Childhood cancer: Estimating regional and global incidence.

BACKGROUND: Most of the world's population is not covered by cancer surveillance systems or vital registration, and worldwide/UN-regional cancer incidence is estimated using a variety of methods. Quantifying the cancer burden in children (<15 years) is more challenging than in adults; childhood cancer is rare and often presents with non-specific symptoms that mimic those of more prevalent infectious and nutritional conditions. METHODS: A Baseline Model (BM) was constructed comprising a set of quality assured sex- and age-specific cancer rates derived from the US Surveillance, Epidemiology and End Results (SEER) program, for diagnostic groups of the International Classification of Childhood Cancers (ICCC-3) 3rd edition, and information on a known risk factor for endemic Burkitt lymphoma and Kaposi's sarcoma. These rates were applied to global country-level population data for 2015 to estimate the global and regional incidence of childhood cancer. Results were compared to GLOBOCAN 2018, extrapolations from the International Incidence of Childhood Cancer (IICC-3) and estimates from the Global Childhood Cancer (GCC) model (based on IICC-3 data combined with information on health care systems and other parameters). RESULTS: The BM estimated 360,114 total childhood cancers occurring worldwide in 2015; 54% in Asia and 28% in Africa. BM estimated standardised rates ranged from ∼178 cases per million in Europe and North America, through to ∼218 cases per million in West and Middle Africa. Totals from GLOBOCAN and extrapolations from the IICC-3 study were lower (44.6% and 34.7% respectively), but the estimate from the GCC model was 10.2% higher. In all models, agreement was good in countries with very high human development index (HDI), but more variable in countries with medium and low HDIs; the discrepancies correlating with registration coverage across these settings. CONCLUSION: Disagreements between the BM estimates and other sources occur in areas where health systems are insufficiently equipped to provide adequate access to diagnosis, treatment, and supportive care. Incorporating aetiological evidence into the BM enabled the estimation of the additional burden of Burkitt lymphoma and Kaposi sarcoma; similar adjustments could be applied to other cancers, as and when information becomes available.

A ten-year study of Retinoblastoma in Uganda: An approach to improving outcome with limited resources.

BACKGROUND: Survival of children with cancer in resource-limited regions is very poor compared to better-resourced regions. Retinoblastoma (RB) is a childhood cancer that is commonly reported in many regions of Africa. RB may be safely and effectively treated by non-specialists, which could facilitate more widespread availability of treatment in under-resourced areas. METHODS: A ten-year consecutive series of children with RB treated at Ruharo Eye Centre between December 2009 and November 2019 was prospectively followed up. Chemoreduction followed by surgery is the standard approach to therapy. Costs of therapy and also of travel and food are borne by the program which is unaffordable to most families and necessitates donors. Survival by stage of RB and number of eyes affected was described using Kaplan-Meier plots. Visual acuity was assessed for all children with bilateral disease and the retention of sight during follow-up assessed. RESULTS: Among 665 children with RB, 18.2 % (121 children) presented with metastatic (Stage 4) RB with only two of these children surviving >24 months. Five-year survival was 60.2 % among all children with RB rising to 93.3 % and 87.2 % for children with unilateral and bilateral Stage 1 disease, respectively. Among 184 children with bilateral disease, 130 (70.7 %) retained some level of sight following primary treatment with 91 of those (49.5 % of all bilateral children) retaining vision up to their death or to the end of follow-up. CONCLUSION: Many children in Uganda present with advanced RB and curative treatment is not possible in this setting. Children diagnosed and treated early have good prospects of survival. Retention of sight among many bilaterally affected children is achievable, facilitating access to normal education. Therefore, the strategic priorities for improving survival are changing community perceptions so that children with eye problems are brought without delay, and widening access to modern treatment by using genereal health workers with standard drugs, backed by financial, social and peer support.

Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome.

BACKGROUND: The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower-risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. OBJECTIVE: The aim of this study was to describe the usage and clinical impact of erythropoiesis-stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. METHODS: The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. RESULTS: ESA treatment (median duration of 27.5 months, range 0-77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65-1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post-ESA treatment transfusion was 6.1 months (IQR: 4.3-15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0-47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7-3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45-0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39-1.29, P = 0.27). CONCLUSION: Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS.

Bovine Tuberculosis Risk Factors for British Herds Before and After the 2001 Foot-and-Mouth Epidemic: What have we Learned from the TB99 and CCS2005 Studies?

Over the last couple of decades, the UK experienced a substantial increase in the incidence and geographical spread of bovine tuberculosis (TB), in particular since the epidemic of foot-and-mouth disease (FMD) in 2001. The initiation of the Randomized Badger Culling Trial (RBCT) in 1998 in south-west England provided an opportunity for an in-depth collection of questionnaire data (covering farming practices, herd management and husbandry, trading and wildlife activity) from herds having experienced a TB breakdown between 1998 and early 2006 and randomly selected control herds, both within and outside the RBCT (the so-called TB99 and CCS2005 case-control studies). The data collated were split into four separate and comparable substudies related to either the pre-FMD or post-FMD period, which are brought together and discussed here for the first time. The findings suggest that the risk factors associated with TB breakdowns may have changed. Higher Mycobacterium bovis prevalence in badgers following the FMD epidemic may have contributed to the identification of the presence of badgers on a farm as a prominent TB risk factor only post-FMD. The strong emergence of contact/trading TB risk factors post-FMD suggests that the purchasing and movement of cattle, which took place to restock FMD-affected areas after 2001, may have exacerbated the TB problem. Post-FMD analyses also highlighted the potential impact of environmental factors on TB risk. Although no unique and universal solution exists to reduce the transmission of TB to and among British cattle, there is an evidence to suggest that applying the broad principles of biosecurity on farms reduces the risk of infection. However, with trading remaining as an important route of local and long-distance TB transmission, improvements in the detection of infected animals during pre- and post-movement testing should further reduce the geographical spread of the disease.

Survival from childhood acute lymphoblastic leukaemia: the impact of social inequality in the United Kingdom.

BACKGROUND: Survival from childhood acute lymphoblastic leukaemia (ALL) has continued to improve in economically-developed regions of the world, but 20% of patients still die within 5-years of diagnosis. Treatment is prolonged and complex; and as survival rates plateau, factors relating to socio-economic status and/or treatment adherence are increasingly scrutinised as potentially important determinants of outcome. METHODS: Predicated on the frame-work of the United Kingdom (UK) NHS, the relationship between socio-demographic factors and ALL survival is examined here using data from a large follow-up study conducted in the 1990s. One thousand five hundred and fifty nine children (0-14 years) diagnosed in England, Scotland &Wales during the era of the national UKALL XI randomized-controlled trial (RCT) were followed-up for an average of 15.9 years (20,826.3 person-years). Area-based deprivation scores and father's occupational social class at the time of the child's birth were used as markers of socio-economic status. Information on deaths was obtained from the NHS Information Centre for Health and Social Care. All children were included in the analyses, irrespective of RCT enrolment or participation in the founding epidemiological study (www.UKCCS.org).Survival effects were assessed using proportional hazards regressions models. RESULTS: Survival varied with both area-based deprivation at diagnosis (hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.05-1.57) and fathers occupational social class at birth (HR 1.12; 95% CI 0.97-1.29); the divergence beginning 6-9 months after diagnosis, and widening thereafter during home-administered therapy. The findings became more marked when analyses were restricted to those enrolled in UKALL XI (n = 1341). As expected, survival differences were also observed with sex, and age at diagnosis. CONCLUSION: The existence of significant social disparities in ALL survival, which are not due to treatment accessibility, is of major clinical importance. Trends should be monitored and further research into potentially modifiable risk factors conducted.

Herd-level risk factors of bovine tuberculosis in England and Wales after the 2001 foot-and-mouth disease epidemic.

OBJECTIVES: We present the results of a 2005 case-control study of bovine tuberculosis (bTB) breakdowns in English and Welsh herds. The herd management, farming practices, and environmental factors of 401 matched pairs of case and control herds were investigated to provide a picture of herd-level risk factors in areas of varying bTB incidence. METHODS: A global conditional logistic regression model, with region-specific variants, was used to compare case herds that had experienced a confirmed bTB breakdown to contemporaneous control herds matched on region, herd type, herd size, and parish testing interval. RESULTS: Contacts with cattle from contiguous herds and sourcing cattle from herds with a recent history of bTB were associated with an increased risk in both the global and regional analyses. Operating a farm over several premises, providing cattle feed inside the housing, and the presence of badgers were also identified as significantly associated with an increased bTB risk. CONCLUSIONS: Steps taken to minimize cattle contacts with neighboring herds and altering trading practices could have the potential to reduce the size of the bTB epidemic. In principle, limiting the interactions between cattle and wildlife may also be useful; however this study did not highlight any specific measures to implement.

Recurrence of bovine tuberculosis breakdowns in Great Britain: risk factors and prediction.

Bovine tuberculosis (bTB) is an important economic disease worldwide with implications for both animal and human health. In Great Britain the number of herds that test positive for bTB, termed "breakdowns", has increased over the last two decades. Despite more intensive testing during a breakdown, around 23% of breakdowns recur within 12 months of the previous breakdown ending, and around 38% within 24 months. These "recurrent" breakdowns may be important for onward transmission of infection. Detailed case-control data were analysed to identify factors associated with recurrence within 12 months. The model predicted 83% of all recurrent breakdowns, with a positive predictive value (PPV) of 44%. A further model, restricted to data currently available nationally, was not sufficient to predict recurrence reliably; at a sensitivity of 72-76%, the PPV was 33-36%, when validated on independent data. Factors identified to be associated with recurrence are consistent with previous studies; namely, the number of reactors, a recent bTB history in the herd and a lack of association with the confirmation status of the initial breakdown. These variables are indicative of a higher level of infection or residual infection, and could be useful in the future development of predictive models for bTB recurrence.

Predicting prolonged bovine tuberculosis breakdowns in Great Britain as an aid to control.

Bovine tuberculosis (bTB) is an important notifiable disease in cattle in Great Britain (GB), and is subject to statutory control measures. Despite this, disease incidence has increased since the mid-1980s, and around 30% of herd breakdowns continue for more than 240 days. This is twice the shortest possible time for confirmed breakdowns to test clear from infection (≈120 days), and four times the shortest possible time for unconfirmed breakdowns (≈60 days). These "prolonged" breakdowns consume substantial resources and may act as an ongoing source of infection. It is not clear why some breakdowns become prolonged. Existing detailed case-control data have been re-analysed to determine risk factors for breakdowns lasting longer than 240 days, the strongest of which was the confirmation status of the breakdown: OR 12.6 (95%CI: 6.7-25.4). A further model restricted to data available early on in a breakdown for all breakdowns nationally, can predict 82-84% of prolonged breakdowns with a positive predictive value of 44-49% when validated using existing national datasets over a 4-year period. Identification of prolonged breakdowns at an earlier stage could help to target bTB controls in GB.

The secret of Turkey red--technology transfer with a Scottish connection.

The successful commercial introduction of the Turkey red textile dyeing process from Western and South Asia into Western Europe occurred via France in the mid 18th century. The French state was deeply involved in facilitating this technology transfer. During the later half of the century, French dyers from Rouen were involved in a further transfer of this process into Great Britain. In particular, the efforts of Scottish dyers to recruit and utilize the knowledge and skills of M. Papillon, the ambiguous role of the Scottish Board of Manufactures, and the assistance of Professors Black and Hope are described. The eventual success of such ventures resulted in the implementation of the Turkey red process industrially in Glasgow by 1785.

The discovery of aniline and the origin of the term "aniline dye".

An historical background is provided for the term, "aniline dye," which is still widely used as a synonym for "synthetic dye." The discovery of aniline and the role of Hofmann in clarifying it are described. The subsequent discovery of mauveine (mauve) by a student of Hofmann's, William Perkin, and his difficulties in transforming an academic synthesis into a commercial product also are discussed. The key role of Scottish dyers, the Pullars of Perth and Thomas Keith in London, in this technology transfer is described. The subsequent ascendancy of the German dyestuff industry over British manufacturers is noted.

The prevalence, distribution and severity of detectable pathological lesions in badgers naturally infected with Mycobacterium bovis.

The Randomized Badger Culling Trial (RBCT) began in 1998 to determine the impact of badger culling in controlling bovine tuberculosis in cattle. A total of 1166 badgers (14% of total) proactively culled during the RBCT were found to be tuberculous, offering a unique opportunity to study the pathology caused by Mycobacterium bovis in a large sample of badgers. Of these, 39% of adults (approximately 6% of all adults culled) had visible lesions (detectable at necropsy) of bovine tuberculosis; cubs had a lower prevalence of infection (9%) but a higher percentage of tuberculous cubs (55.5%) had visible lesions. Only approximately 1% of adult badgers had extensive, severe pathology. Tuberculous badgers with recorded bite wounds (approximately 5%) had a higher prevalence of visible lesions and a different distribution of lesions, suggesting transmission via bite wounds. However, the predominance of lesions in the respiratory tract indicates that most transmission occurs by the respiratory route.

Herd-level risk factors associated with tuberculosis breakdowns among cattle herds in England before the 2001 foot-and-mouth disease epidemic.

A case-control study of the factors associated with the risk of a bovine tuberculosis (TB) breakdown in cattle herds was undertaken within the randomized badger culling trial (RBCT). TB breakdowns occurring prior to the 2001 foot-and-mouth disease epidemic in three RBCT triplets were eligible to be cases; controls were selected from the same RBCT area. Data from 151 case farms and 117 control farms were analysed using logistic regression. The strongest factors associated with an increased TB risk were movement of cattle onto the farm from markets or farm sales, operating a farm over multiple premises and the use of either covered yard or 'other' housing types. Spreading artificial fertilizers or farmyard manure on grazing land were both associated with decreased risk. These first case-control results from the RBCT will be followed by similar analyses as more data become available.

Prophylactic effects of two selective dry cow strategies accounting for interdependence of quarter.

Infusion of a long-acting antibiotic preparation at drying off in dairy cows as a prophylactic therapy is usually recommended for all quarters where it is in use. Studying the effectiveness of such treatment using quarter as the unit of analysis assumes that each quarter within a cow has a risk of being infected independent of the other quarters of the cow. Failure to account for interdependence of quarters within a cow may lead to inaccurate variance estimates and errors in assessing treatment effects. Data from two trials assessing different dry-cow strategies were examined for interdependence of infection between quarters. Logistic regression with a variance inflation factor or a multilevel analysis was used to assess the effect of antibiotic and internal teat-sealant dry cow strategies. Parity and infection status at drying off were covariates in the analysis. Interdependence of the risk of quarter infections within control-group cows was demonstrated in both dry-cow antibiotic and teat-seal trials. However, cows that received either of these treatments did not demonstrate interdependence. Treated quarters in both trials were 3.0 times less likely to acquire a new infection at calving compared with the untreated controls. Quarters in cows of parity 3 or greater were also at an increased risk in the antibiotic treatment trial. In both trials, quarters with either Corynebacterium spp. or coagulase-negative staphylococci infections at drying off had an increased risk of a new intramammary infection at calving. This study has demonstrated the beneficial and comparable effects of antibiotic and teat seal dry cow strategies; both decreased the risk of intramammary infection at calving. The application of dry-cow strategies at the cow level and not the quarter level is also supported.

Modelling host cell availability and the crowding effect in Eimeria infections.

Within-host mathematical models of Eimeria maxima and Eimeria praecox infections of the chicken are presented and used to investigate the role of host cell availability as a possible determinant of the so-called 'crowding effect'; whereby the fecundity of the parasites decreases as infectious dose increases. Assumptions about the number of available host cells, the average lifespan of these cells and the age structure within the host-cell population were made and mathematical models were constructed and combined with experimental data to test whether these conditions could reproduce the crowding effect in the two species. Experimental data demonstrated that crowding during in vivo infections was apparent following very low infectious doses, but none of the models could adequately reproduce crowding at the same doses while maintaining realistic estimates of the dynamics of the enterocyte pool. However, both the size and lifespan of the enterocyte pool were demonstrated to have substantial effects on the fecundity of the infections, particularly at higher doses. These data indicate that host cell availability cannot be solely responsible for the crowding effect. Alternative factors such as the influence of the primary immune response to the parasite may also be explored using within-host models and other applications of these models are discussed.

An investigation of the etiology of a mild diarrhea observed in a group of grower/finisher pigs.

An investigation into a mild diarrhea in a group of grower/finisher pigs was carried out in order to determine the etiology. A tiamulin injection and a carbadox-medicated ration were given to pens of pigs in a 2 x 2 factorial experimental design. Pens of pigs were assessed a score, based on the consistency of the feces in the pen, each week. The clinical investigation looked for the intestinal pathogens Brachyspira pilosicoli, B. hyodysenteriae, Lawsonia intracellularis, Salmonella spp., Yersinia spp., transmissible gastroenteritis virus, and rotavirus. Despite a rigorous investigation, the diarrhea was not attributed to any pathogen. A mild colitis was noted among pigs necropsied while affected with diarrhea. Improved diagnostic tools may allow a more effective response to an outbreak of mild disease, while at the same time reducing the amount of antimicrobials used in swine production.

Effects of 50% ethanol and mechanical epithelial debridement on corneal structure before and after excimer photorefractive keratectomy.

PURPOSE: The corneal epithelium is generally removed before photoablation in photorefractive keratectomy (PRK) because laser transepithelial PRK may result in surface irregularity caused by variability in epithelial thickness and differing ablation rates between epithelium and stroma. We compared the effects of mechanical deepithelialization with chemical epithelial removal by using 50% ethanol on the corneal structure. METHODS: Fourteen rabbits underwent corneal deepithelialization by using a blade in the left eye and 24 h later in the right eye. Another 14 rabbits underwent corneal deepithelialization by using 50% ethanol solution. Half of the eyes treated with each technique underwent PRK after deepithelialization. Pachymetry was performed before and after each procedure on right eyes. Keratocyte and neutrophil densities were assessed by light microscopy. RESULTS: Among non-laser-treatment groups, eyes that underwent mechanical deepithelialization had decreased corneal thickness (p = 0.001), increased keratocyte densities (p = 0.03), and no significant difference in neutrophil densities (p = 0.91) compared with chemically treated eyes 24 h after surgery. Among laser-treatment groups, eyes that underwent mechanical epithelial removal had increased keratocyte densities (p = 0.001), decreased corneal thickness (p = 0.03), and increased neutrophil densities (p = 0.03) 24 h after surgery compared with chemically treated eyes. CONCLUSION: Deepithelialization with 50% ethanol causes more keratocyte loss with perhaps more corneal edema, but less stromal influx of neutrophils, than does a mechanical technique 24 h after PRK in a rabbit model. Corneal deepithelialization with dilute ethanol may be a viable option in PRK. However, further investigation into the safety of this technique is warranted before it can be widely applied clinically.