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.

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.

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.

Respiratory and fecal shedding of porcine respiratory coronavirus (PRCV) in sentinel weaned pigs and sequence of the partial S-gene of the PRCV isolates.

Porcine respiratory coronavirus (PRCV), a spike (S) gene deletion mutant of Transmissible gastroenteritis virus (TGEV), causes mild or subclinical respiratory infections in pigs. The shedding of PRCV/TGEV was studied at different days post-arrival in fecal and nasal swabs from PRCV/TGEV seronegative sentinel pigs introduced into a PRCV seropositive herd with questionable TGEV serology and diarrhea. Nasal shedding of PRCV was detected in 57% and 63% of samples by nested-RT-PCR and cell culture immunofluorescence (CCIF), respectively. However fecal shedding of PRCV was detected in 37% of the samples by nested-RT-PCR and 19% by CCIF. Four respiratory and 5 fecal PRCV strains were isolated in swine testicle cells including nasal/fecal PRCV pairs (isolated at the same time) from 3 pigs. Comparison of nasal/fecal PRCV pairs from individual pigs revealed different deletions in the spike (S) gene (648 or 681 nt) in 2 pairs and a consistent change in nt 790/791 (aa T to V) for all pairs. In preliminary studies, inoculation of gnotobiotic pigs with each plaque-purified pair of the nasal and fecal PRCV isolates, revealed no clinical disease but different tropisms. The nasal isolate was shed both nasally and in feces, but the fecal isolate was shed only marginally in feces, and not nasally. Our results show that nested-RT-PCR was as sensitive as CCIF for PRCV detection in nasal swabs, but was more sensitive than CCIF for PRCV detection in fecal samples; alternatively PRCV shed in feces was more labile with loss of infectivity. The S-gene sequence differences found between the fecal and respiratory PRCV isolates may influence their tissue tropism. These new PRCV isolates should be useful to understand the molecular basis of coronavirus tropism and evolution in infected swine.

The New Zealand rugby injury and performance project. VI. A prospective cohort study of risk factors for injury in rugby union football.

OBJECTIVES: Although the nature of rugby injury has been well documented, little is known about key risk factors. A prospective cohort study was undertaken to examine the association between potential risk factors and injury risk, measured both as an injury incidence rate and as a proportion of the playing season missed. The latter measure incorporates a measure of injury severity. METHODS: A cohort of 258 male players (mean (SD) age 20.6 (3.7) years) were followed through a full competitive season. At a preseason assessment, basic characteristics, health and lifestyle patterns, playing experience, injury experience, training patterns, and anthropometric characteristics were recorded, and then a battery of fitness tests were carried out. RESULTS: A multiple regression model identified grade and previous injury experience as risk factors for in season injury, measured as an injury incidence rate. A second model identified previous injury experience, hours of strenuous physical activity a week, playing position, cigarette smoking status, body mass index, years of rugby participation, stress, aerobic and anaerobic performance, and number of push ups as risk factors for in season injury, measured as proportion of season missed. CONCLUSIONS: The findings emphasise the importance of previous injury as a predictor of injury incidence and of missing play. They also show the importance of considering both the incidence rate and severity of injury when identifying risk factors for injury in sport.

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.

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.

Impact of graduated driver licensing restrictions on crashes involving young drivers in New Zealand.

OBJECTIVE: To determine the impact on young driver crashes of the three main driving restrictions in the New Zealand graduated driver licensing (GDL) system: night-time curfew, no carrying of young passengers, and a blood alcohol limit of 30 mg/100 ml. METHOD: The database for this study was created by linking police crash reports to hospital inpatient records (1980-95). Multivariate logistic regression was used to compare car crashes involving a young driver licensed before GDL (n=2,252) with those who held a restricted graduated licence (n=980) and with those who held a full graduated licence (n=1,273), for each of the main driving restrictions. RESULTS: Compared with the pre-GDL group, the restricted licence drivers had fewer crashes at night (p=0.003), fewer involving passengers of all ages (p=0.018), and fewer where alcohol was suspected (p=0.034), but not fewer involving young casualties (p=0.980). Compared with the pre-GDL drivers, those with the full graduated licence had fewer night crashes (p=0.042) but did not differ significantly for any of the other factors examined. CONCLUSION: These results suggest that some of the GDL restrictions, especially the night-time curfew, have contributed to a reduction in serious crashes involving young drivers.

The prescribing physicians and sick scholars of Oxford: Jeremiah Webbe's apothecarial notebook, 1653-54.

The prescription book of Jeremaih Webbe, apothecary, illuminates the medical practices of a number of Oxford physicians, including those of Thomas Willis, Francis Barkesdale, and William Conyers. It provides an indication of the nature of the illness present in Oxford, especially among the students of the University, in the years 1653 and 1654.

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.

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.

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.

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.

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.

Achieving compliance with pool fencing legislation in New Zealand: a survey of regulatory authorities.

OBJECTIVES: To identify the status of compliance and enforcement of New Zealand's Fencing of Swimming Pools Act (FOSP Act), 10 years after its introduction, and to identify methods for improving both compliance with the act and the process of enforcement. METHODS: A postal questionnaire was sent to all 74 authorities in New Zealand in which they were asked questions about their enforcement of the FOSP Act. Semistructured telephone interviews were conducted with 12 authorities to supplement the data obtained in the postal survey. RESULTS: Based on responses to the survey, it was estimated that there are over 59,000 domestic swimming pools in New Zealand, giving rates of 46 pools/1000 dwellings and 16 pools/1000 persons. The authorities reported that 44% of pools complied with the act, and a further 4% had been granted exemptions. Nineteen per cent of pools were reported to not comply with the act, and the compliance status of a further 33% was not known, or not stated by the authority. Only 9% of authorities had procedures for locating and inspecting pools, while 28% had a programme of reinspection to ensure that pools continued to comply. Pool owner resistance was considered to be the main difficulty with enforcing the act, and nearly half of the authorities believed publicity or education was needed to overcome these barriers. Fifty two per cent of authorities had publicized the act during the 12 months preceding the survey. CONCLUSIONS: Due to ambiguities within the legislation, and differing levels of commitment by authorities to locate pools and monitor compliance, compliance with the FOSP Act is not consistent nationally. If the act were less ambiguous, there would be greater consistency and more enforcement.

The New Zealand Rugby Injury and Performance Project: V. Epidemiology of a season of rugby injury.

OBJECTIVE: To describe the incidence, nature, and circumstances of injury experienced by a cohort of rugby union players during a full competitive club season. METHODS: A prospective cohort study followed up 356 male and female rugby players throughout the 1993 competitive club season. Players were interviewed by telephone each week to obtain information on the amount of rugby played and the injury experienced. RESULTS: Detailed information was collected for 4403 player-games and 8653 player-practices. A total of 671 injury events were reported, of which 569 were rugby related. The injury rate for games was higher than that for practices (rate ratio 8.3). At 10.9 injuries per 100 player-games, males had a higher rate of injury than females at 6.1 injuries per 100 player-games (p<0.001). Injury rates varied by position, with male locks (13.0 injuries per 100 player-games) and female inside backs (12.3 injuries per 100 player-games) having the highest rate in their respective sexes. The lower limb was the body region most often injured in games (42.5%) and practices (58.4%). Sprains/strains were the most common type of injury in games (46.7%) and practices (76.1%). In games the tackle was the phase of play in which the most injuries occurred (40%), followed by rucks (17%) and mauls (12%). Thirteen per cent of game injury events were the result of foul play. CONCLUSIONS: Rugby injury was common among the study subjects and varied according to grade and gender. Identifying the causes of injuries in the tackle, lower limb injuries, and dealing with the issue of foul play are priority areas for the prevention of rugby injury.