Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Weight and glycaemic control in type 2 diabetes: what is the outcome of insulin initiation?

AIMS: Little information is available on the association between obesity at time of insulin initiation and attainment of glycaemic targets in type 2 diabetic (T2DM) patients. This study describes changes in HbA1c, weight and body mass index (BMI) over 24 months postinsulin initiation. METHODS: First-time insulin users with T2DM were selected from the UK General Practice Research Database for the period 1st January 2002 to 31st March 2008. The cohort was stratified into BMI categories (kg/m(2) ) at the time of insulin initiation. Data were reviewed at 6-monthly intervals. A multivariate repeated-measures linear model was fitted assessing weight change over 12 months. RESULTS: 3783 patients were included (normal weight, n = 672; overweight, n = 1259; obese, n = 1070; clinically obese, n = 480; morbidly obese, n = 302). The largest reductions in HbA1c were observed 6 months postinsulin initiation and were greatest in lower BMI categories: median observed HbA1c at initiation and 6 months was 9.7 and 7.9% in normal weight patients and 9.6 and 8.2% in the clinically obese, respectively. A minority of patients achieved HbA1c ≤ 7.5% and by 24 months the proportion achieving this was: normal weight 41%; overweight 34%; obese 30%; clinically obese 26%; morbidly obese 31%; trend p < 0.001. The greatest weight gain occured by 6 months and multivariate adjusted models showed that normal weight patients had the highest gains 5.07 kg (95% CI: 3.35, 6.79), as did those with HbA1c ≥ 12.1%-5.55 kg (95% CI: 3.81, 7.28). CONCLUSION: Obesity is associated with a poorer response to insulin illustrated by higher HbA1c values and lower achievement of targets.

Warfare and the creation of British imperial medicine, 1600-1800.

The literature of British maritime and imperial medicine is reviewed here, noting that the key growth in the area coincided with the wars of the late-seventeenth and early-eighteenth centuries when the navy started to maintain a regular fleet overseas. Thereafter, the literature followed major imperial wars and focused on the needs of the state in war, and male servicemen. Medical prescriptions for cure were universal, empirical, and economical; experimenting on servicemen to develop cures was a necessity. The emphasis was on control of the human environment and regulation of the men.

Playing conditions, player preparation and rugby injury: a case-control study.

This paper investigates the effect of player preparation, ground conditions and weather conditions upon the injury risk for Rugby Union players. A population-based case-control study was performed using a sample (n= 1043) of New Zealand Rugby Union players aged 16 y and above. Details concerning game preparation (warm-up and usual position), and ground and weather conditions (precipitation, wind and temperature) were obtained from the players. If players were injured during the season (n= 624) they were asked to provide details about the game in which they were last injured. Uninjured players (n= 419) provided details about the last game in which they played. Injuries were more likely to occur when games were played on hard grounds or in calm or warm conditions. Playing out of position and the duration of warming up did not significantly alter the risk of injury. When player preparation, ground and weather conditions, grade, age, playing position and rugby experience were simultaneously controlled for, hard ground and the absence of wind were associated with increased risk. The influence of these factors may be indirect, through adaptation to the conditions in which a game is played.

Dying to go on holiday.

OBJECTIVE: The Christmas period road toll is a highly publicized 'summary' of the number of road deaths that occur each year during New Zealand's summer holiday period. Our aims were to identify significant changes in the Christmas road toll during 1968-98, highlight the ability to detect changes and determine if focusing on the changes in the Christmas road toll provided a useful insight into trends in fatal crashes. METHODS: Regression modelling of the number of fatalities was used to examine trends in the Christmas road toll in New Zealand over time. A power analysis was used to investigate the ability to detect significant reductions in the Christmas road toll. RESULTS: The Christmas road toll has not decreased significantly in the past 30 years and has not improved significantly in contrast to the rest of the year. The number of deaths in any given year can be expected to vary 'naturally' between 10 and 39. The statistical power to detect a hypothetical 19% reduction in the Christmas road toll is minimal. CONCLUSIONS: Stochastic fluctuations in the Christmas road toll make it extremely difficult to identify underlying trends, even if substantial. Little insight can be gained from yearly comparisons of road tolls considered over short periods. More focus should be placed on road tolls that are calculated over longer periods, e.g. the previous six months. IMPLICATIONS: Natural fluctuations arising in small counts will make it difficult to highlight real improvements in road tolls.

Under-reporting of motor vehicle traffic crash victims in New Zealand.

Our aim was to ascertain the extent of under-reporting of seriously injured motor vehicle traffic crash victims, as recorded by police in New Zealand, and to what extent this coverage was biased by crash, injury, demographic, and geographic factors. Hospital data and police records were linked using probabilistic methods. During 1995, less than two-thirds of all hospitalised vehicle occupant traffic crash victims were recorded by the police. Reporting rates varied significantly by age, injury severity, length of stay in hospital, month of crash, number of vehicles involved, whether or not a collision occurred, and geographic region, but not by gender, ethnicity or day of the week of the crash. Those using these police files for prioritization, resource allocation and evaluation purposes need to be aware of the extent and nature of these biases contained within these databases.

Head injuries to bicyclists and the New Zealand bicycle helmet law.

The purpose of this study was to examine the effect of helmet wearing and the New Zealand helmet wearing law on serious head injury for cyclists involved in on-road motor vehicle and non-motor vehicle crashes. The study population consisted of three age groups of cyclists (primary school children (ages 5-12 years), secondary school children (ages 13-18 years), and adults (19+ years)) admitted to public hospitals between 1988 and 1996. Data were disaggregated by diagnosis and analysed using negative binomial regression models. Results indicated that there was a positive effect of helmet wearing upon head injury and this effect was relatively consistent across age groups and head injury (diagnosis) types. We conclude that the helmet law has been an effective road safety intervention that has lead to a 19% (90% CI: 14, 23%) reduction in head injury to cyclists over its first 3 years.

An evaluation of the general effect of the New Zealand graduated driver licensing system on motorcycle traffic crash hospitalisations.

In 1987, New Zealand introduced a comprehensive Graduated Driver Licensing System (GDLS) which was designed to allow new drivers to gain driving experience while being excluded from high risk situations. This study sought to evaluate the impact of the GDLS on motorcycle traffic crashes that resulted in serious injury. Injury crash data were obtained from the New Zealand Health Information Services national public hospital inpatient data files for the years 1978-1994, inclusive. Cases were disaggregated into three age groups, 15-19 years, 20-24 years, and 25 years or older, for which injury trends were obtained. In order to determine whether trends in motorcycle traffic crashes simply followed national trends in other injury events, two non-traffic comparison groups for the main target group (15-19 years) were included. Using time series analyses, the introduction of the GDLS was found to be closely followed by a significant reduction (22%) in motorcycle traffic crash hospitalizations for the 15-19 year age group. An examination of vehicle registration and driver licensure data suggests that the reduction in injury crashes may, largely, be attributable to an overall reduction in exposure to motorcycle riding.

Determining first admissions in a hospital discharge file via record linkage.

The aim of this study was to identify first admissions in a public hospital discharge file with the greatest possible accuracy. Computerised data linkage was used to link injury events. This involved the use of "internal" data linkage (unduplication) which, in data linkage terms, is equivalent to matching two identical files. Admission status indicators obtained from deterministic and probabilistic linkages were compared with those obtained from a manual review. Small absolute reductions in error were obtained using a probabilistic linkage over a deterministic linkage. However, these reflected large relative reductions in error. A validity check confirmed initial results and discounted against possible bias due to the subjective nature of the probabilistic linking procedure.

Temporal patterns of injury during a rugby season.

The aim of this study was to describe temporal patterns in the frequency, nature and circumstances of injuries occurring among a cohort of 356 rugby players during a club rugby season in New Zealand. It was found that the rate of injury in games decreased significantly over time in both males and females. The reduction in injury rate over the season was more pronounced in some grades, but no differences were found when examined by gender. playing position, age, ethnicity or by health and fitness types. Trends in injury rate were consistent over the rugby season and did not appear to be the result of a bias involving under-reporting of end-of-season injuries. The types and severity of injury remained relatively constant, but the proportion of injuries occurring in back play fell significantly over the season and injuries were more likely to occur in the trunk body region as the season progressed. This study supported the hypothesis that higher rates of injury occur at the start of the rugby season and decrease over the course of the season. This reduction is consistent over time and across player types, and is not attributable either to decreasing injury severity or to increasing player fitness.

Trends in motorcyclist and occupant fatalities and serious injuries due to traffic crashes.

AIM: To describe trends in motorcycle traffic crashes and compare these trends in other crashes and vehicle registrations. METHOD: National fatality and public hospital inpatient data were used to select cases. Relative changes in both deaths and hospitalisations, and vehicle registrations were examined in each year during the period 1980-98. RESULTS: The results show that deaths and serious injuries to motorcyclists have declined substantially over the period 1980-1995. The trend in serious injuries to motorcyclists closely followed the trend in motorcycle registrations. The association was less evident for motorcyclist fatalities and for occupants there was no clear association with trends in registrations for either outcome. CONCLUSIONS: The reduction in motorcycle injuries has contributed substantially to our improved road safety record. We need to protect these gains but in order to do this we need a clear understanding of how they were achieved. Such an understanding is currently lacking.

Changes in methods of male youth suicide: 1980-95.

AIMS: To determine if there have been changes in the methods used, particularly hangings, for male youth suicides; whether any changes were similar to those for other age groups; and to what degree any changes identified may have impacted on overall suicide rates. METHOD: All males aged fifteen to 24 years of age who died between 1980 and 1995 inclusive, and whose death was assigned one of the WHO external cause codes for "suicide and self-inflicted injury" (E950-E959), were selected from the New Zealand Health Information Services national mortality database. RESULTS: The rate for suicide by hanging was relatively low and stable in the early 1980's. By 1985 it had started to increase dramatically up until 1989, at which point it become stable again. The substantive increase in hangings was largely confined to males aged 24 years and younger. The increase in suicide by hanging cannot be attributed to substitution in methods as the rates for all other methods have also increased, albeit less dramatically. CONCLUSIONS: Much of the increase in suicide among male youths is due to an increase in hanging. The reasons for the choice of this method are unknown, and warrant study.

The work-related fatal injury study: numbers, rates and trends of work-related fatal injuries in New Zealand 1985-1994.

AIMS: To determine the number and rates of work-related fatal injuries by employment status, occupation, industry, age and gender in New Zealand 1985-1994. METHODS: Potential cases of work-related injury deaths of persons aged 15-84 years were identified from the national electronic mortality data files. Main exclusions were deaths due to suicide and deaths due to motor vehicle crashes. The circumstances of the deaths of each fatal incident meeting inclusion criteria were then reviewed directly from coronial files to determine work-relatedness. RESULTS: The rate of work-related fatal injury in New Zealand was 5.03/100000 workers per year for the study period. There was a significant decline in crude rate over the study period. However, this was in substantial part accounted for by changes in occupation and industry mix. Older workers, male workers, self-employed workers, and particular occupational groups, all had substantially elevated rates. Agricultural and helicopter pilots, forestry workers and fishery workers had the highest rates. Farmers, forestry workers, and fishery workers also had high numbers of deaths, together accounting for nearly 40% of all deaths. CONCLUSIONS: This study has demonstrated that work-related fatal injury remains a pressing problem for New Zealand. Several areas in urgent need of prevention efforts were highlighted.

A 13-year review of lisinopril ingestions in children less than 6 years of age.

BACKGROUND: Lisinopril is an angiotensin converting enzyme inhibitor used for treatment of hypertension, congestive heart failure, and acute myocardial infarction. Reports of clinical experience with pediatric ingestions are minimal. METHOD: A 13-year retrospective study of lisinopril ingestions in children reported to the California Poison Control System was analyzed and case notes were reviewed. Institutional Review Board approval was obtained and cases were blinded. Inclusion criteria were lisinopril as a single ingestant, age less than 6 years, treatment in a health care facility, case followed to a known outcome. RESULTS: Inclusion criteria were met in 296 cases. Demographics include 51% of male patients and the mean age was 1.97 years (range: 9 months-5 years). Of the 296 patients, 8 patients (2.7%) developed hypotension (ranges: 55-74 mm Hg systolic and 22-48 mm Hg diastolic). The lowest blood pressure of 55/22 mm Hg was recorded in a 22-month old male who ingested an estimated 120-mg lisinopril (13.3 mg/kg). The lowest dose of lisinopril causing hypotension was with an estimated dose of approximately 50 mg or 3.9 mg/kg in a 2-year old. Two hundred and eighty-two patients (95.3%) were treated and released from the emergency department and 14 patients (4.7%) were admitted. The dose ingested was reported in 189 cases and an exact-dose of lisinopril was reported in 61 patients (20.6%); mean amount ingested was 3.0 mg/kg, median amount ingested was 2.1 mg/kg (range: 0.1-10.9 mg/kg, N = 38); and mean total dose was 33.4 mg, median total dose was 20 mg (range: 2.5-160 mg, N = 61). None of the patients with exact-dose lisinopril ingestions developed hypotension, received intravenous fluids, or were admitted. CONCLUSION: The lowest estimated dose of lisinopril to cause hypotension was 50 mg or 3.9 mg/kg. Although continued evaluation of pediatric lisinopril ingestions is essential to determine more specific thresholds of toxicity, the lack of effect on blood pressure in children with exact-dose ingestions indicate that pediatric lisinopril ingestions (for ages > 9 months) ≤ 4 mg/kg up to 40 mg total may be safely managed at home.