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Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score. © 2014 American Medical Association. All rights reserved.

We have characterized and compared a series of naturally occurring chromosomal truncations involving the terminal region of the short arm of human chromosome 16 (16p13.3). All six broken chromosomes appear to have been stabilized by the direct addition of telomeric repeats (TTAGGG)n to nontelomeric DNA. In five of the six chromosomes, sequence analysis shows that the three of four nucleotides preceding the point of telomere addition are complementary to and in phase with the putative RNA template of human telomerase. Otherwise we have found no common structural features around the breakpoint regions. These findings, together with previously reported in vitro data, suggest that chromosome-healing events in man can be mediated by telomerase and that a small region of complementarity to the RNA template of telomerase at the end of a broken chromosome may be sufficient to prime healing in vivo.

Using frequency-chirped radiation pressure slowing, we precisely control the velocity of a pulsed CaF molecular beam down to a few m/s, compressing its velocity spread by a factor of 10 while retaining high intensity: at a velocity of 15~m/s the flux, measured 1.3~m from the source, is 7$\times$10$^{5}$ molecules per cm$^{2}$ per shot in a single rovibrational state. The beam is suitable for loading a magneto-optical trap or, when combined with transverse laser cooling, improving the precision of spectroscopic measurements that test fundamental physics. We compare the frequency-chirped slowing method with the more commonly used frequency-broadened slowing method., 19 pages, 8 figures. Extension of earlier version to include detailed comparison of slowing methods

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants., Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often the initial treatment for rheumatoid arthritis. NSAID-induced inhibition of cyclooxygenase-2 (COX2) and cyclooxygenase-1 appears to correlate with clinical efficacy and toxicity, respectively. Newer NSAIDs with greater COX2 selectivity offer the promise of less toxic therapy.

Rheumatoid arthritis is a disease of unknown aetiology characterised by persistent joint swelling, functional disability and increased mortality. No curative therapy exists at present but some therapeutic agents, commonly referred to as disease-modifying drugs, offer the potential for suppression of the inflammatory activity and attenuation of the disease process. Since the precise mechanism of action of most disease modifying drugs is uncertain, the selection of a particular therapy must at present be based on the pharmacologic properties of each available agent, appropriately individualised for each clinical setting. The toxicity of disease-modifying agents often limits the dose and/or duration of therapy and makes careful monitoring mandatory. No consensus exists as to the order in which disease-modifying agents should be employed. Less toxic disease-modifying drugs such as auranofin, hydroxychloroquine, minocycline, and sulfasalazine are usually used in early and mild disease. Azathioprine, penicillamine (D-penicillamine), methotrexate and parenteral gold are usually considered to be more toxic and are most often used in the setting of progressive disease while the most toxic agents, such as chlorambucil and cyclophosphamide, are reserved for life-threatening manifestations such as vasculitis. Newer therapeutic approaches presently under study include the use of existing drugs in combination and novel biologic agents which selectively inhibit lymphocyte and cytokine activity. These strategies offer the hope of more efficacious and less toxic therapy in the future.

A 26-year-old man presented with symptoms suggesting idiopathic orbital inflammatory disease. After a poor initial response to oral steroids, an orbital biopsy confirmed the diagnosis. A paucicellular lymphocytic infiltrate with areas of fibrosis was seen to replace normal tissue. With the development of exposure keratopathy and diplopia associated with eyelid retraction, lagophthalmos, and decreased motility, increasing doses of steroids and intralesional steroid injections were instituted without effect. On the basis of successful treatment of malignant lymphocytic lesions, he was treated with CyberKnife radiosurgery and rituximab. This resulted in symptom resolution with improved eyelid closure and motility. Eighteen months after treatment, he is essentially symptom-free, with almost complete radiographic regression of his disease process.

BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. METHODS: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. RESULTS: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2 = .048, p = 1.6 × 10(-4)) and white matter volume (R2 = .051, p = 8.6 × 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. CONCLUSIONS: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.

Objective. To demonstrate the reliability and validity characteristics of a fast, intensively focused functional assessment questionnaire that has been used in rheumatoid arthritis clinical trials by the Cooperative Systematic Studies of Rheumatic Diseases group (CSSRD). Methods. Data from three double-blind, controlled clinical trials by CSSRD were used to examine the properties of the Functional Assessment Survey as a measure of physiologic function. Results. The Functional Assessment Survey has reasonable test-retest reliability and convergent validity with the Steinbrocker et al. functional class. It demonstrated appropriate divergent validity with other clinical measures of response, as well as discriminant validity. Conclusions. The CSSRD Functional Assessment Survey is brief, intensive, and focused. Reliability and validity characteristics have been documented.

This article discusses the use of combinations of disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Patients with RA have a disease that can be disabling and life threatening and current therapies do not prevent these complications. The need for more aggressive therapy is apparent. The rationale for combinations of DMARDs is explored and the efficacy and safety of reported combinations is summarized. The variables to be reviewed in selecting a combination of DMARDs are examined. Newer approaches employing multiple DMARDs will be considered.

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4-8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number or patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.

We have examined the demographic, clinical, and laboratory predictors of the concomitant or subsequent occurrence of lupus nephritis among a cohort of patients with disease manifestations < 1 year diagnosed as systemic lupus erythematosus (SLE) either at entry (baseline) into the cohort or during the subsequent 5 years. Patients studied were from a larger cohort with either early defined or undifferentiated connective tissue diseases; of the possible 74 patients, data were adequate in 58, 44 with SLE at entry and 14 at followup. Demographic, clinical, and laboratory data were examined first by univariate and then by multivariate analyses for their ability to predict lupus nephritis.Thirty of the 54 patients developed lupus nephritis with proteinuria as its most common manifestation. In 25 of the 30, nephritis occurred within the first 2 years of disease. Among those with a renal biopsy, the most common finding was World Health Organization class IV. By univariate analysis, the following variables were found more frequently among those patients who developed lupus nephritis versus those who did not: younger age, hypertension, anti-double-stranded deoxyribonucleic acid and baseline diagnosis of SLE. In the multivariate analysis, only SLE at baseline and hypertension were identified as predictors of nephritis, whereas the presence of nonvasculitic skin rashes were negatively associated.Lupus nephritis is an early event in the course of SLE. Antinuclear antibody negative patients and those with incomplete SLE are less likely to develop lupus nephritis. Concomitant hypertension is associated with an increased risk of nephritis.

The search for better treatments for malignancies has been enhanced by use of a relatively inexpensive clinical protocol that encourages the preliminary screening of a large number of potential anticancer drugs with early elimination of those that are clearly ineffective, preserving resources for more intensive evaluation of those that show some evidence of benefit. We adapted this method to determine whether the herbal medicine TJ-114 was worthy of further study for the treatment of rheumatoid arthritis (RA) patients. TJ-114 is a traditional herbal medicine that has been used extensively in Japan for the treatment of RA, Reports suggest that it may be a useful second-line agent, well-tolerated and safe. For these reasons, a 6-month, open prospective pilot study to evaluate the efficacy, safety and tolerability of TJ-114 in United States RA patients was undertaken. Thirty patients were enrolled; 18 completed the study. There were five responders by predefined composite criteria. Twelve patients withdrew from the trial, six for lack of efficacy, four for non-compliance, one for diarrhea and one for constipation and abdominal pain. The anti-cancer drug screening protocol stipulates that the drug be discarded if there are no responders among the first 14 patients and only 1 or 2 among the first 30 patients. Using this approach, the response rate found in this study justifies placebo-controlled, double-blind studies to determine the relative efficacy and toxicity of TJ-114 in a more definitive manner.

Serum IgG antibody levels to native and denatured bovine type II collagen were elevated in 31.5 and 21.5% sera respectively from 200 American patients with RA. The prevalence of serum antibodies to native type II collagen is significantly higher than previously found in large studies of the prevalence of this autoantibody in Britain and Japan when using the same methodology.

Radiography of the artificial urinary sphincter is done for the postoperative evaluation of recurrent incontinence. We investigated the ability of urologists and radiologists to detect changes in the radiographic appearance of the pressure regulating balloon at various volumes of contrast solution.We obtained 20 sequential radiographs of a pressure regulating balloon lying atop the pelvic region of a body phantom. The volume of contrast solution within the balloon was decreased by 1 cc in each radiograph from 20 to 1 cc. Urologists and radiologists examined the radiographs for changes in balloon size, density and circularity. Radiographs were reviewed in side-by-side comparison with a baseline radiograph and also independently without reference to baseline study.On side-by-side comparison changes in balloon size, density and circularity were first seen at 17, 13 and 8 cc of contrast solution, respectively. On independent review changes in size, density and circularity were first seen at 10, 8 and 6 cc, respectively.If there are no contraindications, contrast solution should be used to fill the balloon component of the artificial urinary sphincter system. Immediately after implantation a baseline radiograph should be obtained. Without a baseline film for comparison radiographic imaging of the balloon does not detect changes until at least 50% of its volume has been lost. Because comparison imaging is invaluable for detecting volume loss, a radiograph should be obtained immediately after initial placement of the artificial urinary sphincter.

Objective. To assess the frequency of breast implantation and the relationship of the implants to the onset of symptoms in patients with differentiated and undifferentiated connective tissue disease (CTD). Methods. We evaluated an inception cohort of patients with differentiated and undifferentiated CTD and symptoms of < 12 months duration when enrolled in 1983–1987. The risk of having breast implants in those patients with early symptoms of CTD was determined in comparison with that in a non-concurrent control group. Results. Only 3 of 323 women in the cohort had historical, physical, or chest radiographic evidence of breast implantation. In 1 of the 3 patients, the symptoms of CTD began before the breast implantation. The odds ratio was calculated at 1.15, with a 95% confidence interval ranging from 0.23 to 3.41. Conclusion. This study showed an absence of significant risk for prior breast implantation surgery in patients with well-defined or undifferentiated CTD.

The randomized controlled trial continues to be the standard for evaluating the clinical utility of new procedures or treatments. The randomized controlled trial seems to affect the clinical practice of physicians. Although the design of the randomized controlled trial is well described, consideration should be given to the questions asked and whether the trial is conducted and analyzed so that the questions can be answered. Comparative trials have become more frequent than placebo trials in the past decade, and clinical research financing is falling increasingly to the pharmaceutical industry. Process and outcome measures are receiving more attention. Various groups and committees are evaluating disease activity measures to delineate a small number that can become core or foundation measures. These measures are also being defined and standardized. The process is much further advanced for rheumatoid arthritis than for other diseases, and some common and perhaps "mundane" disease states are being neglected.

Suppression of rheumatoid factor (RF) production in rheumatoid arthritis (RA) has been variably attributed to the use of remittive agents per se or to clinical improvement associated with their use. There have been conflicting reports with regard to the influence of methotrexate (MTX) on serum RF levels in RA. We determined IgM-RF and IgA-RF levels in paired serum samples (obtained at study entry and completion) from RA patients enrolled in multicenter trials with the Cooperative Systematic Studies of Rheumatic Diseases program. After exclusion of the 14 IgM-RF-negative sera, there were samples from 30 MTX-treated patients and 52 placebo-treated patients. Changes in IgM-RF and IgA-RF levels were weakly associated with each other. Significant decreases in IgM-RF levels were observed in the MTX-treated patients, but not in the placebo group. These changes were most significant in the MTX-treated patients who improved clinically. There were significant decreases in IgA-RF levels at study completion among MTX-treated patients who had improved clinically and those who had not improved clinically, but not in the placebo group. The contributions of clinical improvement and MTX treatment to changes in serum IgM-RF and IgA-RF levels were examined using a logistic regression model. Changes in IgM-RF were strongly related to MTX treatment and, to a lesser extent, to clinical improvement; changes in IgA-RF were related only to MTX treatment. These results indicate that MTX treatment per se decreases both IgM-RF and IgA-RF levels, whereas clinical improvement correlates with decreased IgM-RF levels only.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trials with slow-acting or disease-modifying drugs in rheumatoid arthritis are difficult to design and execute. Such trials are expensive and require long periods of observation. However, there is no acceptable alternative to the properly designed and completed controlled clinical trial. Broad principles for the design of such trials and the basic elements of the study design are outlined and discussed.

Ten patients with isolated subcutaneous nodules histologically similar to rheumatoid nodules were studied. Because of the intense fibroblastic reaction in one such nodule, it was initially mistaken for a fibrosarcoma. The nodules tended to be multiple and recurrent, with eventual spontaneous regression, and they were not associated with any systemic illness. The etiology of these lesions is unclear but the possibility of subsequent development of systemic rheumatoid disease is remote.

Measurement of improvement in clinical trials in chronic diseases commonly compares baseline data to endpoint values by performing t-tests or analysis of variance (ANOVA) on raw gains or percentage changes. This procedure can be misleading and the use of an analysis of covariance (ANCOVA) should be considered. Properly used, ANCOVA increases statistical power in a clinical trial. However, its advantage over t-tests can be nullified by small numbers of patients, violations of assumptions, and incorrect application of the techniques. An evaluation of ANCOVA in chronic disease studies is given, with examples of its strengths and weaknesses as seen in several drug trials in the rheumatic diseases. Recommendations on its use and a decision tree for the nonstatistician are provided.

The majority of patients with rheumatologic problems are seen and followed by nonrheumatologists. Of concern is the perception that a significant number of United States medical schools do not have adequate teaching programs in the rheumatic diseases. Two thousand two hundred and seventy practicing physicians, trainees, and medical students were surveyed in the Intermountain West to determine what they think undergraduate medical students should learn about rheumatology. Most respondents felt that common diseases and problems should be emphasized and that basic skills in history taking and physical examination are more important than disease related information.

Two hundred eight patients were studied in a prospective, controlled, double-blind multicenter trial comparing auranofin (AUR), gold sodium thiomalate (GST), and placebo. One hundred sixty-one patients completed at least 20 weeks of therapy. Response to a variety of measures of efficacy was generally modest for both gold treatment groups although improvement was continuing in both groups at the end of the study. There was statistically significant improvement with both gold preparations compared to placebo for the number of tender joints, the joint tenderness score, and physician assessment of disease severity. GST was also significantly better than placebo for the joint swelling score. GST demonstrated more improvement in patients with anemia and thrombocytosis compared to the other treatment groups and both gold preparations were superior to placebo in improvement of an elevated erythrocyte sedimentation rate. Twenty-seven percent of patients on GST were withdrawn from the study for adverse drug reaction with rash and stomatitis being the predominant cause. Only 6% of patients on AUR were withdrawn for untoward drug effect. The time of onset of the adverse reactions is discussed. The two gold preparations were similar in efficacy although AUR was better tolerated.

Two types of summary measures of joint disease were evaluated in 2 controlled clinical trials in rheumatoid arthritis patients. One measure was based solely on the clinical/biologic judgment approach; the other combined this methodology with statistical approaches using reliability and factor analyses. "Signal joint" indices, summarizing disease activity in 2-5 key joints, were found to be insensitive to deterioriation of nonsignal joints. Therefore, they are not recommended as replacements for the complete articular survey in rheumatoid arthritis. A reduced version of the complete articular survey was found to be desirable based on its validity, reliability, accuracy, precision, and sensitivity to active drugs. Its sensitivity can be slightly higher or lower than that of the full joint survey.

Seven pedigrees with 45 members were evaluated for arthropathy associated with hereditary hemochromatosis (HC). Patients with symptomatic extraarticular disease were compared with asymptomatic patients who had evidence of HC on laboratory findings, and with normal subjects. Patients who were homozygous for HC were compared with heterozygous patients and normal subjects. HC arthritis does not appear to be an early predictor of disease, and chondrocalcinosis is a late manifestation of HC arthropathy.

Two hundred twenty-five patients with active severe rheumatoid arthritis were admitted to a multiclinic, controlled, double-blind trial comparing the use of 500 mg D-penicillamine per day, 125 mg D-penicillamine per day, and placebo. One hundred seventy-one patients completed at least 30 weeks of therapy. The 500 mg D-penicillamine group demonstrated statistically significant improvement over the placebo group in grip strength, average circumference of swollen proximal interphalangeal joints, and patient assessment. While the trend was for greater improvement with the larger dose of D-penicillamine, there was no statistically significant difference among the 3 groups in duration of morning stiffness, walking time, physician's assessment, number of swollen joints, or scores for tender and swollen joints. The slight increase in efficacy of higher dose D-penicillamine was associated with increased toxicity.

SUMMARY Controlled clinical trials can be difficult, expensive, and time-consuming, but are necessary to advance the knowledge concerning rheumatic disease. Proper care in the design of the study and appropriate statistical analysis of the data can result in studies that answer specific questions and are well worth the effort and expense. If the design is well planned before the entry of the first patient, many problems will be avoided and the results will be credible.

One hundred eight-six patients with active rheumatoid arthritis were evaluated in a double-blind, randomized study that compared treatment with sulfasalazine (SSZ) (2 mg/day), gold sodium thiomalate (GST) (50 mg/week), and placebo (PBO). The 37-week course of therapy was completed by 109 patients. While marked improvement was seen in all 3 treatment groups, the only statistically significant differences between SSZ or GST and PBO were in a decreased erythrocyte sedimentation rate and increased grip strength in the right hand. GST is known to be superior to PBO, and the response of the GST-treated group was similar to that seen in other trials. The response of the PBO group, however, was much greater than in other placebo groups we have studied. SSZ was similar in efficacy to injectable gold, but was better tolerated. Because of adverse drug reactions (most commonly, rash, stomatitis, and proteinuria), 41% of patients were withdrawn from the GST treatment. Untoward drug effects (most frequently, rash and gastrointestinal distress) caused 16% of patients to be withdrawn from SSZ therapy.

Two hundred and eight patients entered a prospective, controlled, double-blind multicenter trial comparing auranofin, gold sodium thiomalate (GST), and placebo. One hundred and sixty-one patients completed at least 20 weeks of therapy. No remissions were seen in the trial. Response to a variety of measures of efficacy was generally modest for both gold treatment groups. There was statistically significant improvement with both gold preparations compared to placebo for the number of tender joints, the joint tenderness score, and physician assessment of disease severity. GST was also significantly better than placebo for the joint swelling score. GST demonstrated statistical improvement in patients with anaemia and thrombocytosis compared to the other treatment groups and both gold preparations were statistically superior to placebo in improvement of an elevated erythrocyte sedimentation rate. Approximately 25% of patients on GST were withdrawn from the study for adverse drug reaction with rash and stomatitis being the predominant reaction. Only 6% of patients on auranofin were withdrawn for untoward drug effect. The two gold preparations were similar in efficacy although auranofin was better tolerated.

The use of the Internet as a medium for education has grown exponentially since\ud the mid-1990s. Institutions of higher education are increasingly offering online\ud access to distance education programmes, especially at postgraduate level. Some\ud see e-learning as offering solutions to many problems traditionally associated\ud with distance education.\ud Research into e-learning at a distance has largely focussed on the effectiveness of\ud differing technologies for the delivery of online courses, the emphasis being\ud upon the technology itself, with few studies examining the student experience of\ud this new phenomenon. It is therefore argued that a gap exists, as the views of\ud distance e-learners at postgraduate level have seldom been paid attention, with\ud their specific and individual needs failing to be addressed. This study aims to\ud rectify this gap by examining postgraduates' experiences of e-learning at a\ud distance. The purpose of the study is to inform the future development of elearning\ud at postgraduate level and help determine how higher education can best\ud support this rapidly expanding group of learners.\ud The research presents a qualitative case study of a group of students studying\ud modules from the University of Salford's MSc/Postgraduate Diploma in\ud Occupational Safety and Health in a virtual learning environment called\ud GOLDPhase, which was specifically designed and developed to facilitate the\ud study.\ud Issues related to the students' heightened awareness of their peers, their\ud sensitivity to tutor feedback, and the learning strategies they adopted are\ud identified and discussed. The findings show that e-learning engendered a range\ud of barriers and enhancements for this group of distance learners. The\ud enhancements were largely computer based and barriers were mostly\ud sociological.\ud The findings have implications for both online teaching and online learning\ud strategies. As distance e-learning is in its infancy the study will increase overall\ud understanding in this area and contribute to the growing body of knowledge.