High dietary intake of whole milk and full-fat dairy products does not exert hypotensive effects in adults with elevated blood pressure.

Regular consumption of low- and nonfat dairy products reduces blood pressure (BP) in adults with elevated BP. Currently, it is unknown if conventional full-fat dairy products exert similar hypotensive effects. We hypothesized that adding full-fat dairy products to the normal routine diet would reduce seated office and ambulatory BP (primary outcome) in adults with elevated BP when compared with a no dairy control. Using a randomized controlled crossover design, 60 adults with elevated systolic BP (systolic/diastolic BP: 120-159/<99 mm Hg) participated in a 4-week high-dairy (4 servings a day of full-fat dairy products + regular diet) and a 4-week no-dairy condition (plant-based food items + regular diet) separated by a 2-week washout period. Data were analyzed based on time, condition, and sex. Seated office systolic BP did not change significantly in either condition. There were no changes in systolic BP in male or female participants across either dietary period. Ambulatory (24-hour) systolic BP did not change significantly in the high-dairy (133 ±â€¯2 vs 131 ±â€¯1 mm Hg) or no-dairy conditions (132 ±â€¯2 vs 131 ±â€¯1 mm Hg). No significant changes were observed for diastolic BP or pulse pressure during condition for office or ambulatory measures. The solitary addition of full-fat dairy products to the normal routine diet does not exert hypotensive effects in adults with elevated BP when compared to the no-dairy control.

Estimating sample size in the presence of competing risks - Cause-specific hazard or cumulative incidence approach?

In designing randomised clinical trials involving competing risks endpoints, it is important to consider competing events to ensure appropriate determination of sample size. We conduct a simulation study to compare sample sizes obtained from the cause-specific hazard and cumulative incidence (CMI) approaches, by first assuming exponential event times. As the proportional subdistribution hazard assumption does not hold for the CMI exponential (CMIExponential) model, we further investigate the impact of violation of such an assumption by comparing the results obtained from the CMI exponential model with those of a CMI model assuming a Gompertz distribution (CMIGompertz) where the proportional assumption is tenable. The simulation suggests that the CMIExponential approach requires a considerably larger sample size when treatment reduces the hazards of both the main event, A, and the competing risk, B. When treatment has a beneficial effect on A but no effect on B, the sample sizes required by both methods are largely similar, especially for large reduction in the main risk. If treatment has a protective effect on A but adversely affects B, then the sample size required by CMIExponential is notably smaller than cause-specific hazard for small to moderate reduction in the main risk. Further, a smaller sample size is required for CMIGompertz as compared with CMIExponential. The choice between a cause-specific hazard or CMI model in competing risks outcomes has implications on the study design. This should be made on the basis of the clinical question of interest and the validity of the associated model assumption.

Effects of non-fat dairy products added to the routine diet on vascular function: a randomized controlled crossover trial.

BACKGROUND AND AIMS: High consumption of low- and non-fat dairy products is associated with reduced risk of high blood pressure (BP) and central arterial stiffness. However, interventional studies to determine if the addition of non-fat dairy products to the diet is capable of reducing central BP and improving vascular function are lacking. The aim of this study was to determine if the solitary addition of non-fat dairy products to the normal routine diet would reduce central BP and improve vascular function in middle-aged and older adults with elevated BP. METHODS AND RESULTS: Using a randomized, crossover intervention study design, forty-nine adults (44% men, 53 ± 2 years, 170 ± 2 cm, 88 ± 3 kg; mean ± SEM) with elevated BP (134 ± 1/81 ± 1 mm Hg) underwent a High Dairy condition (+4 servings/day of conventional non-fat dairy products) and No Dairy condition (+4 servings/day fruit products) in which all dairy products were removed. Both dietary conditions lasted 4 weeks with a 2-week washout before crossing over into the alternate condition. The High Dairy condition produced reductions in central systolic BP (-3 ± 1 mm Hg) and carotid-femoral pulse wave velocity (-0.5 ± 0.1 m/sec), with a concomitant increase in brachial flow-mediated dilation (+1.1 ± 0.4%) and cardiovagal baroreflex sensitivity (+5 ± 1 ms/mm Hg) (P < 0.05 for all vs. baseline). In the No Dairy condition, brachial flow-mediated dilation was reduced (-1.0 ± 0.1%, P < 0.05 vs. baseline). CONCLUSIONS: The solitary manipulation of conventional dairy products in the normal routine diet modulates levels of central BP and vascular function in middle-aged and older adults with elevated BP. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01577030.

Risk factors for local recurrence in Wilms tumour and the potential influence of biopsy - the United Kingdom experience.

RATIONALE: The UKW3 trial compared biopsy/pre-operative chemotherapy versus immediate nephrectomy and afforded the opportunity to examine the influence of percutaneous retroperitoneal biopsy and other factors on local and distant relapse of Wilms tumour (WT). METHODS: Patients with unilateral WT (stages I-IV) excluding metachronous relapse or early progressive disease were eligible. Metastatic and 'inoperable' tumours were biopsied electively. 'Local' was defined as relapse within the abdomen, except for liver metastases considered as 'distant' relapse, together with other haematogenous routes. Uni- and multivariable analyses estimated the risk factors for relapse. RESULTS: Overall, 285/635 (44.9%) patients had a biopsy. With a median follow-up of 10.1 years, 35 (5.5%) patients experienced a 'local', 15 a combined (2.4%) and 60 (9.4%) a 'distant' relapse. On univariate analysis, biopsy, anaplasia and tumour size were associated with an increased risk of local relapse. On multivariable analysis, anaplasia and tumour size remained significant for local relapse whereas the elevated risk of biopsy (hazards ratio (HR) = 1.80: 95% confidence interval (CI) 0.97-3.32, p = 0.060) was marginal. Age, anaplasia, tumour size, lymph nodes metastases and stage, but not biopsy, were individually associated with increased risk of distant relapse but only age and anaplasia remained significant following multivariable analysis. CONCLUSIONS: The UKW3 trial provides some reassurance that biopsy should not automatically lead to 'upstaging' of WT. Further assessment of this controversial area is required. Comparison of local relapse rates in a multinational trial in which the United Kingdom (UK) continued the practice of routinely biopsying all patients in contrast to the standard European approach will afford this opportunity and is planned.

The role of post-operative radiographs in predicting risk of flexor pollicis longus tendon rupture after volar plate fixation of distal radius fractures - a case control study.

BACKGROUND AND AIM: Volar plating of distal radius fractures is one of the common procedures performed in trauma surgery. Flexor pollicis longus (FPL) rupture has been described as complication following volar plating of distal radius fractures. The aim of our study was to investigate the possible relation between parameters measured on post-operative radiographs and the occurrence of FPL ruptures. MATERIALS AND METHODS: This was a case control study. The post-operative radiographs of 11 FPL rupture, and 22 non-FPL rupture patients were reviewed with respect to fracture reduction and plate position and the various parameters were calculated by five independent people. Logistic regression was used to examine the importance of the variables. RESULTS: We identified two significant factors to predict FPL rupture after volar plating of distal radial fractures. These were radial tilt and plate distance from the joint line. The odds ratio of ruptures was 0.74 (95% CI 0.57-0.95) for every degree of radial tilt <25° and 0.50 (95% CI 0.28-0.88) for every millimetre that the distal end of the plate was away from the volar lip of the distal radius at the wrist joint. CONCLUSION: Post-operative radiographs could help us predict FPL rupture after distal radius volar plating. The findings also highlight the need for good fracture reduction and thoughtful placement of the volar plate intraoperatively to minimise the risk of FPL tendon rupture.

Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial.

BACKGROUND: The purpose of the present study was to determine whether intrahepatic injection of (131)I-lipiodol (Lipiodol) is effective against recurrence of surgically resected hepatocellular carcinoma (HCC). METHODS: From June 2001 through March 2007, this nationwide multi-center prospective randomized controlled trial enrolled 103 patients 4-6 weeks after curative resection of HCC with complete recovery (52: Lipiodol, 51: Control). Follow-up was every 3 months for 1 year, then every 6 months. Primary and secondary endpoints were recurrence-free survival (RFS) and overall survival (OS), respectively, both of which were evaluated by the Kaplan-Meier technique and summarized by the hazard ratio (HR). The design was based on information obtained from a similar trial that had been conducted in Hong Kong. RESULTS: The Lipiodol group showed a small, and nonsignificant, improvement over control in RFS (HR = 0.75; 95 % confidence interval [95 % CI] 0.46-1.23; p = 0.25) and OS (HR = 0.88; 95 % CI 0.51-1.51; p = 0.64). Only two serious adverse events were reported, both with hypothyroidism caused by (131)I-lipiodol and hepatic artery dissection during angiography. CONCLUSIONS: The randomized trial provides insufficient evidence to recommend the routine use of (131)I-lipiodol in these patients.

Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. We tested megestrol acetate (MA) against placebo in the treatment of advanced HCC. METHODS: From 2002 through 2007, this randomised double-blind trial enrolled 204 patients with treatment-naive advanced HCC (Eastern Cooperative Oncology Group (ECOG) performance rating of 0-3) from specialist care centres in six Asia-Pacific nations. Patients received placebo or MA (320 mg day(-1)). End points were overall survival (OS) and quality of life. RESULTS: An adverse but not statistically significant difference in OS was found for MA vs placebo: median values 1.88 and 2.14 months, respectively (hazard ratio (HR)=1.25, 95% CI=0.92-1.71, P=0.16). However, OS was similar among patients of good functional status (Child-Pugh A and ECOG 0, 1 or 2) (44.3%) in both treatment groups, with the adverse effect of MA confined to those of poor status. Megestrol acetate patients had a worse global health status (not statistically significant) but reduced levels of appetite loss and nausea/vomiting. CONCLUSION: Megestrol acetate has no role in prolonging OS in advanced treatment-naive HCC. Overall survival with placebo differed markedly from that in similar trials conducted elsewhere, suggesting therapeutic outcomes may be strongly dependent on ECOG status and Child-Pugh score.

Minimising the risk of extensor pollicis longus rupture following volar plate fixation of distal radius fractures: a cadaveric study.

INTRODUCTION: Rupture of extensor pollicis longus (EPL) tendon is a recognised complication following volar plate fixation of distal radius fractures, usually from attrition caused by prominent screws. We sought to identify the screw holes in some of the most commonly used plates which may precipitate tendon injury. SUBJECTS AND METHODS: Three fixed-angle volar locking plates were sequentially positioned into 18 cadaveric arms. A wire was passed through each of the holes in the plates using a locking guide and the dorsal relationships noted. RESULTS: Each plate had specific 'high-risk' holes which directed the wire towards the EPL groove. The central screw holes appeared mostly implicated in EPL injury. CONCLUSIONS: Awareness of 'high-risk' holes and appropriate minor alterations in surgical technique may consequently decrease the incidence of EPL irritation and rupture.

Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial.

BACKGROUND: Radiotherapy is an effective adjuvant treatment for brain tumours arising in very young children, but it has the potential to damage the child's developing nervous system at a crucial time - with a resultant reduction in IQ leading to cognitive impairment, associated endocrinopathy and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with malignant brain tumours other than ependymoma, the results of which have already been published. METHODS: Ninety-seven children were enrolled between March 1993 and July 2003 and, following diagnostic review, comprised: medulloblastoma (n=31), astrocytoma (26), choroid plexus carcinoma [CPC] (15), CNS PNET (11), atypical teratoid/rhabdoid tumours [AT/RT] (6) and ineligible (6). Following maximal surgical resection, chemotherapy was delivered every 14 d for 1 year or until disease progression. Radiotherapy was withheld in the absence of progression. FINDINGS: Over all diagnostic groups the cumulative progression rate was 80.9% at 5 years while the corresponding need-for-radiotherapy rate for progression was 54.6%, but both rates varied by tumour type. There was no clear relationship between chemotherapy dose intensity and outcome. Patients with medulloblastoma presented as a high-risk group, 83.9% having residual disease and/or metastases at diagnosis. For these patients, outcome was related to histology. The 5-year OS for desmoplastic/nodular medulloblastoma was 52.9% (95% confidence interval (CI): 27.6-73.0) and for classic medulloblastoma 33.3% (CI: 4.6-67.6); the 5-year EFS were 35.3% (CI: 14.5-57.0) and 33.3% (CI: 4.6-67.6), respectively. All children with large cell or anaplastic variants of medulloblastoma died within 2 years of diagnosis. The 5-year EFS for non-brainstem high-grade gliomas [HGGs] was 13.0% (CI: 2.2-33.4) and the OS was 30.9% (CI: 11.5-52.8). For CPC the 5-year OS was 26.67% (CI: 8.3-49.6) without RT. This treatment strategy was less effective for AT/RT with 3-year OS of 16.7% (CI: 0.8-51.7) and CNS PNET with 1-year OS of 9.1% (CI: 0.5-33.3). INTERPRETATION: The outcome for very young children with brain tumours is dictated by degree of surgical resection and histological tumour type and underlying biology as an indicator of treatment sensitivity. Overall, the median age at radiotherapy was 3 years and radiotherapy was avoided in 45% of patients. Desmoplastic/nodular sub-type of medulloblastoma has a better prognosis than classic histology, despite traditional adverse clinical features of metastatic disease and incomplete surgical resection. A subgroup with HGG and CPC are long-term survivors without RT. This study highlights the differing therapeutic challenges presented by the malignant brain tumours of early childhood, the importance of surgical approaches and the need to explore individualised brain sparing approaches to the range of malignant brain tumours that present in early childhood.

Flexor pollicis longus tendon ruptures after palmar plate fixation of fractures of the distal radius.

Palmar plate fixation of distal radial fractures is becoming a standard treatment for this common injury. Ruptures of the extensor pollicis longus tendon have been reported in 8.6% of cases after this procedure. Although palmar plate fixation has also been associated with flexor pollicis longus (FPL) tendon problems, the majority of reported cases pre-date the use of newer anatomically precontoured locking plates. In this paper seven cases of FPL rupture are presented. This complication does not appear to be unique to one type of implant. The possible aetiologies for FPL ruptures are discussed and ways to reduce the incidence of this complication are suggested.

Concomitant (without adjuvant) temozolomide and radiation to treat glioblastoma: a retrospective study.

Between November 2004 and August 2006 we treated 35 patients with concomitant temozolomide (TMZ) and radiotherapy. Twelve patients had very large or multicentric glioblastoma multiforme with a poor performance status and received TMZ plus radiation doses of 45-50.4 Gy. The median survival of these patients was only 3.8 months. Twenty-three patients would have been eligible for randomisation in the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) trial comparing combined and adjuvant TMZ plus radiation against radiotherapy alone. This group of patients received 60 Gy in 30 fractions plus concomitant TMZ (75 mg/m(2)) but no adjuvant chemotherapy. At a median follow-up of 26 months, five of 23 patients are alive. The median survival time was 17 months (1.43 years; 95% confidence interval 0.96-1.55). Eighteen per cent were alive at 2 years. Toxicity from TMZ was infrequent. This series adds to indirect evidence that the concomitant rather than the adjuvant is the more efficacious part of the EORTC/NCIC schedule for this type of patient. Further trials should include a concomitant chemoradiotherapy regimen as well as concomitant plus adjuvant chemotherapy.

The impact of the International Atomic Energy Agency (IAEA) program on radiation and tissue banking in Uruguay: development of tissues quality control and quality management system in the National Multi-Tissue Bank of Uruguay.

BNOT was created and regulated in 1977 and started its operation in 1978 according to the Decree No. 86/1977. By the Decree 248/005 is transformed in the National Institute of Donation and Transplantation of Cells, Tissues and Organs (Instituto Nacional de Donación y Trasplante de Células, Tejidos y Organos--INDT). The organisation has been operating within the State University Medical School and the Public Health Secretary and it is the governmental organisation responsible for the regulation, policy and management of donation and transplantation in Uruguay. By the Decree 160/2006 is responsible for human cells and tissues regulation too. The participation of the INDT in the IAEA program facilitated the introduction of the radiation sterilisation technique for the first time in the country. The radiation sterilisation of tissues processed by INDT (ex BNOT), was initially carried out in the 60 Cobalt Industrial Plant in the National Atomic Energy Commission of Argentina and now is carried out in INDT, using a Gamma Cell 220 Excel, which was provided by the IAEA through the national project URU/7/005. The results of the implementation of tissues, quality control and quality management system, are showed.

Control of cryopreservation procedures on blood vessels using fiber x-ray diffraction.

AIM: We sought to determine variations in fiber organization at the molecular level using x-ray diffraction analyses on human blood vessel specimens after cryopreservation processes. MATERIALS AND METHODS: Diffractometric profiles were performed on aortic and carotid cryopreserved-thawed vessel samples (CVS) versus the same fresh vessel samples (FVS). X-ray diffraction was performed on vascular tissues from 17 cadaveric donors after informed consent. Measurements utilized a Seifert Scintag PAD-II powder diffractometer with CuK(a) radiation; lambda = 1.5418 A. Scans were evaluated in the 5 degrees to 60 degrees range in theta -2theta mode, in the 5 degrees to 60 degrees range in 2-theta, with steps 0.1 degrees and 10 seconds per step. Ten aortic and 8 carotid diffractometric profiles were analyzed, using differential planimetric surfaces measured under x-ray diffraction curve. Diffractographic profiles were analyzed according to intervals based upon the ages of the donors. An ordering profile coefficient (OPC) was obtained as the quotient between the differential planimetric surface (DPS) of FVS versus CVS vessel ordering diffraction. RESULTS: There was a decreased ordering profile according to age: older donors showed less ordering than younger ones. Clear peaks at d-spacing of 2.86 A and 2.15 A (2-theta = 31.3 degrees and 42.0 degrees , respectively) were always confirmed despite the different profiles of samples. OPC showed a higher ordering profile among the CVS than FVS: 70% aortas and 62.5% carotids. CONCLUSION: The cryopreserved-thawed procedure does not damage the fibrillar organization of vessels.

Preliminary images from an adaptive imaging system.

I-ImaS (Intelligent Imaging Sensors) is a European project aiming to produce real-time adaptive X-ray imaging systems using Monolithic Active Pixel Sensors (MAPS) to create images with maximum diagnostic information within given dose constraints. Initial systems concentrate on mammography and cephalography. In our system, the exposure in each image region is optimised and the beam intensity is a function of tissue thickness and attenuation, and also of local physical and statistical parameters in the image. Using a linear array of detectors, the system will perform on-line analysis of the image during the scan, followed by optimisation of the X-ray intensity to obtain the maximum diagnostic information from the region of interest while minimising exposure of diagnostically less important regions. This paper presents preliminary images obtained with a small area CMOS detector developed for this application. Wedge systems were used to modulate the beam intensity during breast and dental imaging using suitable X-ray spectra. The sensitive imaging area of the sensor is 512 x 32 pixels 32 x 32 microm(2) in size. The sensors' X-ray sensitivity was increased by coupling to a structured CsI(Tl) scintillator. In order to develop the I-ImaS prototype, the on-line data analysis and data acquisition control are based on custom-developed electronics using multiple FPGAs. Images of both breast tissues and jaw samples were acquired and different exposure optimisation algorithms applied. Results are very promising since the average dose has been reduced to around 60% of the dose delivered by conventional imaging systems without decrease in the visibility of details.

Efficacy of carboplatin given in a phase II window study to children and adolescents with newly diagnosed metastatic soft tissue sarcoma.

AIM: The activity of carboplatin was evaluated in a phase II window study in previously untreated children with metastatic soft tissue sarcoma. METHODS: Children with poor-risk metastatic disease (over 10 years and/or with bone/bone marrow involvement) treated in the SIOP MMT 98 study were scheduled to receive two courses of intravenous carboplatin (area under curve [AUC] of 10), 21 days apart. RESULTS: Sixteen eligible patients were entered into the rhabdomyosarcoma (RMS) group. Response (complete remission or partial remission) was seen in five children (31%, 95% confidence interval (CI) 14-56%). Ten eligible patients with other soft tissue sarcomas were recruited into the non-RMS group. Two responses (20%, 95% CI 6-51%) were seen. Toxicity in both groups was predictable nausea, vomiting and marrow suppression and there were no toxic deaths. CONCLUSION: Single-agent carboplatin at AUC of 10 has an acceptable toxicity profile but only moderate efficacy in poor-risk metastatic soft tissue sarcoma.

Computerized administration of health-related quality of life instruments compared to interviewer administration may reduce sample size requirements in clinical research: a pilot randomized controlled trial among rheumatology patients.

OBJECTIVES: Computerized health-related quality of life (HRQoL) administration may facilitate clinical trials incorporating HRQoL assessment in rheumatology patients by reducing sample size requirements. We tested this hypothesis in a pilot randomized controlled trial. METHODS: Chinese-speaking adult rheumatology outpatients were randomized to computerized (PC) or interviewer (IA) administration of the EQ-5D (utility & VAS), Health Utilities Index (HUI2 & HUI3) and Family Functioning Measure (FFM). We compared measurement variability (i.e., variance) between PC and IA for each instrument before (Levene's test) and after adjusting for the effects of age, gender and education (multivariable modeling) and computed the variance ratio (VR) for PC over IA. RESULTS: In 138 patients (mean age: 48), the mean (SD) time for administration was similar for PC (n = 67) and IA (n = 71) at 17.7 (7.94) versus 17.3 minutes (7.49), respectively. More subjects expressed a preference for PC (n = 21) over IA (n = 13). Mean HRQoL scores were not significantly different for PC versus IA except for higher VAS scores with IA (difference -7.7, 95% CI -14.0 to 1.3, p = 0.018). Variances and adjusted VR were smaller with PC for the EQ-5D (adjusted VR 0.34, 95% CI 0.18 to 0.65), HUI3 (0.49, 0.27 to 0.89) and FFM (0.95, 0.61 to 1.46), but larger for the HUI2 (1.30, 0.67 to 2.55) and VAS (1.05, 0.55 to 2.00). CONCLUSION: The reduced variability in 3 of 5 instruments and good acceptance of computerized HRQoL assessment, if confirmed in larger studies, may lead to smaller sample size requirements, with potential reductions in cost and recruitment time for clinical trials and cohort studies.

Response to N7 induction chemotherapy in children more than one year of age diagnosed with metastatic neuroblastoma treated in UKCCSG centers.

BACKGROUND: The highest reported metastatic response rate to induction chemotherapy in patients with neuroblastoma has been achieved by Kushner et al. [Kushner et al.: J Clin Oncol 12:2607-2613,1994; Cheung et al.: Med Pediatr Oncol 36: 227-230, 2001; Kushner et al.: J Clin Oncol 22:4888-4892, 2004] using their N6 and subsequently N7 protocols. This N7 induction was adopted by UKCCSG for new patients in 1999. METHODS: Forty-seven children with metastatic neuroblastoma were recruited between 1999 and 2002. They received the N7 intensive chemotherapy protocol, after full staging including evaluation by I123mIBG imaging where possible. RESULTS: Thirty patients with positive mIBG scans were evaluable for response, and complete resolution of metastatic disease was obtained in 16 (53.3%). Fourteen patients without positive mIBG scans were evaluated for response according to bone marrow and bone scan data and 11 (78.6%) cleared metastatic disease. The toxicity of this induction therapy was similar to that seen in previous UK protocols, although 14 patients had Brock grade 3 or 4 ototoxicity. Thirty-three patients proceeded to high-dose therapy with no unanticipated toxicities. For the whole group of 44 evaluable patients, the 3-year event-free survival (EFS) and overall survival (OS) were 38.3 and 46.7%, respectively. CONCLUSIONS: Although feasible in terms of delivery, when used in the UKCCSG centers, this protocol achieved a much lower response rate than in the previously published series in the US [Kushner et al.: J Clin Oncol 12:2607-2613,1994; Cheung et al.: Med Pediatr Oncol 36: 227-230, 2001; Kushner et al.: J Clin Oncol 22:4888-4892, 2004].

Socioeconomic status, systolic blood pressure and intraocular pressure: the Tanjong Pagar Study.

BACKGROUND: Lower socioeconomic status (SES) is associated with higher morbidity and mortality in many countries. Present evidence suggests that glaucoma has similar risk factors to major chronic diseases such as cardiovascular disease. This study investigates the association between SES and intraocular pressure (IOP), an important risk factor for glaucoma. METHODS: The Tanjong Pagar Study was a population-based cross-sectional survey of Chinese people aged 40-79 years, who were randomly selected from the Singapore electoral register. Of the 2000 people selected, 1717 were considered eligible and 1090 were examined in clinic and included in the present study. IOP was measured using applanation tonometry. SES was assessed using a standardised questionnaire; education and income were used as the main explanatory variables. The effect of systolic blood pressure (SBP) was also examined. RESULTS: Participants with lower levels of education and income had higher mean IOP (both p<0.01). These associations remained after adjusting for age and central corneal thickness, a strong independent predictor. SBP was strongly associated with both SES and IOP (both p<0.01). Adjusting for SBP attenuated the association between SES and IOP. CONCLUSION: Participants with lower education and income have a higher mean IOP. This effect may be mediated, in part, by an association of education and income with SBP. This is the first study to suggest that there is a social gradient in the distribution of the only major modifiable risk factor for glaucoma. Increasing similarities exist between the causation models of chronic diseases and that of glaucoma.

Biometrical aspects of drug development.

Once the activity of a compound has been established in the laboratory (usually by use of experimental animals) the next stage of development is to bring this forward to humans in early-phase clinical trials. A pharmacokinetic study aims to establish an effective dosing regimen for the compound in order to reach concentrations within the therapeutic window as quickly as possible. The aim of the phase I trials is typically to determine a maximal safe dose with which more rigorous investigation of activity in a phase II trial can be conducted. This chapter deals with statistical issues related to the design of phase I studies.