141 survivors (18-45 years), diagnosed before 16 years and >5 years since diagnosis completed questionnaires before and after a follow-up appointment (or an abridged questionnaire if they did not attend an appointment within the study period). We collected data on physical (physical component score [PCS]) and mental (mental component score [MCS]) quality of life, late effects, future vulnerability and expectations about care (clinical: identification of late effects; supportive: employment, relationships). Medical information was extracted from case notes. RESULTS: MCS and PCS were comparable to population norms, but 55.5% of survivors reported > or =1 late effect (range 1-9). Clinical care was rated more highly than supportive care (p<0.001) especially in those with worse PCS (p=0.042). Supportive care was rated highly by survivors who reported more late effects (p=0.040), higher future vulnerability (p<0.001) and lower MCS (p=0.005), and by women (p=0.014). Regardless of risk stratification, consultant-led follow-up was valued higher than other models (nurse-led care, GP-led care or postal/telephone follow-up, p<0.001). CONCLUSION: Childhood cancer survivors are in favour of sustaining long-term follow-up care within the existing consultant-led model but this is not feasible given the increasing number of survivors. In the future we therefore need to develop alternative services which will provide the best medical care for each survivor's needs.

A Monte Carlo algorithm to study polymer translocation through nanopores. II. Scaling laws.

In the first paper of this series, we developed a new one-dimensional Monte Carlo approach for the study of flexible chains that are translocating through a small channel. We also presented a numerical scheme that can be used to obtain exact values for both the escape times and the escape probabilities given an initial pore-polymer configuration. We now present and discuss the fundamental scaling behaviors predicted by this Monte Carlo method. Our most important result is the fact that, in the presence of an external bias E, we observe a change in the scaling law for the translocation time tau as function of the polymer length N: In the general expression tau approximately N(beta)E, the exponent changes from beta=1 for moderately long chains to beta=1+nu or beta=2nu for very large values of N (for Rouse and Zimm dynamics, respectively). We also observe an increase in the effective diffusion coefficient due to the presence of entropic pulling on unbiased polymer chains.

Sequence effects on the forced translocation of heteropolymers through a small channel.

By using a recently developed Monte Carlo algorithm and an exact numerical method, we calculate the translocation probability and the average translocation time for charged heterogeneous polymers driven through a nanopore by an external electric field. The heteropolymer chains are composed of two types of monomers (A and B) which differ only in terms of their electric charge. We present an exhaustive study of chains composed of eight monomers by calculating the average translocation time associated with the 256 possible arrangements for various ratios of the monomer charges (lambda(A)lambda(B)) and electric field intensities E. We find that each sequence leads to a unique value of the translocation probability and time. We also show that the distribution of translocation times is strongly dependent on the two forces felt by the monomers ( approximately lambda(A)E and approximately lambda(B)E). Finally, we present results that highlight the effect of having repetitive patterns by studying the translocation times of various block copolymer structures for a very long chain composed of N=2(18) monomers (all with the same number of A and B monomers).