Cardiovascular mortality and morbidity following radical radiotherapy for lung cancer: Is cardiovascular death under-reported?

BACKGROUND: Lung cancer is the most common malignancy worldwide. Radical radiotherapy is an essential treatment in the management of early and locally advanced lung cancer. Cardiac events are known to occur following radical radiotherapy for lung cancer. This study examines the burden of cardiac events post radiotherapy, and estimates the accuracy of death certification in patients who received radical radiotherapy for lung cancer. METHODS: We conducted a retrospective observational cohort study for all patients receiving radical radiotherapy for non-small cell lung cancer (NSCLC) at a large cancer centre between 01/01/2010 to 31/12/2016. Baseline cardiovascular disease and cancer status and treatment data were collected, along with hospital admission data and documented cause of death from the national registry for a median follow-up period of 34 months. RESULTS: Of 1224 patients included in the analysis, 378 (30.9%) patients had cardiovascular disease at baseline, including 140 (11.4%) with prior myocardial infarction. In the 846 patients without known cardiovascular disease, 451 (53.3%) had a QRISK2 predicted 10-year cardiovascular risk >20% over 10 years. During follow-up, 215 hospitalisations occurred (Incidence rate 6.2 per hundred patient years) which were classified as primarily cardiac, and 622 patients died (18 per 100 patient-years). However, death certificates stated a primary cardiac cause of death in only 33 cases (5.3% of deaths). Notably, 29% of patients dying out of hospital and certified as cancer death did not have documented cancer relapse prior to death, and 61% had no community palliative care input prior to death, implying these events may have been sudden and unexpected. CONCLUSION: There is a high prevalence of baseline cardiovascular disease in people undergoing radiotherapy for NSCLC, accompanied by significant rates of post-radiotherapy cardiovascular hospitalisation. However, only a small proportion of deaths are attributed to cardiovascular disease, together with the large amount of sudden deaths observed, this suggests that cardiovascular death is greatly under-reported in official statistics.

Stereotactic Ablative Radiotherapy (SABR) in Patients with Medically Inoperable Peripheral Early Stage Lung Cancer: Outcomes for the First UK SABR Cohort.

AIMS: To report outcomes for the first UK cohort treated for early stage peripheral lung cancer using stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS: Patients were included who received SABR between May 2009 and May 2012. Electronic medical records were reviewed for baseline characteristics, treatment details and outcomes. Patients were treated according to the UK SABR Consortium Guidelines. Univariate and multivariate Cox regression was used to determine factors that influenced overall survival and local control. RESULTS: In total, 273 patients received SABR for 288 lesions in the time period examined. The median follow-up was 19.7 months. The median overall survival for all patients was 27.3 months, with 1, 2 and 3 year overall survival of 78.0, 54.9 and 38.6%, respectively. The 1, 2 and 3 year rates of local control were 98.2, 95.7 and 95.7%, respectively. All patients completed the planned course of treatment and rates of Common Toxicity Criteria grade 3+ toxicity were low. On multivariate analysis, patients with Medical Research Council (MRC) breathlessness scores of 3-5 had worse overall survival compared with patients with scores of 1-2 (hazard ratio: 2.10; 95% confidence interval: 1.25-3.59) and the presence of histological diagnosis conferred improved overall survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93), probably reflecting that patients who are considered well enough to undergo biopsy are generally fitter overall. No factors were identified that significantly influenced local control. CONCLUSIONS: SABR is an effective and well-tolerated treatment option for patients with early stage peripheral lung cancer who are not suitable for surgery. No patient cohort was identified in whom SABR was considered inappropriate. This series adds to the existing positive data that support SABR for this patient group.

A tillering inhibition gene influences root-shoot carbon partitioning and pattern of water use to improve wheat productivity in rainfed environments.

Genetic modification of shoot and root morphology has potential to improve water and nutrient uptake of wheat crops in rainfed environments. Near-isogenic lines (NILs) varying for a tillering inhibition (tin) gene and representing multiple genetic backgrounds were phenotyped in contrasting, controlled environments for shoot and root growth. Leaf area, shoot and root biomass were similar until tillering, whereupon reduced tillering in tin-containing NILs produced reductions of up to 60% in total leaf area and biomass, and increases in total root length of up to 120% and root biomass to 145%. Together, the root-to-shoot ratio increased two-fold with the tin gene. The influence of tin on shoot and root growth was greatest in the cv. Banks genetic background, particularly in the biculm-selected NIL, and was typically strongest in cooler environments. A separate de-tillering study confirmed greater root-to-shoot ratios with regular tiller removal in non-tin-containing genotypes. In validating these observations in a rainfed field study, the tin allele had a negligible effect on seedling growth but was associated with significantly (P<0.05) reduced tiller number (-37%), leaf area index (-26%), and spike number (-35%) to reduce plant biomass (-19%) at anthesis. Root biomass, root-to-shoot ratio at early stem elongation, and root depth at maturity were all increased in tin-containing NILs. Soil water use was slowed in tin-containing NILs, resulting in greater water availability, greater stomatal conductance, cooler canopy temperatures, and maintenance of green leaf area during grain-filling. Together these effects contributed to increases in harvest index and grain yield. In both the controlled and field environments, the tin gene was commonly associated with increased root length and biomass, but the significant influence of genetic background and environment suggests careful assessment of tin-containing progeny in selection for genotypic increases in root growth.

Benchmarking of a treatment planning system for spot scanning proton therapy: comparison and analysis of robustness to setup errors of photon IMRT and proton SFUD treatment plans of base of skull meningioma.

PURPOSE: Base of skull meningioma can be treated with both intensity modulated radiation therapy (IMRT) and spot scanned proton therapy (PT). One of the main benefits of PT is better sparing of organs at risk, but due to the physical and dosimetric characteristics of protons, spot scanned PT can be more sensitive to the uncertainties encountered in the treatment process compared with photon treatment. Therefore, robustness analysis should be part of a comprehensive comparison between these two treatment methods in order to quantify and understand the sensitivity of the treatment techniques to uncertainties. The aim of this work was to benchmark a spot scanning treatment planning system for planning of base of skull meningioma and to compare the created plans and analyze their robustness to setup errors against the IMRT technique. METHODS: Plans were produced for three base of skull meningioma cases: IMRT planned with a commercial TPS [Monaco (Elekta AB, Sweden)]; single field uniform dose (SFUD) spot scanning PT produced with an in-house TPS (PSI-plan); and SFUD spot scanning PT plan created with a commercial TPS [XiO (Elekta AB, Sweden)]. A tool for evaluating robustness to random setup errors was created and, for each plan, both a dosimetric evaluation and a robustness analysis to setup errors were performed. RESULTS: It was possible to create clinically acceptable treatment plans for spot scanning proton therapy of meningioma with a commercially available TPS. However, since each treatment planning system uses different methods, this comparison showed different dosimetric results as well as different sensitivities to setup uncertainties. The results confirmed the necessity of an analysis tool for assessing plan robustness to provide a fair comparison of photon and proton plans. CONCLUSIONS: Robustness analysis is a critical part of plan evaluation when comparing IMRT plans with spot scanned proton therapy plans.

The impact of playing in matches while injured on injury surveillance findings in professional football.

This study aimed to analyze the frequency, nature, and consequences of footballers playing matches while injured, and to examine the impact on injury surveillance findings. High levels of inter-rater reliability and content validity were established for a tool designed to document players who were already injured at the start of a match. The tool was implemented in three English football teams (a Championship, League 1, and League 2 team) for one season, using a "time loss" definition of injury. One hundred forty-three matches were surveyed, revealing 102 match appearances by players who were already injured. Almost half of all games featured at least one injured player, with episodes of playing with injury occurring more frequently and lasting longer in League 2 players compared with higher level players. No association was observed between the number of injured players starting matches and match outcome [χ(2) (4, N = 143) = 3.27, P = 0.514]. Fifteen percent of all injury episodes captured were only through prospective documentation of playing while injured. The findings show that both traumatic and overuse injuries are managed by footballers through competitive matches, and have important implications for aiding understanding of the epidemiology of injury in professional football.

Associations of morbidity in the underweight.

BACKGROUND/OBJECTIVES: There is little research on the demographic characteristics and morbidity of people categorized as 'underweight' from their body mass index (BMI) although they have often been shown to have greater mortality. This uncertainty makes it difficult to determine whether to include or exclude these individuals when estimating the health and mortality impacts of BMI. This project compares the demographic characteristics and morbidity patterns of the underweight with those of acceptable weight and the overweight. SUBJECTS/METHODS: Data on 10 243 community-living residents from the Health Survey for England (2003) were used. Logistic regression models were constructed to compare demographic, biochemical and anthropometric factors in the underweight (BMI<18.5) with those classified as acceptable weight (BMI 18.5-24.9) or overweight (BMI 25.0-29.9). RESULTS: Univariate analyses found, when compared with other BMI categories, underweight individuals were significantly younger, more likely to smoke, alcohol abstainers, inactive, poorer and were less likely to be ethnically white (all P<0.001). U-shaped relationships between BMI and activities of daily living, respiratory disease, physical activity and mental health variables were seen. In multivariate analysis, the fewest number of significant differences in demographic and morbidity factors were between the underweight and those of acceptable weight. CONCLUSIONS: We recognize that these are cross-sectional data and exclude individuals in institutional settings, but these findings are important. Overall, we could not conclude that the underweight were less healthy than individuals in the other BMI categories. We cannot therefore recommend that the underweight should be excluded from analyses that examine the effects of obesity on mortality.

Coding sports injury surveillance data: has version 10 of the Orchard Sports Injury Classification System improved the classification of sports medicine diagnoses?

OBJECTIVES: To compare versions 8 and 10 of the Orchard Sports Injury Classification System (OSICS) to determine whether the revised version of OSICS has improved its use in a sports medicine setting, and to assess the inter-rater reliability of OSICS-10. METHODS: Injury surveillance data, gathered over a 2 year period in professional football, cricket and rugby union to produce 335 diagnoses, were coded with both OSICS-8 and OSICS-10. Code-diagnosis agreement was assessed for OSICS-8 in terms of whether a diagnosis was codeable or noncodeable, and for OSICS-10 by evaluating the highest available OSICS-10 tier of coding. Eight clinicians coded a list of 20 diagnoses, comprising a range of pathologies to all gross anatomical regions, which were compared to assess inter-rater reliability. RESULTS: All diagnoses could be assigned an appropriate code with OSICS-10, compared with 87% of diagnoses that could be assigned an OSICS-8 code. Contusions comprised almost half of OSICS-8 noncodeable diagnoses. OSICS-10 tier 2 codes accounted for 20% of diagnoses coded with the updated system. Of these 20%, almost half contained a more detailed diagnosis that did not have an available OSICS-10 tier 3 or 4 code. Inter-rater reliability increased with decreasing diagnostic detail, with an overall level shown to be moderate (k = 0.56). CONCLUSIONS: OSICS-10 is a more encompassing system than OSICS-8 to use in classifying sports medicine diagnoses, and has a moderate level of inter-rater reliability. Further minor revision may be required to address lack of detail in some strain, effusion and contusion codes.

A health profile of adults with multiple sclerosis living in the community.

OBJECTIVE: To describe the frequency of impairments, disabilities, and related services used in a community sample of adults with multiple sclerosis (MS) to estimate the service needs of this population. METHODS: A community-based postal survey conducted using a self-completion questionnaire consisting of MSQOL-54 questionnaire, Nottingham Extended Activities of Daily Living (NEADL) and some demographic items as well as items to ask about MS-related symptoms and/or problems and using available services. Adults with a diagnosis of MS confirmed by a neurologist were recruited via primary care services in Southern Derbyshire, UK. RESULTS: Questionnaires were sent to 310 adults with MS and 201 completed questionnaires were returned - a response rate of 65%. The most commonly reported symptoms and/or problems were fatigue, sexual problems, urinary problems, and painful muscle spasms. Most respondents reported at least one contact with their general practitioner (GP) during the previous 12 months. However, contacts with other services potentially able to alleviate specific symptoms and/or problems were low. CONCLUSIONS: The findings suggest under-use of existing health care services by those who experience potentially treatable symptoms and/or problems associated with MS. More needs to be done to raise awareness among people with MS and their carers about the services available to them. Given the very high proportion of people with MS known to make contact with primary care services, GPs have a vital role in providing this information.

Molecular characterization of the fish-pathogenic fungus Aphanomyces invadans.

Aphanomyces invadans (Saprolegniaceae) is a peronosporomycete fungus associated with the serious fish disease, epizootic ulcerative syndrome (EUS), also known as mycotic granulomatosis. In this study, interspecific relationships were examined between A. invadans isolates and other aquatic animal pathogenic Saprolegniaceae, and saprophytic Saprolegniaceae from EUS-affected areas. Restriction fragment length polymorphisms and sequences of ribosomal DNA confirmed that A. invadans is distinct from all other species studied. A sequence from the internal transcribed spacer region ITS1, unique to A. invadans, was used to design primers for a PCR-based diagnostic test. Intraspecific relationships were also examined by random amplification of polymorphic DNA using 20 isolates of A. invadans from six countries. The isolates showed a high degree of genetic homogeneity using 14 random ten-mer primers. This provides evidence that the fungus has spread across Asia in one relatively rapid episode, which is consistent with reports of outbreaks of EUS. Physiological distinctions between A. invadans and other Aphanomyces species based on a data set of 16 growth parameters showed remarkable taxonomic congruence with the molecular phylogeny.

Barriers to gene flow from oilseed rape (Brassica napus) into populations of Sinapis arvensis.

One concern over growing herbicide-tolerant crops is that herbicide-tolerance genes may be transferred into the weeds they are designed to control. Brassica napus (oilseed rape) has a number of wild relatives that cause weed problems and the most widespread of these is Sinapis arvensis (charlock). Sinapis arvensis seed was collected from 102 populations across the UK, within and outside B. napus-growing areas. These populations were tested for sexual compatibility with B. napus and it was found that none of them hybridized readily in the glasshouse. In contrast to previous studies, we have found that hybrids can be formed naturally with S. arvensis as the maternal parent. Six diverse B. napus cultivars (Capricorn, Drakkar, Falcon, Galaxy, Hobson and Regent) were tested for their compatibility with S. arvensis but no cultivar hybridized readily in the glasshouse. We were unable to detect gene transfer from B. napus to S. arvensis in the field, confirming the extremely low probability of hybridization predicted from the glasshouse work.

Effect of macrophages and serum of fish susceptible or resistant to epizootic ulcerative syndrome (EUS) on the EUS pathogen, Aphanomyces invadans.

Epizootic ulcerative syndrome (EUS) is one of the most destructive diseases of fresh and brackish water farmed and wild fish in the Asia-Pacific region. The in vitro germination and growth of the propagules of the EUS pathogen, Aphanomyces invadans (= A. piscicida), were assessed in the presence of the head-kidney macrophages, serum, and serum heated to inactivate complement proteins, of three EUS-susceptible and one resistant fish species. The susceptible species were: striped snakehead (Channa striata), giant gourami (Osphronemus gouramy) and silver barb [Barbodes (= Puntius) gonionotus], and the resistant species was Nile tilapia (Oreochromis niloticus). Fish of all species were acclimatised to either low temperature (20 degrees C +/- 1.6) at which EUS is known to occur, or to high temperature (32 degrees C +/- 5.0) at which EUS does not occur, except for giant gouramis which were only studied at low temperature. The respiratory burst of the macrophages was assessed in the presence of A. invadans or the stimulant phorbol myristate acetate (PMA), and compared to that of controls. Anti-A. invadans antibody concentrations were assessed in all species except silver barbs. All assays were carried out at the same temperature, regardless of the temperature that the fish were kept at. Macrophages of all species other than snakeheads inhibited fungal germination at both temperatures, though only silver barb and gourami macrophages could inhibit germling growth. PMA increased the respiratory burst in nearly all cases. The respiratory burst in the presence of A. invadans was consistently lower than that of controls, though the difference was only significant in the case of snakeheads. The respiratory burst of all macrophage treatments was higher at a low temperature. Except in the case of PMA-stimulated macrophages, regressions between respiratory burst and inhibitory action were only found in susceptible species, suggesting that the respiratory burst is important in those species, but is unable to prevent the proliferation of A. invadans. Serum inhibited fungal germination in all cases other than low temperature tilapia, indicating that the EUS resistance of tilapia is not due to the serum. Inhibition of germling growth by serum only occurred in silver barbs and gourami. Heated serum did not inhibit germination in any case except that of high temperature snakehead, and in fact stimulated germination in the case of tilapia. Heating serum did not affect the growth inhibiting activity of silver barbs and gouramis, but it stimulated growth in some groups. At high temperatures snakeheads had high anti-A. invadans antibody concentrations, which may explain the inhibitory activity of their heated serum. A role for complement and antibodies in defence against A. invadans in susceptible species is suggested.

Characterization of Aphanomyces invadans isolates using pyrolysis mass spectrometry (PyMS).

Twenty-one isolates of Aphanomyces invadans, the fungal pathogen associated with the Asian fish disease epizootic ulcerative syndrome (EUS), were compared with other Oomycete fungi in terms of their pyrolysis mass spectrometry (PvMS) profiles. Canonical variate analysis (CVA) of the pyrolysis mass spectra distinguished the Aphanomyces species from a wide scatter of Achlya and Saprolegnia isolates. Further CVA and hierarchal cluster analysis (HCA) separated the Aphanomyces species into two main groups. The first group clustered A. invadans isolates from EUS outbreaks in Thailand, Bangladesh, Indonesia, Philippines, Australia and Japan together. However, HCA also included the crayfish plague fungus Aphanomyces astaci within this group. Non-pathogenic Aphanomyces strains isolated from ulcerative mycosis (UM)-affected fish were shown to be distinct from A. invadans, and instead clustered with saprophytic Aphanomyces strains to form the second group. Recently, an invasive Aphanomyces pathogen has been isolated from UNI-affected fish, but that was not tested here. This is the first report using PyMS in the study of Oomycete systematics. The technique was not sensitive enough to show any intraspecific differences, but it was considered a useful technique for the discrimination of species where taxonomic relationships are uncertain.

Plasma arginine levels and the response to inhaled nitric oxide in neonates.

Inhaled nitric oxide (iNO) can be an effective vasodilator in pulmonary hypertension of the newborn (PHN). The aim of this study was to determine whether differences in arginine levels, from which endogenous NO is produced, explain the variability in response to NO and whether the arginine levels were lower in term and preterm infants with PHN than in infants without PHN (controls). We prospectively studied 30 infants (17 born preterm) with clinically diagnosed PHN and treated with iNO and 22 controls (14 born preterm). Three NO levels (10, 20, 40 ppm) were administered to the PHN infants to identify that associated with maximum oxygenation. Twenty-seven infants with PHN improved following iNO and had lower arginine levels than those infants who did not respond to iNO (p < 0. 05). No significant relationship, however, was noted between the arginine levels and either the magnitude of change in the oxygenation index in response to iNO or the NO level associated with maximum oxygenation. The median plasma arginine level prior to iNO of the PHN infants was 12.5 (range 2-53) mu mol/l, but not significantly lower than that of the controls (median 24, range 3-82 mu mol/l). We conclude that differences in plasma arginine levels are unlikely to explain the variation in response to iNO and that, although arginine levels tended to be lower in infants with PHN, this is not a consistent finding in either the term or preterm infants.

Effect of vitamin D receptor gene alleles on bone loss in early rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a polygenic disease characterized by localized joint destruction and generalized osteoporosis resulting in increased fracture risk. The pathogenetic mechanisms that determine the severity of generalized bone loss in RA are poorly understood. Polymorphisms in the vitamin D receptor (VDR) gene have been described as a significant determinant of bone turnover and mass. In this prospective study we describe VDR gene allele effects on bone loss in patients with early RA. METHODS: We recruited 232 patients with early RA. Bone mineral density measurements were repeated in 167 patients. Serial clinical and laboratory measures were recorded during the period of followup. DNA extraction, polymerase chain reaction amplification, and restriction fragment length polymorphism analysis of VDR alleles were performed using standard techniques. Presence of the Taq restriction site for both alleles was denoted "tt", and absence "TT". RESULTS: In women with RA the tt genotype group lost bone more rapidly than subjects with TT genotype at both the lumbar spine (-0.1 vs -4.9% p.a, respectively; p < 0.05) and femoral neck (-3.9 vs -9.6%, respectively; p < 0.01). The effect was independent of other disease characteristics. CONCLUSION: The presence of the VDR gene "t" allele in female patients with RA was associated with accelerated bone loss.

Food safety knowledge and practice among elderly people living at home.

OBJECTIVE: To assess the food storage knowledge and practice of elderly people living at home. METHODS: Three phase survey data collection: face to face interviews; dietary diaries with a food frequency questionnaire; and follow up interviews. SETTING: Urban Nottingham. PARTICIPANTS: 809 elderly people (aged 65+) randomly selected from general practitioner lists. MAIN OUTCOME MEASURES: Respondent's refrigerator temperature; knowledge of freezer star rating; understanding of "use by" and "sell by" dates; reported ability to read food product safety labels. RESULTS: From a weighted total of 645 refrigerators measured, 451 (70%) were too warm for the safe storage of food (> or = 6 degrees Celsius). Only 41% of respondents (n = 279) knew the star rating of their freezer. Within a smaller sub-sample knowledge of the "use by" and "sell by" dates was good, but 45% of these respondents reported difficulty reading food labels. The storage of foods at inappropriate temperatures was not independent of socioeconomic or demographic status, and tended to be more likely among the poorer and those not living alone. CONCLUSIONS: Food storage practices among the majority of elderly people interviewed in this study do not meet recommended safety standards to minimise the risk of food poisoning.